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Sample records for rapid drug dissolution

  1. Rapid analysis of drug dissolution by paper spray ionization mass spectrometry.

    Science.gov (United States)

    Liu, Yang; Liu, Ning; Zhou, Ya-Nan; Lin, Lan; He, Lan

    2017-03-20

    With a great quantity of solid dosage tested by dissolution technology, developing a rapid and sensitive method to access the content of drug within dissolution media is highly desired by analysts and scientists. Traditionally, dissolution media is not compatible with mass spectrometry since the inorganic salts in the media might damage the mass spectrometer. Here, paper spray ionization mass spectrometry (PSI-MS), one of the ambient mass spectrometry technologies, is developed to characterize the content of drugs in dissolution media. The porous structure of paper can effectively retain salts from entering mass spectrometer. This makes the measurement of drug content within dissolution media by mass spectrometer possible. After the experimental parameters were optimized, calibration curves of model drugs - enalapril, quinapril and benazepril were established by using corresponding deuterated internal standards. PSI-MS was then deployed to characterize the content of enalapril from the dissolution testing of enalapril tablets. The results from PSI-MS are comparable to those from HPLC characterization. More importantly, the analysis time of 6 samples is shortened from 90min to 6min. Detection limit of enalapril maleate tablets by PSI-MS is 1/300 of LC. PSI-MS is rapid, sensitive and accurate in analyzing drug content from dissolution tests. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Novel ultra-rapid freezing particle engineering process for enhancement of dissolution rates of poorly water-soluble drugs.

    Science.gov (United States)

    Overhoff, Kirk A; Engstrom, Josh D; Chen, Bo; Scherzer, Brian D; Milner, Thomas E; Johnston, Keith P; Williams, Robert O

    2007-01-01

    An ultra-rapid freezing (URF) technology has been developed to produce high surface area powders composed of solid solutions of an active pharmaceutical ingredient (API) and a polymer stabilizer. A solution of API and polymer excipient(s) is spread on a cold solid surface to form a thin film that freezes in 50 ms to 1s. This study provides an understanding of how the solvent's physical properties and the thin film geometry influence the freezing rate and consequently the final physico-chemical properties of URF-processed powders. Theoretical calculations of heat transfer rates are shown to be in agreement with infrared images with 10ms resolution. Danazol (DAN)/polyvinylpyrrolidone (PVP) powders, produced from both acetonitrile (ACN) and tert-butanol (T-BUT) as the solvent, were amorphous with high surface areas (approximately 28-30 m2/g) and enhanced dissolution rates. However, differences in surface morphology were observed and attributed to the cooling rate (film thickness) as predicted by the model. Relative to spray-freezing processes that use liquid nitrogen, URF also offers fast heat transfer rates as a result of the intimate contact between the solution and cold solid surface, but without the complexity of cryogen evaporation (Leidenfrost effect). The ability to produce amorphous high surface area powders with submicron primary particles with a simple ultra-rapid freezing process is of practical interest in particle engineering to increase dissolution rates, and ultimately bioavailability.

  3. Nanosizing of drugs: Effect on dissolution rate

    Science.gov (United States)

    Dizaj, S. Maleki; Vazifehasl, Zh.; Salatin, S.; Adibkia, Kh.; Javadzadeh, Y.

    2015-01-01

    The solubility, bioavailability and dissolution rate of drugs are important parameters for achieving in vivo efficiency. The bioavailability of orally administered drugs depends on their ability to be absorbed via gastrointestinal tract. For drugs belonging to Class II of pharmaceutical classification, the absorption process is limited by drug dissolution rate in gastrointestinal media. Therefore, enhancement of the dissolution rate of these drugs will present improved bioavailability. So far several techniques such as physical and chemical modifications, changing in crystal habits, solid dispersion, complexation, solubilization and liquisolid method have been used to enhance the dissolution rate of poorly water soluble drugs. It seems that improvement of the solubility properties ofpoorly water soluble drugscan translate to an increase in their bioavailability. Nowadays nanotechnology offers various approaches in the area of dissolution enhancement of low aqueous soluble drugs. Nanosizing of drugs in the form of nanoparticles, nanocrystals or nanosuspensions not requiring expensive facilities and equipment or complicated processes may be applied as simple methods to increase the dissolution rate of poorly water soluble drugs. In this article, we attempted to review the effects of nanosizing on improving the dissolution rate of poorly aqueous soluble drugs. According to the reviewed literature, by reduction of drug particle size into nanometer size the total effective surface area is increased and thereby dissolution rate would be enhanced. Additionally, reduction of particle size leads to reduction of the diffusion layer thickness surrounding the drug particles resulting in the increment of the concentration gradient. Each of these process leads to improved bioavailability. PMID:26487886

  4. Dissolution Enhancement of Drugs. Part II: Effect of Carriers ...

    African Journals Online (AJOL)

    ... surfactants, in dissolution enhancement. This part describes the use of cyclodextrin, carbohydrates, hydrotropes, polyglocolized glycerides, dendrimers, acids and miscellaneous carriers in enhancing dissolution of drugs. Keywords: Dissolution enhancement; aqueous solubility, water soluble carriers; lipophilic, excipients.

  5. Molecular-level elucidation of saccharin-assisted rapid dissolution and high supersaturation level of drug from Eudragit®E solid dispersion.

    Science.gov (United States)

    Ueda, Keisuke; Kanaya, Harunobu; Higashi, Kenjirou; Yamamoto, Keiji; Moribe, Kunikazu

    2018-01-16

    In this work, the effect of saccharin (SAC) addition on the dissolution and supersaturation level of phenytoin (PHT)/Eudragit® E (EUD-E) solid dispersion (SD) at neutral pH was examined. The PHT/EUD-E SD showed a much slower dissolution of PHT compared to the PHT/EUD-E/SAC SD. EUD-E formed a gel layer after the dispersion of the PHT/EUD-E SD into an aqueous medium, resulting in a slow dissolution of PHT. Pre-dissolving SAC in the aqueous medium significantly improved the dissolution of the PHT/EUD-E SD. Solid-state 13 C NMR measurements showed an ionic interaction between the tertiary amino group of EUD-E and the amide group of SAC in the EUD-E gel layer. Consequently, the ionized EUD-E could easily dissolve from the gel layer, promoting PHT dissolution. Solution-state 1 H NMR measurements revealed the presence of ionic interactions between SAC and the amino group of EUD-E in the PHT/EUD-E/SAC solution. In contrast, interactions between PHT and the hydrophobic group of EUD-E strongly inhibited the crystallization of the former from its supersaturated solution. The PHT supersaturated solution was formed from the PHT/EUD-E/SAC SD by the fast dissolution of PHT and the strong crystallization inhibition effect of EUD-E after aqueous dissolution. Copyright © 2018 Elsevier B.V. All rights reserved.

  6. Initial Drug Dissolution from Amorphous Solid Dispersions Controlled by Polymer Dissolution and Drug-Polymer Interaction.

    Science.gov (United States)

    Chen, Yuejie; Wang, Shujing; Wang, Shan; Liu, Chengyu; Su, Ching; Hageman, Michael; Hussain, Munir; Haskell, Roy; Stefanski, Kevin; Qian, Feng

    2016-10-01

    To identify the key formulation factors controlling the initial drug and polymer dissolution rates from an amorphous solid dispersion (ASD). Ketoconazole (KTZ) ASDs using PVP, PVP-VA, HMPC, or HPMC-AS as polymeric matrix were prepared. For each drug-polymer system, two types of formulations with the same composition were prepared: 1. Spray dried dispersion (SDD) that is homogenous at molecular level, 2. Physical blend of SDD (80% drug loading) and pure polymer (SDD-PB) that is homogenous only at powder level. Flory-Huggins interaction parameters (χ) between KTZ and the four polymers were obtained by Flory-Huggins model fitting. Solution (13)C NMR and FT-IR were conducted to investigate the specific drug-polymer interaction in the solution and solid state, respectively. Intrinsic dissolution of both the drug and the polymer from ASDs were studied using a Higuchi style intrinsic dissolution apparatus. PXRD and confocal Raman microscopy were used to confirm the absence of drug crystallinity on the tablet surface before and after dissolution study. In solid state, KTZ is completely miscible with PVP, PVP-VA, or HPMC-AS, demonstrated by the negative χ values of -0.36, -0.46, -1.68, respectively; while is poorly miscible with HPMC shown by a positive χ value of 0.23. According to solution (13)C NMR and FT-IR studies, KTZ interacts with HPMC-AS strongly through H-bonding and dipole induced interaction; with PVPs and PVP-VA moderately through dipole-induced interactions; and with HPMC weakly without detectable attractive interaction. Furthermore, the "apparent" strength of drug-polymer interaction, measured by the extent of peak shift on NMR or FT-IR spectra, increases with the increasing number of interacting drug-polymer pairs. For ASDs with the presence of considerable drug-polymer interactions, such as KTZ/PVPs, KTZ/PVP-VA, or KTZ /HPMC-AS systems, drug released at the same rate as the polymer when intimate drug-polymer mixing was ensured (i.e., the SDD systems

  7. Dissolution enhancement of drugs. part i: technologies and effect of ...

    African Journals Online (AJOL)

    V Saharan, V Kukkar, M Kataria, M Gera, P Choudhury ... Since aqueous solubility and slow dissolution rate of BCS class II and class IV drugs is a major challenge in the drug development and delivery processes, improving aqueous solubility and slow dissolution of BCS Class II and Class IV drugs have been investigated ...

  8. Controlled precipitation for enhanced dissolution rate of flurbiprofen: development of rapidly disintegrating tablets.

    Science.gov (United States)

    Essa, Ebtessam A; Elmarakby, Amira O; Donia, Ahmed M A; El Maghraby, Gamal M

    2017-09-01

    The aim of this work was to investigate the potential of controlled precipitation of flurbiprofen on solid surface, in the presence or absence of hydrophilic polymers, as a tool for enhanced dissolution rate of the drug. The work was extended to develop rapidly disintegrated tablets. This strategy provides simple technique for dissolution enhancement of slowly dissolving drugs with high scaling up potential. Aerosil was dispersed in ethanolic solution of flurbiprofen in the presence and absence of hydrophilic polymers. Acidified water was added as antisolvent to produce controlled precipitation. The resultant particles were centrifuged and dried at ambient temperature before monitoring the dissolution pattern. The particles were also subjected to FTIR spectroscopic, X-ray diffraction and thermal analyses. The FTIR spectroscopy excluded any interaction between flurbiprofen and excipients. The thermal analysis reflected possible change in the crystalline structure and or crystal size of the drug after controlled precipitation in the presence of hydrophilic polymers. This was further confirmed by X-ray diffraction. The modulation in the crystalline structure and size was associated with a significant enhancement in the dissolution rate of flurbiprofen. Optimum formulations were successfully formulated as rapidly disintegrating tablet with subsequent fast dissolution. Precipitation on a large solid surface area is a promising strategy for enhanced dissolution rate with the presence of hydrophilic polymers during precipitation process improving the efficiency.

  9. Comminution of ibuprofen to produce nano-particles for rapid dissolution.

    Science.gov (United States)

    Plakkot, S; de Matas, M; York, P; Saunders, M; Sulaiman, B

    2011-08-30

    A critical problem associated with poorly soluble drugs is low and variable bioavailability derived from slow dissolution and erratic absorption. The preparation of nano-formulations has been identified as an approach to enhance the rate and extent of drug absorption for compounds demonstrating limited aqueous solubility. A new technology for the production of nano-particles using high speed, high efficiency processes that can rapidly generate nano-particles with rapid dissolution rate has been developed. Size reduction of a low melting ductile model compound was achieved in periods less than 1h. Particle size reduction of ibuprofen using this methodology resulted in production of crystalline particles with average diameter of approximately 270nm. Physical stability studies showed that the nano-suspension remained homogeneous with slight increases in mean particle size, when stored at room temperature and under refrigerated storage conditions 2-8°C for up to 2 days. Powder containing crystalline drug was prepared by spray-drying ibuprofen nano-suspensions with mannitol dissolved in the aqueous phase. Dissolution studies showed similar release rates for the nano-suspension and powder which were markedly improved compared to a commercially available drug product. Ibuprofen nano-particles could be produced rapidly with smaller sizes achieved at higher suspension concentrations. Particles produced in water with stabilisers demonstrated greatest physical stability, whilst rapid dissolution was observed for the nano-particles isolated in powder form. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. Effects of amorphous silicon dioxides on drug dissolution.

    Science.gov (United States)

    Yang, K Y; Glemza, R; Jarowski, C I

    1979-05-01

    The dissolution profiles of prednisone, digoxin, and griseofulvin in simulated GI fluids were determined after solvent deposition or ball milling with three commercially available grades of amorphous silicon dioxide. The former procedure resulted in adsorbates showing evidence of drug entrapment by the two grades with larger average pore diameters. Ball milling the drugs with the grade possessing the largest average particle diameter produced triturations with the slowest dissolution rates. A relationship between drug dissolution and extent of dilution with the amorphous silicon dioxides was shown. Particle-size measurements revealed that the ball milling procedure was more apt to broaden the size distribution as compared with the solvent-deposition method of drug incorporation.

  11. Mesoporous Silica Molecular Sieve based Nanocarriers: Transpiring Drug Dissolution Research.

    Science.gov (United States)

    Pattnaik, Satyanarayan; Pathak, Kamla

    2017-01-01

    Improvement of oral bioavailability through enhancement of dissolution for poorly soluble drugs has been a very promising approach. Recently, mesoporous silica based molecular sieves have demonstrated excellent properties to enhance the dissolution velocity of poorly water-soluble drugs. Current research in this area is focused on investigating the factors influencing the drug release from these carriers, the kinetics of drug release and manufacturing approaches to scale-up production for commercial manufacture. This comprehensive review provides an overview of different methods adopted for synthesis of mesoporous materials, influence of processing factors on properties of these materials and drug loading methods. The drug release kinetics from mesoporous silica systems, the manufacturability and stability of these formulations are reviewed. Finally, the safety and biocompatibility issues related to these silica based materials are discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. Polymeric Nanosuspensions for Enhanced Dissolution of Water Insoluble Drugs

    Directory of Open Access Journals (Sweden)

    Roya Yadollahi

    2013-01-01

    Full Text Available The aim of the present research is to formulate and evaluate polymeric nanosuspensions containing three model water insoluble drugs, nifedipine (NIF, carbamazepine (CBZ, and ibuprofen (IBU with various physicochemical properties. The nanosuspensions were prepared from hydroxypropyl methylcellulose (HPMC and polyvinylpyrrolidone (PVP by a cosolvent technique with polyethylene glycol (PEG-300 and water as the cosolvents. Physicochemical and morphological characteristics of the nanosuspensions (particle size, polydispersity index, and crystallinity have been correlated with the drug release behaviour. The effects of polymer, drug ratio on the physical, morphological, and dissolution characteristics of the drugs are reported. Drug release is significantly enhanced from the nanosuspensions; for example, the maximum NIF, IBU, and CBZ concentrations after 8-hour dissolution are increased approximately 37, 2, and 1.2 times, respectively, in comparison with the pure powdered drugs. Based on this solubilization enhancement performance, the nanosuspensions have potential for increasing the orally dosed bioavailability of NIF, IBU, and CBZ.

  13. Theoretical Analysis of Drug Dissolution: I. Solubility and Intrinsic Dissolution Rate.

    Science.gov (United States)

    Shekunov, Boris; Montgomery, Eda Ross

    2016-09-01

    The first-principles approach presented in this work combines surface kinetics and convective diffusion modeling applied to compounds with pH-dependent solubility and in different dissolution media. This analysis is based on experimental data available for approximately 100 compounds of pharmaceutical interest. Overall, there is a linear relationship between the drug solubility and intrinsic dissolution rate expressed through the total kinetic coefficient of dissolution and dimensionless numbers defining the mass transfer regime. The contribution of surface kinetics appears to be significant constituting on average ∼20% resistance to the dissolution flux in the compendial rotating disk apparatus at 100 rpm. The surface kinetics contribution becomes more dominant under conditions of fast laminar or turbulent flows or in cases when the surface kinetic coefficient may decrease as a function of solution composition or pH. Limitations of the well-known convective diffusion equation for rotating disk by Levich are examined using direct computational modeling with simultaneous dissociation and acid-base reactions in which intrinsic dissolution rate is strongly dependent on pH profile and solution ionic strength. It is shown that concept of diffusion boundary layer does not strictly apply for reacting/interacting species and that thin-film diffusion models cannot be used quantitatively in general case. Copyright © 2016. Published by Elsevier Inc.

  14. Rapidly separating microneedles for transdermal drug delivery.

    Science.gov (United States)

    Zhu, Dan Dan; Wang, Qi Lei; Liu, Xu Bo; Guo, Xin Dong

    2016-09-01

    The applications of polymer microneedles (MNs) into human skin emerged as an alternative of the conventional hypodermic needles. However, dissolving MNs require many minutes to be dissolved in the skin and typically have difficulty being fully inserted into the skin, which may lead to the low drug delivery efficiency. To address these issues, we introduce rapidly separating MNs that can rapidly deliver drugs into the skin in a minimally invasive way. For the rapidly separating MNs, drug loaded dissolving MNs are mounted on the top of solid MNs, which are made of biodegradable polylactic acid which eliminate the biohazardous waste. These MNs have sufficient mechanical strength to be inserted into the skin with the drug loaded tips fully embedded for subsequent dissolution. Compared with the traditional MNs, rapidly separating MNs achieve over 90% of drug delivery efficiency in 30s while the traditional MNs needs 2min to achieve the same efficiency. With the in vivo test in mice, the micro-holes caused by rapidly separating MNs can heal in 1h, indicating that the rapidly separating MNs are safe for future applications. These results indicate that the design of rapidly separating dissolvable MNs can offer a quick, high efficient, convenient, safe and potentially self-administered method of drug delivery. Polymer microneedles offer an attractive, painless and minimally invasive approach for transdermal drug delivery. However, dissolving microneedles require many minutes to be dissolved in the skin and typically have difficulty being fully inserted into the skin due to the skin deformation, which may lead to the low drug delivery efficiency. In this work we proposed rapidly separating microneedles which can deliver over 90% of drug into the skin in 30s. The in vitro and in vivo results indicate that the new design of these microneedles can offer a quick, high efficient, convenient and safe method for transdermal drug delivery. Copyright © 2016 Acta Materialia Inc

  15. Stability and drug dissolution evaluation of Qingkailing soft/hard ...

    African Journals Online (AJOL)

    Stability and drug dissolution evaluation of Qingkailing soft/hard capsules based on multi-component quantification and fingerprint pattern statistical analysis. Ruyu Sun, Huihui Teng, Xiaonan Chen, Shuang Guo, Shan Jia, Mengcheng Zheng, Yang Lu, Jie Bai, Pengyue Li, Shouying Du ...

  16. DISSOLUTION KINETICS OF KETANSERIN TARTRATE, THE SALT OF A WEAKLY BASIC DRUG

    NARCIS (Netherlands)

    VANDERVEEN, J; BUITENDIJK, HH; LERK, CF

    1992-01-01

    The rotating disc method was used to study the dissolution kinetics of ketanserin tartrate, the salt of a weakly basic drug. Both solubility and dissolution rate decrease exponentially with increasing pH of the dissolution medium. A plot of the logarithm of the ratio of dissolution rate to

  17. Drying of crystalline drug nanosuspensions-the importance of surface hydrophobicity on dissolution behavior upon redispersion.

    Science.gov (United States)

    Van Eerdenbrugh, Bernard; Froyen, Ludo; Van Humbeeck, Jan; Martens, Johan A; Augustijns, Patrick; Van den Mooter, Guy

    2008-09-02

    d-alpha-Tocopherol polyethylene glycol 1000 succinate (TPGS)-stabilized nanosuspensions (25wt%, relative to the drug weight) were produced by media milling for 9 model drug compounds [cinnarizine, griseofulvin, indomethacin, itraconazole, loviride, mebendazole, naproxen, phenylbutazone and phenytoin]. After 3 months of storage at room temperature, Ostwald ripening occurred in all of the samples, except for indomethacin. Whereas lowering the temperature could slow down the ripening, it markedly increased upon storage at 40 degrees C. As for ripening, settling generally became more pronounced at 40 degrees C compared to 4 degrees C. As the nanosuspensions were afflicted by Ostwald ripening and settling, we explored nanosuspension drying as a strategy to circumvent these stability issues. Spray-drying and freeze-drying were evaluated for nanosuspensions and coarse reference suspensions of the compounds. Nanoparticle agglomeration could be visually observed in all of the powders. To evaluate the effect of agglomeration on the key characteristic of drug nanocrystals (i.e. rapid dissolution), dissolution experiments were performed under poor sink conditions. It was found that the compounds could be categorized into 3 groups: (i) compounds for which it was impossible to differentiate between coarse and nanosized products (griseofulvin, mebendazole, naproxen), (ii) compounds that gave clear differences in dissolution profiles between the nanosized and the coarse products, but for which drying of the nanosuspensions did not decrease the dissolution performance of the product (indomethacin, loviride, phenytoin) and (iii) compounds that showed differences between coarse and nanosized products, but for which drying of the nanosuspensions resulted in a significant decrease of the dissolution rate (cinnarizine, itraconazole, phenylbutazone). To gain insight on the influence of the drug compound characteristics on the dissolution of the dried products, the dissolution behavior of

  18. Rapid dissolution of ZnO nanocrystals in acidic cancer microenvironment leading to preferential apoptosis

    Science.gov (United States)

    Sasidharan, Abhilash; Chandran, Parwathy; Menon, Deepthy; Raman, Sreerekha; Nair, Shantikumar; Koyakutty, Manzoor

    2011-09-01

    The microenvironment of cancer plays a very critical role in the survival, proliferation and drug resistance of solid tumors. Here, we report an interesting, acidic cancer microenvironment-mediated dissolution-induced preferential toxicity of ZnO nanocrystals (NCs) against cancer cells while leaving primary cells unaffected. Irrespective of the size-scale (5 and 200 nm) and surface chemistry differences (silica, starch or polyethylene glycol coating), ZnO NCs exhibited multiple stress mechanisms against cancer cell lines (IC50 ~150 μM) while normal human primary cells (human dermal fibroblast, lymphocytes, human umbilical vein endothelial cells) remain less affected. Flow cytometry and confocal microscopy studies revealed that ZnO NCs undergo rapid preferential dissolution in acidic (pH ~5-6) cancer microenvironment causing elevated ROS stress, mitochondrial superoxide formation, depolarization of mitochondrial membrane, and cell cycle arrest at S/G2 phase leading to apoptosis. In effect, by elucidating the unique toxicity mechanism of ZnO NCs, we show that ZnO NCs can destabilize cancer cells by utilizing its own hostile acidic microenvironment, which is otherwise critical for its survival.The microenvironment of cancer plays a very critical role in the survival, proliferation and drug resistance of solid tumors. Here, we report an interesting, acidic cancer microenvironment-mediated dissolution-induced preferential toxicity of ZnO nanocrystals (NCs) against cancer cells while leaving primary cells unaffected. Irrespective of the size-scale (5 and 200 nm) and surface chemistry differences (silica, starch or polyethylene glycol coating), ZnO NCs exhibited multiple stress mechanisms against cancer cell lines (IC50 ~150 μM) while normal human primary cells (human dermal fibroblast, lymphocytes, human umbilical vein endothelial cells) remain less affected. Flow cytometry and confocal microscopy studies revealed that ZnO NCs undergo rapid preferential dissolution in

  19. Improvement of dissolution property of poorly water-soluble drug by supercritical freeze granulation.

    Science.gov (United States)

    Sonoda, Ryoichi; Hara, Yuko; Iwasaki, Tomohiro; Watano, Satoru

    2009-10-01

    The dissolution property of the poorly water-soluble drug, flurbiprofen (FP) was improved by a novel supercritical freeze granulation using supercritical carbon dioxide. Supercritical freeze granulation was defined as a production method of the granulated substances by using the dry ice to generate intentionally for the rapid atomization of the supercritical carbon dioxide to the atmospheric pressure. This process utilized a rapid expansion of supercritical solutions (RESS) process with the mixture of the drug and lactose. In the supercritical freeze granulation, needle-like FP fine particles were obtained which adhered to the surface of lactose particles, which did not dissolve in supercritical carbon dioxide. The number of FP particles that adhered to the surface of particles decreased with an increase in the ratio of lactose added, leading to markedly improve the dissolution rate. This improvement was caused not only by the increase in the specific surface area but also the improvement of the dispersibility of FP in water. It is thus concluded that the supercritical freeze granulation is a useful technique to improve the dissolution property of the poorly water-soluble flurbiprofen.

  20. Pure drug nanoparticles in tablets: what are the dissolution limitations?

    Science.gov (United States)

    Heng, Desmond; Ogawa, Keiko; Cutler, David J.; Chan, Hak-Kim; Raper, Judy A.; Ye, Lin; Yun, Jimmy

    2010-06-01

    There has been increasing interests for drug companies to incorporate drug nanoparticles into their existing formulations. However, technical knowledge in this area is still in its infancy and more study needs to be done to stimulate growth in this fledging field. There is a need to scrutinize the performance of pure drug nanoparticles in tablets, particularly relating formulation variables to their dissolution performance. Application of the pure form, synthesized without the use of surfactants or stabilizers, is often preferred to maximize drug loading and also to minimize toxicity. Cefuroxime axetil, a poorly water-soluble cephalosporin antibiotic, was used as the model drug in the formulation development. Drug release rate, tablet disintegration time, tensile strength and energy of failure were predominantly influenced by the amount of super-disintegrant, amount of surfactant, compression force and diluent species, respectively. The compression rate had minimal impact on the responses. The main hurdle confronting the effective use of pure drug nanoparticles in tablets is the difficulty in controlling aggregation in solution, which could potentially be aggravated by the tabletting process. Through the use of elevated levels of surfactants (8 w/w% sodium dodecyl sulphate), drug release from the nanoparticle preparation was enhanced from 58.0 ± 2.7% to 72.3 ± 0.7% in 10 min. Hence, it is recommended that physical formulations for pure drug nanoparticles be focused on the particle de-aggregation step in solution, if much higher rates are to be desired. In conclusion, even though pure drug nanoparticles could be easily synthesized, limitations from aggregation may need to be overcome, before successful application in tablets can be fully realized.

  1. Dissolution Failure of Solid Oral Drug Products in Field Alert Reports.

    Science.gov (United States)

    Sun, Dajun; Hu, Meng; Browning, Mark; Friedman, Rick L; Jiang, Wenlei; Zhao, Liang; Wen, Hong

    2017-05-01

    From 2005 to 2014, 370 data entries of dissolution failures of solid oral drug products were assessed with respect to the solubility of drug substances, dosage forms [immediate release (IR) vs. modified release (MR)], and manufacturers (brand name vs. generic). The study results show that the solubility of drug substances does not play a significant role in dissolution failures; however, MR drug products fail dissolution tests more frequently than IR drug products. When multiple variables were analyzed simultaneously, poorly water-soluble IR drug products failed the most dissolution tests, followed by poorly soluble MR drug products and very soluble MR drug products. Interestingly, the generic drug products fail dissolution tests at an earlier time point during a stability study than the brand name drug products. Whether the dissolution failure of these solid oral drug products has any in vivo implication will require further pharmacokinetic, pharmacodynamic, clinical, and drug safety evaluation. Food and Drug Administration is currently conducting risk-based assessment using in-house dissolution testing, physiologically based pharmacokinetic modeling and simulation, and post-market surveillance tools. At the meantime, this interim report will outline a general scheme of monitoring dissolution failures of solid oral dosage forms as a pharmaceutical quality indicator. Published by Elsevier Inc.

  2. Influence of Solid Drug Delivery System Formulation on Poorly Water-Soluble Drug Dissolution and Permeability

    Directory of Open Access Journals (Sweden)

    Marko Krstić

    2015-08-01

    Full Text Available The majority of drugs have a low dissolution rate, which is a limiting step for their absorption. In this manuscript, solid dispersions (SD, solid self-microemulsifying drug delivery systems (S-SMEDDS and solid self-nanoemulsifying drug delivery systems (S-SNEDDS were evaluated as potential formulation strategies to increase the dissolution rate of carbamazepine. Influence of increased dissolution rate on permeability of carbamazepine was evaluated using PAMPA test. In S-SMEDDS and S-SNEDDS formulations, the ratio of liquid SMEDDS/SNEDDS and solid carrier (Neusilin® UFL2 was varied, and carbamazepine content was constant. In SD formulations, the ratio of carbamazepine and Neusilin® UFL2, was varied. Formulations that showed the best dissolution rate of carbamazepine (SD_1:6, SMEDDS_1:1, SNEDDS_1:6 were mutually compared, characterization of these formulations was performed by DSC, PXRD and FT-IR analyses, and a PAMPA test was done. All formulations have shown a significant increase in dissolution rate compared to pure carbamazepine and immediate-release carbamazepine tablets. Formulation S-SMEDDS_1:1 showed the fastest release rate and permeability of carbamazepine. DSC, PXRD and FT-IR analyses confirmed that in S-SMEDDS and S-SNEDDS carbamazepine remained in polymorph form III, and that it was converted to an amorphous state in SD formulations. All formulations showed increased permeability of carbamazepine, compared to pure carbamazepine.

  3. Dissolution properties of co-amorphous drug-amino acid formulations in buffer and biorelevant media

    DEFF Research Database (Denmark)

    Heikkinen, A. T.; DeClerck, L.; Löbmann, Korbinian

    2015-01-01

    in biorelevant media suggesting that a dissolution advantage observed in aqueous buffers may overestimate the advantage in vivo. However, the results show that, in addition to stability advantage shown earlier, co-amorphous drug-amino acid formulations provide dissolution advantage over crystalline drugs in both......Co-amorphous formulations, particularly binary drug-amino acid mixtures, have been shown to provide enhanced dissolution for poorly-soluble drugs and improved physical stability of the amorphous state. However, to date the dissolution properties (mainly intrinsic dissolution rate) of the co......-amorphous formulations have been tested only in buffers and their supersaturation ability remain unexplored. Consequently, dissolution studies in simulated intestinal fluids need to be conducted in order to better evaluate the potential of these systems in increasing the oral bioavailability of biopharmaceutics...

  4. DDSolver: An Add-In Program for Modeling and Comparison of Drug Dissolution Profiles

    OpenAIRE

    Zhang, Yong; Huo, Meirong; Zhou, Jianping; Zou, Aifeng; Li, Weize; Yao, Chengli; Xie, Shaofei

    2010-01-01

    In recent years, several mathematical models have been developed for analysis of drug dissolution data, and many different mathematical approaches have been proposed to assess the similarity between two drug dissolution profiles. However, until now, no computer program has been reported for simplifying the calculations involved in the modeling and comparison of dissolution profiles. The purposes of this article are: (1) to describe the development of a software program, called DDSolver, for f...

  5. Interactions between a poorly soluble cationic drug and sodium dodecyl sulfate in dissolution medium and their impact on in vitro dissolution behavior.

    Science.gov (United States)

    Huang, Zongyun; Parikh, Shuchi; Fish, William P

    2017-11-18

    In the pharmaceutical industry, in vitro dissolution testing ofsolid oral dosage forms is a very important tool for drug development and quality control. However, ion-pairing interaction between the ionic drugand surfactants in dissolution medium often occurs, resulting in inconsistent and incomplete drug release. The aim of this study is toevaluate the effects ofsodium dodecyl sulfate (SDS) mediated medium onthe dissolution behaviors of a poorly soluble cationic drug (Drug B). The study was carried out by measuring solubility of Drug B substance and dissolution rate of Drug B product in media containing SDS.Desolubilization of Drug B substance was observed at pH 4.5 in the presence of SDS at concentrations below critical micelle concentration (CMC) which is attributed to the formation of an insoluble di-dodecyl sulfate salt between SDS and Drug B. This ion-pairing effect is less significant with increasing medium pH where Drug B is less ionized and CMC of SDS is lower. In medium at pH 4.5, dissolution of Drug B product was found incomplete with SDS concentration below CMC due to the desolubilization of Drug B substance. In media with SDS level above CMC, the dissolution rate is rather slower with higher inter-vessel variations compared to that obtained in pH 4.5 medium without SDS. The dissolution results demonstrate that the presence of SDS in medium generates unexpected irregular dissolution profiles for Drug B which are attributed to incompatible dissolution medium for this particular drug. Therefore, non-ionic surfactant was selected for Drug B product dissolution method and ion-pairing effect in SDS mediated medium should be evaluated when developing a dissolution method for any poorly soluble cationic drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Dissolution properties of co-amorphous drug-amino acid formulations in buffer and biorelevant media.

    Science.gov (United States)

    Heikkinen, A T; DeClerck, L; Löbmann, K; Grohganz, H; Rades, T; Laitinen, R

    2015-07-01

    Co-amorphous formulations, particularly binary drug-amino acid mixtures, have been shown to provide enhanced dissolution for poorly-soluble drugs and improved physical stability of the amorphous state. However, to date the dissolution properties (mainly intrinsic dissolution rate) of the co-amorphous formulations have been tested only in buffers and their supersaturation ability remain unexplored. Consequently, dissolution studies in simulated intestinal fluids need to be conducted in order to better evaluate the potential of these systems in increasing the oral bioavailability of biopharmaceutics classification system class II drugs. In this study, solubility and dissolution properties of the co-amorphous simvastatin-lysine, gibenclamide-serine, glibenclamide-threonine and glibenclamide-serine-threonine were studied in phosphate buffer pH 7.2 and biorelevant media (fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, respectively)). The co-amorphous formulations were found to provide a long-lasting supersaturation and improve the dissolution of the drugs compared to the crystalline and amorphous drugs alone in buffer. Similar improvement, but in lesser extent, was observed in biorelevant media suggesting that a dissolution advantage observed in aqueous buffers may overestimate the advantage in vivo. However, the results show that, in addition to stability advantage shown earlier, co-amorphous drug-amino acid formulations provide dissolution advantage over crystalline drugs in both aqueous and biorelevant conditions.

  7. Characteristics of drug-phospholipid coprecipitates I: Physical properties and dissolution behavior of griseofulvin-dimyristoylphosphatidylcholine systems.

    Science.gov (United States)

    Venkataram, S; Rogers, J A

    1984-06-01

    Solid dispersions of griseofulvin and dimyristoylphosphatidylcholine (lecithin) have been prepared as both coprecipitates and physical mixtures, and their physical characteristics and dissolution behavior compared with pure griseofulvin. The dissolution of the physical mixtures was similar to pure drug, but the coprecipitates yielded a 3.5-fold greater initial dissolution rate and a limiting concentration after 60 min which was 72% greater at a griseofulvin-lecithin weight ratio of 19:1. Increasing the lecithin content to 1.5:1 compositions resulted in only a further 50% increase in the initial dissolution rate and a further 12% increase in the limiting concentration. The effect of the pH of the medium on dissolution was slight, but varied with the composition of the system. The phase diagram indicated that these systems have no significant eutectic or solid solution formation. X-ray diffraction spectra further showed that freshly prepared or aged coprecipitates contained griseofulvin crystals, and photomicrographs showed that the crystals essentially retained their characteristic shapes and sizes in all systems. Differential thermal analysis yielded heats of fusion that gave a good linear correlation with the percent of griseofulvin dissolved from coprecipitates at all time intervals, but not with physical mixtures. Furthermore, aged coprecipitates underwent a slower rate of dissolution compared with fresh samples. The results are interpreted to suggest that griseofulvin undergoes improved dissolution from coprecipitates due to the formation of crystals of lower stability. In addition, the rapid dispersion of lecithin in the aqueous medium (as seen microscopically) entraps griseofulvin in myelinic structures and liposomes and effectively increases the saturation concentration of drug in the diffusion layer during the dissolution process.

  8. Rapid disintegrating tablets of simvastatin dispersions in polyoxyethylene–polypropylene block copolymer for maximized disintegration and dissolution

    Science.gov (United States)

    Balata, Gehan F; Zidan, Ahmad S; Abourehab, Mohamad AS; Essa, Ebtessam A

    2016-01-01

    The objective of this research was to improve the dissolution of simvastatin and to incorporate it in rapid disintegrating tablets (RDTs) with an optimized disintegration and dissolution characteristics. Polyoxyethylene–polypropylene block copolymer (poloxamer 188) was employed as a hydrophilic carrier to prepare simvastatin solid dispersions (SDs). Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC) and X-ray diffractometry were employed to understand the interaction between the drug and the carrier in the solid state. The results obtained from Fourier transform infrared spectroscopy showed absence of any chemical interaction between the drug and poloxamer. The results of differential scanning calorimetry and X-ray diffractometry confirmed the conversion of simvastatin to distorted crystalline state. The SD of 1:2 w/w drug to carrier ratio showed the highest dissolution; hence, it was incorporated in RDT formulations using a 32 full factorial design and response surface methodology. The initial assessments of RDTs demonstrated an acceptable flow, hardness, and friability to indicate good mechanical strength. The interaction and Pareto charts indicated that percentage of croscarmellose sodium incorporated was the most important factor affecting the disintegration time and dissolution parameter followed by the hardness value and their interaction effect. Compression force showed a superior influence to increase RDT’s porosity and to fasten disintegration rather than swelling action by croscarmellose sodium. On the other hand, croscarmellose sodium was most important for the initial simvastatin release. The results suggest the potential use of poloxamer 188-based SD in RDT for the oral delivery of poor water-soluble antihyperlipidemic drug, simvastatin. PMID:27757012

  9. Rapid disintegrating tablets of simvastatin dispersions in polyoxyethylene-polypropylene block copolymer for maximized disintegration and dissolution.

    Science.gov (United States)

    Balata, Gehan F; Zidan, Ahmad S; Abourehab, Mohamad As; Essa, Ebtessam A

    2016-01-01

    The objective of this research was to improve the dissolution of simvastatin and to incorporate it in rapid disintegrating tablets (RDTs) with an optimized disintegration and dissolution characteristics. Polyoxyethylene-polypropylene block copolymer (poloxamer 188) was employed as a hydrophilic carrier to prepare simvastatin solid dispersions (SDs). Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC) and X-ray diffractometry were employed to understand the interaction between the drug and the carrier in the solid state. The results obtained from Fourier transform infrared spectroscopy showed absence of any chemical interaction between the drug and poloxamer. The results of differential scanning calorimetry and X-ray diffractometry confirmed the conversion of simvastatin to distorted crystalline state. The SD of 1:2 w/w drug to carrier ratio showed the highest dissolution; hence, it was incorporated in RDT formulations using a 3 2 full factorial design and response surface methodology. The initial assessments of RDTs demonstrated an acceptable flow, hardness, and friability to indicate good mechanical strength. The interaction and Pareto charts indicated that percentage of croscarmellose sodium incorporated was the most important factor affecting the disintegration time and dissolution parameter followed by the hardness value and their interaction effect. Compression force showed a superior influence to increase RDT's porosity and to fasten disintegration rather than swelling action by croscarmellose sodium. On the other hand, croscarmellose sodium was most important for the initial simvastatin release. The results suggest the potential use of poloxamer 188-based SD in RDT for the oral delivery of poor water-soluble antihyperlipidemic drug, simvastatin.

  10. Role of Solvents in Improvement of Dissolution Rate of Drugs: Crystal Habit and Crystal Agglomeration

    Directory of Open Access Journals (Sweden)

    Maryam Maghsoodi

    2015-03-01

    Full Text Available Crystallization is often used for manufacturing drug substances. Advances of crystallization have achieved control over drug identity and purity, but control over the physical form remains poor. This review discusses the influence of solvents used in crystallization process on crystal habit and agglomeration of crystals with potential implication for dissolution. According to literature it has been known that habit modification of crystals by use of proper solvents may enhance the dissolution properties by changing the size, number and the nature of crystal faces exposed to the dissolution medium. Also, the faster dissolution rate of drug from the agglomerates of crystals compared with the single crystals may be related to porous structure of the agglomerates and consequently their better wettability. It is concluded from this review that in-depth understanding of role of the solvents in crystallization process can be applied to engineering of crystal habit or crystal agglomeration, and predictably dissolution improvement in poorly soluble drugs.

  11. Using fluid bed granulation to improve the dissolution of poorly water-soluble drugs

    Directory of Open Access Journals (Sweden)

    Andrea Ikeda Takahashi

    2012-06-01

    Full Text Available In this study, fluid bed granulation was applied to improve the dissolution of nimodipine and spironolactone, two very poorly water-soluble drugs. Granules were obtained with different amounts of sodium dodecyl sulfate and croscarmellose sodium and then compressed into tablets. The dissolution behavior of the tablets was studied by comparing their dissolution profiles and dissolution efficiency with those obtained from physical mixtures of the drug and excipients subjected to similar conditions. Statistical analysis of the results demonstrated that the fluid bed granulation process improves the dissolution efficiency of both nimodipine and spironolactone tablets. The addition of either the surfactant or the disintegrant employed in the study proved to have a lower impact on this improvement in dissolution than the fluid bed granulation process.

  12. A new rapidly absorbed paracetamol tablet containing sodium bicarbonate. II. Dissolution studies and in vitro/in vivo correlation.

    Science.gov (United States)

    Rostami-Hodjegan, A; Shiran, M R; Tucker, G T; Conway, B R; Irwin, W J; Shaw, L R; Grattan, T J

    2002-05-01

    The objective of this study was to compare the in vitro dissolution profile of a new rapidly absorbed paracetamol tablet containing sodium bicarbonate (PS) with that of a conventional paracetamol tablet (P), and to relate these by deconvolution and mapping to in vivo release. The dissolution methods used include the standard procedure described in the USP monograph for paracetamol tablets, employing buffer at pH 5.8 or 0.05 M HCl at stirrer speeds between 10 and 50 rpm. The mapping process was developed and implemented in Microsoft Excel worksheets that iteratively calculated the optimal values of scale and shape factors which linked in vivo time to in vitro time. The in vitro-in vivo correlation (IVIVC) was carried out simultaneously for both formulations to produce common mapping factors. The USP method, using buffer at pH 5.8, demonstrated no difference between the two products. However, using an acidic medium the rate of dissolution of P but not of PS decreased with decreasing stirrer speed. A significant correlation (r = 0.773; p dissolution using the profiles obtained with 0.05 M HCl and a stirrer speed of 30 rpm. The scale factor for optimal simultaneous IVIVC in the fasting state was 2.54 and the shape factor was 0.16; corresponding values for mapping in the fed state were 3.37 and 0.13 (implying a larger in vitro-in vivo time difference but reduced shape difference in the fed state). The current IVIVC explains, in part, the observed in vivo variability of the two products. The approach to mapping may also be extended to different batches of these products, to predict the impact of any changes of in vitro dissolution on in vivo release and plasma drug concentration-time profiles.

  13. In vitro dissolution methodology, mini-Gastrointestinal Simulator (mGIS), predicts better in vivo dissolution of a weak base drug, dasatinib.

    Science.gov (United States)

    Tsume, Yasuhiro; Takeuchi, Susumu; Matsui, Kazuki; Amidon, Gregory E; Amidon, Gordon L

    2015-08-30

    USP apparatus I and II are gold standard methodologies for determining the in vitro dissolution profiles of test drugs. However, it is difficult to use in vitro dissolution results to predict in vivo dissolution, particularly the pH-dependent solubility of weak acid and base drugs, because the USP apparatus contains one vessel with a fixed pH for the test drug, limiting insight into in vivo drug dissolution of weak acid and weak base drugs. This discrepancy underscores the need to develop new in vitro dissolution methodology that better predicts in vivo response to assure the therapeutic efficacy and safety of oral drug products. Thus, the development of the in vivo predictive dissolution (IPD) methodology is necessitated. The major goals of in vitro dissolution are to ensure the performance of oral drug products and the support of drug formulation design, including bioequivalence (BE). Orally administered anticancer drugs, such as dasatinib and erlotinib (tyrosine kinase inhibitors), are used to treat various types of cancer. These drugs are weak bases that exhibit pH-dependent and high solubility in the acidic stomach and low solubility in the small intestine (>pH 6.0). Therefore, these drugs supersaturate and/or precipitate when they move from the stomach to the small intestine. Also of importance, gastric acidity for cancer patients may be altered with aging (reduction of gastric fluid secretion) and/or co-administration of acid-reducing agents. These may result in changes to the dissolution profiles of weak base and the reduction of drug absorption and efficacy. In vitro dissolution methodologies that assess the impact of these physiological changes in the GI condition are expected to better predict in vivo dissolution of oral medications for patients and, hence, better assess efficacy, toxicity and safety concerns. The objective of this present study is to determine the initial conditions for a mini-Gastrointestinal Simulator (mGIS) to assess in vivo

  14. Improvement of the dissolution rate of poorly soluble drugs by solid crystal suspensions.

    Science.gov (United States)

    Thommes, Markus; Ely, David R; Carvajal, M Teresa; Pinal, Rodolfo

    2011-06-06

    We present a novel extrusion based approach where the dissolution rate of poorly soluble drugs (griseofulvin, phenytoin and spironolactone) is significantly accelerated. The drug and highly soluble mannitol are coprocessed in a hot melt extrusion operation. The obtained product is an intimate mixture of the crystalline drug and crystalline excipient, with up to 50% (w/w) drug load. The in vitro drug release from the obtained solid crystalline suspensions is over 2 orders of magnitude faster than that of the pure drug. Since the resulting product is crystalline, the accelerated dissolution rate does not bear the physical stability concerns inherent to amorphous formulations. This approach is useful in situations where the drug is not a good glass former or in cases where it is difficult to stabilize the amorphous drug. Being thermodynamically stable, the dissolution profile and the solid state properties of the product are maintained after storage at 40 °C, 75% RH for at least 90 days.

  15. DDSolver: an add-in program for modeling and comparison of drug dissolution profiles.

    Science.gov (United States)

    Zhang, Yong; Huo, Meirong; Zhou, Jianping; Zou, Aifeng; Li, Weize; Yao, Chengli; Xie, Shaofei

    2010-09-01

    In recent years, several mathematical models have been developed for analysis of drug dissolution data, and many different mathematical approaches have been proposed to assess the similarity between two drug dissolution profiles. However, until now, no computer program has been reported for simplifying the calculations involved in the modeling and comparison of dissolution profiles. The purposes of this article are: (1) to describe the development of a software program, called DDSolver, for facilitating the assessment of similarity between drug dissolution data; (2) to establish a model library for fitting dissolution data using a nonlinear optimization method; and (3) to provide a brief review of available approaches for comparing drug dissolution profiles. DDSolver is a freely available program which is capable of performing most existing techniques for comparing drug release data, including exploratory data analysis, univariate ANOVA, ratio test procedures, the difference factor f (1), the similarity factor f (2), the Rescigno indices, the 90% confidence interval (CI) of difference method, the multivariate statistical distance method, the model-dependent method, the bootstrap f (2) method, and Chow and Ki's time series method. Sample runs of the program demonstrated that the results were satisfactory, and DDSolver could be served as a useful tool for dissolution data analysis.

  16. Rapid disintegrating tablets of simvastatin dispersions in polyoxyethylene–polypropylene block copolymer for maximized disintegration and dissolution

    Directory of Open Access Journals (Sweden)

    Balata GF

    2016-10-01

    Full Text Available Gehan F Balata,1,2 Ahmad S Zidan,2 Mohamad AS Abourehab,1,3 Ebtessam A Essa4 1Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia; 2Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig, 3Department of Pharmaceutics, Faculty of Pharmacy, El-Minia University, El-Minia, 4Department of Pharmaceutics, Faculty of Pharmacy, Tanta University, Tanta, Egypt Abstract: The objective of this research was to improve the dissolution of simvastatin and to incorporate it in rapid disintegrating tablets (RDTs with an optimized disintegration and dissolution characteristics. Polyoxyethylene–polypropylene block copolymer (poloxamer 188 was employed as a hydrophilic carrier to prepare simvastatin solid dispersions (SDs. Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC and X-ray diffractometry were employed to understand the interaction between the drug and the carrier in the solid state. The results obtained from Fourier transform infrared spectroscopy showed absence of any chemical interaction between the drug and poloxamer. The results of differential scanning calorimetry and X-ray diffractometry confirmed the conversion of simvastatin to distorted crystalline state. The SD of 1:2 w/w drug to carrier ratio showed the highest dissolution; hence, it was incorporated in RDT formulations using a 32 full factorial design and response surface methodology. The initial assessments of RDTs demonstrated an acceptable flow, hardness, and friability to indicate good mechanical strength. The interaction and Pareto charts indicated that percentage of croscarmellose sodium incorporated was the most important factor affecting the disintegration time and dissolution parameter followed by the hardness value and their interaction effect. Compression force showed a superior influence to increase RDT’s porosity and to fasten disintegration rather than swelling action by

  17. Drug-polymer-water interaction and its implication for the dissolution performance of amorphous solid dispersions.

    Science.gov (United States)

    Chen, Yuejie; Liu, Chengyu; Chen, Zhen; Su, Ching; Hageman, Michael; Hussain, Munir; Haskell, Roy; Stefanski, Kevin; Qian, Feng

    2015-02-02

    The in vitro dissolution mechanism of an amorphous solid dispersion (ASD) remains elusive and highly individualized, yet rational design of ASDs with optimal performance and prediction of their in vitro/in vivo performance are very much desirable in the pharmaceutical industry. To this end, we carried out comprehensive investigation of various ASD systems of griseofulvin, felodipine, and ketoconazole, in PVP-VA or HPMC-AS at different drug loading. Physiochemical properties and processes related to drug-polymer-water interaction, including the drug crystallization tendency in aqueous medium, drug-polymer interaction before and after moisture exposure, supersaturation of drug in the presence of polymer, polymer dissolution kinetics, etc., were characterized and correlated with the dissolution performance of ASDs at different dose and different drug/polymer ratio. It was observed that ketoconazole/HPMC-AS ASD outperformed all other ASDs in various dissolution conditions, which was attributed to the drug's low crystallization tendency, the strong ketoconazole/HPMC-AS interaction and the robustness of this interaction against water disruption, the dissolution rate and the availability of HPMC-AS in solution, and the ability of HPMC-AS in maintaining ketoconazole supersaturation. It was demonstrated that all these properties have implications for the dissolution performance of various ASD systems, and further quantification of them could be used as potential predictors for in vitro dissolution of ASDs. For all ASDs investigated, HPMC-AS systems performed better than, or at least comparably with, their PVP-VA counterparts, regardless of the drug loading or dose. This observation cannot be solely attributed to the ability of HPMC-AS in maintaining drug supersaturation. We also conclude that, for fast crystallizers without strong drug-polymer interaction, the only feasible option to improve dissolution might be to lower the dose and the drug loading in the ASD. In this

  18. Combining the incompatible : inulin glass dispersions for fast dissolution, stabilization and formulation of lipophilic drugs

    NARCIS (Netherlands)

    Drooge, Dirk Jan van

    2006-01-01

    Solid dispersions offer a drug delivery platform that may overcome problems related to the absorption of poorly water-soluble drugs in-vivo. This is ascribed to accelerated dissolution of the drug. Nevertheless, up to now a small number of products based on solid dispersions have reached the market.

  19. 21 CFR 343.90 - Dissolution and drug release testing.

    Science.gov (United States)

    2010-04-01

    ... as contained in USP 23 at page 139. (g) Aspirin effervescent tablets for oral solution. Aspirin effervescent tablets for oral solution must meet the dissolution standard for aspirin effervescent tablets for... delayed-release tablets. Aspirin delayed-release capsules and aspirin delayed-release tablets must meet...

  20. Effect of ingested lipids on drug dissolution and release with concurrent digestion: a modeling approach

    Science.gov (United States)

    Buyukozturk, Fulden; Di Maio, Selena; Budil, David E.; Carrier, Rebecca L.

    2014-01-01

    Purpose To mechanistically study and model the effect of lipids, either from food or self-emulsifying drug delivery systems (SEDDS), on drug transport in the intestinal lumen. Methods Simultaneous lipid digestion, dissolution/release, and drug partitioning were experimentally studied and modeled for two dosing scenarios: solid drug with a food-associated lipid (soybean oil) and drug solubilized in a model SEDDS (soybean oil and Tween 80 at 1:1 ratio). Rate constants for digestion, permeability of emulsion droplets, and partition coefficients in micellar and oil phases were measured, and used to numerically solve the developed model. Results Strong influence of lipid digestion on drug release from SEDDS and solid drug dissolution into food-associated lipid emulsion were observed and predicted by the developed model. 90 minutes after introduction of SEDDS, there was 9% and 70% drug release in the absence and presence of digestion, respectively. However, overall drug dissolution in the presence of food-associated lipids occurred over a longer period than without digestion. Conclusion A systems-based mechanistic model incorporating simultaneous dynamic processes occurring upon dosing of drug with lipids enabled prediction of aqueous drug concentration profile. This model, once incorporated with a pharmacokinetic model considering processes of drug absorption and drug lymphatic transport in the presence of lipids, could be highly useful for quantitative prediction of impact of lipids on bioavailability of drugs. PMID:24234918

  1. Hybrid systems based on "drug - in cyclodextrin - in nanoclays" for improving oxaprozin dissolution properties.

    Science.gov (United States)

    Mura, Paola; Maestrelli, Francesca; Aguzzi, Carola; Viseras, César

    2016-07-25

    A combined approach based on drug complexation with cyclodextrins, and complex entrapment in nanoclays has been investigated, to join in a single delivery system the benefits of these carriers and potentiate their ability to improve the dissolution properties of oxaprozin (OXA), a poorly water-soluble anti-inflammatory drug. Based on previous studies, randomly methylated ß-cyclodextrin (RAMEB) was chosen as the most effective cyclodextrin for OXA complexation. Adsorption equilibrium studies performed on three different clays (sepiolite, attapulgite, bentonite) allowed selection of sepiolite (SV) for its greater adsorption power towards OXA. DSC and XRPD studies indicated drug amorphization in both binary OXA-RAMEB coground and OXA-SV cofused products, due to its complexation or very fine dispersion in the clay structure, respectively. The drug amorphous state was maintained also in the ternary OXA-RAMEB-SV cofused system. Dissolution studies evidenced a clear synergistic effect of RAMEB complexation and clay nanoencapsulation in improving the OXA dissolution properties, with an almost 100% increase in percent dissolved and dissolution efficiency compared to the OXA-RAMEB coground system. Therefore, the proposed combined approach represents an interesting tool for improving the therapeutic effectiveness of poorly soluble drugs, and reducing the CD amount necessary for obtaining the desired drug solubility and dissolution rate increase. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. A mathematical analysis of drug dissolution in the USP flow through apparatus

    Science.gov (United States)

    McDonnell, David; D'Arcy, D. M.; Crane, L. J.; Redmond, Brendan

    2017-10-01

    This paper applies boundary layer theory to the process of drug dissolution in the USP (United States Pharmacopeia) Flow Through Apparatus. The mass transfer rate from the vertical planar surface of a compact within the device is examined. The theoretical results obtained are then compared with those of experiment. The paper also examines the effect on the dissolution process caused by the interaction between natural and forced convection within the apparatus and the introduction of additional boundaries.

  3. In Vitro Dissolution of Fluconazole and Dipyridamole in Gastrointestinal Simulator (GIS), Predicting in Vivo Dissolution and Drug-Drug Interaction Caused by Acid-Reducing Agents.

    Science.gov (United States)

    Matsui, Kazuki; Tsume, Yasuhiro; Amidon, Gregory E; Amidon, Gordon L

    2015-07-06

    Weakly basic drugs typically exhibit pH-dependent solubility in the physiological pH range, displaying supersaturation or precipitation along the gastrointestinal tract. Additionally, their oral bioavailabilities may be affected by coadministration of acid-reducing agents that elevate gastric pH. The purpose of this study was to assess the feasibility of a multicompartmental in vitro dissolution apparatus, Gastrointestinal Simulator (GIS), in predicting in vivo dissolution of certain oral medications. In vitro dissolution studies of fluconazole, a BCS class I, and dipyridamole, a BCS class II weak bases (class IIb), were performed in the GIS as well as United States Pharmacopeia (USP) apparatus II and compared with the results of clinical drug-drug interaction (DDI) studies. In both USP apparatus II and GIS, fluconazole completely dissolved within 60 min regardless of pH, reflecting no DDI between fluconazole and acid-reducing agents in a clinical study. On the other hand, seven-fold and 15-fold higher concentrations of dipyridamole than saturation solubility were observed in the intestinal compartments in GIS with gastric pH 2.0. Precipitation of dipyridamole was also observed in the GIS, and the percentage of dipyridamole in solution was 45.2 ± 7.0%. In GIS with gastric pH 6.0, mimicking the coadministration of acid-reducing agents, the concentration of dipyridamole was equal to its saturation solubility, and the percentage of drug in solution was 9.3 ± 2.7%. These results are consistent with the clinical DDI study of dipyridamole with famotidine, which significantly reduced the Cmax and area under the curve. An In situ mouse infusion study combined with GIS revealed that high concentration of dipyridamole in the GIS enhanced oral drug absorption, which confirmed the supersaturation of dipyridamole. In conclusion, GIS was shown to be a useful apparatus to predict in vivo dissolution for BCS class IIb drugs.

  4. Effect of drug-carrier interaction on the dissolution behavior of solid dispersion tablets

    NARCIS (Netherlands)

    Srinarong, Parinda; Kouwen, Sander; Visser, Marinella R; Hinrichs, Wouter L J; Frijlink, Henderik W

    2010-01-01

    The objective of this study was to compare the dissolution behavior of tablets prepared from solid dispersions with and without drug-carrier interactions. Diazepam and nifedipine were used as model drugs. Two types of carriers were used; polyvinylpyrrolidone (PVP K12, K30 and K60) and saccharides

  5. A new self-emulsifying formulation of mefenamic acid with enhanced drug dissolution

    Directory of Open Access Journals (Sweden)

    Pornsak Sriamornsak

    2015-04-01

    Full Text Available To enhance the dissolution of poorly soluble mefenamic acid, self-emulsifying formulation (SEF, composing of oil, surfactant and co-surfactant, was formulated. Among the oils and surfactants studied, Imwitor® 742, Tween® 60, Cremophore® EL and Transcutol® HP were selected as they showed maximal solubility to mefenamic acid. The ternary phase diagram was constructed to find optimal concentration that provided the highest drug loading. The droplet size after dispersion and drug dissolution of selected formulations were investigated. The results showed that the formulation containing Imwitor® 742, Tween® 60 and Transcutol® HP (10:30:60 can encapsulate high amount of mefenamic acid. The dissolution study demonstrated that, in the medium containing surfactant, nearly 100% of mefenamic acid were dissolved from SEF within 5 min while 80% of drugs were dissolved from the commercial product in 45 min. In phosphate buffer (without surfactant, 80% of drug were dissolved from the developed SEF within 5 min while only about 13% of drug were dissolved in 45 min, from the commercial product. The results suggested that the SEF can enhance the dissolution of poorly soluble drug and has a potential to enhance drug absorption and improve bioavailability of drug.

  6. Solid formulation of a supersaturable self-microemulsifying drug delivery system for valsartan with improved dissolution and bioavailability.

    Science.gov (United States)

    Yeom, Dong Woo; Chae, Bo Ram; Kim, Jin Han; Chae, Jun Soo; Shin, Dong Jun; Kim, Chang Hyun; Kim, Sung Rae; Choi, Ji Ho; Song, Seh Hyon; Oh, Dongho; Sohn, Se Il; Choi, Young Wook

    2017-11-07

    In order to improve the dissolution and oral bioavailability of valsartan (VST), and reduce the required volume for treatment, we previously formulated a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) composed of VST (80 mg), Capmul ® MCM (13.2 mg), Tween ® 80 (59.2 mg), Transcutol ® P (59.2 mg), and Poloxamer 407 (13.2 mg). In the present study, by using Florite ® PS-10 (119.1 mg) and Vivapur ® 105 (105.6 mg) as solid carriers, VST-loaded solidified SuSMEDDS (S-SuSMEDDS) granules were successfully developed, which possessed good flow properties and rapid drug dissolution. By introducing croscarmellose sodium (31 mg) as a superdisintegrant, S-SuSMEDDS tablets were also successfully formulated, which showed fast disintegration and high dissolution efficiency. Preparation of granules and tablets was successfully optimized using D-optimal mixture design and 3-level factorial design, respectively, resulting in percentage prediction errors of <10%. In pharmacokinetic studies in rats, the relative bioavailability of the optimized granules was 107% and 222% of values obtained for SuSMEDDS and Diovan ® powder, respectively. Therefore, we conclude that novel S-SuSMEDDS formulations offer great potential for developing solid dosage forms of a liquefied formulation such as SuSMEDDS, while improving oral absorption of drugs with poor water solubility.

  7. Biopharmaceutical classification of drugs using intrinsic dissolution rate (IDR) and rat intestinal permeability.

    Science.gov (United States)

    Zakeri-Milani, Parvin; Barzegar-Jalali, Mohammad; Azimi, Mandana; Valizadeh, Hadi

    2009-09-01

    The solubility and dissolution rate of active ingredients are of major importance in preformulation studies of pharmaceutical dosage forms. In the present study, passively absorbed drugs are classified based on their intrinsic dissolution rate (IDR) and their intestinal permeabilities. IDR was determined by measuring the dissolution of a non-disintegrating disk of drug, and effective intestinal permeability of tested drugs in rat jejunum was determined using single perfusion technique. The obtained intrinsic dissolution rate values were in the range of 0.035-56.8 mg/min/cm(2) for tested drugs. The minimum and maximum intestinal permeabilities in rat intestine were determined to be 1.6 x 10(-5) and 2 x 10(-4)cm/s, respectively. Four classes of drugs were defined: Category I: P(eff,rat)>5 x 10(-5) (cm/s) or P(eff,human)>4.7 x 10(-5) (cm/s), IDR>1(mg/min/cm(2)), Category II: P(eff,rat)>5 x 10(-5) (cm/s) or P(eff,human)>4.7 x 10(-5) (cm/s), IDR1 (mg/min/cm(2)) and Category IV: P(eff,rat)drugs, it is concluded that drugs could be categorized correctly based on their IDR and intestinal permeability values.

  8. Near infrared spectroscopy to monitor drug release in-situ during dissolution tests.

    Science.gov (United States)

    Sarraguça, Mafalda Cruz; Matias, Rita; Figueiredo, Raquel; Ribeiro, Paulo Roberto S; Martins, Ana Teixeira; Lopes, João Almeida

    2016-11-20

    Dissolution tests can be used to demonstrate suitable in vivo drug release through in vivo/in vitro correlations. This work explores the possibility of using near infrared spectroscopy (NIRS) to monitor in-situ dissolution tests. It aims at expanding surrogate methods in quality control of drug products. Laboratory designed tablets of an immediate-release formulation containing folic acid and four excipients were used as case study. The dissolution tests were performed on a 1L vessel filled with 500ml of Milli-Q water with a rotating paddle apparatus (apparatus 2, Ph. Eur.) at 50rpm and 37±0.5°C. Near infrared (NIR) spectra were acquired in-situ with a transflectance probe connected to a Fourier-transform near infrared spectrometer. NIR spectra were regressed against folic acid concentration by partial least squares (PLS) regression. Folic acid concentrations during dissolution tests were obtained by periodically sampling the dissolution vessel and resourcing to an UV method. The proposed real-time NIR method was tested on a validation run yielding a root mean squared error of 0.25μgml(-1) (0.16μgml(-1) for the calibration runs) and a R(2) of 0.93 (0.95 for the calibration runs). The results suggest that NIRS is a suitable analytical technique for monitoring in-situ dissolution tests. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. International harmonization of generic drugs: in vitro dissolution tests for Japanese and American generic tablets.

    Science.gov (United States)

    Otsuka, Makoto; Tomita, Hisako; Otsuka, Kuniko; Kamae, Isao; Jorgenson, James A

    2006-01-01

    Ibuprofen tablets on the market in Japan and the USA were compared by manual- and automatic-dissolution tests according to USP24 criteria. Dissolution test were performed in 900 ml of phosphate buffer of pH 7.2 at 37.0+/-0.5 degrees C at 50 rpm for 60 min, and the time required for 70% dissolution (T70%) and 5% dissolution after 60 min (A60) were evaluated. The dissolution profiles of both Japanese and American tablets by the automatic-method showed almost the same profiles as those of the manual method. T70% of the American and Japanese tablets by the manual method were not significantly different (p>0.05) from the automatic-method at various sampling positions. The A60 of the American and Japanese tablets by the manual-method was not significantly different (p>0.05) except at one position. The results indicate that the automatic-method was more reproducible than the manual-method, and also that systematic error was negligible. The T70% and A60 of the American tablets were significantly different (p<0.05) from the Japanese tablets. The American tablets were a film-coated over-the-counter drug and the Japanese tablets were a sugar-coated prescription drug. There was a difference in dissolution behavior between the dosage forms of the two countries.

  10. Refining stability and dissolution rate of amorphous drug formulations

    DEFF Research Database (Denmark)

    Grohganz, Holger; Priemel, Petra A; Löbmann, Korbinian

    2014-01-01

    and on the interaction of APIs with small molecular compounds rather than polymers. Finally, in situ formation of an amorphous form might be an option to avoid storage problems altogether. Expert opinion: The diversity of poorly soluble APIs formulated in an amorphous drug delivery system will require different......Introduction: Poor aqueous solubility of active pharmaceutical ingredients (APIs) is one of the main challenges in the development of new small molecular drugs. Additionally, the proportion of poorly soluble drugs among new chemical entities is increasing. The transfer of a crystalline drug to its...

  11. Studies on Dissolution Enhancement of Prednisolone, a Poorly Water-Soluble Drug by Solid Dispersion Technique

    Directory of Open Access Journals (Sweden)

    Parvin Zakeri-Milani

    2011-06-01

    Full Text Available Introduction: Prednisolone is a class II substance according to the Biopharmaceutics Classification System. It is a poorly water soluble agent. The aim of the present study was to improve dissolution rate of a poorly water-soluble drug, prednisolone, by a solid dispersion technique. Methods: Solid dispersion of prednisolone was prepared with PEG 6000 or different carbohydrates such as lactose and dextrin with various ratios of the drug to carrier i.e., 1:10, 1:20 and 1:40. Solid dispersions were prepared by coevaporation method. The evaluation of the properties of the dispersions was performed using dissolution studies, Fourier-transform infrared spectroscopy and x-ray powder diffractometery. Results: The results indicated that lactose is suitable carriers to enhance the in vitro dissolution rate of prednisolone. The data from the x-ray diffraction showed that the drug was still detectable in its solid state in all solid dispersions except solid dispersions prepared by dextrin as carrier. The results from infrared spectroscopy showed no well-defined drug–carrier interactions for coevaporates. Conclusion: Solid dispersion of a poorly water-soluble drug, prednisolone may alleviate the problems of delayed and inconsistent rate of dissolution of the drug.

  12. Tablet disintegration and drug dissolution in viscous media: paracetamol IR tablets.

    Science.gov (United States)

    Parojcić, Jelena; Vasiljević, Dragana; Ibrić, Svetlana; Djurić, Zorica

    2008-05-01

    An investigation into the influence of viscous media on tablet disintegration and drug dissolution was performed with the aim to simulate the potential formulation-specific food effect for a selected highly soluble model drug. Literature data on the in vivo drug absorption in fasted and fed state have been evaluated for in vitro-in vivo correlation (IVIVC) purposes. In vitro studies were conducted in simple buffer media with or without addition of HPMC K4M as a viscosity enhancing agent. Good IVIVC correlation (r>0.95) was obtained for paracetamol dissolution in viscous media at 50rpm and fed state absorption profiles, while in vitro dissolution in simple media at lower stirring speed was predictable of drug products in vivo behaviour in the fasted state. The data obtained support the existing idea that relatively simple dissolution media and/or set of experimental conditions may be used to differentiate formulation-specific food-drug interactions. Such tests would be a useful tool in the development of formulations that would not be susceptible to the influence of co-administered meal and, furthermore, facilitate regulatory decision on the necessity to conduct food effect studies in vivo.

  13. Impact of sodium dodecyl sulphate on the dissolution of poorly soluble drug into biorelevant medium from drug-surfactant discs

    DEFF Research Database (Denmark)

    Madelung, Peter; Ostergaard, Jesper; Bertelsen, Poul

    2014-01-01

    in the discs is not caused by an increased surface area as SDS dissolves, micelles in the bulk medium or changes in the solid state properties of the drugs. The proposed mechanism involves a high local concentration of SDS at the solid-liquid interface as SDS dissolves and this solubilizes the drug....... The improved solubility at the solid-liquid interface provided a much steeper concentration gradient resulted in a faster dissolution. The total amount of SDS in the discs only gave a minor increase in total surfactant concentration in the dissolution medium and did therefore not to any large extent affect...

  14. Rapidly dissolving polymeric microneedles for minimally invasive intraocular drug delivery.

    Science.gov (United States)

    Thakur, Raghu Raj Singh; Tekko, Ismaiel A; Al-Shammari, Farhan; Ali, Ahlam A; McCarthy, Helen; Donnelly, Ryan F

    2016-12-01

    In this study, dissolving microneedles (MNs) were used to enhance ocular drug delivery of macromolecules. MNs were fabricated using polyvinylpyrrolidone (PVP) polymer of various molecular weights (MWs) containing three model molecules of increasing MW, namely fluorescein sodium and fluorescein isothiocyanate-dextrans (with MW of 70 k and 150 k Da). Arrays (3 × 3) of PVP MNs with conical shape measuring about 800 μm in height with a 300 μm base diameter, containing the model drugs, were fabricated and characterized for their fracture forces, insertion forces (in the sclera and cornea), depth of penetration (using OCT and confocal imaging), dissolution time and in vitro permeation. The average drug content of the MNs (only in MN shafts) ranged from 0.96 to 9.91 μg, and the average moisture content was below 11 %. High MW PVP produced MNs that can withstand higher forces with minimal reduction in needle height. PVP MNs showed rapid dissolution that ranged from 10 to 180 s, which was dependent upon PVP's MW. In vitro studies showed significant enhancement of macromolecule permeation when MNs were used, across both the corneal and scleral tissues, in comparison to topically applied aqueous solutions. Confocal images showed that the macromolecules formed depots within the tissues, which led to sustained permeation. However, use of MNs did not significantly benefit the permeation of small molecules; nevertheless, MN application has the potential for drug retention within the selected ocular tissues unlike topical application for small molecules. The material used in the fabrication of the MNs was found to be biocompatible with retinal cells (i.e. ARPE-19). Overall, this study reported the design and fabrication of minimally invasive rapidly dissolving polymeric MN arrays which were able to deliver high MW molecules to the eye via the intrastromal or intrascleral route. Thus, dissolving MNs have potential applications in enhancing ocular delivery of both small

  15. Measurement of humic and fulvic acid concentrations and dissolution properties by a rapid batch procedure

    Energy Technology Data Exchange (ETDEWEB)

    Van Zomeren, A.; Comans, R.N.J. [ECN Biomass, Coal and Environmental Research, Petten (Netherlands)

    2007-08-29

    Although humic substances (HS) strongly facilitate the transport of metals and hydrophobic organic contaminants in environmental systems, their measurement is hampered by the time-consuming nature of currently available methods for their isolation and purification. We present and apply a new rapid batch method to measure humic (HA) and fulvic (FA) acid concentrations and dissolution properties in both solid and aqueous samples. The method is compared with the conventional procedures and is shown to substantially facilitate HS concentration measurements, particularly for applications such as geochemical modeling where HS purification is not required. The new method can be performed within 1.5-4 h per sample and multiple samples can be processed simultaneously, while the conventional procedures typically require approximately 40 h for a single sample. In addition, specific dissolution properties of HS are identified and are consistent with recent views on the molecular structure of HS that emphasize molecular interactions of smaller entities over distinct macromolecular components. Because the principles of the new method are essentially the same as those of generally accepted conventional procedures, the identified HA and FA properties are of general importance for the interpretation of the environmental occurrence and behavior of HS.

  16. Theoretical dissolution model of poly-disperse drug particles in biorelevant media.

    Science.gov (United States)

    Okazaki, Arimichi; Mano, Takashi; Sugano, Kiyohiko

    2008-05-01

    The purpose of the present study was to construct the theoretical dissolution model of poly-disperse drug particles in biorelevant media containing bile salt/ lecithin aggregates (micelles or vesicles). The effective diffusion coefficient in the biorelevant medium and the particle size distribution of drug particles were simultaneously factored into the Nernst-Brunner equation. The effective diffusion coefficient of a drug in the biorelevant medium was calculated to be smaller than that in the blank buffer, since the diffusion coefficient of a drug bound to the aggregates became similar to that of the aggregates. The particle size distribution of a drug powder was simulated as the sum of mono-disperse fractions covering the particle size range. To verify the modified equation, the dissolution profile of griseofulvin and danazol in a taurocholic acid/egg lecithin (4:1 mixture, taurocholic acid = 0-30 mM) system was investigated. It was clearly demonstrated that both modifications on the Nernst-Brunner equation improved the prediction accuracy. When the effect of the particle size distribution was neglected, the theoretical curve underestimated the observed value at the early phase of dissolution process. When the diffusion coefficient of a free drug was used instead of the effective diffusion coefficient, the theoretical curve overestimated the observed value. The results of the present study suggested that the effect of the particle size distribution and the effective diffusion coefficient should be taken into consideration.

  17. Investigation of Biowaivers for Immediate Release Formulations Containing BCS III Drugs, Acyclovir, Atenolol, and Ciprofloxacin Hydrochloride, Using Dissolution Testing.

    Science.gov (United States)

    Reddy, Nallagundla H S; Patnala, Srinivas; Kanfer, Isadore

    2017-02-01

    The dissolution of several products containing Biopharmaceutical Classification System (BCS) class III drugs, acyclovir, atenolol, and ciprofloxacin hydrochloride, listed in the WHO essential drug list (EDL), was tested and compared with their respective comparator pharmaceutical products (CPPs) marketed in South Africa and India. US Pharmacopeia (USP) buffers of pH 1.2, 4.5, and 6.8 were used as dissolution media and tested using USP apparatus 2 at 75 rpm and 900 ml. Nine acyclovir products were tested, and only three dissolved very rapidly in all media; i.e., they showed a release of >85% in 15 min. Eight atenolol products tested were all very rapidly dissolving in all three pH media. Ten ciprofloxacin hydrochloride products were tested, and the results showed that only five products met the WHO biowaiver criteria. This study indicates that not all marketed products containing the same BCS III active pharmaceutical ingredient (API) in similar strength and dosage form are necessarily in vitro equivalent as per the WHO biowaiver criteria. Furthermore, selection and availability of an innovator product as CPP are important considerations that can affect the outcomes of such studies.

  18. Synthesis of novel core-shell structured dual-mesoporous silica nanospheres and their application for enhancing the dissolution rate of poorly water-soluble drugs

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Chao, E-mail: wuchao27@126.com [Department of Pharmaceutics, Liaoning Medical University, 40 Songpo Road, Linghe District, Jinzhou, Liaoning Province 121001 (China); Sun, Xiaohu [Management Center for Experiments, Bohai University, 19 Keji Road, Songshan District, Jinzhou, Liaoning Province 121000 (China); Zhao, Zongzhe; Zhao, Ying; Hao, Yanna; Liu, Ying [Department of Pharmaceutics, Liaoning Medical University, 40 Songpo Road, Linghe District, Jinzhou, Liaoning Province 121001 (China); Gao, Yu, E-mail: gaoyu_1116@163.com [Department of Medical Oncology, First Affiliated Hospital of Liaoning Medical University, 40 Songpo Road, Linghe District, Jinzhou, Liaoning Province 121001 (China)

    2014-11-01

    Novel core-shell dual-mesoporous silica nanospheres (DMSS) with a tunable pore size were synthesized successfully using a styrene monomer as a channel template for the core and cetyltrimethyl ammonium bromide (CTAB) as a channel template for the shell in order to improve the dissolution rate of poorly water-soluble drugs. Simvastatin was used as a model drug and loaded into DMSS and the mesoporous core without the shell (MSC) by the solvent evaporation method. The drug loading efficiency of DMSS and MSC were determined by thermogravimetric analysis (TGA) and ultraviolet spectroscopy (UV). Characterization, using scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption, powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR) showed that simvastatin adsorbed in DMSS and MSC was in an amorphous state, and in vitro release test results demonstrated that both DMSS and MSC increased the water solubility and dissolution rate of simvastatin. The shell structure of DMSS was able to regulate the release of simvastatin compared with MSC. It is worth noting that DMSS has significant potential as a carrier for improving the dissolution of poorly water-soluble drugs and reducing the rapid release. - Highlights: • A novel core-shell DMSS is prepared for improving the dissolution rate of simvastatin. • The diffusional resistance of the mesoporous shell can delay and regulate drug release. • Simvastatin absorbed in DMSS exists in amorphous form due to spatial confinement.

  19. Evaluation of in vivo dissolution behavior and GI transit of griseofulvin, a BCS class II drug.

    Science.gov (United States)

    Fujioka, Yoshitsugu; Metsugi, Yukiko; Ogawara, Ken-Ichi; Higaki, Kazutaka; Kimura, Toshikiro

    2008-03-20

    Mean plasma concentration-time profile of griseofulvin, a BCS class II drug, orally administered as powders into rats, was predicted based on GITA model. However, it was very difficult to predict the individual plasma profile because of large inter-individual difference. As the absorption of griseofulvin would be rate-limited by the dissolution process, we tried to analyze the in vivo dissolution kinetics of griseofulvin by focusing on gastric emptying and intestinal transit as physiological factors influencing the in vivo dissolution kinetics. After oral administration of griseofulvin, theophylline and sulfasalazine into rats, gastric emptying and intestinal transit were simultaneously estimated by analyzing the absorption kinetics of theophylline and observing the appearance of sulfapyridine in plasma, respectively. Gastric emptying kinetics was not significantly correlated with absorption or dissolution behavior of griseofulvin. On the other hand, the cecum-arriving time reflecting the intestinal transit was significantly correlated with both AUC and total dissolved amount of griseofulvin. T(max) of griseofulvin also increased with the increase of cecum-arriving time. These results clearly indicate that the longer residence time could lead to the higher dissolution and absorption of griseofulvin and that the variance of intestinal transit could be responsible for the inter-individual difference of the in vivo absorption behavior.

  20. Facts, fallacies and future of dissolution testing of polysaccharide based colon-specific drug delivery.

    Science.gov (United States)

    Kotla, Niranjan Goud; Gulati, Monica; Singh, Sachin Kumar; Shivapooja, Ashwini

    2014-03-28

    Colonic diseases like ulcerative colitis, Crohn's disease, and colon cancer are on rise due to variations in the dietary and lifestyle habits. Increase in prevalence of such diseases has augmented the interest of researchers in colon targeted drug delivery systems. Polysaccharide coating has emerged as one of the most successful approaches in this direction. Evaluation of such systems, however, demands an efficient dissolution method in terms of convenience, economy, relevance and reproducibility. It is problematic to mimic the dynamic and ecologically diverse features of the colon. A number of dissolution approaches were tried which include incorporation of polysaccharide-degrading enzymes, rat caecal contents, human faecal slurries, and multi-stage culture systems. Till date, pursuit for cost-effective and animal-sparing colon-specific bio-relevant dissolution media has been a foremost challenge facing pharmaceutical scientists over many decades. This article reviews various dissolution methods adopted to mimic the in vivo performance of dosage forms that are used for colon targeting. It also highlights limitations of the available methods and conditions that should be taken into account while designing a bio-relevant dissolution method for such systems. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Dissolution kinetics and mechanism of Mg-Al layered double hydroxides: a simple approach to describe drug release in acid media.

    Science.gov (United States)

    Parello, Mara L; Rojas, Ricardo; Giacomelli, Carla E

    2010-11-01

    Layered double hydroxides (LDHs) weathering in acidic media is one of the main features that affects their applications in drug delivery systems. In this work, the dissolution kinetics of biocompatible Mg-Al LDHs was studied at different initial pH values and solid concentrations using a simple and fast experimental method that coupled flow injection analysis and amperometric detection. A carbonate intercalated sample was used to determine the controlling step of the process and the dissolution mechanism. Finally, the study was extended to an ibuprofen intercalated LDH. The obtained results showed that the weathering process was mainly controlled by the exposed area and surface reactivity of LDHs particles. The dissolution mechanism at the particle surface was described in two steps: fast formation of surface reactive sites by hydroxyl group protonation and slow detachment of metal ions from surface. At strongly acidic conditions, the reaction rate was pH dependent due to the equilibrium between protonated (active) and deprotonated (inactive) hydroxyl groups. On the other hand, at mildly acidic conditions, the dissolution behavior was also ruled by the equilibrium attained between the particle surface reactive sites and the dissolved species. LDHs solubility and dissolution rate presented strong dependence with the interlayer anion. The ibuprofen intercalated sample was more soluble and more rapidly dissolved than the carbonate intercalated one in acetic/acetate buffer. On the other hand, the dissolution mechanism was invariant with the interlayer anion. Copyright 2010 Elsevier Inc. All rights reserved.

  2. Design and optimization of self-nanoemulsifying drug delivery systems (SNEDDS) for enhanced dissolution of gemfibrozil.

    Science.gov (United States)

    Villar, Ana Maria Sierra; Naveros, Beatriz Clares; Campmany, Ana Cristina Calpena; Trenchs, Monserrat Aróztegui; Rocabert, Coloma Barbé; Bellowa, Lyda Halbaut

    2012-07-15

    Self-nanoemulsifying drug delivery systems of gemfibrozil were developed under Quality by Design approach for improvement of dissolution and oral absorption. Preliminary screening was performed to select proper components combination. Box-Behnken experimental design was employed as statistical tool to optimize the formulation variables, X(1) (Cremophor(®) EL), X(2) (Capmul(®) MCM-C8), and X(3) (lemon essential oil). Systems were assessed for visual characteristics (emulsification efficacy), turbidity, droplet size, polydispersity index and drug release. Different pH media were also assayed for optimization. Following optimization, the values of formulation components (X(1), X(2), and X(3)) were 32.43%, 29.73% and 21.62%, respectively (16.22% of gemfibrozil). Transmission electron microscopy demonstrated spherical droplet morphology. SNEEDS release study was compared to commercial tablets. Optimized SNEDDS formulation of gemfibrozil showed a significant increase in dissolution rate compared to conventional tablets. Both formulations followed Weibull mathematical model release with a significant difference in t(d) parameter in favor of the SNEDDS. Equally amodelistic parameters were calculated being the dissolution efficiency significantly higher for SNEDDS, confirming that the developed SNEDDS formulation was superior to commercial formulation with respect to in vitro dissolution profile. This paper provides an overview of the SNEDDS of the gemfibrozil as a promising alternative to improve oral absorption. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Dissolution of Danazol Amorphous Solid Dispersions: Supersaturation and Phase Behavior as a Function of Drug Loading and Polymer Type.

    Science.gov (United States)

    Jackson, Matthew J; Kestur, Umesh S; Hussain, Munir A; Taylor, Lynne S

    2016-01-04

    Amorphous solid dispersions (ASDs) are of great interest as enabling formulations because of their ability to increase the bioavailability of poorly soluble drugs. However, the dissolution of these formulations under nonsink dissolution conditions results in highly supersaturated drug solutions that can undergo different types of phase transitions. The purpose of this study was to characterize the phase behavior of solutions resulting from the dissolution of model ASDs as well as the degree of supersaturation attained. Danazol was chosen as a poorly water-soluble model drug, and three polymers were used to form the dispersions: polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), and hydroxypropylmethyl cellulose acetate succinate (HPMCAS). Dissolution studies were carried out under nonsink conditions, and solution phase behavior was characterized using several orthogonal techniques. It was found that liquid-liquid phase separation (LLPS) occurred following dissolution and prior to crystallization for most of the dispersions. Using flux measurements, it was further observed that the maximum attainable supersaturation following dissolution was equivalent to the amorphous solubility. The dissolution of the ASDs led to sustained supersaturation, the duration of which varied depending on the drug loading and the type of polymer used in the formulation. The overall supersaturation profile observed thus depended on a complex interplay between dissolution rate, polymer type, drug loading, and the kinetics of crystallization.

  4. Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution.

    Science.gov (United States)

    Millière, Raphaël

    2017-01-01

    There is converging evidence that high doses of hallucinogenic drugs can produce significant alterations of self-experience, described as the dissolution of the sense of self and the loss of boundaries between self and world. This article discusses the relevance of this phenomenon, known as "drug-induced ego dissolution (DIED)", for cognitive neuroscience, psychology and philosophy of mind. Data from self-report questionnaires suggest that three neuropharmacological classes of drugs can induce ego dissolution: classical psychedelics, dissociative anesthetics and agonists of the kappa opioid receptor (KOR). While these substances act on different neurotransmitter receptors, they all produce strong subjective effects that can be compared to the symptoms of acute psychosis, including ego dissolution. It has been suggested that neuroimaging of DIED can indirectly shed light on the neural correlates of the self. While this line of inquiry is promising, its results must be interpreted with caution. First, neural correlates of ego dissolution might reveal the necessary neurophysiological conditions for the maintenance of the sense of self, but it is more doubtful that this method can reveal its minimally sufficient conditions. Second, it is necessary to define the relevant notion of self at play in the phenomenon of DIED. This article suggests that DIED consists in the disruption of subpersonal processes underlying the "minimal" or "embodied" self, i.e., the basic experience of being a self rooted in multimodal integration of self-related stimuli. This hypothesis is consistent with Bayesian models of phenomenal selfhood, according to which the subjective structure of conscious experience ultimately results from the optimization of predictions in perception and action. Finally, it is argued that DIED is also of particular interest for philosophy of mind. On the one hand, it challenges theories according to which consciousness always involves self-awareness. On the other

  5. Dissolution and powder flow characterization of solid self-emulsified drug delivery system (SEDDS).

    Science.gov (United States)

    Agarwal, Vikas; Siddiqui, Akhtar; Ali, Hazem; Nazzal, Sami

    2009-01-21

    In this study, the dynamics of powder flow upon griseofulvin-self-emulsified drug delivery system (SEDDS) addition to silica and silicates and the effect of these adsorbents on drug release were investigated. SEDDS was adsorbed at SEDDS/adsorbent ratios from 0.25:1 to 3:1 on magnesium aluminum silicate [5 and 80 microm], calcium silicate [25 microm], and silicon dioxide [3.6, 20, and 300 microm]. Powder flow was evaluated using the powder rheometer and compared to angle of repose. Release of drug from a 1:1 SEDDS/adsorbent powder was determined by dissolution using USP Type 2 apparatus. Powder rheometer profiles indicated that effect of SEDDS on the flow behavior of the adsorbents could be correlated to stepwise or continuous growing behavior as observed in wet granulation process. However, due to their porous nature, adsorbents exhibited an initial lag phase during which no change in flow was observed. Dissolution of drug from adsorbed-SEDDS was found to be dependent on pore length and nucleation at the lipid/adsorbent interface. Increase in dissolution rate was observed with an increase in surface area and was independent of the chemical nature of the adsorbents. Therefore, in order to manufacture free flowing powder containing liquid SEDDS, special attention should be given to particle size, specific surface area, type and amount of adsorbent.

  6. Rapid Automated Dissolution and Analysis Techniques for Radionuclides in Recycle Process Streams

    Energy Technology Data Exchange (ETDEWEB)

    Sudowe, Ralf [Univ. of Nevada, Las Vegas, NV (United States). Radiochemistry Program and Health Physics Dept.; Roman, Audrey [Univ. of Nevada, Las Vegas, NV (United States). Radiochemistry Program; Dailey, Ashlee [Univ. of Nevada, Las Vegas, NV (United States). Radiochemistry Program; Go, Elaine [Univ. of Nevada, Las Vegas, NV (United States). Radiochemistry Program

    2013-07-18

    The analysis of process samples for radionuclide content is an important part of current procedures for material balance and accountancy in the different process streams of a recycling plant. The destructive sample analysis techniques currently available necessitate a significant amount of time. It is therefore desirable to develop new sample analysis procedures that allow for a quick turnaround time and increased sample throughput with a minimum of deviation between samples. In particular, new capabilities for rapid sample dissolution and radiochemical separation are required. Most of the radioanalytical techniques currently employed for sample analysis are based on manual laboratory procedures. Such procedures are time- and labor-intensive, and not well suited for situations in which a rapid sample analysis is required and/or large number of samples need to be analyzed. To address this issue we are currently investigating radiochemical separation methods based on extraction chromatography that have been specifically optimized for the analysis of process stream samples. The influence of potential interferences present in the process samples as well as mass loading, flow rate and resin performance is being studied. In addition, the potential to automate these procedures utilizing a robotic platform is evaluated. Initial studies have been carried out using the commercially available DGA resin. This resin shows an affinity for Am, Pu, U, and Th and is also exhibiting signs of a possible synergistic effects in the presence of iron.

  7. Better understanding of dissolution behaviour of amorphous drugs by in situ solid-state analysis using Raman spectroscopy

    DEFF Research Database (Denmark)

    Savolainen, M; Kogermann, K; Heinz, A

    2009-01-01

    of two amorphous drugs, indomethacin (IMC) and carbamazepine (CBZ). The dissolution rate was higher from amorphous IMC compared to the crystalline alpha- and gamma-forms. However, the dissolution rate started to slow down during the experiment. In situ Raman analysis verified that at that time point...

  8. Rapid and near-complete dissolution of wood lignin at ≤80°C by a recyclable acid hydrotrope

    Science.gov (United States)

    Liheng Chen; Jinze Dou; Qianli Ma; Ning Li; Ruchun Wu; Huiyang Bian; Daniel J. Yelle; Tapani Vuorinen; Shiyu Fu; Xuejun Pan; Junyong (J.Y.) Zhu

    2017-01-01

    We report the discovery of the hydrotropic properties of a recyclable aromatic acid, p-toluenesulfonic acid (p-TsOH), for potentially low-cost and efficient fractionation of wood through rapid and near-complete dissolution of lignin. Approximately 90% of poplar wood (NE222) lignin can be dissolved at 80°C in 20 min. Equivalent delignification using...

  9. Population data analysis of dissolution time profiles: Assessment of physicochemical properties of the drug, drug particles and the pharmaceutical formulation.

    Science.gov (United States)

    Horkovics-Kovats, Stefan; Brunovský, Pavel; Pichler, Arthur; Bulitta, Jürgen B

    2015-10-12

    Disintegration of finished dosage forms (FDF) and drug dissolution are fundamentally important processes that affect bioavailability. Established theories do not account for disintegration and usually assume sink conditions for drug dissolution that often do not apply. We present the theory to describe the disintegration of FDF with subsequent dissolution of liberated particles containing the active pharmaceutical ingredient (API) and its application using population data analysis. Population modeling, using dissolution profiles of 400mg cefditoren pivoxil tablets manufactured under various tableting pressures, characterized the intrinsic lifetime distribution of the particles and identified the presence of crystalline API in the formulation that was proven by X-ray diffraction. Modeling further estimated the disintegration time of FDF, the solubility of the amorphous API and its chemical instability in the medium that were in agreement with the experimentally determined values. This novel approach provides a quantitative understanding of the manufacturing process of FDF and can substantially contribute to the targeted development of finished dosage forms. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Prediction of drug interaction between oral adsorbent AST-120 and concomitant drugs based on the in vitro dissolution and in vivo absorption behavior of the drugs.

    Science.gov (United States)

    Koya, Yohei; Uchida, Shinya; Machi, Yoshiki; Shobu, Yuko; Namiki, Noriyuki; Kotegawa, Tsutomu

    2016-11-01

    AST-120 is used to decrease the abundance of serum uremic toxins in treatment of chronic kidney disease; however, it could also adsorb concomitantly administered drugs. This study aimed to develop a prediction method for drug interaction between AST-120 and concomitantly administered drugs based on in vitro dissolution and in vivo absorption behavior. Sixty-eight drugs were selected for the analysis. For each drug, theoretical dissolution (R d ) and absorption (R a ) rates at estimated dosing intervals (1, 30, 60, 90, 120, and 240 min) were calculated using the Noyes-Whitney formula and compartment analysis, respectively. The optimal thresholds for R d and R a (R dth and R ath ) were estimated by comparing the results with those of previous drug interaction studies for six drugs. Four drug interaction risk categories for 68 drugs at each dose interval were defined according to the indices of dissolution and absorption against their thresholds. The in vitro dissolution and in vivo absorption behavior of the selected drugs were well fitted to the Noyes-Whitney formula and one- or two-compartment models. The optimal R dth and R ath that gave the highest value of consistency with the equivalence of drug interaction studies were 90 and 30 %, respectively. As the dosing intervals were lengthened, the number of drugs classified into the low-risk categories increased. A new drug interaction prediction method based on the pharmacokinetic parameters of drugs was developed. The new model is useful for estimating the risk of drug interaction in clinical practice when AST-120 is used in combination with other drugs.

  11. Compression of coated drug beads for sustained release tablet of glipizide: formulation, and dissolution.

    Science.gov (United States)

    Nguyen, Chien; Christensen, J Mark; Ayres, James W

    2014-02-01

    A promising glipizide formulation comprising compression of four-layer coated beads into tablets was prepared. The tablet offered the advantages of: a two-hour lag time before drug release, retaining sustained release characteristics and providing approximately zero-order drug release. Drug release was nearly independent of paddle speeds of 50 and 100 rpm releasing 80% over 14 h similar to the commercial glipizide osmotic pump tablet during dissolution testing while keeping the benefits of multiparticular dosage forms. The tablets contain beads with four layers: (1) the innermost layer consists of 2.5 g glipizide and 3.75 g solid ethylcellulose (Surelease®) coated onto 71.25 g of sugar beads; (2) next a hardening layer of 5 g of hypromellose; (3) the controlled release layer of 7.5 g of Surelease®:lactose at a solids ratio of 100:7 and (4) an outermost layer of 20 g of lactose:sodium starch glycolate (Explotab®) at a 2:1 ratio. Then, beads were compressed into tablets containing 11 mg of glipizide using 1500 lbs of compression pressure. The dissolution test similarity factor (f2) was above 50 for all test conditions for formulation F13 and Glucotrol® with a high of 69.9. The two Surelease® layers both aid controlling drug release, with the Surelease®-drug layer affecting drug release to a greater extent.

  12. Dissolution enhancement of a poorly water-soluble antimalarial drug by means of a modified multi-fluid nozzle pilot spray drier

    Energy Technology Data Exchange (ETDEWEB)

    Sahoo, Nanda Gopal; Kakran, Mitali [School of Mechanical and Aerospace Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798 (Singapore); Li Lin, E-mail: mlli@ntu.edu.sg [School of Mechanical and Aerospace Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798 (Singapore); Judeh, Zaher [School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive, Singapore 637459 (Singapore); Mueller, Rainer H. [Free University of Berlin, Department of Pharmacy, Biopharmaceutics and Nutricosmetics, Kelchstrass 31, Berlin (Germany)

    2011-03-12

    A spray drier with a modified multi-fluid nozzle was used to prepare microparticles of a poorly water-soluble antimalarial drug, artemisinin (ART), with the aim of improving its dissolution in water. ART was co-spray dried with a hydrophilic polymer, polyethylene glycol (PEG). The differential scanning calorimetry and X-ray diffraction studies showed that the crystallinity of ART decreased after spray drying. Compared to the physical mixture of ART and PEG, the amorphous phase of ART in the spray dried ART-PEG composites increased, which depended on the weight ratio of drug to polymer. The phase-solubility studies revealed that the aqueous solubility of ART was improved by the presence of PEG. The dissolution of ART from the spray dried ART-PEG composites was more rapid than that from their respective physical mixture and the original ART powder. For example, the dissolution of ART from the spray dried ART-PEG composite (1:6) was 6.5 times higher than that from the original ART powder in the first 30 min. In the mathematical modeling, the Weibull and Korsemeyer-Peppas models were found to best fit to the in vitro dissolution data and then the drug release mechanism was considered as the Fickian diffusion.

  13. Formulation of 3D Printed Tablet for Rapid Drug Release by Fused Deposition Modeling (FDM): Screening Polymers for Drug Release, Drug-Polymer Miscibility and Printability.

    Science.gov (United States)

    Solanki, Nayan; Tahsin, Md; Shah, Ankita; Serajuddin, Abu T M

    2017-10-21

    The primary aim of this study was to identify pharmaceutically acceptable amorphous polymers for producing 3D printed tablets of a model drug, haloperidol, for rapid release by fused deposition modeling (FDM). Filaments for 3D printing were prepared by hot melt extrusion at 150°C with 10 and 20% w/w of haloperidol using Kollidon(®) VA64, Kollicoat(®) IR, Affinsiol(™)15 cP and HPMCAS either individually or as binary blends (Kollidon(®) VA64+Affinisol(™)15 cP, 1:1; Kollidon(®) VA64+HPMCAS, 1:1). Dissolution of crushed extrudates was studied at pH 2 and 6.8, and formulations demonstrating rapid dissolution rates were then analyzed for drug-polymer, polymer-polymer and drug-polymer-polymer miscibility by film casting. Polymer-polymer (1:1) and drug-polymer-polymer (1:5:5 and 2:5:5) mixtures were found to be miscible. Tablets with 100 and 60 % infill were printed using MakerBot printer at 210°C, and dissolution tests of tablets were conducted at pH 2 and 6.8. Extruded filaments of Kollidon(®) VA64-Affinisol(™)15 cP mixtures were flexible and had optimum mechanical strength for 3D printing. Tablets containing 10% drug with 60 and 100% infill showed complete drug release at pH 2 in 45 and 120 min, respectively. Relatively high dissolution rates were also observed at pH 6.8. The 1:1-mixture of Kollidon(®) VA64 and Affinisol(™)15 cP was thus identified as a suitable polymer system for 3D printing and rapid drug release. Copyright © 2017. Published by Elsevier Inc.

  14. Gastrointestinal release behaviour of modified-release drug products: dynamic dissolution testing of mesalazine formulations.

    Science.gov (United States)

    Goyanes, Alvaro; Hatton, Grace B; Merchant, Hamid A; Basit, Abdul W

    2015-04-30

    The aminosalicylate mesalazine (mesalamine) forms the mainstay of treatment in ulcerative colitis (UC), a disease for which many commercial modified-release products have been developed with the aim of providing targeted gastrointestinal release. The release profiles of five of these commercial formulations were evaluated in bicarbonate buffer using a novel dissolution model that mimics the dynamic conditions of the gastrointestinal tract. Monolithic and multi-particulate mesalazine formulations with pH-dependent and/or independent release mechanisms were evaluated (Asacol(®) 800, Octasa(®), Mezavant(®) XL, Salofalk(®), Pentasa(®)), and each of the products displayed a distinctive dissolution profile. The dissolution results for Mezavant(®) XL (Lialda(®)) (lag time 290 min) demonstrated good correlation with previously reported in vivo disintegration times assessed by gamma-scintigraphy in humans. Octasa(®) showed a similar lag time to Mezavant(®) XL. Drug release from Asacol(®) 800 (Asacol(®) HD) showed a wide standard deviation, reflecting the great variability in vivo. Salofalk(®) displayed both delayed release and extended release characteristics. Pentasa(®) released more than 50% of its drug load in the stomach compartment of the model, which is attributed to the absence of a gastro-resistant coating in this product. The new dissolution method provided a realistic and discriminative in vitro assessment of mesalazine release from different formulations. These results demonstrate that this strategy can be used to predict intestinal release behaviour, and potentially aid the rational design of products developed to target different sites of the gut. Copyright © 2015. Published by Elsevier B.V.

  15. Dissolution and coarsening of polydisperse, polymorph drug particles liberated from a disintegrating finished dosage form: Theoretical considerations.

    Science.gov (United States)

    Horkovics-Kovats, Stefan

    2016-08-25

    In order to improve the bioavailability of substances with limited water-solubility, they are often formulated as nanoparticles. Nanoparticles show enhanced dissolution properties when compared to large particles. In this paper a dissolution theory is presented that comprehensively describes the dissolution properties of both large- and nanoparticles. It comprises non-sink conditions and arbitrary shaped isometrically dissolving particles, considering particle-size-independent dissolution layer thickness and several polymorphic drug forms. The known root-laws of dissolution kinetics happen to be special cases that depend on particle-size in relation to the diffusion layer thickness i.e. whether the particles are much larger, comparable, or much smaller than the diffusion layer thickness. The presented theory explains the improved dissolution properties of nanoparticles, such as their increased solubility, almost immediate dissolution, and the dissolution kinetics which is independent from hydrodynamic conditions. For polydisperse, polymorphic particles of arbitrary shapes that are liberated from a disintegrating finished dosage form, the Ostwald ripening (coarsening of particles and transition of metastable polymorphic forms into a more stable crystalline form) is described as water mediated mass transport. The presented theory points to certain limitations of the Ostwald-Freundlich equation for nanoparticles and provides their better characterization. This way it may contribute to a more specifically targeted development of finished dosage forms and may help to reduce the bias of toxicological and environmental assessments especially for drugs that are formed as nanoparticles. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Justification of Drug Product Dissolution Rate and Drug Substance Particle Size Specifications Based on Absorption PBPK Modeling for Lesinurad Immediate Release Tablets.

    Science.gov (United States)

    Pepin, Xavier J H; Flanagan, Talia R; Holt, David J; Eidelman, Anna; Treacy, Don; Rowlings, Colin E

    2016-09-06

    In silico absorption modeling has been performed, to assess the impact of in vitro dissolution on in vivo performance for ZURAMPIC (lesinurad) tablets. The dissolution profiles of lesinurad tablets generated using the quality control method were used as an input to a GastroPlus model to estimate in vivo dissolution in the various parts of the GI tract and predict human exposure. A model was set up, which accounts for differences of dosage form transit, dissolution, local pH in the GI tract, and fluid volumes available for dissolution. The predictive ability of the model was demonstrated by confirming that it can reproduce the Cmax observed for independent clinical trial. The model also indicated that drug product batches that pass the proposed dissolution specification of Q = 80% in 30 min are anticipated to be bioequivalent to the clinical reference batch. To further explore the dissolution space, additional simulations were performed using a theoretical dissolution profile below the proposed specification. The GastroPlus modeling indicates that such a batch will also be bioequivalent to standard clinical batches despite having a dissolution profile, which would fail the proposed dissolution specification of Q = 80% in 30 min. This demonstrates that the proposed dissolution specification sits comfortably within a region of dissolution performance where bioequivalence is anticipated and is not near an edge of failure for dissolution, providing additional confidence to the proposed specifications. Finally, simulations were performed using a virtual drug substance batch with a particle size distribution at the limit of the proposed specification for particle size. Based on these simulations, such a batch is also anticipated to be bioequivalent to clinical reference, demonstrating that the proposed specification limits for particle size distribution would give products bioequivalent to the pivotal clinical batches.

  17. Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution

    Science.gov (United States)

    Millière, Raphaël

    2017-01-01

    There is converging evidence that high doses of hallucinogenic drugs can produce significant alterations of self-experience, described as the dissolution of the sense of self and the loss of boundaries between self and world. This article discusses the relevance of this phenomenon, known as “drug-induced ego dissolution (DIED)”, for cognitive neuroscience, psychology and philosophy of mind. Data from self-report questionnaires suggest that three neuropharmacological classes of drugs can induce ego dissolution: classical psychedelics, dissociative anesthetics and agonists of the kappa opioid receptor (KOR). While these substances act on different neurotransmitter receptors, they all produce strong subjective effects that can be compared to the symptoms of acute psychosis, including ego dissolution. It has been suggested that neuroimaging of DIED can indirectly shed light on the neural correlates of the self. While this line of inquiry is promising, its results must be interpreted with caution. First, neural correlates of ego dissolution might reveal the necessary neurophysiological conditions for the maintenance of the sense of self, but it is more doubtful that this method can reveal its minimally sufficient conditions. Second, it is necessary to define the relevant notion of self at play in the phenomenon of DIED. This article suggests that DIED consists in the disruption of subpersonal processes underlying the “minimal” or “embodied” self, i.e., the basic experience of being a self rooted in multimodal integration of self-related stimuli. This hypothesis is consistent with Bayesian models of phenomenal selfhood, according to which the subjective structure of conscious experience ultimately results from the optimization of predictions in perception and action. Finally, it is argued that DIED is also of particular interest for philosophy of mind. On the one hand, it challenges theories according to which consciousness always involves self-awareness. On

  18. Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution

    Directory of Open Access Journals (Sweden)

    Raphaël Millière

    2017-05-01

    Full Text Available There is converging evidence that high doses of hallucinogenic drugs can produce significant alterations of self-experience, described as the dissolution of the sense of self and the loss of boundaries between self and world. This article discusses the relevance of this phenomenon, known as “drug-induced ego dissolution (DIED”, for cognitive neuroscience, psychology and philosophy of mind. Data from self-report questionnaires suggest that three neuropharmacological classes of drugs can induce ego dissolution: classical psychedelics, dissociative anesthetics and agonists of the kappa opioid receptor (KOR. While these substances act on different neurotransmitter receptors, they all produce strong subjective effects that can be compared to the symptoms of acute psychosis, including ego dissolution. It has been suggested that neuroimaging of DIED can indirectly shed light on the neural correlates of the self. While this line of inquiry is promising, its results must be interpreted with caution. First, neural correlates of ego dissolution might reveal the necessary neurophysiological conditions for the maintenance of the sense of self, but it is more doubtful that this method can reveal its minimally sufficient conditions. Second, it is necessary to define the relevant notion of self at play in the phenomenon of DIED. This article suggests that DIED consists in the disruption of subpersonal processes underlying the “minimal” or “embodied” self, i.e., the basic experience of being a self rooted in multimodal integration of self-related stimuli. This hypothesis is consistent with Bayesian models of phenomenal selfhood, according to which the subjective structure of conscious experience ultimately results from the optimization of predictions in perception and action. Finally, it is argued that DIED is also of particular interest for philosophy of mind. On the one hand, it challenges theories according to which consciousness always involves

  19. In Vitro and In Vivo Evaluation of Casein as a Drug Carrier for Enzymatically Triggered Dissolution Enhancement from Solid Dispersions.

    Science.gov (United States)

    Bani-Jaber, Ahmad; Alshawabkeh, Iyad; Abdullah, Samaa; Hamdan, Imad; Ardakani, Adel; Habash, Maha

    2017-07-01

    Due to its unique properties, such as biodegradability, biocompatibility, high amphiphilic property, and micelle formation, casein (CS) has been increasingly studied for drug delivery. We used CS as a drug carrier in solid dispersions (SDs) and evaluated the effect of its degradation by trypsin on drug dissolution from the dispersions. SDs of CS and mefenamic acid (MA) were prepared by physical mixing, kneading, and coprecipitation methods. In comparison to pure MA, the dispersions were evaluated for drug-protein interaction, loss of drug crystalinity, and drug morphology by differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared spectroscopy, and scanning electron microscopy. Drug dissolution from the dispersions was evaluated in simulated intestinal fluid as enzyme free and trypsin-enriched media. Furthermore, in vivo drug absorption of MA from CS-MA coprecipitate was evaluated in rats, in comparison with a reference SD of polyethylene glycol and MA (PEG-MA SD). Relative to other CS preparations, CS-MA coprecipitate showed the highest loss of drug crystallinity, drug micronization, and CS-MA interaction. CS remarkably enhanced the dissolution rate and extent of MA from the physical and kneaded mixtures. However, the highest dissolution enhancement was obtained when MA was coprecipitated with CS. Trypsin that can hydrolyze CS during dissolution resulted in further enhancement of MA dissolution from the physical and kneaded mixtures. However, a corresponding retardation effect was obtained for the coprecipitate. In correlation with in vitro drug release, CS-MA coprecipitate also showed significantly higher MA bioavailability in rats than PEG-MA SD.

  20. Influence of drug load on dissolution behavior of tablets containing a poorly water-soluble drug: estimation of the percolation threshold.

    Science.gov (United States)

    Wenzel, Tim; Stillhart, Cordula; Kleinebudde, Peter; Szepes, Anikó

    2017-08-01

    Drug load plays an important role in the development of solid dosage forms, since it can significantly influence both processability and final product properties. The percolation threshold of the active pharmaceutical ingredient (API) corresponds to a critical concentration, above which an abrupt change in drug product characteristics can occur. The objective of this study was to identify the percolation threshold of a poorly water-soluble drug with regard to the dissolution behavior from immediate release tablets. The influence of the API particle size on the percolation threshold was also studied. Formulations with increasing drug loads were manufactured via roll compaction using constant process parameters and subsequent tableting. Drug dissolution was investigated in biorelevant medium. The percolation threshold was estimated via a model dependent and a model independent method based on the dissolution data. The intragranular concentration of mefenamic acid had a significant effect on granules and tablet characteristics, such as particle size distribution, compactibility and tablet disintegration. Increasing the intragranular drug concentration of the tablets resulted in lower dissolution rates. A percolation threshold of approximately 20% v/v could be determined for both particle sizes of the API above which an abrupt decrease of the dissolution rate occurred. However, the increasing drug load had a more pronounced effect on dissolution rate of tablets containing the micronized API, which can be attributed to the high agglomeration tendency of micronized substances during manufacturing steps, such as roll compaction and tableting. Both methods that were applied for the estimation of percolation threshold provided comparable values.

  1. The improved dissolution performance of a post processing treated spray-dried crystalline solid dispersion of poorly soluble drugs.

    Science.gov (United States)

    Chan, Siok-Yee; Toh, Seok-Ming; Khan, Nasir Hayat; Chung, Yin-Ying; Cheah, Xin-Zi

    2016-11-01

    Solution-mediated transformation has been cited as one of the main problems that deteriorate dissolution performances of solid dispersion (SD). This is mainly attributed by the recrystallization tendency of poorly soluble drug. Eventually, it will lead to extensive agglomeration which is a key process in reducing the dissolution performance of SD and offsets the true benefit of SD system. Here, a post-processing treatment is suggested in order to reduce the recrystallization tendency and hence bring forth the dissolution advantage of SD system. The current study investigates the effect of a post processing treatment on dissolution performance of SD in comparison to their performances upon production. Two poorly soluble drugs were spray dried into SD using polyvinyl alcohol (PVA) as hydrophilic carrier. The obtained samples were post processing treated by exposure to high humidity, i.e. 75% RH at room temperature. The physical properties and release rate of the SD system were characterized upon production and after the post-processing treatment. XRPD, Infrared and DSC results showed partial crystallinity of the fresh SD systems. Crystallinity of these products was further increased after the post-processing treatment at 75% RH. This may be attributed to the high moisture absorption of the SD system that promotes recrystallization process of the drug. However, dissolution efficiencies of the post-treated systems were higher and more consistent than the fresh SD. The unexpected dissolution trend was further supported by the results intrinsic dissolution and solubility studies. An increase of crystallinity in a post humidity treated SD did not exert detrimental effect to their dissolution profiles. A more stabilized system with a preferable enhanced dissolution rate was obtained by exposing the SD to a post processing humidity treatment.

  2. A novel particle engineering technology to enhance dissolution of poorly water soluble drugs: spray-freezing into liquid.

    Science.gov (United States)

    Rogers, True L; Nelsen, Andrew C; Hu, Jiahui; Brown, Judith N; Sarkari, Marazban; Young, Timothy J; Johnston, Keith P; Williams, Robert O

    2002-11-01

    A novel cryogenic spray-freezing into liquid (SFL) process was developed to produce microparticulate powders consisting of an active pharmaceutical ingredient (API) molecularly embedded within a pharmaceutical excipient matrix. In the SFL process, a feed solution containing the API was atomized beneath the surface of a cryogenic liquid such that the liquid-liquid impingement between the feed and cryogenic liquids resulted in intense atomization into microdroplets, which were frozen instantaneously into microparticles. The SFL micronized powder was obtained following lyophilization of the frozen microparticles. The objective of this study was to develop a particle engineering technology to produce micronized powders of the hydrophobic drug, danazol, complexed with hydroxypropyl-beta-cyclodextrin (HPbetaCD) and to compare these SFL micronized powders to inclusion complex powders produced from other techniques, such as co-grinding of dry powder mixtures and lyophilization of bulk solutions. Danazol and HPbetaCD were dissolved in a water/tetrahydrofuran cosolvent mixture prior to SFL processing or slow freezing. Identical quantities of the API and HPbetaCD used in the solutions were co-ground in a mortar and pestle and blended to produce a co-ground physical mixture for comparison. The powder samples were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), Fourier transform infrared spectrometry (FTIR), scanning electron microscopy, surface area analysis, and dissolution testing. The results provided by DSC, XRD, and FTIR suggested the formation of inclusion complexes by both slow-freezing and SFL. However, the specific surface area was significantly higher for the latter. Dissolution results suggested that equilibration of the danazol/HPbetaCD solution prior to SFL processing was required to produce the most soluble conformation of the resulting inclusion complex following SFL. SFL micronized powders exhibited better dissolution

  3. Evaluation of ammonium bifluoride fusion for rapid dissolution in post-detonation nuclear forensic analysis

    Energy Technology Data Exchange (ETDEWEB)

    Hubley, Nicholas T. [Missouri Univ., Columbia, MO (United States). Dept. of Chemistry; Brockman, John D. [Missouri Univ., Columbia, MO (United States). Research Reactor Center; Robertson, J. David [Missouri Univ., Columbia, MO (United States). Research Reactor Center; Missouri Univ., Columbia, MO (United States). Dept. of Chemistry

    2017-10-01

    Dissolution of geological reference materials by fusion with ammonium bifluoride, NH{sub 4}HF{sub 2} or ABF, was evaluated for its potential use in post-detonation nuclear forensics. The fusion procedure was optimized such that the total dissolution time was <3 h without compromising recovery. Geological reference materials containing various levels of silicates were dissolved and measured by ICP-MS to quantify elemental recovery. Dissolutions of NIST 278 obsidian and urban canyon matrix were performed with radiotracer spikes to measure potential loss of volatile elements during the fusion procedure via gamma-ray spectroscopy. Elemental percent recoveries obtained by ICP-MS were found to be 80-120% while recoveries of radiotracers were observed to be 90-100% with the exception of iodine.

  4. Improved dissolution behavior of lipophilic drugs by solid dispersions : the production process as starting point for formulation considerations

    NARCIS (Netherlands)

    Srinarong, Parinda; de Waard, Hans; Frijlink, Henderik W.; Hinrichs, Wouter L. J.

    Introduction: Many new drug substances have low aqueous solubility which can cause poor bioavailability after oral administration. The application of solid dispersions is a useful method to increase the dissolution rate of these drugs and thereby improve their bioavailability. So far, several

  5. Dissolution and solid-state characterization of poorly water-soluble drugs in the presence of a hydrophilic carrier.

    Science.gov (United States)

    Talukder, Rahmat; Reed, Chase; Dürig, Thomas; Hussain, Muhammad

    2011-12-01

    The aim of this study was to investigate the effects of a hydrophilic carrier on the solid-state and dissolution characteristics of poorly water-soluble drugs. Three poorly water-soluble drugs, ibuprofen, carbamazepine, and nifedipine, were studied in combination with hydroxypropyl cellulose (HPC), a low molecular weight hydrophilic polymer, without the use of solvent. A 1:1 drug-polymer ratio was used to evaluate the percent drug release, crystallinity, and wettability. A drug-polymer ratio of 1:4 was also used in co-grinding process to evaluate the effect of polymer levels on drug release. Dissolution studies were carried out in deionized water. Mean dissolution time (MDT) was calculated, and statistical analysis of MDTs was done following a single factor one-way analysis of variance. The dissolution rate of the drugs was enhanced by several folds by the simple process of co-grinding with HPC. X-ray diffraction studies were done to investigate the effects of physical and co-ground mix with HPC on the crystallinity of the drugs, which indicated a partial loss in crystallinity upon grinding. Differential scanning calorimetry studies were performed in order to identify possible solid-state interactions between the respective drugs and HPC. Wettability of the drugs by a 0.5% aqueous HPC solution was compared with that of water and n-hexane using the "Washburn method." Increased wetting and hydrophilization of the drugs by HPC, enlarged surface area due to particle size reduction, and a decrease in the degree of crystallinity were identified as the likely contributors to dissolution rate enhancement.

  6. Influence of Dissolution Media and Presence of Alcohol on the In Vitro Performance of Pharmaceutical Products Containing an Insoluble Drug.

    Science.gov (United States)

    Friuli, Valeria; Bruni, Giovanna; Musitelli, Giorgio; Conte, Ubaldo; Maggi, Lauretta

    2017-06-15

    The purpose of this investigation is to determine how the dissolution media may influence the release rate of an insoluble drug in in vitro conditions. Some oral dosage forms containing ibuprofen, a molecule that shows pH-dependent solubility, are tested. They are evaluated in different media to simulate the gastrointestinal transit at paddle rotation speeds of 50 and 100 rpm. Moreover, the potential effect of different ethanol concentrations on drug release is tested. The dissolution profiles of the tablets show a similar behavior in water (pH 1.0) and phosphate buffer (pH 4.5) where the 2 doses are not completely dissolved. The soft capsules show a different behavior: a certain amount of ibuprofen, which is in solution inside the capsule, reprecipitates in water and in the pH 4.5 buffer. Instead, ibuprofen dissolves rapidly in the pH 6.8 buffer from all the formulations. In the water-ethanol solutions, the dissolution curves show a valuable increase in the drug dissolved at higher ethanol concentrations. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  7. Understanding the impact of media viscosity on dissolution of a highly water soluble drug within a USP 2 mini vessel dissolution apparatus using an optical planar induced fluorescence (PLIF) method.

    Science.gov (United States)

    Stamatopoulos, Konstantinos; Batchelor, Hannah K; Alberini, Federico; Ramsay, John; Simmons, Mark J H

    2015-11-10

    In this study, planar induced fluorescence (PLIF) was used for the first time to evaluate variability in drug dissolution data using Rhodamine-6G doped tablets within small volume USP 2 apparatus. The results were compared with tablets contained theophylline (THE) drug for conventional dissolution analysis. The impact of hydrodynamics, sampling point, dissolution media viscosity and pH were investigated to note effects on release of these two actives from the hydrophilic matrix tablets. As expected mixing performance was poor with complex and reduced velocities at the bottom of the vessel close to the tablet surface; this mixing became even worse as the viscosity of the fluid increased. The sampling point for dissolution can affect the results due to in-homogenous mixing within the vessel; this effect is exacerbated with higher viscosity dissolution fluids. The dissolution profiles of RH-6G measured via PLIF and THE measured using UV analysis were not statistically different demonstrating that RH-6G is an appropriate probe to mimic the release profile of a highly soluble drug. A linear correlation was accomplished between the release data of the drug and the dye (R(2)>0.9). The dissolution profile of the dye, obtained with the analysis of the PLIF images, can be used in order to evaluate how the viscosity and the mixing performance of USP 2 mini vessel affect the interpretation of the dissolution data of the targeted drug. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. In vitro dissolution study of acetylsalicylic acid solid dispersions. Tunable drug release allowed by the choice of polymer matrix.

    Science.gov (United States)

    Policianova, Olivia; Brus, Jiri; Hruby, Martin; Urbanova, Martina

    2014-07-22

    Abstract Due to their high versatility and diverse excipient options, solid dispersions (SDs) are an elegant choice for the formulation of active pharmaceutical ingredients with inconvenient solubility. Four distinct types of polymers with different physicochemical properties [polyvinylpyrrolidone, poly[N-(2-hydroxypropyl)-metacrylamide], poly(2-ethyl-2-oxazoline), and polyethylene glycol] and variable molecular weights were compared to investigate the influence of the polymer matrix on drug release. To probe the extent of intercomponent interactions, acetylsalicylic acid (ASA) was used as a model active substance. Controlled drug release was demonstrated for all four types of polymer-ASA SDs created by the freeze-drying method. While the polyethylene glycol-ASA SD exhibited an increased dissolution rate, the other polymer-ASA systems exhibited significantly reduced drug dissolution kinetics compared to free ASA. Furthermore, in contrast to physical mixtures, the prepared SDs all exhibited zero-order dissolution kinetics for ASA. The dissolution rate was strongly dependent on the molecular weight of the polymer. These results demonstrate that the type of SD may be controlled by the chemical constitutions of the polymers and that appropriate selection of the molecular weight of the polymer matrix enables finely tuned drug release over a wide range of dissolution rates.

  9. Enhanced dissolution of poorly soluble antiviral drugs from nanoparticles of cellulose acetate based solid dispersion matrices

    Directory of Open Access Journals (Sweden)

    Sonal Mazumder

    2017-11-01

    Full Text Available Polysaccharide-based polymers were used to produce nanoparticles of poorly soluble antiviral drugs using a rapid precipitation process. The structure-property relationships of four novel cellulose acetate-based polymers were studied for their solubility enhancement of poorly soluble drugs. Particles were purified by dialysis, and dried powders were recovered after freeze-drying. The particle diameters were 150–200 nm. The target drug loading in the particles was 25 wt%, and the drug loading efficiencies were 80–96%. The effects of the formulation process and nanoparticle properties on drug solubility were investigated. All nanoparticles afforded increased solubility and faster release compared to pure drugs. Drug release was a function of the relative hydrophobicity (or solubility parameters of the polymers.

  10. A novel dissolution media for testing drug release from a nanostructured polysaccharide-based colon specific drug delivery system: an approach to alternative colon media.

    Science.gov (United States)

    Kotla, Niranjan G; Singh, Sima; Maddiboyina, Balaji; Sunnapu, Omprakash; Webster, Thomas J

    2016-01-01

    The aim of this study was to develop a novel microbially triggered and animal-sparing dissolution method for testing of nanorough polysaccharide-based micron granules for colonic drug delivery. In this method, probiotic cultures of bacteria present in the colonic region were prepared and added to the dissolution media and compared with the performance of conventional dissolution methodologies (such as media with rat cecal and human fecal media). In this study, the predominant species (such as Bacteroides, Bifidobacterium, Lactobacillus species, Eubacterium and Streptococcus) were cultured in 12% w/v skimmed milk powder and 5% w/v grade "A" honey. Approximately 10(10)-10(11) colony forming units m/L of probiotic culture was added to the dissolution media to test the drug release of polysaccharide-based formulations. A USP dissolution apparatus I/II using a gradient pH dissolution method was used to evaluate drug release from formulations meant for colonic drug delivery. Drug release of guar gum/Eudragit FS30D coated 5-fluorouracil granules was assessed under gastric and small intestine conditions within a simulated colonic environment involving fermentation testing with the probiotic culture. The results with the probiotic system were comparable to those obtained from the rat cecal and human fecal-based fermentation model, thereby suggesting that a probiotic dissolution method can be successfully applied for drug release testing of any polysaccharide-based oral formulation meant for colonic delivery. As such, this study significantly adds to the nanostructured biomaterials' community by elucidating an easier assay for colonic drug delivery.

  11. Characterization of an active pharmaceutical ingredient by its dissolution properties: amoxicillin trihydrate as a model drug.

    Science.gov (United States)

    Horkovics-Kovats, Stefan

    2004-11-01

    To characterize the dissolution of particles, a dissolution rate coefficient alpha, consisting of a geometric factor gamma and material constant mu, was introduced. The impact of the particle geometry on the initial rate of dissolution was assessed for spherical, cubic and tetrahedral particles. Additionally, a description of dissolution of samples containing multiple populations of particles was derived. A two-population model was employed to characterize sieved fractions of amoxicillin trihydrate. The investigation, using factor analysis, of the influence of dose, particle size and agitation intensity on the dissolution rate coefficient alpha indicated the presence of disintegrating agglomerates in larger particles. Based on the dissolution characteristics of particular particle size fractions and on the determined particle size distribution, the dissolution profile of the mixed sample containing nine sieved fractions in size was successfully predicted. Finally, the limitations of the film theory are discussed in light of the multiple-population dissolution theory.

  12. Physicochemical characterisation, drug polymer dissolution and in vitro evaluation of phenacetin and phenylbutazone solid dispersions with polyethylene glycol 8000.

    Science.gov (United States)

    Khan, Sheraz; Batchelor, Hannah; Hanson, Peter; Perrie, Yvonne; Mohammed, Afzal R

    2011-10-01

    Poor water solubility leads to low dissolution rate and consequently, it can limit bioavailability. Solid dispersions, where the drug is dispersed into an inert, hydrophilic polymer matrix can enhance drug dissolution. Solid dispersions were prepared using phenacetin and phenylbutazone as model drugs with polyethylene glycol (PEG) 8000 (carrier), by melt fusion method. Phenacetin and phenylbutazone displayed an increase in the dissolution rate when formulated as solid dispersions as compared with their physical mixture and drug alone counterparts. Characterisation of the solid dispersions was performed using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). DSC studies revealed that drugs were present in the amorphous form within the solid dispersions. FTIR spectra for the solid dispersions of drugs suggested that there was a lack of interaction between PEG 8000 and the drug. However, the physical mixture of phenacetin with PEG 8000 indicated the formation of hydrogen bond between phenacetin and the carrier. Permeability of phenacetin and phenylbutazone was higher for solid dispersions as compared with that of drug alone across Caco-2 cell monolayers. Permeability studies have shown that both phenacetin and phenylbutazone, and their solid dispersions can be categorised as well-absorbed compounds. Copyright © 2011 Wiley-Liss, Inc.

  13. Impact of polymers on dissolution performance of an amorphous gelleable drug from surface-coated beads.

    Science.gov (United States)

    Fan, Chong; Pai-Thakur, Rashmi; Phuapradit, Wantanee; Zhang, Lin; Tian, Hung; Malick, Waseem; Shah, Navnit; Kislalioglu, M Serpil

    2009-04-11

    drugs. The anionic polymers may protect drugs of similar nature from gelling when exposed to the dissolution media. An understanding of mechanisms involved in drug-polymer interactions will be useful to screen the polymers that are useful in engineering suitable delivery systems for such drugs.

  14. Transglycosylated stevia and hesperidin as pharmaceutical excipients: dramatic improvement in drug dissolution and bioavailability.

    Science.gov (United States)

    Uchiyama, Hiromasa; Tozuka, Yuichi; Imono, Masaaki; Takeuchi, Hirofumi

    2010-10-01

    The capability of transglycosylated materials, α-glycosyltransferase-treated stevia (Stevia-G) and α-glycosyl hesperidin (Hsp-G), to enhance the bioavailability of poorly water-soluble drugs was investigated. Spray-dried particles (SDPs) of drug/transglycosylated material, such as, flurbiprofen (FP)/Stevia-G, probucol (PRO)/Stevia-G, FP/Hsp-G, and PRO/Hsp-G were prepared. All SDPs showed pronounced improvement in both dissolution rate and apparent drug solubility. The amount of dissolved PRO was significantly improved to that of untreated PRO crystals when prepared as SDPs of PRO/Stevia-G or PRO/Hsp-G. There was no cytotoxicity to Caco-2 cells at levels of 10% Stevia-G or Hsp-G solution. Values for the area under the plasma concentration-time curve (AUC) of untreated PRO, SDPs of PRO/Hsp-G and PRO/Stevia-G after oral administration to rats were 4.94±2.06, 26.08±4.52 and 48.79±9.97μgh/mL, respectively. Interestingly, AUC values in cases of the FP system were in the order of untreated FPStevia-GStevia-G, a newly investigated material for this purpose, was found to have good potential for use as a pharmaceutical excipient. Copyright © 2010 Elsevier B.V. All rights reserved.

  15. Advantage of the Dissolution/Permeation System for Estimating Oral Absorption of Drug Candidates in the Drug Discovery Stage.

    Science.gov (United States)

    Miyaji, Yoshihiro; Fujii, Yoshimine; Takeyama, Shoko; Kawai, Yukinori; Kataoka, Makoto; Takahashi, Masayuki; Yamashita, Shinji

    2016-05-02

    In order to increase the success rate in the development of oral drugs, an in vitro method, which can accurately estimate human oral absorption of a large variety of compounds from solid formulations, is required in the drug discovery stage. A dissolution/permeation (D/P) system is an in vitro system that simultaneously evaluates dissolution and permeation processes of drugs administered orally. In this study, we have investigated the advantages of a D/P system for use in the provisional estimation of human oral absorption of a drug (absorbed fraction, Fa) by applying it in its solid state. The D/P system mounted with a Madin-Darby canine kidney (MDCK) II cell monolayer was used to simultaneously evaluate the dissolved and the permeated amounts (% of dose) of 48 marketed drugs. Slightly modified, fasted-state simulated intestinal fluid (FaSSIFmod, 8 mL) was used as the apical medium of the D/P system. Each test drug was applied to the apical side of the D/P system as a suspension at one-hundredth of the clinical dose. The apparent permeability coefficient across the MDCK II cell monolayer was estimated in a buffer solution (pH 6.5). The octanol/water distribution coefficient (Log D) was measured at pH 6.5 by a flask shaking method. Transport medium (TM, pH 6.5), a buffer solution removing lecithin and taurocholate from FaSSIFmod, was used to determine the solubility at 24 h after applying drugs. The solubility in TM was used as a free drug concentration in FaSSIFmod. A good correlation was obtained between observed human Fa and the permeated amount in the D/P system. When the sigmoidal curve was obtained by the curve fitting to the data, the determination coefficient was R(2) = 0.79 and the 95% interval of the predicted Fa values was about ±24% for all drugs tested in the present study. For comparison, the permeated amount was calculated by multiplying the permeability of each drug (in vitro Papp) by the solubility in FaSSIFmod. However, the calculated permeated

  16. Dissolution Methods Database

    Data.gov (United States)

    U.S. Department of Health & Human Services — For a drug product that does not have a dissolution test method in the United States Pharmacopeia (USP), the FDA Dissolution Methods Database provides information on...

  17. Development of a novel starch-derived porous silica monolith for enhancing the dissolution rate of poorly water soluble drug

    Energy Technology Data Exchange (ETDEWEB)

    Wu Chao; Wang Jing; Hu Yanchen [Department of Pharmaceutics, Shenyang Pharmaceutical University P.O. Box 32, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning Province 110016 (China); Zhi Zhuangzhi [Department of Physics, School of Basic Science, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning 110016 (China); Jiang Tongying [Department of Pharmaceutics, Shenyang Pharmaceutical University P.O. Box 32, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning Province 110016 (China); Zhang Jinghai [Key laboratory of Pharmaceutical Biotechnology, School of Life Science and Bio- Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province 110016 (China); Wang Siling, E-mail: silingwang@hotmail.com [Department of Pharmaceutics, Shenyang Pharmaceutical University P.O. Box 32, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning Province 110016 (China)

    2012-02-01

    A novel starch-derived porous silica monolith (PSM) and porous starch foam (PSF) were developed as a carrier in order to improve the dissolution of lovastatin. PSM was prepared by the starch gel template method and PSF was prepared by the solvent exchange method. The morphology and structure of PSM and PSF were characterized by scanning electron microscopy (SEM) and nitrogen adsorption/desorption analysis. Lovastatin was loaded into PSM and PSF by immersion/solvent evaporation. Nano-pore spatial confinement effect on the drug dissolution was systematically studied by SEM, Fourier transform infrared spectroscopy (FTIR), thermogravametric analysis (TGA), x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and in-vitro drug dissolution studies. Lovastatin adsorbed in PSM was amorphous and lovastatin absorbed on PSF was partially present as microcrystal in the pores of PSF and partially in crystalline form distributed on the surface of PSF. PSM and PSF allowed immediate release of lovastatin and enhanced the dissolution rate. These results provide important information about the mechanism of drug adsorption and release. Accordingly, PSM and PSF have a promising future as a vehicle for the oral delivery of poorly water soluble drugs. Moreover, the effect of PSM is better than that of PSF.

  18. Insight into the Development of Dissolution Media for BCS Class II Drugs: A Review from Quality Control and Prediction of In Vivo Performance Perspectives.

    Science.gov (United States)

    Wu, Chunnuan; Liu, Yan; He, Zhonggui; Sun, Jin

    2016-01-01

    To assess in vivo behavior through in vitro method, the dissolution test is mostly used, both for quality control (QC) and for development purpose. In view of the fact that a dissolution test can hardly achieve two goals at the same time, the design of dissolution testing generally varies along with the development stage of drug products and therefore the selection of dissolution media may change with the goals of the dissolution test. To serve the QC purpose, a dissolution medium is designed to provide a sink condition; for development purpose, the dissolution medium is required to simulate the physiological conditions in the gastrointestinal tract as far as possible. In this review, we intended to provide an initial introduction to the various dissolution media applied for QC and formulation development purposes for poorly water soluble drugs. We focused on these methods like addition of cosolvents, surfactants and utilization of biphasic media, applied to provide sink conditions which are difficult to be achieved by simple aqueous buffers for lipophilic drugs, and introduced the development of physiologically relevant media for human and animals like dog and rat with respect to the choice of buffers, bile salts, lipids and so on. In addition, we further discussed the influence of biorelevant dissolution media on the modification of drug Biopharmaceutical Classification System (BCS) classification, especially for BCS class II drugs with low solubility and high permeability, the solubility of which is relatively sensitive to the presence of bile salts and lipids.

  19. In vitro dissolution profile study of mucolytic drug ambroxol hydrochloride from solid oral dosage form by UHPLC-MS/MS

    OpenAIRE

    Vujović Maja M.; Jokanović Milan; Nikolić Goran M.

    2017-01-01

    In this paper a simplified dissolution test was performed for the release of ambroxol from tablets according to the European Pharmacopoeia. In vitro, three different dissolution media; 0.1 M HCl pH 1.2, acetate buffer (ABS) pH 4.5 and phosphate buffer (PBS) pH 6.8 were used for the simulation of the gastrointestinal conditions at temperature of 37.0±0.5°C. The drug release was evaluated by a new ultra - high performance liquid chromatography (UHPLC) - tande...

  20. Dissolution enhancement of a model poorly water-soluble drug, atorvastatin, with ordered mesoporous silica: comparison of MSF with SBA-15 as drug carriers.

    Science.gov (United States)

    Maleki, Aziz; Hamidi, Mehrdad

    2016-01-01

    The purpose of this study was to develop mesoporous silica materials incorporated with poorly water-soluble drug atorvastatin calcium (AC) in order to improve drug dissolution, and intended to be orally administrated. A comparison between 2D-hexagonal silica nanostructured SBA-15 and mesocellular siliceous foam (MSF) with continuous 3D pore system on drug release rate was investigated. AC-loaded mesoporous silicas were characterized thorough N2 adsorption-desorption analysis, Fourier transform infrared (FT-IR) spectroscopy, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and dynamic light scattering (DLS). Results demonstrated a successful incorporation of AC into the silica-based hosts. The results taken from the drug release tests were also analyzed using different parameters, namely similarity factor (f2), difference factor (f1), dissolution efficiency (DE%), mean dissolution rate (MDR) and dissolution time (tm%). It confirmed a significant enhancement in the release profile of atorvastatin calcium with SBA-15, and MSF as drug carrier. Moreover, in comparison with SBA-15, MSF showed faster release rate of AC in enzyme-free simulated gastric fluid (pH 1.2). We believed that our findings can help the use of mesoporous silica materials in improving bioavailability of poorly water-soluble drugs.

  1. Investigating the impact of drug crystallinity in amorphous tacrolimus capsules on pharmacokinetics and bioequivalence using discriminatory in vitro dissolution testing and PBPK modeling and simulation.

    Science.gov (United States)

    Purohit, Hitesh S; Trasi, Niraj S; Sun, Dajun D; Chow, Edwin C Y; Wen, Hong; Zhang, Xinyuan; Gao, Yi; Taylor, Lynne S

    2017-12-28

    Delivering a drug in amorphous form in a formulated product is a strategy used to enhance the apparent solubility of a drug substance and its oral bioavailability. Drug crystallization in such products may occur during the manufacturing process or upon storage, reducing the solubility advantage of the amorphous drug. However, the impact of partial drug crystallization in the drug product on the resulting bioavailability and pharmacokinetics is unknown. In this study, dissolution testing of commercial tacrolimus capsules (which are formulated to contain amorphous drug), both fresh and those containing different amounts of crystalline drug, was conducted using both USP and non-compendial dissolution tests with different dissolution media and volumes. A physiologically based pharmacokinetic (PBPK) absorption model was developed to predict the impact of crystallinity extent on the oral absorption of the products and to evaluate the discriminatory ability of the different dissolution methods. Virtual bioequivalence simulations between partially crystallized tacrolimus capsules versus fresh Prograf or generic tacrolimus capsules were performed using the PBPK model and in vitro dissolution data of the various fresh and partially crystallized capsules under USP and non-compendial dissolution conditions. The results suggest that compendial dissolution tests may not be sufficiently discriminatory with respect to the presence of crystallinity in an amorphous formulation. Non-sink dissolution tests using lower dissolution volumes generate more discriminatory profiles that predict different pharmacokinetics of tacrolimus capsules containing different extents of drug crystallinity. In conclusion, the PBPK modeling approach can be used to assess the impact of partial drug crystallinity in the formulated product and to guide the development of appropriate dissolution methods. Copyright © 2017. Published by Elsevier Inc.

  2. Encapsulation of solid dispersion in solid lipid particles for dissolution enhancement of poorly water-soluble drug.

    Science.gov (United States)

    Tran, Khanh Thi My; Vo, Toi Van; Tran, Phuong Ha-Lien; Lee, Beom-Jin; Duan, Wei; Tran, Thao Truong-Dinh

    2017-06-05

    The aim of this research was to engineer solid dispersion lipid particles (SD-SLs) in which a solid dispersion (SD) was encapsulated to form the core of solid lipid particles (SLs), thereby achieving an efficient enhancement in the dissolution of a poorly water-soluble drug. Ultrasonication was introduced into the process to obtain micro/nanoscale SLs. The mechanism of dissolution enhancement was investigated by analysing the crystalline structure, molecular interactions, and particle size of the formulations. The drug release from the SD-SLs was significantly greater than that from the SD or SLs alone. This enhancement in drug release was dependent on the preparation method and the drug-to-polymer ratio of the SD. With an appropriate amount of polymer in the SD, the solidification method had the potential to alter the drug crystallinity to an amorphous state, resulting in particle uniformity and molecular interactions in the SD-SLs. The proposed system provides a new strategy for enhancing the dissolution rate of poorly water-soluble drugs and further improving their bioavailability. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. A rapid approach for measuring silver nanoparticle concentration and dissolution in seawater by UV-Vis.

    Science.gov (United States)

    Sikder, Mithun; Lead, Jamie R; Chandler, G Thomas; Baalousha, Mohammed

    2017-04-12

    Detection and quantification of engineered nanoparticles (NPs) in environmental systems is challenging and requires sophisticated analytical equipment. Furthermore, dissolution is an important environmental transformation process for silver nanoparticles (AgNPs) which affects the size, speciation and concentration of AgNPs in natural water systems. Herein, we present a simple approach for the detection, quantification and measurement of dissolution of PVP-coated AgNPs (PVP-AgNPs) based on monitoring their optical properties (extinction spectra) using UV-vis spectroscopy. The dependence of PVP-AgNPs extinction coefficient (ɛ) and maximum absorbance wavelength (λmax) on NP size was experimentally determined. The concentration, size, and extinction spectra of PVP-AgNPs were characterized during dissolution in 30ppt synthetic seawater. AgNPs concentration was determined as the difference between the total and dissolved Ag concentrations measured by inductively coupled plasma-mass spectroscopy (ICP-MS); extinction spectra of PVP-AgNPs were monitored by UV-vis; and size evolution was monitored by atomic force microscopy (AFM) over a period of 96h. Empirical equations for the dependence of maximum absorbance wavelength (λmax) and extinction coefficient (ɛ) on NP size were derived. These empirical formulas were then used to calculate the size and concentration of PVP-AgNPs, and dissolved Ag concentration released from PVP-AgNPs in synthetic seawater at variable particle concentrations (i.e. 25-1500μgL(-1)) and in natural seawater at particle concentration of 100μgL(-1). These results suggest that UV-vis can be used as an easy and quick approach for detection and quantification (size and concentration) of sterically stabilized PVP-AgNPs from their extinction spectra. This approach can also be used to monitor the release of Ag from PVP-AgNPs and the concurrent NP size change. Finally, in seawater, AgNPs dissolve faster and to a higher extent with the decrease in NP

  4. Rapid subsidence in damaging sinkholes: Measurement by high-precision leveling and the role of salt dissolution

    Science.gov (United States)

    Desir, G.; Gutiérrez, F.; Merino, J.; Carbonel, D.; Benito-Calvo, A.; Guerrero, J.; Fabregat, I.

    2018-02-01

    Investigations dealing with subsidence monitoring in active sinkholes are very scarce, especially when compared with other ground instability phenomena like landslides. This is largely related to the catastrophic behaviour that typifies most sinkholes in carbonate karst areas. Active subsidence in five sinkholes up to ca. 500 m across has been quantitatively characterised by means of high-precision differential leveling. The sinkholes occur on poorly indurated alluvium underlain by salt-bearing evaporites and cause severe damage on various human structures. The leveling data have provided accurate information on multiple features of the subsidence phenomena with practical implications: (1) precise location of the vaguely-defined edges of the subsidence zones and their spatial relationships with surveyed surface deformation features; (2) spatial deformation patterns and relative contribution of subsidence mechanisms (sagging versus collapse); (3) accurate subsidence rates and their spatial variability with maximum and mean vertical displacement rates ranging from 1.0 to 11.8 cm/yr and 1.9 to 26.1 cm/yr, respectively; (4) identification of sinkholes that experience continuous subsidence at constant rates or with significant temporal changes; and (5) rates of volumetric surface changes as an approximation to rates of dissolution-induced volumetric depletion in the subsurface, reaching as much as 10,900 m3/yr in the largest sinkhole. The high subsidence rates as well as the annual volumetric changes are attributed to rapid dissolution of high-solubility salts.

  5. In Silico Prediction of Drug Dissolution and Absorption with variation in Intestinal pH for BCS Class II Weak Acid Drugs: Ibuprofen and Ketoprofen§

    Science.gov (United States)

    Tsume, Yasuhiro; Langguth, Peter; Garcia-Arieta, Alfredo; Amidon, Gordon L.

    2012-01-01

    The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS Class III and BCS class II have been proposed, particularly, BCS class II weak acids. However, a discrepancy between the in vivo- BE results and in vitro- dissolution results for a BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs. The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlus™. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH=6.0. Further the experimental dissolution of ibuprofen tablets in the low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol L-1/pH) was dramatically reduced compared to the dissolution in SIF (the average buffer capacity 12.6 mmol L -1/pH). Thus these predictions for oral absorption of BCS class II acids indicate that the absorption patterns largely depend on the intestinal pH and buffer strength and must be carefully considered for a bioequivalence test. Simulation software may be very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard. PMID:22815122

  6. Quiescent and Agitated Redispersion as a Tool for Evaluating Dispersant Effectiveness in Dissolution Enhancement of Drug-Laden Nanocomposites.

    Science.gov (United States)

    Bhakay, A; Davé, R N; Bilgili, E

    2018-01-01

    Nanocomposite microparticles (NCMPs) have been used in various solid dosage forms with the goal of enhancing the dissolution rate and bioavailability of poorly water-soluble drugs. Nanoparticle recovery from NCMPs, i.e., redispersion, is the preliminary step in drug dissolution. This study aims at exploring aqueous redispersion of NCMPs with various dispersants under quiescent vs. agitated conditions as potential dispersant screening tool in the development of fast-dissolving NCMP formulations. NCMPs were prepared by coating wet-milled suspensions of a poorly water-soluble drug, griseofulvin (GF), formulated with the dispersants hydroxypropyl cellulose (HPC), sodium dodecyl sulfate (SDS), as-received/wet co-milled croscarmellose sodium (CCS), and mannitol, onto Pharmatose® carrier particles in a fluidized bed dryer. The NCMPs were added to quiescent water kept in a cuvette, and the redispersion was visualized and investigated by turbidimetry and dynamic light scattering. The morphological evolution of a single NCMP exposed to a drop of water was studied via optical microscopy, which provided further insight into the self-redispersibility. As a comparison, the NCMPs were also redispersed in water agitated by a paddle stirrer followed by centrifugation and drug assay of the resultant supernatant, which yielded the percentage of GF recovered as nanoparticles. Both quiescent and agitated redispersion methods yielded similar rank-ordering of the dispersants: NCMPs with either HPC/SDS or HPC/CCS exhibited effective nanoparticle recovery and fast dissolution, whereas those with HPC or HPC/mannitol led to poor redispersibility and slow dissolution. This study demonstrates that both quiescent and agitated redispersion tests could be used for screening/optimizing dispersants for fast-dissolving drug NCMP formulations.

  7. Aqueous boundary layers related to oral absorption of a drug: from dissolution of a drug to carrier mediated transport and intestinal wall metabolism.

    Science.gov (United States)

    Sugano, Kiyohiko

    2010-10-04

    The aqueous boundary layer (ABL) affects various aspects of oral absorption of a drug, from dissolution of the drug to the apparent K(m) value of intestinal wall metabolism and carrier mediated transport. However, the importance of ABL has often been entirely ignored in oral absorption investigation. In this minireview, the effect of ABL on oral absorption of a drug is discussed in an easy-to-understand manner. This review starts with an introduction of the boundary layer theory with many illustrations (and links to public web movies visualizing the ABL), and then discusses some specific cases of interest in pharmaceutical science, such as dissolution of floating drug particles in the USP paddle apparatus. The effect of the boundary layer on the membrane permeation is also discussed from the viewpoint of structure permeability relationship, carrier mediated transport/metabolism and estimation of the fraction of a dose absorbed for poor solubility compounds.

  8. Effect of guest drug character encapsulated in the cavity and intermolecular spaces of γ-cyclodextrins on the dissolution property of ternary γ-cyclodextrin complex.

    Science.gov (United States)

    Liu, Nan; Higashi, Kenjirou; Ueda, Keisuke; Moribe, Kunikazu

    2017-10-15

    Various ternary Guest 2/(Guest 1/γ-cyclodextrin (CD)) complexes were prepared using a cogrinding and subsequent heating method, wherein Guest 1 was incorporated in the cavity of γ-CD and Guest 2 was incorporated into the intermolecular spaces between γ-CD columns. Dissolution fluxes of Guest 1 and Guest 2 from all ternary complexes were almost identical. The dissolution flux of flurbiprofen (Guest 1) from the ternary complexes depended on the solubility of Guest 2 drugs (naproxendissolution medium of pH 1.2. It is noteworthy that the dissolution flux of flurbiprofen from the ternary complexes with ketoprofen and ethenzamide as Guest 2 drugs was further enhanced compared with that from the flurbiprofen/γ-CD inclusion complex. The ternary complex of the acidic drug ketoprofen as Guest 1 and the neutral drug hydrocortisone as Guest 2 showed an increased dissolution flux, which was dependent on the increase in pH of the dissolution medium. The pH-dependent dissolution should reflect the solubility of ketoprofen/γ-CD inclusion complex in each dissolution medium. These results indicated that the dissolution flux of the ternary γ-CD complexes could be controlled by selecting the appropriate Guest 1 and Guest 2 species. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Enhancement of dissolution rate of class II drugs (Hydrochlorothiazide); a comparative study of the two novel approaches; solid dispersion and liqui-solid techniques.

    Science.gov (United States)

    Khan, Amjad; Iqbal, Zafar; Shah, Yasar; Ahmad, Lateef; Ismail; Ullah, Zia; Ullah, Aman

    2015-11-01

    Liqui-solid technique and solid dispersion formation are two novel approaches for enhancement of dissolution rate of BCS class II drugs. Liqui-solid compact converts a liquid drug or drug solution into a free flowing powder with enhanced dissolution rate. In case of solid dispersion drug is molecularly dispersed in a hydrophilic polymer in solid state. In the present study, Liqui-solid and solid dispersion techniques were applied to enhance the dissolution of the Hydrochlorothiazide. Three formulations of Hydrochlorothiazide were prepared by liqui-solid technique using micro crystalline cellulose as carrier material and colloidal silicon dioxide as coating material. Water, poly ethylene glycol-400 and Tween-60 were used as solvent system. Solid dispersions of Hydrochlorothiazide were prepared by solvent fusion method using PEG-4000 as carrier polymer. Tablets were subjected to evaluation of various physical and chemical characteristics. Dissolution profiles of tablets prepared by the novel techniques were compared with marketed conventional tablets. Model independent techniques including similarity factor, dissimilarity factor and dissolution efficiency were applied for comparison of dissolution profiles. The results obtained indicated that liqui-solid compact formulations were more effective in enhancing the dissolution rate compared with solid dispersion technique. The liqui-solid compacts improved the dissolution rate up to 95% while the solid dispersion increased it to 88%.

  10. Interlaboratory validation of small-scale solubility and dissolution measurements of poorly water-soluble drugs

    DEFF Research Database (Denmark)

    Andersson, Sara B. E.; Alvebratt, Caroline; Bevernage, Jan

    2016-01-01

    The purpose of this study was to investigate the interlaboratory variability in determination of apparent solubility (Sapp) and intrinsic dissolution rate (IDR) using a miniaturized dissolution instrument. Three poorly water-soluble compounds were selected as reference compounds and measured...... at multiple laboratories using the same experimental protocol. Dissolution was studied in fasted-state simulated intestinal fluid and phosphate buffer (pH 6.5). An additional 6 compounds were used for the development of an IDR measurement guide, which was then validated with 5 compounds. The results clearly...

  11. Measurement of humic and fulvic acid concentrations and dissolution properties by a rapid batch procedure.

    NARCIS (Netherlands)

    Zomeren, van A.; Comans, R.N.J.

    2007-01-01

    Although humic substances (HS) strongly facilitate the transport of metals and hydrophobic organic contaminants in environmental systems, their measurement is hampered by the time-consuming nature of currently available methods for their isolation and purification. We present and apply a new rapid

  12. Dried blood spots on carboxymethyl cellulose sheets: Rapid sample preparation based on dissolution and precipitation

    DEFF Research Database (Denmark)

    Skoglund Ask, Kristine; Pedersen-Bjergaard, Stig; Gjelstad, Astrid

    2016-01-01

    This short communication describes the use of carboxymethyl cellulose sheets as sampling material for dried blood spots. Whole blood, spiked with quetiapine, a hydrophobic and basic small molecule drug substance, was spotted on the sheet and subsequently dried. The dried spot was then almost...

  13. Setting accelerated dissolution test for PLGA microspheres containing peptide, investigation of critical parameters affecting drug release rate and mechanism.

    Science.gov (United States)

    Tomic, I; Vidis-Millward, A; Mueller-Zsigmondy, M; Cardot, J-M

    2016-05-30

    The objective of this study was development of accelerated in vitro release method for peptide loaded PLGA microspheres using flow-through apparatus and assessment of the effect of dissolution parameters (pH, temperature, medium composition) on drug release rate and mechanism. Accelerated release conditions were set as pH 2 and 45°C, in phosphate buffer saline (PBS) 0.02M. When the pH was changed from 2 to 4, diffusion controlled phases (burst and lag) were not affected, while release rate during erosion phase decreased two-fold due to slower ester bonds hydrolyses. Decreasing temperature from 45°C to 40°C, release rate showed three-fold deceleration without significant change in release mechanism. Effect of medium composition on drug release was tested in PBS 0.01M (200 mOsm/kg) and PBS 0.01M with glucose (380 mOsm/kg). Buffer concentration significantly affected drug release rate and mechanism due to the change in osmotic pressure, while ionic strength did not have any effect on peptide release. Furthermore, dialysis sac and sample-and-separate techniques were used, in order to evaluate significance of dissolution technique choice on the release process. After fitting obtained data to different mathematical models, flow-through method was confirmed as the most appropriate for accelerated in vitro dissolution testing for a given formulation. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. In vitro dissolution profile study of mucolytic drug ambroxol hydrochloride from solid oral dosage form by UHPLC-MS/MS

    Directory of Open Access Journals (Sweden)

    Vujović Maja M.

    2017-01-01

    Full Text Available In this paper a simplified dissolution test was performed for the release of ambroxol from tablets according to the European Pharmacopoeia. In vitro, three different dissolution media; 0.1 M HCl pH 1.2, acetate buffer (ABS pH 4.5 and phosphate buffer (PBS pH 6.8 were used for the simulation of the gastrointestinal conditions at temperature of 37.0±0.5°C. The drug release was evaluated by a new ultra - high performance liquid chromatography (UHPLC - tandem mass spectrometry (MS/MS method. The method was validated to meet requirements as per ICH guidelines which include linearity, specificity, precision, accuracy and robustness. The corresponding dissolution profiles showed more than 80% drug release within 30 minutes without significant differences. Further, the developed and validated UHPLC-MS/MS method could find a useful application in the process of production, quality control and bioavailability/bioequivalence studies of new pharmaceutical formulations of drugs in order to achieve a safe therapeutic efficacy. [Projekat Ministarstva nauke Republike Srbije, br. 175045

  15. Comprehensive validation scheme for in situ fiber optics dissolution method for pharmaceutical drug product testing.

    Science.gov (United States)

    Mirza, Tahseen; Liu, Qian Julie; Vivilecchia, Richard; Joshi, Yatindra

    2009-03-01

    There has been a growing interest during the past decade in the use of fiber optics dissolution testing. Use of this novel technology is mainly confined to research and development laboratories. It has not yet emerged as a tool for end product release testing despite its ability to generate in situ results and efficiency improvement. One potential reason may be the lack of clear validation guidelines that can be applied for the assessment of suitability of fiber optics. This article describes a comprehensive validation scheme and development of a reliable, robust, reproducible and cost-effective dissolution test using fiber optics technology. The test was successfully applied for characterizing the dissolution behavior of a 40-mg immediate-release tablet dosage form that is under development at Novartis Pharmaceuticals, East Hanover, New Jersey. The method was validated for the following parameters: linearity, precision, accuracy, specificity, and robustness. In particular, robustness was evaluated in terms of probe sampling depth and probe orientation. The in situ fiber optic method was found to be comparable to the existing manual sampling dissolution method. Finally, the fiber optic dissolution test was successfully performed by different operators on different days, to further enhance the validity of the method. The results demonstrate that the fiber optics technology can be successfully validated for end product dissolution/release testing. (c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association

  16. Modeling gastrointestinal drug absorption requires more in vivo biopharmaceutical data: experience from in vivo dissolution and permeability studies in humans.

    Science.gov (United States)

    Lennernäs, Hans

    2007-10-01

    The majority (84%) of the 50 most-sold pharmaceutical products in the US and European markets are given orally. The dominating role of this route in drug therapy is a consequence of it being safe, efficient and easily accessible with minimal discomfort to the patient in comparison with other routes of drug administration. A successful drug discovery and development of oral pharmaceutical products require an in-depth understanding of multiple biochemical and physiological processes that determine the dissolution rate, intestinal permeability, gastrointestinal transit, first-pass extraction and systemic exposure-time profiles of drugs. It is crucial to realize that these basic biopharmaceutic and pharmacokinetic properties are crucial to focus on to allow successful drug development. Identification of the rate-limiting step(s) in order to overcome these barriers and understanding of the sources of variability are important in the selection of suitable candidate molecules in drug development. Several reports based on in vitro investigations in various cell models have suggested that carrier-mediated intestinal efflux may be a major reason for incomplete absorption and variable bioavailability of drugs, as well being a site for drug-drug and specific food-drug interactions. However, many drugs which were initially suggested to undergo significant efflux in vitro were later shown to be completely absorbed in vivo. This apparent discrepancy between in vitro and in vivo results may be due to several factors that will be discussed in this review. Novel data on solubility and dissolution in human gastrointestinal derived fluids will be reviewed. The effect of food intake on solubility and dissolution rate of a range of drugs including felodipine, danazol, griseofulvin, cyclosporine, probucol and ubiquinone in simulated and real intestinal fluids is discussed. The biopharmaceutic and physicochemical data discussed here can potentially be used as a benchmark set for

  17. Surfactants enhance recovery of poorly soluble drugs during microdialysis sampling: Implications for in vitro dissolution-/permeation-studies.

    Science.gov (United States)

    Koplin, Sebastian; Kumpugdee-Vollrath, Mont; Bauer-Brandl, Annette; Brandl, Martin

    2017-10-25

    Aim of this project was to investigate the applicability of a recently developed in vitro microdialysis-sampling approach in connection with a dissolution-/permeation (D/P) system, especially the impact of surfactants within the perfusion fluid. The D/P-system is based on side-by-side chambers, separated by a barrier that simulates the intestinal barrier. Here, in contrast to conventional D/P-systems, the dissolution of the drug (donor chamber concentration) is followed by microdialysis sampling. This approach appears promising, because it is expected not to disturb the dynamic interplay between drug-dissolution (-release) and drug permeation. Furthermore, it should allow quantification of the unbound (free) drug concentration. In the first step, it was assessed, if the addition of the anionic surfactant sodium dodecyl sulphate (SDS) to the perfusate of the microdialysis system affects the recovery of the (slightly) water-soluble model drug acyclovir and the poorly water soluble model drug celecoxib (CXB). SDS had no influence on acyclovir-recovery, but substantially enhanced CXB-recovery, partly due to improved extraction efficiency, partly due to inhibition of loss of CXB due to non-specific binding to surfaces and the probe. The fraction of CXB recovered from aqueous CXB-solutions by microdialysis sampling using SDS-containing perfusates correlated well with the celecoxib concentration in the samples, but was found independent of the SDS-concentrations (above critical micelle concentration). In the next step microdialysis sampling with SDS-containing perfusates was assessed for celecoxib solutions in fasted state simulated intestinal fluid (FaSSIF) and compared to that in buffer. In FaSSIF, the measured CXB-concentrations were far below the overall CXB concentration, likely representing the free celecoxib, i.e. the fraction of drug, which is not associated with taurocholate surfactant micelles. In buffer, the measured concentrations matched the overall CXB

  18. Nanocomposite formation between alpha-glucosyl stevia and surfactant improves the dissolution profile of poorly water-soluble drug.

    Science.gov (United States)

    Uchiyama, Hiromasa; Tozuka, Yuichi; Nishikawa, Masahiro; Takeuchi, Hirofumi

    2012-05-30

    The formation of a hybrid-nanocomposite using α-glucosyl stevia (Stevia-G) and surfactant was explored to improve the dissolution of flurbiprofen (FP). As reported previously, the dissolution amount of FP was enhanced in the presence of Stevia-G, induced by the formation of an FP and Stevia-G-associated nanostructure. When a small amount of sodium dodecyl sulfate (SDS) was present with Stevia-G, the amount of dissolved FP was extremely enhanced. This dissolution-enhancement effect was also observed with the cationic surfactant of dodecyl trimethyl ammonium bromide, but not with the non-ionic surfactant of n-octyl-β-D-maltopyranoside. To investigate the dissolution-enhancement effect of Stevia-G/SDS mixture, the pyrene I(1)/I(3) ratio was plotted versus the Stevia-G concentration. The pyrene I(1)/I(3) ratio of Stevia-G/SDS mixture had a sigmoidal curve at lower Stevia-G concentrations compared to the Stevia-G solution alone. These results indicate that the Stevia-G/SDS mixture provides a hydrophobic core around pyrene molecules at lower Stevia-G concentrations, leading to nanocomposite formation between Stevia-G and SDS. The nanocomposite of Stevia-G/SDS showed no cytotoxicity to Caco-2 cells at a mixture of 0.1% SDS and 1% Stevia-G solution, whereas 0.1% SDS solution showed high toxicity. These results suggest that the nanocomposite formation of Stevia-G/SDS may be useful way to enhance the dissolution of poorly water-soluble drugs without special treatment. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Dry coating of micronized API powders for improved dissolution of directly compacted tablets with high drug loading.

    Science.gov (United States)

    Han, Xi; Ghoroi, Chinmay; Davé, Rajesh

    2013-02-14

    Motivated by our recent study showing improved flow and dissolution rate of the active pharmaceutical ingredient (API) powders (20 μm) produced via simultaneous micronization and surface modification through continuous fluid energy milling (FEM) process, the performance of blends and direct compacted tablets with high drug loading is examined. Performance of 50 μm API powders dry coated without micronization is also considered for comparison. Blends of micronized, non-micronized, dry coated or uncoated API powders at 30, 60 and 70% drug loading, are examined. The results show that the blends containing dry coated API powders, even micronized ones, have excellent flowability and high bulk density compared to the blends containing uncoated API, which are required for direct compaction. As the drug loading increases, the difference between dry coated and uncoated blends is more pronounced, as seen in the proposed bulk density-FFC phase map. Dry coating led to improved tablet compactibility profiles, corresponding with the improvements in blend compressibility. The most significant advantage is in tablet dissolution where for all drug loadings, the t(80) for the tablets with dry coated APIs was well under 5 min, indicating that this approach can produce nearly instant release direct compacted tablets at high drug loadings. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. Dry powder inhalers: An overview of the in vitro dissolution methodologies and their correlation with the biopharmaceutical aspects of the drug products.

    Science.gov (United States)

    Velaga, Sitaram P; Djuris, Jelena; Cvijic, Sandra; Rozou, Stavroula; Russo, Paola; Colombo, Gaia; Rossi, Alessandra

    2017-09-05

    In vitro dissolution testing is routinely used in the development of pharmaceutical products. Whilst the dissolution testing methods are well established and standardized for oral dosage forms, i.e. tablets and capsules, there are no pharmacopoeia methods or regulatory requirements for testing the dissolution of orally inhaled powders. Despite this, a wide variety of dissolution testing methods for orally inhaled powders has been developed and their bio-relevance has been evaluated. This review provides an overview of the in vitro dissolution methodologies for dry inhalation products, with particular emphasis on dry powder inhalers, where the dissolution behavior of the respirable particles can have a role on duration and absorption of the drug. Dissolution mechanisms of respirable particles as well as kinetic models have been presented. A more recent biorelevant dissolution set-ups and media for studying inhalation biopharmaceutics were also reviewed. In addition, factors affecting interplay between dissolution and absorption of deposited particles in the context of biopharmaceutical considerations of inhalation products were examined. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Development of a μDissolution-Permeation model with in situ drug concentration monitoring

    DEFF Research Database (Denmark)

    Berthelsen, Ragna; Byrialsen, Julie Pelle; Holm, René

    2016-01-01

    A μD/P model consisting of two connected compartments made of acrylic plastic was designed and constructed to fit in the μDiss Profiler™. A Caco-2 cell monolayer grown on a Snapwell™ membrane insert was mounted between the apical and basolateral compartment serving as a permeability barrier. Fasted...... state biorelevant medium consisting of HBSS pH 6.5 supplemented with bile salts and lecithin was used as the apical dissolution media, while HBSS pH 7.4 was used as the basolateral medium. The apparent permeability (Papp) and dissolution-time profiles for albendazole, felodipine and fenofibrate were...

  2. Rapid and near-complete dissolution of wood lignin at ≤80°C by a recyclable acid hydrotrope.

    Science.gov (United States)

    Chen, Liheng; Dou, Jinze; Ma, Qianli; Li, Ning; Wu, Ruchun; Bian, Huiyang; Yelle, Daniel J; Vuorinen, Tapani; Fu, Shiyu; Pan, Xuejun; Zhu, Junyong J Y

    2017-09-01

    We report the discovery of the hydrotropic properties of a recyclable aromatic acid, p-toluenesulfonic acid (p-TsOH), for potentially low-cost and efficient fractionation of wood through rapid and near-complete dissolution of lignin. Approximately 90% of poplar wood (NE222) lignin can be dissolved at 80°C in 20 min. Equivalent delignification using known hydrotropes, such as aromatic salts, can be achieved only at 150°C or higher for more than 10 hours or at 150°C for 2 hours with alkaline pulping. p-TsOH fractionated wood into two fractions: (i) a primarily cellulose-rich water-insoluble solid fraction that can be used for the production of high-value building blocks, such as dissolving pulp fibers, lignocellulosic nanomaterials, and/or sugars through subsequent enzymatic hydrolysis; and (ii) a spent acid liquor stream containing mainly dissolved lignin that can be easily precipitated as lignin nanoparticles by diluting the spent acid liquor to below the minimal hydrotrope concentration. Our nuclear magnetic resonance analyses of the dissolved lignin revealed that p-TsOH can depolymerize lignin via ether bond cleavage and can separate carbohydrate-free lignin from the wood. p-TsOH has a relatively low water solubility, which can facilitate efficient recovery using commercially proven crystallization technology by cooling the concentrated spent acid solution to ambient temperatures to achieve environmental sustainability through recycling of p-TsOH.

  3. Cocrystal habit engineering to improve drug dissolution and alter derived powder properties.

    Science.gov (United States)

    Serrano, Dolores R; O'Connell, Peter; Paluch, Krzysztof J; Walsh, David; Healy, Anne Marie

    2016-05-01

    Cocrystallization of sulfadimidine (SDM) with suitable coformers, such as 4-aminosalicylic acid (4-ASA), combined with changes in the crystal habit can favourably alter its physicochemical properties. The aim of this work was to engineer SDM : 4-ASA cocrystals with different habits to investigate the effect on dissolution, and the derived powder properties of flow and compaction. Cocrystals were prepared in a 1 : 1 molar ratio by solvent evaporation using ethanol (habit I) or acetone (habit II), solvent evaporation followed by grinding (habit III) and spray drying (habit IV). Powder X-ray diffraction showed Bragg peak position was the same in all the solid products. The peak intensity varied, indicating different preferred crystal orientation confirmed by SEM micrographs: large prismatic crystals (habit I), large plate-like crystals (habit II), small cube-like crystals (habit III) and microspheres (habit IV). The habit III exhibited the fasted dissolution rate; however, it underwent a polymorphic transition during dissolution. Habits I and IV exhibited the highest Carr's compressibility index, indicating poor flowability. However, habits II and III demonstrated improved flow. Spray drying resulted in cocrystals with improved compaction properties. Even for cocrystals with poor pharmaceutical characteristics, a habit can be engineered to alter the dissolution, flowability and compaction behaviour. © 2015 Royal Pharmaceutical Society.

  4. In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow-through dissolution method with biorelevant dissolution media

    DEFF Research Database (Denmark)

    Sunesen, Vibeke Hougaard; Pedersen, Betty Lomstein; Kristensen, Henning Gjelstrup

    2005-01-01

    phospholipids, were used as the bile source. The effect of adding different concentrations and molar ratios of monoglycerides and fatty acids to the fed state media was investigated. In vivo release profiles under fasted and fed conditions were obtained from a previous study by deconvolution [Sunesen, V......The purpose of the study was to design dissolution tests that were able to distinguish between the behaviour of danazol under fasted and fed conditions, by using biorelevant media. In vitro dissolution of 100mg danazol capsules was performed using the flow-through dissolution method. Flow rates...... were 8, 16 or 32 ml/min, corresponding to total volumes dissolution medium of 960, 1920 and 3840 ml, respectively. The media used contained bile salt and phospholipid levels relevant for either fasted or fed conditions in vivo. Crude and inexpensive bile components, Porcine Bile Extract and soybean...

  5. Accelerating the dissolution of enteric coatings in the upper small intestine: evolution of a novel pH 5.6 bicarbonate buffer system to assess drug release.

    Science.gov (United States)

    Varum, Felipe J O; Merchant, Hamid A; Goyanes, Alvaro; Assi, Pardis; Zboranová, Veronika; Basit, Abdul W

    2014-07-01

    Despite rapid dissolution in compendial phosphate buffers, gastro resistant (enteric coated) products can take up to 2 h to disintegrate in the human small intestine, which clearly highlights the inadequacy of the in vitro test method to predict in vivo behaviour of these formulations. The aim of this study was to establish the utility of a novel pH 5.6 bicarbonate buffer, stabilized by an Auto pH™ System, as a better surrogate of the conditions of the proximal small intestine to investigate the dissolution behaviour of standard and accelerated release enteric double coating formulations. Prednisolone tablets were coated with 3 or 5 mg/cm(2) of partially neutralized EUDRAGIT(®) L 30 D-55, HP-55 or HPMC adjusted to pH 6 or 8. An outer layer of EUDRAGIT(®) L 30 D-55 was applied at 5mg/cm(2). For comparison purposes, a standard single layer of EUDRAGIT(®) L 30 D-55 was applied to the tablets. Dissolution was carried out using USP II apparatus in 0.1 M HCl for 2 h, followed by pH 5.6 bicarbonate buffer. EUDRAGIT(®) L 30 D-55 single-coated tablets showed a slow drug release with a lag time of 75 min in buffer, whereas release from the EUDRAGIT(®) L 30 D-55 double-coated tablets was accelerated. These in vitro lag times closely match the in vivo disintegration times for these coated tablets reported previously. Drug release was further accelerated from modified double coatings, particularly in the case of coatings with a thinner inner layer of HP-55 or HPMC (pH 8 and KH2PO4). This study confirms that the pH 5.6 bicarbonate buffer system offers significant advantages during the development of dosage forms designed to release the drug in the upper small intestine. Copyright © 2014. Published by Elsevier B.V.

  6. Comparative study of the pharmacopeial quality and dissolution profiles of generic and other drug forms of sodium metamizole (dipyrone sold in Brazil

    Directory of Open Access Journals (Sweden)

    Morenna Alana Giordani

    2012-08-01

    Full Text Available In Brazil, in order for a pharmaceutical company to register a drug form as generic or ‘similar’ with the Brazilian food and drug agency (Anvisa, it must be proved bioequivalent to its innovatory branded form (reference drug. This requires comparative trials, carried out in conformity with official compendia (Brazilian Pharmacopeia or another officially recognized code. Additionally, according to the Anvisa resolution RDC 31/2010, the dissolution profile of the drug must be tested and compared with that of the branded reference, as a benchmark of quality. The aim of this study was to assess the quality of 500 mg sodium metamizole (dipyrone tablets produced by seven different laboratories in Brazil: three generic drugs (G1, G2, G3, three (branded similar drugs (S1, S2,S3 and their reference branded product (Novalgina®, Sanofi-Aventis, drug R. All tests were carried out by methods specified in the Brazilian Pharmacopeia 4th edition (Farmacopeia Brasileira IV. The following tests were performed: uniformity of mass, friability, disintegration time, hardness, assay, uniformity of dosage units, salicylic acid limit assay, dissolution and identification. The dissolution profile was also recorded, as recommended in RDC 31/2010. Whereas every sample was approved in all the Farmacopeia Brasileira IV tests, the results in the dissolution profile test showed that four of the test drugs (G1, G2, S1 and S2 were notpharmaceutically equivalent to drug R. Thus, only drugs G3 and S3 showed dissolution profiles similar to that of drug R and the other four drugs could not be considered equivalent to it and were not approved.

  7. From Heuristic to Mathematical Modeling of Drugs Dissolution Profiles: Application of Artificial Neural Networks and Genetic Programming.

    Science.gov (United States)

    Mendyk, Aleksander; Güres, Sinan; Jachowicz, Renata; Szlęk, Jakub; Polak, Sebastian; Wiśniowska, Barbara; Kleinebudde, Peter

    2015-01-01

    The purpose of this work was to develop a mathematical model of the drug dissolution (Q) from the solid lipid extrudates based on the empirical approach. Artificial neural networks (ANNs) and genetic programming (GP) tools were used. Sensitivity analysis of ANNs provided reduction of the original input vector. GP allowed creation of the mathematical equation in two major approaches: (1) direct modeling of Q versus extrudate diameter (d) and the time variable (t) and (2) indirect modeling through Weibull equation. ANNs provided also information about minimum achievable generalization error and the way to enhance the original dataset used for adjustment of the equations' parameters. Two inputs were found important for the drug dissolution: d and t. The extrudates length (L) was found not important. Both GP modeling approaches allowed creation of relatively simple equations with their predictive performance comparable to the ANNs (root mean squared error (RMSE) from 2.19 to 2.33). The direct mode of GP modeling of Q versus d and t resulted in the most robust model. The idea of how to combine ANNs and GP in order to escape ANNs' black-box drawback without losing their superior predictive performance was demonstrated. Open Source software was used to deliver the state-of-the-art models and modeling strategies.

  8. Improving the dissolution rate of hydrophobic drugs through encapsulation in porous lactose as a new biocompatible porous carrier.

    Science.gov (United States)

    Ebrahimi, Amirali; Saffari, Morteza; Langrish, Timothy

    2017-04-15

    T he dissolution rates of indomethacin (IMC) and nifedipine (NIF) as poorly water-soluble model drugs have been significantly improved by encapsulating their molecules in the porous structure of engineered-particles of lactose as a new biocompatible porous carrier. The formulation method used in this study utilized a template-based spray-drying technique for in-situ production of porous lactose followed by two solvent-based drug-loading methods: (i) adsorption from organic solution, and (ii) incipient wetness impregnation to incorporate the drugs inside the porous lactose. In both cases, the results of DSC and XRD have revealed the deposition of nano-sized crystals of drugs inside the nanopores due to the nanoconfinement phenomenon. Greater extents of drug loadings have been achieved during the indomethacin adsorption due to the hydrogen-bonding interaction with the surface of lactose, as determined by FTIR spectroscopy. The in vitro release studies in simulated gastric fluid (SGF) have shown faster release rates for the impregnated particles compared with drug-loaded particles via the adsorption method. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Improvement of dissolution of poorly soluble drugs by solid deposition on a super disintegrant .2. The choice of super disintegrants and effect of granulation

    NARCIS (Netherlands)

    Bolhuis, GK; Zuurman, K; teWierik, GHP

    It is demonstrated that the dissolution from capsules and tablets of poorly soluble, hydrophobic drugs can be strongly improved by solid deposition of the drug upon hydrophilic, strongly swelling carriers like the super disintegrants sodium starch glycolate and croscarmellose sodium. As an effect of

  10. Coamorphous drug systems: enhanced physical stability and dissolution rate of indomethacin and naproxen

    DEFF Research Database (Denmark)

    Löbmann, Korbinian; Laitinen, Riikka; Grohganz, Holger

    2011-01-01

    . In this study, a coamorphous drug/drug combination between the two nonsteroidal anti-inflammatory drugs, naproxen and ¿-indomethacin, was prepared and investigated. At molar ratios of 2:1, 1:1 and 1:2, the drugs were quench cooled in order to obtain a coamorphous binary phase. Physical stability was examined......-Taylor equation. Results showed that naproxen could be made amorphous in combination with indomethacin while this was not possible with naproxen alone. Peak shifts in the FTIR spectra indicated molecular interactions between both drugs, and it is suggested that the two drugs formed a heterodimer. Therefore...

  11. Prediction of oral absorption of griseofulvin, a BCS class II drug, based on GITA model: utilization of a more suitable medium for in-vitro dissolution study.

    Science.gov (United States)

    Fujioka, Yoshitsugu; Kadono, Keitaro; Fujie, Yasuko; Metsugi, Yukiko; Ogawara, Ken-ichi; Higaki, Kazutaka; Kimura, Toshikiro

    2007-06-04

    The in-vivo absorbability of drugs categorized into the biopharmaceutics classification system (BCS) class II is very difficult to be predicted because of the large variability in the absorption and/or dissolution kinetics and the lack of an adequate in-vitro system for evaluating the dissolution behavior. We tried to predict the in-vivo absorption kinetics of griseofulvin, categorized into BCS class II, orally administrated as powders into rats, based on Gastrointestinal-Transit-Absorption model (GITA model), consisting of the absorption, dissolution and GI-transit processes. Using the dissolution rate constants (k(dis)) of griseofulvin obtained with JP 1st solution, JP 2nd solution, FaSSIF, FeSSIF and modified SIBLM as a medium, simulation lines were not able to describe the observed mean plasma profile at all. On the other hand, a calculated line provided by employing k(dis) obtained with MREVID 2 (medium reflecting in-vivo dissolution 2), a new medium, was in better agreement with the observed mean plasma profile than existing media, indicating that the utilization of adequate k(dis) value made it possible to predict the in-vivo absorption kinetics of drugs classified into BCS class II based on GITA model and that MREVID 2 could be a useful medium for describing the in-vivo dissolution kinetics.

  12. Non-destructive prediction of enteric coating layer thickness and drug dissolution rate by near-infrared spectroscopy and X-ray computed tomography.

    Science.gov (United States)

    Ariyasu, Aoi; Hattori, Yusuke; Otsuka, Makoto

    2017-06-15

    The coating layer thickness of enteric-coated tablets is a key factor that determines the drug dissolution rate from the tablet. Near-infrared spectroscopy (NIRS) enables non-destructive and quick measurement of the coating layer thickness, and thus allows the investigation of the relation between enteric coating layer thickness and drug dissolution rate. Two marketed products of aspirin enteric-coated tablets were used in this study, and the correlation between the predicted coating layer thickness and the obtained drug dissolution rate was investigated. Our results showed correlation for one product; the drug dissolution rate decreased with the increase in enteric coating layer thickness, whereas, there was no correlation for the other product. Additional examination of the distribution of coating layer thickness by X-ray computed tomography (CT) showed homogenous distribution of coating layer thickness for the former product, whereas the latter product exhibited heterogeneous distribution within the tablet, as well as inconsistent trend in the thickness distribution between the tablets. It was suggested that this heterogeneity and inconsistent trend in layer thickness distribution contributed to the absence of correlation between the layer thickness of the face and side regions of the tablets, which resulted in the loss of correlation between the coating layer thickness and drug dissolution rate. Therefore, the predictability of drug dissolution rate from enteric-coated tablets depended on the homogeneity of the coating layer thickness. In addition, the importance of micro analysis, X-ray CT in this study, was suggested even if the macro analysis, NIRS in this study, are finally applied for the measurement. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. pH-Dependent Solubility and Dissolution Behavior of Carvedilol--Case Example of a Weakly Basic BCS Class II Drug.

    Science.gov (United States)

    Hamed, Rania; Awadallah, Areeg; Sunoqrot, Suhair; Tarawneh, Ola; Nazzal, Sami; AlBaraghthi, Tamadur; Al Sayyad, Jihan; Abbas, Aiman

    2016-04-01

    The objective of this study was to investigate the pH-dependent solubility and dissolution of weakly basic Biopharmaceutical Classification Systems (BCS) class II drugs, characterized by low solubility and high permeability, using carvedilol, a weak base with a pK a value of 7.8, as a model drug. A series of solubility and in vitro dissolution studies was carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH range of the GI from 1.2 to 7.8. The effect of ionic strength, buffer capacity, and buffer species of the dissolution media on the solubility and dissolution behavior of carvedilol was also investigated. The study revealed that carvedilol exhibited a typical weak base pH-dependent solubility profile with a high solubility at low pH (545.1-2591.4 μg/mL within the pH range 1.2-5.0) and low solubility at high pH (5.8-51.9 μg/mL within the pH range 6.5-7.8). The dissolution behavior of carvedilol was consistent with the solubility results, where carvedilol release was complete (95.8-98.2% released within 60 min) in media simulating the gastric fluid (pH 1.2-5.0) and relatively low (15.9-86.2% released within 240 min) in media simulating the intestinal fluid (pH 6.5-7.8). It was found that the buffer species of the dissolution media may influence the solubility and consequently the percentage of carvedilol released by forming carvedilol salts of varying solubilities. Carvedilol solubility and dissolution decreased with increasing ionic strength, while lowering the buffer capacity resulted in a decrease in carvedilol solubility and dissolution rate.

  14. DissolvIt: An In Vitro Method for Simulating the Dissolution and Absorption of Inhaled Dry Powder Drugs in the Lungs.

    Science.gov (United States)

    Gerde, Per; Malmlöf, Maria; Havsborn, Lina; Sjöberg, Carl-Olof; Ewing, Pär; Eirefelt, Stefan; Ekelund, Katarina

    The main purpose of this work was to develop an in vitro method for simulating the dissolution and absorption of inhaled dry powder drugs that also mimics systemic pharmacokinetic data. A second purpose was to evaluate this method. DissolvIt(®) was developed as a simulation of the air-blood barrier of the upper airways, constituting: "airborne" particles deposited on a glass cover slip, a mucus simulant, a polycarbonate (basal) membrane, and a pumped albumin buffer simulating the pulmonary blood flow. The PreciseInhale(®) exposure system was used to aerosolize and deposit test formulations onto cover slips. The particle dissolution was observed by optical microscopy as particle disappearance, and it was started directly when the particles came into contact with the mucus simulant. Solute from the dissolving particles diffused through the barrier and was absorbed into the perfusate. The drug concentration in the perfusate over time and the remaining drug in the barrier at the end of the experiment were quantitated by using liquid chromatography-tandem mass spectrometry. Budesonide and fluticasone propionate generated different pharmacokinetic dissolution/absorption profiles in DissolvIt. This study indicates that DissolvIt simulates dissolution and absorption of drugs in the lung, and that DissolvIt also mimics pharmacokinetic profiles and parameters.

  15. Species differences in the dissolution and absorption of griseofulvin and albendazole, biopharmaceutics classification system class II drugs, in the gastrointestinal tract.

    Science.gov (United States)

    Tanaka, Yusuke; Waki, Ryoichi; Nagata, Shunji

    2013-01-01

    It is well known that large differences exist in the bioavailability of orally administered drugs between species. Dissolution is the first step in the oral absorption of solid drugs. In this study, we measured the in vivo luminal concentrations of griseofulvin (GF) and albendazole (AZ), Biopharmaceutics Classification System (BCS) class II drugs, and the GF fraction absorbed (Fa) in rats. Then, we compared the GF Fa in rat with that in other species reported previously to evaluate differences in drug dissolution and oral absorption. The Fa of GF has been reported to decrease from 80% to 40% with an increase in the oral dose in dogs and humans, because the rate-limiting step for absorption shifts from dissolution to solubility. However, such non-linearity was not observed in rats that were administered doses in the same ranges as those in humans, and the Fa values in rats were higher than those in dogs or humans. The in vivo luminal concentration of GF after oral administration in rats was much higher than the saturated solubility of GF in fasted-state simulated dog (FaSSIF(dog)) or human intestinal fluid (FaSSIF(human)). Furthermore, oral administration of AZ showed similar tendencies of interspecies differences in dissolution and oral absorption.

  16. Crystal Structures, Thermal Analysis, and Dissolution Behavior of New Solid Forms of the Antiviral Drug Arbidol with Dicarboxylic Acids

    Directory of Open Access Journals (Sweden)

    Alex N. Manin

    2015-12-01

    Full Text Available Salts of the antiviral drug arbidol (umifenovir (Arb with maleate (Mlc and fumarate (Fum anions have been obtained, and their crystal structures have been described. The crystal structure of arbidol maleate has been redetermined by single crystal X-ray diffraction at 180K. A new arbidol cocrystal in zwitterion form with succinic acid (Suc has also been found and characterized. The arbidol zwitterion was not previously seen in any of the drug crystal forms, and the [Arb + Suc] cocrystal seems to be the first found instance. Analysis of the conformational preferences of the arbidol molecule in the crystal structures has shown that it adopts two types of conformations, namely “open” and “closed” ones. Thermal stability of the arbidol salts and cocrystal have been analyzed by means of differential scanning calorimetry, thermogravimetric, and mass-spectrometry analysis. The dissolution study of the arbidol salts and cocrystal performed in aqueous buffer solutions with pH 1.2 and 6.8 has shown that both the salts and the cocrystal dissolve incongruently to form an arbidol hydrochloride monohydrate at pH 1.2 and an arbidol base at pH 6.8, respectively. The cocrystal reaches the highest solubility level in both pH 1.2 and pH 6.8 solutions.

  17. Toxoplasma gondii infection shifts dendritic cells into an amoeboid rapid migration mode encompassing podosome dissolution, secretion of TIMP-1, and reduced proteolysis of extracellular matrix.

    Science.gov (United States)

    Ólafsson, Einar B; Varas-Godoy, Manuel; Barragan, Antonio

    2018-03-01

    Dendritic cells (DCs) infected by Toxoplasma gondii rapidly acquire a hypermigratory phenotype that promotes systemic parasite dissemination by a "Trojan horse" mechanism in mice. Recent paradigms of leukocyte migration have identified the amoeboid migration mode of DCs as particularly suited for rapid locomotion in extracellular matrix and tissues. Here, we have developed a microscopy-based high-throughput approach to assess motility and matrix degradation by Toxoplasma-challenged murine and human DCs. DCs challenged with T. gondii exhibited dependency on metalloproteinase activity for hypermotility and transmigration but, strikingly, also dramatically reduced pericellular proteolysis. Toxoplasma-challenged DCs up-regulated expression and secretion of tissue inhibitor of metalloproteinases-1 (TIMP-1) and their supernatants impaired matrix degradation by naïve DCs and by-stander DCs dose dependently. Gene silencing of TIMP-1 by short hairpin RNA restored matrix degradation activity in Toxoplasma-infected DCs. Additionally, dissolution of podosome structures in parasitised DCs coincided with abrogated matrix degradation. Toxoplasma lysates inhibited pericellular proteolysis in a MyD88-dependent fashion whereas abrogated proteolysis persevered in Toxoplasma-infected MyD88-deficient DCs. This indicated that both TLR/MyD88-dependent and TLR/MyD88-independent signalling pathways mediated podosome dissolution and the abrogated matrix degradation. We report that increased TIMP-1 secretion and cytoskeletal rearrangements encompassing podosome dissolution are features of Toxoplasma-induced hypermigration of DCs with an impact on matrix degradation. Jointly, the data highlight how an obligate intracellular parasite orchestrates key regulatory cellular processes consistent with non-proteolytic amoeboid migration of the vehicle cells that facilitate its dissemination. © 2017 John Wiley & Sons Ltd.

  18. pH-Triggered controlled drug release from mesoporous silica nanoparticles via intracelluar dissolution of ZnO nanolids.

    Science.gov (United States)

    Muhammad, Faheem; Guo, Mingyi; Qi, Wenxiu; Sun, Fuxing; Wang, Aifei; Guo, Yingjie; Zhu, Guangshan

    2011-06-15

    Acid-decomposable, luminescent ZnO quantum dots (QDs) have been employed to seal the nanopores of mesoporous silica nanoparticles (MSNs) in order to inhibit premature drug (doxorubicin) release. After internalization into HeLa cells, the ZnO QD lids are rapidly dissolved in the acidic intracellular compartments, and as a result, the loaded drug is released into the cytosol from the MSNs. The ZnO QDs behave as a dual-purpose entity that not only acts as a lid but also has a synergistic antitumor effect on cancer cells. We anticipate that these nanoparticles may prove to be a significant step toward the development of a pH-sensitive drug delivery system that minimizes drug toxicity. © 2011 American Chemical Society

  19. Development of Dissolution Test Method for Drotaverine ...

    African Journals Online (AJOL)

    Methods: Sink conditions, drug stability and specificity in different dissolution media were tested to optimize a dissolution test method using a USP paddle type dissolution test apparatus set at a speed of. 50 rpm. The dissolution medium consisted of 900 ml of phosphate buffer (pH 6.8) containing 0.25% w/v cetrimide at 37 ...

  20. The impact of supersaturation level for oral absorption of BCS class IIb drugs, dipyridamole and ketoconazole, using in vivo predictive dissolution system: Gastrointestinal Simulator (GIS).

    Science.gov (United States)

    Tsume, Yasuhiro; Matsui, Kazuki; Searls, Amanda L; Takeuchi, Susumu; Amidon, Gregory E; Sun, Duxin; Amidon, Gordon L

    2017-05-01

    The development of formulations and the assessment of oral drug absorption for Biopharmaceutical Classification System (BCS) class IIb drugs is often a difficult issue due to the potential for supersaturation and precipitation in the gastrointestinal (GI) tract. The physiological environment in the GI tract largely influences in vivo drug dissolution rates of those drugs. Thus, those physiological factors should be incorporated into the in vitro system to better assess in vivo performance of BCS class IIb drugs. In order to predict oral bioperformance, an in vitro dissolution system with multiple compartments incorporating physiologically relevant factors would be expected to more accurately predict in vivo phenomena than a one-compartment dissolution system like USP Apparatus 2 because, for example, the pH change occurring in the human GI tract can be better replicated in a multi-compartmental platform. The Gastrointestinal Simulator (GIS) consists of three compartments, the gastric, duodenal and jejunal chambers, and is a practical in vitro dissolution apparatus to predict in vivo dissolution for oral dosage forms. This system can demonstrate supersaturation and precipitation and, therefore, has the potential to predict in vivo bioperformance of oral dosage forms where this phenomenon may occur. In this report, in vitro studies were performed with dipyridamole and ketoconazole to evaluate the precipitation rates and the relationship between the supersaturation levels and oral absorption of BCS class II weak base drugs. To evaluate the impact of observed supersaturation levels on oral absorption, a study utilizing the GIS in combination with mouse intestinal infusion was conducted. Supersaturation levels observed in the GIS enhanced dipyridamole and ketoconazole absorption in mouse, and a good correlation between their supersaturation levels and their concentration in plasma was observed. The GIS, therefore, appears to represent in vivo dissolution phenomena and

  1. Development of a modified - solid dispersion in an uncommon approach of melting method facilitating properties of a swellable polymer to enhance drug dissolution.

    Science.gov (United States)

    Nguyen, Tuong Ngoc-Gia; Tran, Phuong Ha-Lien; Tran, Thanh Van; Vo, Toi Van; Truong-DinhTran, Thao

    2015-04-30

    The study aimed to develop a modified-solid dispersion method using a swellable hydrophilic polymers accompanied by a conventional carrier to enhance the dissolution of a drug that possesses poor water solubility. Two swellable polymers (hydroxypropyl methylcellulose and polyethylene oxide) were swelled in melted polyethylene glycol 6000 (PEG 6000) in different ratios and under different conditions. The type, amount, and, especially, incorporation method of the swellable polymers were crucial factors affecting the dissolution rate, crystallinity, and molecular interaction of the drug. Interestingly, the method in which the swellable polymer was thoroughly mixed with the melted PEG 6000 as the first step was more effective in increasing drug dissolution than the method in which the drug was introduced to the melted PEG 6000 followed by the addition of the swellable polymer. This system has potential for controlling drug release due to high swelling capabilities of these polymers. Therefore, the current study can be considered to be a promising model for formulations of controlled release systems containing solid dispersions. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Rapid diagnosis of tuberculosis. Detection of drug resistance mechanisms.

    Science.gov (United States)

    Viñuelas-Bayón, Jesús; Vitoria, María Asunción; Samper, Sofía

    2017-10-01

    Tuberculosis is still a serious public health problem, with 10.8 million new cases and 1.8 million deaths worldwide in 2015. The diversity among members of the Mycobacterium tuberculosis complex, the causal agent of tuberculosis, is conducive to the design of different methods for rapid diagnosis. Mutations in the genes involved in resistance mechanisms enable the bacteria to elude the treatment. We have reviewed the methods for the rapid diagnosis of M. tuberculosis complex and the detection of susceptibility to drugs, both of which are necessary to prevent the onset of new resistance and to establish early, appropriate treatment. Copyright © 2017 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  3. Rapid interferometric imaging of printed drug laden multilayer structures

    DEFF Research Database (Denmark)

    Sandler, Niklas; Kassamakov, Ivan; Ehlers, Henrik

    2014-01-01

    /and active pharmaceutical ingredients (API) adhere to each other. This is crucial in order to have predetermined drug release profiles. We also demonstrate non-invasive measurement of a polymer structure in a microfluidic channel. It shown that traceable interferometric 3D microscopy is a viable technique......The developments in printing technologies allow fabrication of micron-size nano-layered delivery systems to personal specifications. In this study we fabricated layered polymer structures for drug-delivery into a microfluidic channel and aimed to interferometrically assure their topography...... and adherence to each other. We present a scanning white light interferometer (SWLI) method for quantitative assurance of the topography of the embedded structure. We determined rapidly in non-destructive manner the thickness and roughness of the structures and whether the printed layers containing polymers or...

  4. Dissolution study of nanocrystal powders of a poorly soluble drug by UV imaging and channel flow methods

    DEFF Research Database (Denmark)

    Sarnes, Annika; Østergaard, Jesper; Jensen, Sabrine Smedegaard

    2013-01-01

    , indomethacin. Nanocrystal suspensions were prepared using a top-down wet milling technique with three stabilizers: poloxamer F68, poloxamer F127 and polysorbate 80. The dissolution of the differently sized indomethacin nanocrystals were investigated using a channel flow dissolution method and by UV imaging...

  5. HPLC-MS/MS determination of a hardly soluble drug in human urine through drug-albumin binding assisted dissolution.

    Science.gov (United States)

    Rodila, Ramona; Kim, Grace E; Fan, Leimin; Chang, Min S; Zhang, Jun; Wu, Huaiqin; El-Shourbagy, Tawakol A

    2008-09-01

    ABT-263 is under development for treatment of cancer. In order to support clinical trials, an analytical method for ABT-263 quantification in human urine became necessary. Due to the extremely poor solubility of ABT-263 in aqueous and most common organic solvents, a critical step was to dissolve the drug into urine matrix. Although other potential approaches could be used, addition of powder albumin was found to be the most advantageous. Albumin powder does not significantly alter urine sample volume (< or = 2.8%) and a range of albumin to urine sample volume ratios can be allowed for full recovery of drug and thus accurate quantification. The procedure is fairly simple and can potentially be a universal approach for compounds with low solubility in urine, but strong protein binding. The method has been validated to support clinical trials.

  6. Instant and supersaturated dissolution of naproxen and sesamin (poorly water-soluble drugs and supplements) nanoparticles prepared by continuous expansion of liquid carbon dioxide solution through long dielectric nozzle

    Energy Technology Data Exchange (ETDEWEB)

    Arita, Toshihiko, E-mail: tarita@tagen.tohoku.ac.jp [Tohoku University, Institute of Multidisciplinary Research for Advanced Materials (Japan); Manabe, Noriyoshi [Tohoku University, Graduate School of Engineering (Japan); Nakahara, Koichi [Suntory Bussiness Expert Limited, Frontier Center for Value Creation (Japan)

    2012-11-15

    Nanoparticles (NPs) of naproxen (a nonsteroidal anti-inflammatory drug, BCS Class 2) and sesamin (a poorly water-soluble lignan) were investigated. By applying a newly developed rapid expansion system of liquid carbon dioxide solutions equipped with a dielectric nozzle, well-separated and fine both naproxen NPs (averaged particle size (APS) = 46.9 nm) and sesamin NPs (APS = 60.2 nm) were obtained without heating, surfactants, and co-solvents. Obtained naproxen and sesamin NPs had large surface/weight ratio, therefore, they showed instant dissolution to water until about ten percent higher than the saturated concentrations. In addition, the technique developed in the study has big advantage on producing especially drug NPs because the NPs produced by the method never includes neither poisonous additives (especially co-solvents and detergents) nor thermally denatured compounds.

  7. Biorelevant dissolution of candesartan cilexetil

    Directory of Open Access Journals (Sweden)

    Lucie Gruberová

    2017-03-01

    Full Text Available The choice of an appropriate medium for dissolution tests is an essential step during a dosage form development. The adequate design of dissolution testing enables forecasting in vivo behavior of drug formulation. Biorelevant media were developed for this purpose because dissolution media described in the International Pharmacopoeia are not thoroughly suitable. Therefore, we carried out solubility and dissolution tests in biorelevant media and we compared the results with data measured in compendial dissolution media. A shake-flask method and standard paddle apparatus were used. The concentration was measured by a UV-Vis spectrophotometer. An oral solid dosage form with poorly soluble drug candesartan cilexetil was tested. Significant differences in the solubility and dissolution profiles of candesartan cilexetil were observed. The study offers the overview of compendial and biorelevant media simulating fasted state that can be analyzed by a spectrophotometric technique.

  8. Drug-coated microneedles for rapid and painless local anesthesia.

    Science.gov (United States)

    Baek, Sung-Hyun; Shin, Ju-Hyung; Kim, Yeu-Chun

    2017-03-01

    This study showed that drug-coated PLLA (Poly (L-lactide)) microneedle arrays can induce rapid and painless local anesthesia. Microneedle arrays were fabricated using a micro-molding technique, and the needle tips were coated with 290.6 ± 45.9 μg of lidocaine, the most widely used local anesthetic worldwide. A dip-coating device was newly designed for the coating step using an optimized coating formulation. Lidocaine coated on the arrays was released rapidly into PBS within 2 min, and its stability in storage lasted 3 weeks at 4, 25, and 37°C. Furthermore, the microneedle arrays showed consistent in vitro skin penetration and delivered 200.8 ± 43.9, 224.2 ± 39.3, and 244.1 ± 19.6 μg of lidocaine into the skin 1, 2, and 5 min after application with a high delivery efficiency of 69, 77, and 84%. Compared to a commercially available topical anesthetic EMLA® cream, a 22.0, 13.6, and 14.0-fold higher amount of lidocaine was delivered into the skin. Note, in vitro skin permeation of Lidocaine was also notably enhanced by a 2-min-application of the lidocaine-coated microneedle arrays. Altogether, these results suggest that the biocompatible lidocaine-coated PLLA microneedle arrays could provide significantly rapid local anesthesia in a painless manner without any of the issues from topical applications or hypodermic injections of local anesthetics.

  9. Erythrocyte adenosine transport. A rapid screening test for cardiovascular drugs.

    Science.gov (United States)

    Yeung, P K; Mosher, S J; Li, R; Farmer, P S; Klassen, G A; Pollak, P T; McMullen, M; Ferrier, G

    1993-11-01

    An erythrocyte (RBC) model based on whole blood was used to investigate the effect of cardiovascular drugs on the uptake of adenosine in vitro. Fresh whole blood obtained from healthy volunteers was allowed to equilibrate with various concentrations (5-1000 microM) of a tested agent. (2-3H)-Adenosine was used as a substrate, and the reaction was terminated after 2 sec of incubation at room temperature by rapid addition of a "Stopping Solution" which was a mixture of erythro-9-(2-hydroxy-3-nonyl)adenine, dipyridamole, and EDTA. The mixture was centrifuged (1760 g, 4 degrees C, 10 min), and the radioactivity of an aliquot of the supernatant was determined by a scintillation counter. The results showed that dipyridamole was the most potent agent tested (IC50 = 0.2 microM). Amongst the calcium antagonists studied, isradipine was most potent, followed by verapamil, clentiazem, diltiazem, and then nifedipine. The racemates of two metabolites of diltiazem, MX and MB, were more potent than the parent drug. The antiarrhythmic agents, amiodarone and sotalol, the two new lipid peroxidation inhibitors, U-74389F and U-78517F, and the anxiolytic agent, alprazolam, were as active as verapamil. The beta-receptor antagonist propranolol and the angiotensin converting enzyme (ACE) inhibitor, enalapril, were practically inactive. In addition, the model was stereoselective such that the S(-)-enantiomer of verapamil was considerably more potent than the R(+)-antipote, whereas d(+)-sotalol was practically inactive compared to racemic sotalol.

  10. Influence of dissolution media composition on drug release and in-vitro/in-vivo correlation for paracetamol matrix tablets prepared with novel carbomer polymers.

    Science.gov (United States)

    Parojcić, J; Ethurić, Z; Jovanović, M; Ibrić, S; Jovanović, D

    2004-06-01

    The influence of dissolution media composition on drug release kinetics and in-vitro/in-vivo correlation (IVIVC) for hydrophilic matrix tablets based on Carbopol 971P and Carbopol 71G was investigated. A number of buffered and unbuffered media differing with respect to their pH value, ionic strength and ionic species was evaluated. The observed in-vitro drug release profiles were compared with the hypothetical drug release profiles in-vivo calculated by numerical deconvolution from the results of an in-vivo study. The obtained IVIVC plots were examined using linear and non-linear (proportional odds, proportional hazards and proportional reversed hazards) mathematical models. Although the studied sustained release agents were chemically identical, they exhibited pronounced differences in drug product behaviour both in-vitro and in-vivo. The use of non-linear modelling resulted in an improved level of correlation, especially in the case of Carbopol 71G matrices. The obtained results indicated the susceptibility of drug release kinetics and hence IVIVC in the case of anionic polymer matrices to media composition, and emphasized the need for thorough evaluation of applied media during the development of biorelevant dissolution methodology. Although the use of non-linear modelling could be advantageous, the need for a simple and meaningful non-linear relationship is pointed out. Copyright 2004 The Authors

  11. Critical material attributes (CMAs) of strip films loaded with poorly water-soluble drug nanoparticles: I. Impact of plasticizer on film properties and dissolution.

    Science.gov (United States)

    Krull, Scott M; Patel, Hardik V; Li, Meng; Bilgili, Ecevit; Davé, Rajesh N

    2016-09-20

    Recent studies have demonstrated polymer films to be a promising platform for delivery of poorly water-soluble drug particles. However, the impact of critical material attributes, for example plasticizer, on the properties of and drug release from such films has yet to be investigated. In response, this study focuses on the impact of plasticizer and plasticizer concentration on properties and dissolution rate of polymer films loaded with poorly water-soluble drug nanoparticles. Glycerin, triacetin, and polyethylene glycol were selected as film plasticizers. Griseofulvin was used as a model Biopharmaceutics Classification System class II drug and hydroxypropyl methylcellulose was used as a film-forming polymer. Griseofulvin nanoparticles were prepared via wet stirred media milling in aqueous suspension. A depression in film glass transition temperature was observed with increasing plasticizer concentration, along with a decrease in film tensile strength and an increase in film elongation, as is typical of plasticizers. However, the type and amount of plasticizer necessary to produce strong yet flexible films had no significant impact on the dissolution rate of the films, suggesting that film mechanical properties can be effectively manipulated with minimal impact on drug release. Griseofulvin nanoparticles were successfully recovered upon redispersion in water regardless of plasticizer or content, even after up to 6months' storage at 40°C and 75% relative humidity, which contributed to similar consistency in dissolution rate after 6months' storage for all films. Good content uniformity (<4% R.S.D. for very small film sample size) was also maintained across all film formulations. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Preparation of a novel starch-derived three-dimensional ordered macroporous carbon for improving the dissolution rate and oral bioavailability of water-insoluble drugs.

    Science.gov (United States)

    Liu, Ying; Wu, Chao; Hao, Yanna; Xu, Jie; Zhao, Ying; Qiu, Yang; Jiang, Jie; Yu, Tong; Ji, Peng

    2016-01-25

    In our study, soluble starch was applied as a novel carbon source for preparing three-dimensional ordered macroporous carbon (3DOMC) using monodisperse silica nanospheres as the hard template. The 3DOMC was used as an insoluble drug carrier when it was found that it could markedly improve the water solubility of felodipine (FDP). The structural features of 3DOMC were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The 3DOMC structure was found to have a higher drug loading than microporous and mesoporous structures, and the interconnected nanostructure effectively inhibited the formation of drug crystals. FDP, belonging to the Biopharmaceutics Classification System II (BCSII), was chosen as the model drug and was loaded into the 3DOMC structure by solvent evaporation. The state of FDP in the 3DOMC structure was characterized by powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). The results obtained showed that FDP was present in the pores in an amorphous or microcrystalline state. In vivo and in vitro experiments indicated that 3DOMC could significantly improve the drug dissolution rate, but the FDP-3DOMC self-made common tablets had the disadvantage of a burst effect. For this reason, osmotic pump technology was used to control the drug release rate. We developed a potentially useful insoluble drug carrier for pharmaceutical applications. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Dissolution rates of over-the-counter painkillers: a comparison among formulations.

    Science.gov (United States)

    Alemanni, Matteo; Gatoulis, Sergio C; Voelker, Michael

    2016-06-01

    We wanted to compare the dissolution profile of several over-the-counter analgesics to understand whether the different formulation techniques employed to enhance absorption were associated with variations in the dissolution rate, a parameter known to affect drug absorption. We considered 5 formulations currently marketed in Italy: aspirin tablets (Aspirina Dolore e Infiammazione®), ibuprofen tablets and liquid capsules (Moment®), ibuprofen lysine tablets (Nurofenimmedia®) and dexketoprofen trometamol tablets (Enantyum®). Dissolution tests were performed according to the current USP/NF monograph dissolution procedure. Drug dissolution was evaluated at 1, 3, 6, 15, and 30 minutes since the start of the test. Dissolution was evaluated at three different pH: 1.2, 4.5 and 6.8. Every test was repeated 12 times. The aspirin formulation was by far the most rapid dissolving formulation, among those tested, with more than 80% of the tablet dissolved at 6 minutes for every pH considered. At pH 1.2 and 4.5, only the dexketoprofen formulation was able to reach the dissolution level of aspirin at 30 minutes, but had lower levels of dissolution at the previous time points. Instead, at pH 6.8, most of the formulations approached aspirin dissolution level, but only after 15 minutes. Ibuprofen capsules had the slowest kinetics, with a lag phase the first 6 minutes. Different formulation strategies can lead to great differences in the dissolution rates even among drugs of the same class, suggesting that enhancements in the formulation of painkillers can lead to improvements in drug absorption, and thus in the onset of analgesia.

  14. Comparison of nanomilling and coprecipitation on the enhancement of in vitro dissolution rate of poorly water-soluble model drug aripiprazole.

    Science.gov (United States)

    Abdelbary, Aly A; Li, Xiaoling; El-Nabarawi, Mohamed; Elassasy, Abdelhalim; Jasti, Bhaskara

    2014-06-01

    The aim of this study was to evaluate the effect of coprecipitation and nanomilling on the crystallinity of a model drug, aripiprazole and evaluate the in vitro dissolution rate (IDR). Aripiprazole compositions were prepared by physical mixing, coprecipitation and nanomilling using hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP) K17 and pluronic F127. The particle size, solubility, IDR and drug crystallinity were studied. Aripiprazole pluronic compositions were compressed into tablets and dissolution rate was evaluated. The particle size of nanomilled compositions was significantly smaller than that of the other compositions. The saturation solubility of aripiprazole from nanoparticle (NP) and coprecipitate (CP) from PVP and Pluronic was comparable, however, NP of HPC containing composition showed higher solubility when compared to its CP compositions. The crystallinity of aripiprazole decreased from physical mixtures to coprecipitates and further in NPs. The increased aripiprazole IDR was due to decreased crystallinity from coprecipitate compositions and disruption of crystallinity from nanomilled compositions. Aripiprazole tablets prepared from nanomilled powder dissolved >75% within 10 min compared with 17% and 20% for tablets prepared from physical mixture and coprecipitate powders, respectively. The increase in IDR due to nanomilling was more significant than coprecipitation and NPs retained the IDR after compression into tablets.

  15. Rapid Methods for detection of Veterinary Drug residues in Meat

    Directory of Open Access Journals (Sweden)

    Chandan

    2010-10-01

    Full Text Available The use of substances having hormonal or thyreostatic action as well as b-agonists is banned in many countries. However, sometimes forbidden drugs may be added to feeds for illegal administration to farm animals for promoting increased muscle development or increased water retention and thus obtain an economical benefit. The result is a fraudulent overweight of meat but, what is worse, residues of these substances may remain in meat and may pose a real threat to the consumer either through exposure to the residues, transfer of antibiotic resistance or allergy risk. This has exerted a great concern among the meat consumers. The control of the absence of these forbidden substances in animal foods and feeds is regulated in the European Union by Directive 96/23/EC on measures to monitor certain substances and residues in live animals and animal products. Analytical methodology, including criteria for identification and confirmation, for the monitoring of compliance was also given in Decisions 93/256/EEC and 93/257/EEC. More recently, Decision 2002/657/EC provided rules for the analytical methods to be used in testing of official samples. New substances with anabolic properties are being detected year by year increasing the list of forbidden compounds to be tested. Furthermore, the extended practice consisting in the use of “cocktails” (mixtures of low amounts of several substances that exert a synergistic effect to have a similar growth promotion, reduces the margin for an effective analytical detection. Thus, the evolution of the “black market” is making really difficult to have an effective analytical control of the residues of these substances in foods of animal origin. Control laboratories must face an increasing demand of analysis like the growing number of residues to be analysed in different types of samples, the strict guidelines for analytical methodologies according to the latest Directives, the increased costs of such new

  16. Cost-effectiveness of rapid susceptibility testing against second-line drugs for tuberculosis

    NARCIS (Netherlands)

    Dowdy, D. W.; van't Hoog, A.; Shah, M.; Cobelens, F.

    2014-01-01

    Drug susceptibility testing (DST) against second-line tuberculosis drugs (SLDs) is essential for improving outcomes among multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) cases. To evaluate the potential cost-effectiveness of rapid DST for SLDs. We constructed a

  17. Development of a Novel Milling System Using Supercritical Carbon Dioxide for Improvement of Dissolution Characteristics of Water-Poorly Soluble Drugs.

    Science.gov (United States)

    Fern, Jennifer Chia Wee; Nakamura, Hideya; Watano, Satoru

    2016-01-01

    The aim of this study is to develop a novel milling system using supercritical carbon dioxide (SC-CO2) for the improvement of dissolution characteristics of water-poorly soluble drugs. SC-CO2 possesses high potential in the application of nanotechnology, due to the attractive properties of SC-CO2 fluid such as cheap, inert and non-polluting. In addition, SC-CO2 has density comparable to a liquid, viscosity similar to a gas, and high diffusion capacity. Most of all, carbon dioxide exists as gas in room temperature and pressure, which enables the removal of fluid instantaneously. In this study, a novel method of milling using SC-CO2 was proposed to produce fine-drug particles. SC-CO2 milling was conducted and its performance was compared with the ones by various milling methods such as jet milling, dry milling and wet milling. A comparison on the effect of each milling medium on its milling performance, drug size distribution, and particle morphology was conducted. Operating variables of the SC-CO2 milling system were also investigated to clarify the factors affecting the milling properties and to improve drug release characteristics of water-poorly soluble drugs.

  18. Computational fluid dynamics (CFD) studies of a miniaturized dissolution system.

    Science.gov (United States)

    Frenning, G; Ahnfelt, E; Sjögren, E; Lennernäs, H

    2017-04-15

    Dissolution testing is an important tool that has applications ranging from fundamental studies of drug-release mechanisms to quality control of the final product. The rate of release of the drug from the delivery system is known to be affected by hydrodynamics. In this study we used computational fluid dynamics to simulate and investigate the hydrodynamics in a novel miniaturized dissolution method for parenteral formulations. The dissolution method is based on a rotating disc system and uses a rotating sample reservoir which is separated from the remaining dissolution medium by a nylon screen. Sample reservoirs of two sizes were investigated (SR6 and SR8) and the hydrodynamic studies were performed at rotation rates of 100, 200 and 400rpm. The overall fluid flow was similar for all investigated cases, with a lateral upward spiraling motion and central downward motion in the form of a vortex to and through the screen. The simulations indicated that the exchange of dissolution medium between the sample reservoir and the remaining release medium was rapid for typical screens, for which almost complete mixing would be expected to occur within less than one minute at 400rpm. The local hydrodynamic conditions in the sample reservoirs depended on their size; SR8 appeared to be relatively more affected than SR6 by the resistance to liquid flow resulting from the screen. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Low Buffer Capacity and Alternating Motility along the Human Gastrointestinal Tract: Implications for in Vivo Dissolution and Absorption of Ionizable Drugs.

    Science.gov (United States)

    Hens, Bart; Tsume, Yasuhiro; Bermejo, Marival; Paixao, Paulo; Koenigsknecht, Mark J; Baker, Jason R; Hasler, William L; Lionberger, Robert; Fan, Jianghong; Dickens, Joseph; Shedden, Kerby; Wen, Bo; Wysocki, Jeffrey; Loebenberg, Raimar; Lee, Allen; Frances, Ann; Amidon, Greg; Yu, Alex; Benninghoff, Gail; Salehi, Niloufar; Talattof, Arjang; Sun, Duxin; Amidon, Gordon L

    2017-12-04

    In this study, we determined the pH and buffer capacity of human gastrointestinal (GI) fluids (aspirated from the stomach, duodenum, proximal jejunum, and mid/distal jejunum) as a function of time, from 37 healthy subjects after oral administration of an 800 mg immediate-release tablet of ibuprofen (reference listed drug; RLD) under typical prescribed bioequivalence (BE) study protocol conditions in both fasted and fed states (simulated by ingestion of a liquid meal). Simultaneously, motility was continuously monitored using water-perfused manometry. The time to appearance of phase III contractions (i.e., housekeeper wave) was monitored following administration of the ibuprofen tablet. Our results clearly demonstrated the dynamic change in pH as a function of time and, most significantly, the extremely low buffer capacity along the GI tract. The buffer capacity on average was 2.26 μmol/mL/ΔpH in fasted state (range: 0.26 and 6.32 μmol/mL/ΔpH) and 2.66 μmol/mL/ΔpH in fed state (range: 0.78 and 5.98 μmol/mL/ΔpH) throughout the entire upper GI tract (stomach, duodenum, and proximal and mid/distal jejunum). The implication of this very low buffer capacity of the human GI tract is profound for the oral delivery of both acidic and basic active pharmaceutical ingredients (APIs). An in vivo predictive dissolution method would require not only a bicarbonate buffer but also, more significantly, a low buffer capacity of dissolution media to reflect in vivo dissolution conditions.

  20. Modeling dissolution of sparingly soluble multisized powders

    OpenAIRE

    Almeida, Luís Pereira de; Simões, Sérgio; Brito, Paulo; Portugal, António; Figueiredo, Margarida

    1997-01-01

    The dissolution of powder drugs, besides being a topic of utmost importance, especially for the sparingly soluble ones, is far from being well-explained. The purpose of the present study is, on the one hand, to obtain experimental dissolution profiles and, on the other hand, to analyze and process the data for dissolution modeling. Three different size fractions of a widely used sparingly soluble drug - ibuprofen - were fully characterized with regard to its particle size distribution, specif...

  1. Enhanced dissolution of oxcarbazepine microcrystals using a static mixer process.

    Science.gov (United States)

    Douroumis, D; Fahr, A

    2007-10-01

    The purpose of this study was to form micronized powders of Oxcarbazepine (OXC), a poorly water-soluble drug, using a static mixer technique to enhance the dissolution rate. Controlled precipitation was achieved injecting the organic OXC solution rapidly into an aqueous methylcellulose (MC) protective solution by means of a static mixer thus providing turbulent and homogeneous mixing. Furthermore, a factorial design was implemented for data analysis. The physicochemical properties of the freeze-dried dispersions were evaluated by differential scanning calorimetry (DSC), infrared spectroscopy (FTIR) and X-ray diffraction (XRD). Drug microcrystals showed a narrow size distribution with approximately 2 microm mean particle size and high drug loading. DSC and FTIR studies revealed that the drug remained in crystalline state and no drug-polymer interaction occurred. The dissolution studies showed enhanced dissolution of OXC microcrystals compared to the pure drug. The static mixer technique was proved capable for micro-sized polymeric particles. This is an inexpensive, less time consuming and fully scalable process for development of poorly soluble drugs.

  2. Optimization of Dissolution Compartments in a Biorelevant Dissolution Apparatus Golem v2, Supported by Multivariate Analysis

    Directory of Open Access Journals (Sweden)

    Ivan Stupák

    2017-11-01

    Full Text Available Biorelevant dissolution instruments represent an important tool for pharmaceutical research and development. These instruments are designed to simulate the dissolution of drug formulations in conditions most closely mimicking the gastrointestinal tract. In this work, we focused on the optimization of dissolution compartments/vessels for an updated version of the biorelevant dissolution apparatus—Golem v2. We designed eight compartments of uniform size but different inner geometry. The dissolution performance of the compartments was tested using immediate release caffeine tablets and evaluated by standard statistical methods and principal component analysis. Based on two phases of dissolution testing (using 250 and 100 mL of dissolution medium, we selected two compartment types yielding the highest measurement reproducibility. We also confirmed a statistically ssignificant effect of agitation rate and dissolution volume on the extent of drug dissolved and measurement reproducibility.

  3. Roller compaction, granulation and capsule product dissolution of drug formulations containing a lactose or mannitol filler, starch, and talc.

    Science.gov (United States)

    Chang, Chialu Kevin; Alvarez-Nunez, Fernando A; Rinella, Joseph V; Magnusson, Lars-Erik; Sueda, Katsuhiko

    2008-01-01

    This study investigated the influence of excipient composition to the roller compaction and granulation characteristics of pharmaceutical formulations that were comprised of a spray-dried filler (lactose monohydrate or mannitol), pregelatinized starch, talc, magnesium stearate (1% w/w) and a ductile active pharmaceutical ingredient (25% w/w) using a mixed-level factorial design. The main and interaction effects of formulation variables (i.e., filler type, starch content, and talc content) to the response factors (i.e., solid fraction and tensile strength of ribbons, particle size, compressibility and flow of granules) were analyzed using multi-linear stepwise regression analysis. Experimental results indicated that roller compacted ribbons of both lactose and mannitol formulations had similar tensile strength. However, resulting lactose-based granules were finer than the mannitol-based granules because of the brittleness of lactose compared to mannitol. Due to the poor compressiblility of starch, increasing starch content in the formulation from 0% to 20% w/w led to reduction in ribbon solid fraction by 10%, ribbon tensile strength by 60%, and granule size by 30%. Granules containing lactose or more starch showed less cohesive flow than granules containing mannitol and less starch. Increasing talc content from 0% to 5% w/w had little effect to most physical properties of ribbons and granules while the flow of mannitol-based granules was found improved. Finally, it was observed that stored at 40 degrees C/75% RH over 12 weeks, gelatin capsules containing lactose-based granules had reduced dissolution rates due to pellicle formation inside capsule shells, while capsules containing mannitol-based granules remained immediate dissolution without noticeable pellicle formation.

  4. Phase Behavior of Ritonavir Amorphous Solid Dispersions during Hydration and Dissolution.

    Science.gov (United States)

    Purohit, Hitesh S; Taylor, Lynne S

    2017-09-27

    The aim of this research was to study the interplay of solid and solution state phase transformations during the dissolution of ritonavir (RTV) amorphous solid dispersions (ASDs). RTV ASDs with polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) were prepared at 10-50% drug loading by solvent evaporation. The miscibility of RTV ASDs was studied before and after exposure to 97% relative humidity (RH). Non-sink dissolution studies were performed on fresh and moisture-exposed ASDs. RTV and polymer release were monitored using ultraviolet-visible spectroscopy. Techniques including fluorescence spectroscopy, confocal imaging, scanning electron microscopy (SEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC) and nanoparticle tracking analysis (NTA) were utilized to monitor solid and the solution state phase transformations. All RTV-PVP and RTV-PVPVA ASDs underwent moisture-induced amorphous-amorphous phase separation (AAPS) on high RH storage whereas RTV-HPMCAS ASDs remained miscible. Non-sink dissolution of PVP- and PVPVA-based ASDs at low drug loadings led to rapid RTV and polymer release resulting in concentrations in excess of amorphous solubility, liquid-liquid phase separation (LLPS) and amorphous nanodroplet formation. High drug loading PVP- and PVPVA-based ASDs did not exhibit LLPS upon dissolution as a consequence of extensive AAPS in the hydrated ASD matrix. All RTV-HPMCAS ASDs led to LLPS upon dissolution. RTV ASD dissolution is governed by a competition between the dissolution rate and the rate of phase separation in the hydrated ASD matrix. LLPS was observed for ASDs where the drug release was polymer controlled and only ASDs that remained miscible during the initial phase of dissolution led to LLPS. Techniques such as fluorescence spectroscopy, confocal imaging and SEM were useful in understanding the phase behavior of ASDs upon hydration and dissolution

  5. The effect of pH and ionic strength of dissolution media on in-vitro release of two model drugs of different solubilities from HPMC matrices.

    Science.gov (United States)

    Asare-Addo, Kofi; Conway, Barbara R; Larhrib, Hassan; Levina, Marina; Rajabi-Siahboomi, Ali R; Tetteh, John; Boateng, Joshua; Nokhodchi, Ali

    2013-11-01

    The evaluation of the effects of different media ionic strengths and pH on the release of hydrochlorothiazide, a poorly soluble drug, and diltiazem hydrochloride, a cationic and soluble drug, from a gel forming hydrophilic polymeric matrix was the objective of this study. The drug to polymer ratio of formulated tablets was 4:1. Hydrochlorothiazide or diltiazem HCl extended release (ER) matrices containing hypromellose (hydroxypropyl methylcellulose (HPMC)) were evaluated in media with a pH range of 1.2-7.5, using an automated USP type III, Bio-Dis dissolution apparatus. The ionic strength of the media was varied over a range of 0-0.4M to simulate the gastrointestinal fed and fasted states and various physiological pH conditions. Sodium chloride was used for ionic regulation due to its ability to salt out polymers in the midrange of the lyotropic series. The results showed that the ionic strength had a profound effect on the drug release from the diltiazem HCl K100LV matrices. The K4M, K15M and K100M tablets however withstood the effects of media ionic strength and showed a decrease in drug release to occur with an increase in ionic strength. For example, drug release after the 1h mark for the K100M matrices in water was 36%. Drug release in pH 1.2 after 1h was 30%. An increase of the pH 1.2 ionic strength to 0.4M saw a reduction of drug release to 26%. This was the general trend for the K4M and K15M matrices as well. The similarity factor f2 was calculated using drug release in water as a reference. Despite similarity occurring for all the diltiazem HCl matrices in the pH 1.2 media (f2=64-72), increases of ionic strength at 0.2M and 0.4M brought about dissimilarity. The hydrochlorothiazide tablet matrices showed similarity at all the ionic strength tested for all polymers (f2=56-81). The values of f2 however reduced with increasing ionic strengths. DSC hydration results explained the hydrochlorothiazide release from their HPMC matrices. There was an increase in

  6. On the variability of dissolution data.

    Science.gov (United States)

    Elkoshi, Z

    1997-10-01

    To investigate dissolution data variability and its origins. The Weibull function with four parameters t0 (dissolution lag-time), K (the rate parameter), beta (the shape parameter) and D (the fraction dissolved as t-->infinity), is used to describe the dissolution curve. The variance of the dissolution data is expressed in terms of these parameters and their individual variances sigma t02, sigma K2, sigma beta 2, and sigma D2. These four variances originate from variable physical properties of the dosage units and from a variable dissolution environment. Therefore, dissolution data variability depends on both, the functional form of the curve and on the variance of the physical conditions. The use of this method enables the elucidation of the sources of dissolution data variability. In the case of a sigmoidal dissolution curve (beta > 1), data variance is zero as dissolution begins (following dissolution lag-time). This initial variance diverges when the dissolution curve is non-sigmoidal (with beta point (corresponding to the curve inflection point, when the main source of variability is dissolution lag-time t0, or around t = 1/K + t0, when the main sources of variability are the rate parameter K or the shape parameter beta). When the curve is sigmoidal (beta > 1) and the main source of variability relates to the dissolution extent, the overall variance grows with time all the way to the plateau of the dissolution curve. With a non-sigmoidal dissolution curve (beta point. The dissolution relative variance, on the other hand, diverges as dissolution begins and decreases with time at least until 63% of the drug is released, irrespective to the Weibull parameter values. Later, it may decrease or increase, attaining a fixed value (sigma D2/D2) at the plateau of the dissolution curve. The particular time dependence of dissolution data variance is well defined in terms of the Weibull shape parameters and their individual variances. Dissolution data variability may

  7. Rapid enzymatic test for phenotypic HIV protease drug resistance

    OpenAIRE

    Hoffmann, D.; Assfalg-Machleidt, Irmgard; Nitschko, H; Helm, K. von der; Koszinowski, U.; Machleidt, Werner

    2003-01-01

    A phenotypic resistance test based on recombinant expression of the active HIV protease in E. coli from patient blood samples was developed. The protease is purified in a rapid onestep procedure as active enzyme and tested for inhibition by five selected synthetic inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir) used presently for chemotherapy of HIVinfected patients. The HPLC system used in a previous approach was replaced by a continuous fluorogenic assay suitable f...

  8. Carbon Nanotube Micro-Needles for Rapid Transdermal Drug Delivery

    Science.gov (United States)

    Lyon, Bradley; Aria, Adrianus Indrat; Gat, Amir; Cosse, Julia; Montemayor, Lauren; Beizaie, Masoud; Gharib, Morteza

    2012-11-01

    By catalyst patterning, bundles of vertically-aligned carbon nanotubes (CNT) can be assembled to create 2D arrays of hollow micro-needles with feature size as small as a few microns. For transdermal drug delivery, the most challenging mechanical requirement is to make the CNT micro-needle small enough so that delivery is painless yet large enough so that the micro-needle can achieve skin penetration. By taking advantage of capillary action and the nanoporosity of CNT bundles, we can wick high strength polymer into the inter-spacing between nanotubes to augment the stiffness of our micro-needles. For low viscous polymers, the large ratio between the micron sized center hole of the micro-needle and the nanopores of the surrounding CNT allow us to wick polymer through the nanotubes while maintaining an open central hole for drug transport. For a transdermal patch prototype with a delivery area less than 1cm x 1cm square, we can fabricate 50 CNT micro-needles that produces a total flow rate up to 100 uL/s with actuation pressure provided by a mere finger tap. From in vitro experiments, we will demonstrate that CNT micro-needles provide a much faster convective delivery of drugs than conventional topical diffusion based patches. We acknowledge Zcube s.r.l for their support of this work.

  9. High-performance liquid chromatographic analysis of verapamil and its application to determination in tablet dosage forms and to drug dissolution studies.

    Science.gov (United States)

    Ozkan, Y; Yilmaz, N; Ozkan, S A; Biryol, I

    2000-05-01

    A high-performance liquid chromatographic procedure with two detectors is presented for the determination of verapamil in pharmaceutical dosage forms. The procedure is based on the use of reversed-phase high-performance liquid chromatography with UV and fluorimetric detectors. Each analysis required no longer than 6 min for both detection procedures. Quantification was achieved by measurement of the ratio of the peak area of the drug to the internal standard (fluoxetine) and the detection limit was 10 ng/ml for the UV detector and 750 pg/ml for the fluorimetric detector. There was no significant difference between inter- and intra-day studies for verapamil determined for two different concentrations (0.05 and 1.00 microgram/ml). This process could be used to determine verapamil concentrations in the range 0.025-50 and 0.0008-20 micrograms/ml for UV and fluorimetric detection, respectively. These methods were applied, without any interference from the excipients, for the determination of the drug in tablets and in drug dissolution studies. It is suggested that the proposed HPLC procedures could be used for routine quality control and dosage form assay of verapamil hydrochloride.

  10. Methods of solving rapid binding target-mediated drug disposition model for two drugs competing for the same receptor.

    Science.gov (United States)

    Yan, Xiaoyu; Chen, Yang; Krzyzanski, Wojciech

    2012-10-01

    The target-mediated drug disposition (TMDD) model has been adopted to describe pharmacokinetics for two drugs competing for the same receptor. A rapid binding assumption introduces total receptor and total drug concentrations while free drug concentrations C (A) and C (B) are calculated from the equilibrium (Gaddum) equations. The Gaddum equations are polynomials in C (A) and C (B) of second degree that have explicit solutions involving complex numbers. The aim of this study was to develop numerical methods to solve the rapid binding TMDD model for two drugs competing for the same receptor that can be implemented in pharmacokinetic software. Algebra, calculus, and computer simulations were used to develop algorithms and investigate properties of solutions to the TMDD model with two drugs competitively binding to the same receptor. A general rapid binding approximation of the TMDD model for two drugs competing for the same receptor has been proposed. The explicit solutions to the equilibrium equations employ complex numbers, which cannot be easily solved by pharmacokinetic software. Numerical bisection algorithm and differential representation were developed to solve the system instead of obtaining an explicit solution. The numerical solutions were validated by MATLAB 7.2 solver for polynomial roots. The applicability of these algorithms was demonstrated by simulating concentration-time profiles resulting from exogenous and endogenous IgG competing for the neonatal Fc receptor (FcRn), and darbepoetin competing with endogenous erythropoietin for the erythropoietin receptor. These models were implemented in ADAPT 5 and Phoenix WinNonlin 6.0, respectively.

  11. A cluster randomised trial introducing rapid diagnostic tests into registered drug shops in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Magnussen, Pascal; Lal, Sham

    2015-01-01

    the impact of introducing rapid diagnostic tests for malaria (mRDTs) in registered drug shops in Uganda, with the aim to increase appropriate treatment of malaria with artemisinin-based combination therapy (ACT) in patients seeking treatment for fever in drug shops. METHODS: A cluster-randomized trial...

  12. Rapid culture-based methods for drug-resistance detection in Mycobacterium tuberculosis.

    Science.gov (United States)

    Palomino, Juan Carlos; Martin, Anandi; Von Groll, Andrea; Portaels, Francoise

    2008-10-01

    Tuberculosis still represents a major public health problem, especially in low-resource countries where the burden of the disease is more important. Multidrug-resistant and extensively drug drug-resistant tuberculosis constitute serious problems for the efficient control of the disease stressing the need to investigate resistance to first- and second-line drugs. Conventional methods for detecting drug-resistance in Mycobacterium tuberculosis are slow and cumbersome. The most commonly used proportion method on Löwenstein-Jensen medium or Middlebrook agar requires a minimum of 3-4 weeks to produce results. Several new approaches have been proposed in the last years for the rapid and timely detection of drug-resistance in tuberculosis. This review will address phenotypic culture-based methods for rapid drug susceptibility testing in M. tuberculosis.

  13. Microscopic Observation Drug Susceptibility Assay for Rapid Diagnosis of Lymph Node Tuberculosis and Detection of Drug Resistance.

    Science.gov (United States)

    Kirwan, Daniela E; Ugarte-Gil, Cesar; Gilman, Robert H; Caviedes, Luz; Rizvi, Hasan; Ticona, Eduardo; Chavez, Gonzalo; Cabrera, José Luis; Matos, Eduardo D; Evans, Carlton A; Moore, David A J; Friedland, Jon S

    2016-01-01

    In this study, 132 patients with lymphadenopathy were investigated. Fifty-two (39.4%) were diagnosed with tuberculosis (TB). The microscopic observation drug susceptibility (MODS) assay provided rapid (13 days), accurate diagnosis (sensitivity, 65.4%) and reliable drug susceptibility testing (DST). Despite its lower sensitivity than that of other methods, its faster results and simultaneous DST are advantageous in resource-poor settings, supporting the incorporation of MODS into diagnostic algorithms for extrapulmonary TB. Copyright © 2015 Kirwan et al.

  14. In vitro evaluation of magaldrate antacid efficacy in the presence of some drugs and its effect on their dissolution rates: Part I.

    Science.gov (United States)

    al Gohary, O M

    1996-12-01

    A comparison of the antacid efficacy of magaldrate powder and its dosage forms on an equal weight basis by an in vitro technique revealed that: suspensions > chew tablets > powder. This was also evidenced by acid neutralizing capacity test USP XXIII, which also showed that riopan and rioplus suspensions were equipotent. All tested doses of different antacid dosage forms were found to regulate acid level to pH 3.0 within 10 seconds. This rapidity of action depends on its dose, dosage forms, and extent of chewing the tablets. The antacid efficacy of tested antacid was not affected by the concomitant presence of two tablets of duspatalin, faverin and panadol (group I) or their equivalent weights of pure powders, whilst, the duration of action, buffering capacity and total acid consumption was significantly suppressed with two dosage units of inderal, aspirin, and indocid (group II) or their equivalents of pure powder. However, antacid tested was still regulating gastric acid level within the comfort zone for a period of 70-110 min, and possessing (20.01-25.10 mEq/g) with group (II). These results are consistent with that obtained from acid neutralizing capacity test. The dissolution of magaldrate was pH dependent, with fast magnesium release and sustained aluminum hydroxide conversion. A significant (p 0.05) effect on that of group (I) was observed in the presence of different doses of antacid tested in all dissolution media. The presence of riopan suspension (20 ml) had a significant suppression on the release rates in all systems.

  15. Dissolution processes. [224 references

    Energy Technology Data Exchange (ETDEWEB)

    Silver, G.L.

    1976-10-22

    This review contains more than 100 observations and 224 references on the dissolution phenomenon. The dissolution processes are grouped into three categories: methods of aqueous attack, fusion methods, and miscellaneous observations on phenomena related to dissolution problems. (DLC)

  16. Biorelevant dissolution media

    DEFF Research Database (Denmark)

    Ilardia-Arana, David; Kristensen, Henning G; Müllertz, Anette

    2006-01-01

    Biorelevant dissolution media containing bile salt and lecithin at concentrations appropriate for fed and fasted state are useful when testing oral solid formulations of poorly water-soluble drugs. Dilution of amphiphile solutions affects the aggregation state of the amphiphiles because bile salt....... Dilution of the two- and four component media caused enlargement of the mixed micelles and formation of vesicles. The solubility of estradiol in the buffer solution was increased with addition of the amphiphiles. A good correlation (R(2) = 0.987) was found between estradiol solubility and mass...

  17. Rapid identification of mycobacteria and rapid detection of drug resistance in Mycobacterium tuberculosis in cultured isolates and in respiratory specimens.

    Science.gov (United States)

    Yam, Wing-Cheong; Siu, Kit-Hang Gilman

    2013-01-01

    Recent advances in molecular biology and better understanding of the genetic basis of drug resistance have allowed rapid identification of mycobacteria and rapid detection of drug resistance of Mycobacterium tuberculosis present in cultured isolates or in respiratory specimens. In this chapter, several simple nucleic acid amplification-based techniques are introduced as molecular approach for clinical diagnosis of tuberculosis. A one-tube nested IS6110-based polymerase chain reaction (PCR) is used for M. tuberculosis complex identification; the use of a multiplex allele-specific PCR is demonstrated to detect the isoniazid resistance; PCR-sequencing assays are applied for rifampicin and ofloxacin resistance detection and 16S rDNA sequencing is utilized for identification of mycobacterial species from cultures of acid fast bacilli (AFB). Despite the high specificity and sensitivity of the molecular techniques, mycobacterial culture remains the "Gold Standard" for tuberculosis diagnosis. Negative results of molecular tests never preclude the infection or the presence of drug resistance. These technological advancements are, therefore, not intended to replace the conventional tests, but rather have major complementary roles in tuberculosis diagnosis.

  18. Dissolution enhancement of tadalafil by liquisolid technique.

    Science.gov (United States)

    Lu, Mei; Xing, Haonan; Yang, Tianzhi; Yu, Jiankun; Yang, Zhen; Sun, Yanping; Ding, Pingtian

    2017-02-01

    This study aimed to enhance the dissolution of tadalafil, a poorly water-soluble drug by applying liquisolid technique. The effects of two critical formulation variables, namely drug concentration (17.5% and 35%, w/w) and excipients ratio (10, 15 and 20) on dissolution rates were investigated. Pre-compression tests, including particle size distribution, flowability determination, Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and scanning electron microscopy (SEM), were carried out to investigate the mechanism of dissolution enhancement. Tadalafil liquisolid tablets were prepared and their quality control tests, dissolution study, contact angle measurement, Raman mapping, and storage stability test were performed. The results suggested that all the liquisolid tablets exhibited significantly higher dissolution rates than the conventional tablets and pure tadalafil. FT-IR spectrum reflected no drug-excipient interactions. DSC and XRD studies indicated reduction in crystallinity of tadalafil, which was further confirmed by SEM and Raman mapping outcomes. The contact angle measurement demonstrated obvious increase in wetting property. Taken together, the reduction of particle size and crystallinity, and the improvement of wettability were the main mechanisms for the enhanced dissolution rate. No significant changes were observed in drug crystallinity and dissolution behavior after storage based on XRD, SEM and dissolution results.

  19. Mechanistic Basis of Cocrystal Dissolution Advantage.

    Science.gov (United States)

    Cao, Fengjuan; Amidon, Gordon L; Rodríguez-Hornedo, Naír; Amidon, Gregory E

    2018-01-01

    Current interest in cocrystal development resides in the advantages that the cocrystal may have in solubility and dissolution compared with the parent drug. This work provides a mechanistic analysis and comparison of the dissolution behavior of carbamazepine (CBZ) and its 2 cocrystals, carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) under the influence of pH and micellar solubilization. A simple mathematical equation is derived based on the mass transport analyses to describe the dissolution advantage of cocrystals. The dissolution advantage is the ratio of the cocrystal flux to drug flux and is defined as the solubility advantage (cocrystal to drug solubility ratio) times the diffusivity advantage (cocrystal to drug diffusivity ratio). In this work, the effective diffusivity of CBZ in the presence of surfactant was determined to be different and less than those of the cocrystals. The higher effective diffusivity of drug from the dissolved cocrystals, the diffusivity advantage, can impart a dissolution advantage to cocrystals with lower solubility than the parent drug while still maintaining thermodynamic stability. Dissolution conditions where cocrystals can display both thermodynamic stability and a dissolution advantage can be obtained from the mass transport models, and this information is useful for both cocrystal selection and formulation development. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  20. Real-time PCR using mycobacteriophage DNA for rapid phenotypic drug susceptibility results for Mycobacterium tuberculosis.

    Science.gov (United States)

    Pholwat, Suporn; Ehdaie, Beeta; Foongladda, Suporn; Kelly, Kimberly; Houpt, Eric

    2012-03-01

    Managing drug-resistant Mycobacterium tuberculosis requires drug susceptibility testing, yet conventional drug susceptibility testing is slow, and molecular testing does not yield results for all antituberculous drugs. We addressed these challenges by utilizing real-time PCR of mycobacteriophage D29 DNA to evaluate the drug resistance of clinical M. tuberculosis isolates. Mycobacteriophages infect and replicate in viable bacterial cells faster than bacterial cells replicate and have been used for detection and drug resistance testing for M. tuberculosis either by using reporter cells or phages with engineered reporter constructs. Our primary protocol involved culturing M. tuberculosis isolates for 48 h with and without drugs at critical concentrations, followed by incubation with 10(3) PFU/ml of D29 mycobacteriophage for 24 h and then real-time PCR. Many drugs could be incubated instantly with M. tuberculosis and phage for 24 h alone. The change in phage DNA real-time PCR cycle threshold (C(T)) between control M. tuberculosis and M. tuberculosis treated with drugs was calculated and correlated with conventional agar proportion drug susceptibility results. Specifically, 9 susceptible clinical isolates, 22 multidrug-resistant (MDR), and 1 extensively drug-resistant (XDR) M. tuberculosis strains were used and C(T) control-C(T) drug cutoffs of between +0.3 and -6.0 yielded 422/429 (98%) accurate results for isoniazid, rifampin, streptomycin, ethambutol, amikacin, kanamycin, capreomycin, ofloxacin, moxifloxacin, ethionamide, para-aminosalicylic acid, cycloserine, and linezolid. Moreover, the ΔC(T) values correlated with isolate MIC for most agents. This D29 quantitative PCR assay offers a rapid, accurate, 1- to 3-day phenotypic drug susceptibility test for first- and second-line drugs and may suggest an approximate MIC.

  1. [Phytobezoar dissolution with Coca-Cola].

    Science.gov (United States)

    Martínez de Juan, F; Martínez-Lapiedra, C; Picazo, V

    2006-05-01

    The treatment of phytobezoar is empiric. The various therapeutic choices include dietary modifications, prokinetic drugs, gastric lavage, enzymatic dissolution, endoscopic treatment, and surgery. We present two cases of phytobezoar with successful outcome after Coca-Cola administration.

  2. An In Vivo Platform for Rapid High-Throughput Antitubercular Drug Discovery

    Directory of Open Access Journals (Sweden)

    Kevin Takaki

    2012-07-01

    Full Text Available Treatment of tuberculosis, like other infectious diseases, is increasingly hindered by the emergence of drug resistance. Drug discovery efforts would be facilitated by facile screening tools that incorporate the complexities of human disease. Mycobacterium marinum-infected zebrafish larvae recapitulate key aspects of tuberculosis pathogenesis and drug treatment. Here, we develop a model for rapid in vivo drug screening using fluorescence-based methods for serial quantitative assessment of drug efficacy and toxicity. We provide proof-of-concept that both traditional bacterial-targeting antitubercular drugs and newly identified host-targeting drugs would be discovered through the use of this model. We demonstrate the model’s utility for the identification of synergistic combinations of antibacterial drugs and demonstrate synergy between bacterial- and host-targeting compounds. Thus, the platform can be used to identify new antibacterial agents and entirely new classes of drugs that thwart infection by targeting host pathways. The methods developed here should be widely applicable to small-molecule screens for other infectious and noninfectious diseases.

  3. Development and validation of dissolution test for Metoprolol ...

    African Journals Online (AJOL)

    GREGO

    2007-03-02

    Mar 2, 2007 ... gelatin capsules. The average fill weight of one capsule is. 169 mg. Dissolution test was conducted in USP XXV dissolution test apparatus type I with basket rotation at. 100 rpm. The dissolution medium was 900 ml 0.1 .... REFERENCES. Food and Drug Administration (2000). Draft Guidance for Industry on.

  4. Improving the dissolution properties of spironolactone using liquisolid technique

    Directory of Open Access Journals (Sweden)

    Jafar Akbari

    2015-09-01

    Full Text Available In this study the effect of liquisolid technique on the dissolution profile of spironolactone was evaluated. Different formulations of spironolactone liquisolid compacts were prepared using various amounts of non-volatile vehicles (Poly ethylene glycol 400 and glycerin. The ratio of microcrystalline cellulose (as carrier to silica (as coating powder material was 20 for all formulations. After preparing tablets by direct compression with constant compression load, the release profiles were evaluated by USP paddle method. Differential scanning calorimeter (DSC and FTIR were used to evaluate any interaction between spironolactone and other ingredients. The liquisolid tablets exhibited significantly higher dissolution rates in comparison with conventionally direct compressed tablets. Furthermore results showed dissolution rate enhancement of liquisolid tablets by increase in the amounts of non-volatile vehicles. Differential scanning calorimetry showed that, the drug has got solubilized in the liquid vehicle. FT-IR spectroscopy studies of pure spironolactone, liquisolid compacts, glycerin and PEG400 supported solubilization of the drug in the liquid vehicle too. The FT-IR spectra also showed that no interactions have been occurred between spironolactone and other ingredients. In conclusion the liquisolid technique can be a suitable method in order to prepare rapid release tablets of poorly water-soluble drugs such as spironolactone.

  5. Rapid identification of antifungal compounds against Exserohilum rostratum using high throughput drug repurposing screens.

    Science.gov (United States)

    Sun, Wei; Park, Yoon-Dong; Sugui, Janyce A; Fothergill, Annette; Southall, Noel; Shinn, Paul; McKew, John C; Kwon-Chung, Kyung J; Zheng, Wei; Williamson, Peter R

    2013-01-01

    A recent large outbreak of fungal infections by Exserohilum rostratum from contaminated compounding solutions has highlighted the need to rapidly screen available pharmaceuticals that could be useful in therapy. The present study utilized two newly-developed high throughput assays to screen approved drugs and pharmaceutically active compounds for identification of potential antifungal agents. Several known drugs were found that have potent effects against E. rostratum including the triazole antifungal posaconazole. Posaconazole is likely to be effective against infections involving septic joints and may provide an alternative for refractory central nervous system infections. The anti-E. rostratum activities of several other drugs including bithionol (an anti-parasitic drug), tacrolimus (an immunosuppressive agent) and floxuridine (an antimetabolite) were also identified from the drug repurposing screens. In addition, activities of other potential antifungal agents against E. rostratum were excluded, which may avoid unnecessary therapeutic trials and reveals the limited therapeutic alternatives for this outbreak. In summary, this study has demonstrated that drug repurposing screens can be quickly conducted within a useful time-frame. This would allow clinical implementation of identified alternative therapeutics and should be considered as part of the initial public health response to new outbreaks or rapidly-emerging microbial pathogens.

  6. Rapid identification of antifungal compounds against Exserohilum rostratum using high throughput drug repurposing screens.

    Directory of Open Access Journals (Sweden)

    Wei Sun

    Full Text Available A recent large outbreak of fungal infections by Exserohilum rostratum from contaminated compounding solutions has highlighted the need to rapidly screen available pharmaceuticals that could be useful in therapy. The present study utilized two newly-developed high throughput assays to screen approved drugs and pharmaceutically active compounds for identification of potential antifungal agents. Several known drugs were found that have potent effects against E. rostratum including the triazole antifungal posaconazole. Posaconazole is likely to be effective against infections involving septic joints and may provide an alternative for refractory central nervous system infections. The anti-E. rostratum activities of several other drugs including bithionol (an anti-parasitic drug, tacrolimus (an immunosuppressive agent and floxuridine (an antimetabolite were also identified from the drug repurposing screens. In addition, activities of other potential antifungal agents against E. rostratum were excluded, which may avoid unnecessary therapeutic trials and reveals the limited therapeutic alternatives for this outbreak. In summary, this study has demonstrated that drug repurposing screens can be quickly conducted within a useful time-frame. This would allow clinical implementation of identified alternative therapeutics and should be considered as part of the initial public health response to new outbreaks or rapidly-emerging microbial pathogens.

  7. Use of refractometry and colorimetry as field methods to rapidly assess antimalarial drug quality.

    Science.gov (United States)

    Green, Michael D; Nettey, Henry; Villalva Rojas, Ofelia; Pamanivong, Chansapha; Khounsaknalath, Lamphet; Grande Ortiz, Miguel; Newton, Paul N; Fernández, Facundo M; Vongsack, Latsamy; Manolin, Ot

    2007-01-04

    The proliferation of counterfeit and poor-quality drugs is a major public health problem; especially in developing countries lacking adequate resources to effectively monitor their prevalence. Simple and affordable field methods provide a practical means of rapidly monitoring drug quality in circumstances where more advanced techniques are not available. Therefore, we have evaluated refractometry, colorimetry and a technique combining both processes as simple and accurate field assays to rapidly test the quality of the commonly available antimalarial drugs; artesunate, chloroquine, quinine, and sulfadoxine. Method bias, sensitivity, specificity and accuracy relative to high-performance liquid chromatographic (HPLC) analysis of drugs collected in the Lao PDR were assessed for each technique. The HPLC method for each drug was evaluated in terms of assay variability and accuracy. The accuracy of the combined method ranged from 0.96 to 1.00 for artesunate tablets, chloroquine injectables, quinine capsules, and sulfadoxine tablets while the accuracy was 0.78 for enterically coated chloroquine tablets. These techniques provide a generally accurate, yet simple and affordable means to assess drug quality in resource-poor settings.

  8. A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaoguang [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Department of Medical Microbiology, Harbin Medical University, Harbin 150086 (China); Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 (Japan); Qian, Hua [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 (Japan); Miyamoto, Fusako [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Naito, Takeshi [Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Kawaji, Kumi [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Kajiwara, Kazumi [Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); JST Innovation Plaza Kyoto, Japan Science and Technology Agency, Nishigyo-ku, Kyoto 615-8245 (Japan); Hattori, Toshio [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Matsuoka, Masao [Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Watanabe, Kentaro; Oishi, Shinya; Fujii, Nobutaka [Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); and others

    2012-07-27

    Highlights: Black-Right-Pointing-Pointer We established a novel, simple and rapid in vivo system for evaluation of anti-HIV-1 drugs with rats. Black-Right-Pointing-Pointer The system may be applicable for other antiviral drugs, and/or useful for initial screening in vivo. Black-Right-Pointing-Pointer In this system, TRI-1144 displayed the most potent anti-HIV-1 activity in vivo. -- Abstract: The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1{sub IIIB} and HIV-1{sub BaL} as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1{sub IIIB} activity, whereas fusion inhibitors showed both anti-HIV-1{sub IIIB} and anti-HIV-1{sub BaL} activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, 'phenotypic drug evaluation', may be applicable for the evaluation of various antiviral drugs in vivo.

  9. TranScreen-N: Method for rapid screening of trans-ungual drug delivery enhancers.

    Science.gov (United States)

    Murthy, S Narasimha; Vaka, Siva Ram Kiran; Sammeta, Srinivasa Murthy; Nair, Anroop B

    2009-11-01

    Topical monotherapy of nail diseases such as onychomycosis and nail psoriasis has been less successful due to poor permeability of the human nail plate to topically administered drugs. Chemical enhancers are utilized to improve the drug delivery across the nail plate. Choosing the most effective chemical enhancers for the given drug and formulation is highly critical in determining the efficacy of topical therapy of nail diseases. Screening the large pool of enhancers using currently followed diffusion cell experiments would be tedious and expensive. The main objective of this study is to develop TranScreen-N, a high throughput method of screening trans-ungual drug permeation enhancers. It is a rapid microwell plate based method which involves two different treatment procedures; the simultaneous exposure treatment and the sequential exposure treatment. In the present study, several chemicals were evaluated by TranScreen-N and by diffusion studies in the Franz diffusion cell (FDC). Good agreement of in vitro drug delivery data with TranScreen-N data provided validity to the screening technique. In TranScreen-N technique, the enhancers can be grouped according to whether they need to be applied before or simultaneously with drugs (or by either procedures) to enhance the drug delivery across the nail plate. TranScreen-N technique can significantly reduce the cost and duration required to screen trans-ungual drug delivery enhancers. (c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association

  10. The Influence of Drug Physical State on the Dissolution Enhancement of Solid Dispersions Prepared Via Hot-Melt Extrusion: A Case Study Using Olanzapine

    Science.gov (United States)

    Pina, Maria Fátima; Zhao, Min; Pinto, João F; Sousa, João J; Craig, Duncan Q M

    2014-01-01

    In this study, we examine the relationship between the physical structure and dissolution behavior of olanzapine (OLZ) prepared via hot-melt extrusion in three polymers [polyvinylpyrrolidone (PVP) K30, polyvinylpyrrolidone-co-vinyl acetate (PVPVA) 6:4, and Soluplus® (SLP)]. In particular, we examine whether full amorphicity is necessary to achieve a favorable dissolution profile. Drug–polymer miscibility was estimated using melting point depression and Hansen solubility parameters. Solid dispersions were characterized using differential scanning calorimetry, X-ray powder diffraction, and scanning electron microscopy. All the polymers were found to be miscible with OLZ in a decreasing order of PVP>PVPVA>SLP. At a lower extrusion temperature (160°C), PVP generated fully amorphous dispersions with OLZ, whereas the formulations with PVPVA and SLP contained 14%–16% crystalline OLZ. Increasing the extrusion temperature to 180°C allowed the preparation of fully amorphous systems with PVPVA and SLP. Despite these differences, the dissolution rates of these preparations were comparable, with PVP showing a lower release rate despite being fully amorphous. These findings suggested that, at least in the particular case of OLZ, the absence of crystalline material may not be critical to the dissolution performance. We suggest alternative key factors determining dissolution, particularly the dissolution behavior of the polymers themselves. PMID:24765654

  11. Introducing rapid diagnostic tests for malaria into registered drug shops in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Clarke, Sîan E; Lal, Sham

    2015-01-01

    BACKGROUND: Malaria is a major public health problem in Uganda and the current policy recommends introduction of rapid diagnostic tests for malaria (RDTs) to facilitate effective case management. However, provision of RDTs in drug shops potentially raises a new set of issues, such as adherence...... to RDTs results, management of severe illnesses, referral of patients, and relationship with caretakers. The main objective of the study was to examine the impact of introducing RDTs in registered drug shops in Uganda and document lessons and policy implications for future scale-up of malaria control...... in the private health sector. METHODS: A cluster-randomized trial introducing RDTs into registered drug shops was implemented in central Uganda from October 2010 to July 2012. An evaluation was undertaken to assess the impact and the processes involved with the introduction of RDTs into drug shops, the lessons...

  12. Rapid characterization of the biomechanical properties of drug-treated cells in a microfluidic device

    Science.gov (United States)

    Zhang, Xiaofei; Chu, Henry K.; Zhang, Yang; Bai, Guohua; Wang, Kaiqun; Tan, Qiulin; Sun, Dong

    2015-10-01

    Cell mechanics is closely related to many cell functions. Recent studies have suggested that the deformability of cells can be an effective biomarker to indicate the onset and progression of diseases. In this paper, a microfluidic chip is designed for rapid characterization of the mechanics of drug-treated cells through stretching with dielectrophoresis (DEP) force. This chip was fabricated using PDMS and micro-electrodes were integrated and patterned on the ITO layer of the chip. Leukemia NB4 cells were considered and the effect of all-trans retinoic acid (ATRA) drug on NB4 cells were examined via the microfluidic chip. To induce a DEP force onto the cell, a relatively weak ac voltage was utilized to immobilize a cell at one side of the electrodes. The applied voltage was then increased to 3.5 V pp and the cell started to be stretched along the applied electric field lines. The elongation of the cell was observed using an optical microscope and the results showed that both types of cells were deformed by the induced DEP force. The strain of the NB4 cell without the drug treatment was recorded to be about 0.08 (time t = 180 s) and the drug-treated NB4 cell was about 0.21 (time t = 180 s), indicating a decrease in the stiffness after drug treatment. The elastic modulus of the cell was also evaluated and the modulus changed from 140 Pa to 41 Pa after drug treatment. This microfluidic chip can provide a simple and rapid platform for measuring the change in the biomechanical properties of cells and can potentially be used as the tool to determine the biomechanical effects of different drug treatments for drug discovery and development applications.

  13. A Microfluidic Channel Method for Rapid Drug-Susceptibility Testing of Pseudomonas aeruginosa

    Science.gov (United States)

    Matsumoto, Yoshimi; Grushnikov, Andrey; Kikuchi, Kazuma; Noji, Hiroyuki; Yamaguchi, Akihito; Yagi, Yasushi

    2016-01-01

    The recent global increase in the prevalence of antibiotic-resistant bacteria and lack of development of new therapeutic agents emphasize the importance of selecting appropriate antimicrobials for the treatment of infections. However, to date, the development of completely accelerated drug susceptibility testing methods has not been achieved despite the availability of a rapid identification method. We proposed an innovative rapid method for drug susceptibility testing for Pseudomonas aeruginosa that provides results within 3 h. The drug susceptibility testing microfluidic (DSTM) device was prepared using soft lithography. It consisted of five sets of four microfluidic channels sharing one inlet slot, and the four channels are gathered in a small area, permitting simultaneous microscopic observation. Antimicrobials were pre-introduced into each channel and dried before use. Bacterial suspensions in cation-adjusted Mueller–Hinton broth were introduced from the inlet slot and incubated for 3 h. Susceptibilities were microscopically evaluated on the basis of differences in cell numbers and shapes between drug-treated and control cells, using dedicated software. The results of 101 clinically isolated strains of P. aeruginosa obtained using the DSTM method strongly correlated with results obtained using the ordinary microbroth dilution method. Ciprofloxacin, meropenem, ceftazidime, and piperacillin caused elongation in susceptible cells, while meropenem also induced spheroplast and bulge formation. Morphological observation could alternatively be used to determine the susceptibility of P. aeruginosa to these drugs, although amikacin had little effect on cell shape. The rapid determination of bacterial drug susceptibility using the DSTM method could also be applicable to other pathogenic species, and it could easily be introduced into clinical laboratories without the need for expensive instrumentation. PMID:26872134

  14. A Microfluidic Channel Method for Rapid Drug-Susceptibility Testing of Pseudomonas aeruginosa.

    Directory of Open Access Journals (Sweden)

    Yoshimi Matsumoto

    Full Text Available The recent global increase in the prevalence of antibiotic-resistant bacteria and lack of development of new therapeutic agents emphasize the importance of selecting appropriate antimicrobials for the treatment of infections. However, to date, the development of completely accelerated drug susceptibility testing methods has not been achieved despite the availability of a rapid identification method. We proposed an innovative rapid method for drug susceptibility testing for Pseudomonas aeruginosa that provides results within 3 h. The drug susceptibility testing microfluidic (DSTM device was prepared using soft lithography. It consisted of five sets of four microfluidic channels sharing one inlet slot, and the four channels are gathered in a small area, permitting simultaneous microscopic observation. Antimicrobials were pre-introduced into each channel and dried before use. Bacterial suspensions in cation-adjusted Mueller-Hinton broth were introduced from the inlet slot and incubated for 3 h. Susceptibilities were microscopically evaluated on the basis of differences in cell numbers and shapes between drug-treated and control cells, using dedicated software. The results of 101 clinically isolated strains of P. aeruginosa obtained using the DSTM method strongly correlated with results obtained using the ordinary microbroth dilution method. Ciprofloxacin, meropenem, ceftazidime, and piperacillin caused elongation in susceptible cells, while meropenem also induced spheroplast and bulge formation. Morphological observation could alternatively be used to determine the susceptibility of P. aeruginosa to these drugs, although amikacin had little effect on cell shape. The rapid determination of bacterial drug susceptibility using the DSTM method could also be applicable to other pathogenic species, and it could easily be introduced into clinical laboratories without the need for expensive instrumentation.

  15. Modeling dissolution of sparingly soluble multisized powders.

    Science.gov (United States)

    de Almeida, L P; Simöes, S; Brito, P; Portugal, A; Figueiredo, M

    1997-06-01

    The dissolution of powder drugs, besides being a topic of utmost importance, especially for the sparingly soluble ones, is far from being well-explained. The purpose of the present study is, on the one hand, to obtain experimental dissolution profiles and, on the other hand, to analyze and process the data for dissolution modeling. Three different size fractions of a widely used sparingly soluble drug--ibuprofen--were fully characterized with regard to its particle size distribution, specific surface area, density, solubility, and diffusion coefficient. The dissolution profiles were obtained making use of a technique that counts and sizes particles--the Coulter counter technique--which is capable of following the number and size of the particles in suspension throughout time. The knowledge of these parameters allowed a critical study of the assumptions associated with the models currently used to describe the dissolution process. It was concluded that most of the assumptions were not valid for the present experimental conditions. This motivated the proposal of a new methodology, which uses the experimentally determined characteristics of the drug and takes into account the polydisperse nature of the powder. By applying an adequate dissolution equation to each of the many size classes in which the primary particle size distribution was divided, it was possible to obtain a large agreement between the simulated and the experimental dissolution profile.

  16. Chitosan and chitosan chlorhydrate based various approaches for enhancement of dissolution rate of carvedilol

    Directory of Open Access Journals (Sweden)

    Shete Amol S

    2012-12-01

    Full Text Available Abstract Background and the purpose of the study Carvedilol nonselective β-adrenoreceptor blocker, chemically (±-1-(Carbazol-4-yloxy-3-[[2-(o-methoxypHenoxy ethyl] amino]-2-propanol, slightly soluble in ethyl ether; and practically insoluble in water, gastric fluid (simulated, TS, pH 1.1, and intestinal fluid (simulated, TS without pancreatin, pH 7.5 Compounds with aqueous solubility less than 1% W/V often represents dissolution rate limited absorption. There is need to enhance the dissolution rate of carvedilol. The objective of our present investigation was to compare chitosan and chitosan chlorhydrate based various approaches for enhancement of dissolution rate of carvedilol. Methods The different formulations were prepared by different methods like solvent change approach to prepare hydrosols, solvent evaporation technique to form solid dispersions and cogrind mixtures. The prepared formulations were characterized in terms of saturation solubility, drug content, infrared spectroscopy (FTIR, differential scanning calorimetry (DSC, powder X-ray diffraction (PXRD, electron microscopy, in vitro dissolution studies and stability studies. Results The practical yield in case of hydrosols was ranged from 59.76 to 92.32%. The drug content was found to uniform among the different batches of hydrosols, cogrind mixture and solid dispersions ranged from 98.24 to 99.89%. There was significant improvement in dissolution rate of carvedilol with chitosan chlorhdyrate as compare to chitosan and explanation to this behavior was found in the differences in the wetting, solubilities and swelling capacity of the chitosan and chitosan salts, chitosan chlorhydrate rapidly wet and dissolve upon its incorporation into the dissolution medium, whereas the chitosan base, less water soluble, would take more time to dissolve. Conclusion This technique is scalable and valuable in manufacturing process in future for enhancement of dissolution of poorly water soluble

  17. Introducing rapid diagnostic tests for malaria into drug shops in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Magnussen, Pascal; Chandler, Clare Ir

    2014-01-01

    BACKGROUND: An intervention was designed to introduce rapid diagnostics tests for malaria (mRDTs) into registered drug shops in Uganda to encourage rational and appropriate treatment of malaria with artemisinin-based combination therapy (ACT). We conducted participatory training of drug shop...... through a cluster randomized trial. In this paper, we present detailed design, implementation and evaluation experiences in order to help inform future studies of a complex nature. METHODS: Three preparatory studies (formative, baseline and willingness-to-pay) were conducted to explore perceptions...

  18. Rapid detoxification of benzodiazepine or Z-drugs dependence using acetylcholinesterase inhibitors.

    Science.gov (United States)

    Lin, Shih-Ku

    2014-07-01

    Dependence on benzodiazepines (BZDs) or Z-drugs (zolpidem, zopicline and zaleplon) is a common clinical phenomenon. Traditional detoxification of BZDs dependence includes tapering used dose gradually and using equivalent doses of long-acting BZDs as substitutes. This kind of regimen tends to take a long time (up to 4weeks) and may require hospitalization. Acetylcholinesterase inhibitors have been shown to reverse BZDs induced sedation. We propose that oral form acetylcholinesterase inhibitors (donepezil, galantamine and rivastigmine) also posses the effect of inhibiting GABA receptors, and act as indirect antagonist, to be applied in the rapid detoxification treatment of BZDs and Z-drug dependence. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Studies of second phase particles in different zirconium alloys using extractive carbon replica and an electrolytic anodic dissolution procedure [rapid communication

    Science.gov (United States)

    Toffolon-Masclet, Caroline; Brachet, Jean-Christophe; Jago, Gilles

    2002-10-01

    Zirconium alloys are widely studied for applications as cladding tubes and structural components of PWR fuel assemblies. Due to their influence on some of the alloys properties (corrosion resistance, irradiation growth, …), the crystallographic structure and the chemical stoichiometry of the second phase particles (SPP) precipitated in these alloys have to be well established. The aim of this paper is to present the results obtained using two methods of SPP extractions. The first one, the extractive carbon replica method, allowed us to determine the chemical composition of SPP in different zirconium alloys: Zr-Sn-Fe-Cr (Zircaloy-4 ®), Zr-Sn-Fe-Cr-(V,Mo), Zr-Nb and Zr-Nb-Fe alloys. The second one, an anodic dissolution procedure of the matrix, is an interesting way of isolating SPP from the surrounding α-Zr matrix, giving access to a precise determination of the crystallographic structure and lattice parameters of the SPP by X-ray diffraction. This procedure was validated for Zy-4 by comparing the SPP size distribution obtained by extraction with that directly measured on a massive Zy-4 alloy (i.e. the SPP size distributions were the same for both measurements).

  20. Feasibility Study of Carbon Nanotube Microneedles for Rapid Transdermal Drug Delivery

    OpenAIRE

    Lyon, Bradley J.; Aria, Adrianus I.; Gharib, Morteza

    2013-01-01

    We introduce a new approach for fabricating hollow microneedles using vertically-aligned carbon nanotubes (VA-CNTs) for rapid transdermal drug delivery. Here, we discuss the fabrication of the microneedles emphasizing the overall simplicity and flexibility of the method to allow for potential industrial application. By capitalizing on the nanoporosity of the CNT bundles, uncured polymer can be wicked into the needles ultimately creating a high strength composite of aligned nanotubes and polym...

  1. Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences

    KAUST Repository

    Coll, Francesc

    2015-05-27

    Mycobacterium tuberculosis drug resistance (DR) challenges effective tuberculosis disease control. Current molecular tests examine limited numbers of mutations, and although whole genome sequencing approaches could fully characterise DR, data complexity has restricted their clinical application. A library (1,325 mutations) predictive of DR for 15 anti-tuberculosis drugs was compiled and validated for 11 of them using genomic-phenotypic data from 792 strains. A rapid online ‘TB-Profiler’ tool was developed to report DR and strain-type profiles directly from raw sequences. Using our DR mutation library, in silico diagnostic accuracy was superior to some commercial diagnostics and alternative databases. The library will facilitate sequence-based drug-susceptibility testing.

  2. The influence of thermal treatment and type of insoluble poly(meth)acrylates on dissolution behavior of very soluble drug from hypromellose matrix tablets evaluated by multivariate data analysis.

    Science.gov (United States)

    Kubova, Katerina; Peček, Daniel; Hasserová, Kristýna; Doležel, Petr; Pavelková, Miroslava; Vyslouzil, Jakub; Muselík, Jan; Vetchy, David

    2017-03-01

    Hypromellose matrices exhibit extended burst effect immediately after contact with aqueous medium, especially when a water-soluble drug is incorporated. The objective of this study was to reduce burst effect and maintain complete dissolution of a very soluble levetiracetam over 12 h period from hypromellose K4M matrices to obtain zero-order kinetics. Desired changes were achieved by applying water dispersions of insoluble Eudragits(®) (NE, NM, RL, RS) as a granulation liquid to the drug/microcrystalline cellulose mixture during high-shear granulation (non-thermal treated set) and consequently by thermally treating granules or final tablets (TT), respectively. Applying Eudragit(®) water dispersions to the drug/microcrystalline cellulose mixture was recognized as an effective method of significantly reducing the burst release (25.4-33.7%) of levetiracetam in comparison with a reference sample without Eudragit(®). Multivariate data analysis showed that the addition of Eudragit(®) reduced burst effect, increased fitting with zero-order kinetics, and supported matrix erosion as the supplementary mechanism to predominant diffusion. Moreover, resulting PCA sub-model revealed the addition of Eudragit(®) RL and thermal treatment of tablets to be the most suitable method of all. For a 12 h dissolution profile, characterized by low burst effect and drug release close to 100% at the 12th hour, sample RL_TT was the most suitable.

  3. Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection.

    Directory of Open Access Journals (Sweden)

    Tianyu Zhang

    Full Text Available Buruli ulcer (BU caused by Mycobacterium ulcerans is the world's third most common mycobacterial infection. There is no vaccine against BU and surgery is needed for patients with large ulcers. Although recent experience indicates combination chemotherapy with streptomycin and rifampin improves cure rates, the utility of this regimen is limited by the 2-month duration of therapy, potential toxicity and required parenteral administration of streptomycin, and drug-drug interactions caused by rifampin. Discovery and development of drugs for BU is greatly hampered by the slow growth rate of M. ulcerans, requiring up to 3 months of incubation on solid media to produce colonies. Surrogate markers for evaluating antimicrobial activity in real-time which can be measured serially and non-invasively in infected footpads of live mice would accelerate pre-clinical evaluation of new drugs to treat BU. Previously, we developed bioluminescent M. ulcerans strains, demonstrating proof of concept for measuring luminescence as a surrogate marker for viable M. ulcerans in vitro and in vivo. However, the requirement of exogenous substrate limited the utility of such strains, especially for in vivo experiments.For this study, we engineered M. ulcerans strains that express the entire luxCDABE operon and therefore are autoluminescent due to endogenous substrate production. The selected reporter strain displayed a growth rate and virulence similar to the wild-type parent strain and enabled rapid, real-time monitoring of in vitro and in vivo drug activity, including serial, non-invasive assessments in live mice, producing results which correlated closely with colony-forming unit (CFU counts for a panel of drugs with various mechanisms of action.Our results indicate that autoluminescent reporter strains of M. ulcerans are exceptional tools for pre-clinical evaluation of new drugs to treat BU due to their potential to drastically reduce the time, effort, animals, compound

  4. Rapid Identification of Potential Drugs for Diabetic Nephropathy Using Whole-Genome Expression Profiles of Glomeruli

    Directory of Open Access Journals (Sweden)

    Jingsong Shi

    2016-01-01

    Full Text Available Objective. To investigate potential drugs for diabetic nephropathy (DN using whole-genome expression profiles and the Connectivity Map (CMAP. Methodology. Eighteen Chinese Han DN patients and six normal controls were included in this study. Whole-genome expression profiles of microdissected glomeruli were measured using the Affymetrix human U133 plus 2.0 chip. Differentially expressed genes (DEGs between late stage and early stage DN samples and the CMAP database were used to identify potential drugs for DN using bioinformatics methods. Results. (1 A total of 1065 DEGs (FDR 1.5 were found in late stage DN patients compared with early stage DN patients. (2 Piperlongumine, 15d-PGJ2 (15-delta prostaglandin J2, vorinostat, and trichostatin A were predicted to be the most promising potential drugs for DN, acting as NF-κB inhibitors, histone deacetylase inhibitors (HDACIs, PI3K pathway inhibitors, or PPARγ agonists, respectively. Conclusion. Using whole-genome expression profiles and the CMAP database, we rapidly predicted potential DN drugs, and therapeutic potential was confirmed by previously published studies. Animal experiments and clinical trials are needed to confirm both the safety and efficacy of these drugs in the treatment of DN.

  5. Melanin binding study of clinical drugs with cassette dosing and rapid equilibrium dialysis inserts.

    Science.gov (United States)

    Pelkonen, Laura; Tengvall-Unadike, Unni; Ruponen, Marika; Kidron, Heidi; Del Amo, Eva M; Reinisalo, Mika; Urtti, Arto

    2017-11-15

    Melanin pigment is a negatively charged polymer found in pigmented human tissues. In the eye, iris, ciliary body, choroid and retinal pigment epithelium (RPE) are heavily pigmented. Several drug molecules are known to bind to melanin, but larger sets of drugs have not been compared often in similar test conditions. In this study, we introduce a powerful tool for screening of melanin binding. The binding of a set of 34 compounds to isolated porcine RPE melanin was determined by cassette (n-in-one) dosing in rapid equilibrium dialysis inserts and the binding was quantitated with LC-MS/MS analytics. The compounds represented large variety in melanin binding (from 8.6%, ganciclovir) to over 95% bound (ampicillin and ciprofloxacin). The data provides information on melanin binding of small molecular weight compounds that are used for ocular (e.g. brinzolamide, ganciclovir) and systemic (e.g. tizanidine, indomethacin) therapy. Interestingly, competition among compounds was seen for melanin binding and the binding did not show any correlation with plasma protein binding. These results increase the understanding of melanin binding of ocular drugs and can be further exploited to predict pharmacokinetics in the eye. Pigment binding provides an interesting option for improved drug distribution to retina and choroid that are difficult target tissues in drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Dissolution rate enhancement of repaglinide by solid dispersion

    African Journals Online (AJOL)

    solvency are some of the approaches to improve the dissolution rate of the drugs [3]. Solid dispersion (SD) is one of the most widely used techniques to improve solubility as well as dissolution rate of poorly water soluble drugs. This method involves a ...

  7. Rapid identification of a Mycobacterium tuberculosis full genetic drug resistance profile through whole genome sequencing directly from sputum

    Directory of Open Access Journals (Sweden)

    Camus Nimmo

    2017-09-01

    Discussion: Compared to rapid molecular tests (which can only examine a limited number of mutations and WGS of culture isolates (which requires a culture step, WGS directly from sputum can quickly generate a complete genetic drug resistance profile. In this case, WGS altered the clinical management of drug-resistant tuberculosis and demonstrated potential for guiding individualized drug treatment where second-line drug resistance is common.

  8. A Platform for Rapid, Quantitative Assessment of Multiple Drug Combinations Simultaneously in Solid Tumors In Vivo.

    Directory of Open Access Journals (Sweden)

    Joyoti Dey

    Full Text Available While advances in high-throughput screening have resulted in increased ability to identify synergistic anti-cancer drug combinations, validation of drug synergy in the in vivo setting and prioritization of combinations for clinical development remain low-throughput and resource intensive. Furthermore, there is currently no viable method for prospectively assessing drug synergy directly in human patients in order to potentially tailor therapies. To address these issues we have employed the previously described CIVO platform and developed a quantitative approach for investigating multiple combination hypotheses simultaneously in single living tumors. This platform provides a rapid, quantitative and cost effective approach to compare and prioritize drug combinations based on evidence of synergistic tumor cell killing in the live tumor context. Using a gemcitabine resistant model of pancreatic cancer, we efficiently investigated nine rationally selected Abraxane-based combinations employing only 19 xenografted mice. Among the drugs tested, the BCL2/BCLxL inhibitor ABT-263 was identified as the one agent that synergized with Abraxane® to enhance acute induction of localized apoptosis in this model of human pancreatic cancer. Importantly, results obtained with CIVO accurately predicted the outcome of systemic dosing studies in the same model where superior tumor regression induced by the Abraxane/ABT-263 combination was observed compared to that induced by either single agent. This supports expanded use of CIVO as an in vivo platform for expedited in vivo drug combination validation and sets the stage for performing toxicity-sparing drug combination studies directly in cancer patients with solid malignancies.

  9. Selective aluminum dissolution as a means to observe the microstructure of nanocrystalline intermetallic phases from Al-Fe-Cr-Ti-Ce rapidly solidified alloy.

    Science.gov (United States)

    Michalcová, Alena; Vojtěch, Dalibor; Novák, Pavel

    2013-02-01

    Rapidly solidified aluminum alloys are promising materials with very fine microstructure. The microscopy observation of these materials is complicated due to overlay of fcc-Al matrix and different intermetallic phases. A possible way to solve this problem is to dissolve the Al matrix. By this process powder formed by single intermetallic phase particles is obtained. In this paper a new aqueous based dissolving agent for Al-based alloy is presented. The influence of oxidation agent (FeCl(3)) concentration on quality of extraction process was studied. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Systematic review of the performance of rapid rifampicin resistance testing for drug-resistant tuberculosis.

    Directory of Open Access Journals (Sweden)

    Matthew Arentz

    Full Text Available INTRODUCTION: Rapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB. However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid tests for rifampicin resistance detection. METHODS: We searched MEDLINE, Embase and the Cochrane Library through January 1, 2012. For each rapid test, we determined pooled sensitivity and specificity estimates using a hierarchical random effects model. Predictive values of the tests were determined at different prevalence rates of rifampicin resistance and MDR-TB. RESULTS: We identified 60 publications involving six different tests (INNO-LiPA Rif. TB assay, Genotype MTBDR assay, Genotype MTBDRplus assay, Colorimetric Redox Indicator (CRI assay, Nitrate Reductase Assay (NRA and MODS tests: for all tests, negative predictive values were high when rifampicin resistance prevalence was ≤ 30%. However, positive predictive values were considerably reduced for the INNO-LiPA Rif. TB assay, the MTBDRplus assay and MODS when rifampicin resistance prevalence was < 5%. LIMITATIONS: In many studies, it was unclear whether patient selection or index test performance could have introduced bias. In addition, we were unable to evaluate critical concentration thresholds for the colorimetric tests. DISCUSSION: Rapid tests for rifampicin resistance alone cannot accurately predict rifampicin resistance or MDR-TB in areas with a low prevalence of rifampicin resistance. However, in areas with a high prevalence of rifampicin resistance and MDR-TB, these tests may be a valuable component of an MDR-TB management strategy.

  11. Rapidly Progrediating Aortic Valve Infective Endocarditis in an Intravenous Drug User Treated by Antibiotics and Surgery

    Directory of Open Access Journals (Sweden)

    Malkia S. Swedi

    2012-01-01

    Full Text Available We report the case of a 22-year old male, a self-confessed recreational drug user who developed cardiogenic shock because of severe destruction of the aortic valve by rapidly progressive aortic valve endocarditis. The disease progression was acute; in a matter of days, the clinical manifestations were life-threatening necessitating urgent aortic valve replacement surgery. Cultivation revealed Streptococcus viridans as the microbial agent. Subsequent recovery with antibiotic treatment was without complication. This case report shows that immediately performed transoesophageal echocardiography and early consultation with a cardiac surgeon has fundamental importance in diagnosis and management of acute infective endocarditis in haemodynamically instable patients.

  12. Influence of dissolution media pH and USP1 basket speed on erosion and disintegration characteristics of immediate release metformin hydrochloride tablets.

    Science.gov (United States)

    Desai, Divyakant; Wong, Benjamin; Huang, Yande; Tang, Dan; Hemenway, Jeffrey; Paruchuri, Srinivasa; Guo, Hang; Hsieh, Daniel; Timmins, Peter

    2015-01-01

    To investigate the influence of the pH of the dissolution medium on immediate release 850 mg metformin hydrochloride tablets. A traditional wet granulation method was used to manufacture metformin hydrochloride tablets with or without a disintegrant. Tablet dissolution was conducted using the USP apparatus I at 100 rpm. In spite of its pH-independent high solubility, metformin hydrochloride tablets dissolved significantly slower in 0.1 N HCl (pH 1.2) and 50 mM pH 4.5 acetate buffer compared with 50 mM pH 6.8 phosphate buffer, the dissolution medium in the USP. Metformin hydrochloride API compressed into a round 1200 mg disk showed a similar trend. When basket rotation speed was increased from 100 to 250 rpm, the dissolution of metformin hydrochloride tablets was similar in all three media. Incorporation of 2% w/w crospovidone in the tablet formulation improved the dissolution although the pH-dependent trend was still evident, but incorporation of 2% w/w croscarmellose sodium resulted in rapid pH-independent tablet dissolution. In absence of a disintegrant in the tablet formulation, the dissolution was governed by the erosion-diffusion process. Even for a highly soluble drug, a super-disintegrant was needed in the formulation to overcome the diffusion layer limitation and change the dissolution mechanism from erosion-diffusion to disintegration.

  13. Development and Validation of a Rapid Turbidimetric Assay to Determine the Potency of Cefuroxime Sodium in Powder for Dissolution for Injection

    Directory of Open Access Journals (Sweden)

    Daniela C. M. Vieira

    2014-07-01

    Full Text Available The cefuroxime sodium is a second generation cephalosporin indicated for infections caused by Gram-positive and Gram-negative microorganisms. Although this drug is highly studied and researched regarding the antimicrobial activity, pharmacokinetics and pharmacodynamics, there are few studies regarding the development of analytical methodology for this cephalosporin. Thus, research involving analytical methods is essential and highly relevant to optimize its analysis in the pharmaceutical industry and guarantee the quality of the product already sold. This study describes the development and validation of a microbiological assay applying the turbidimetric method for the determination of cefuroxime, using Micrococcus luteus ATCC 9341 as micro-organism test and 3x3 parallel line assay design, with nine tubes for each assay, as recommended by the Brazilian Pharmacopoeia. The developed and validated method showed excellent results of linearity, seletivity, precision and robustness, in the concentration range from 30.0 to 120.0 mg/mL, with 100.21% accuracy and content 99.97% to cefuroxime sodium in injectable pharmaceutical form.

  14. Monitoring Lidocaine Single-Crystal Dissolution by Ultraviolet Imaging

    DEFF Research Database (Denmark)

    Ostergaard, Jesper; Ye, Fengbin; Rantanen, Jukka

    2011-01-01

    ) imaging for conducting single‐crystal dissolution studies was performed. Using lidocaine as a model compound, the aim was to develop a setup capable of monitoring and quantifying the dissolution of lidocaine into a phosphate buffer, pH 7.4, under stagnant conditions. A single crystal of lidocaine...... was placed in the quartz dissolution cell and UV imaging was performed at 254 nm. Spatially and temporally resolved mapping of lidocaine concentration during the dissolution process was achieved from the recorded images. UV imaging facilitated the monitoring of lidocaine concentrations in the dissolution...... media adjacent to the single crystals. The concentration maps revealed the effects of natural convection due to density gradients on the dissolution process of lidocaine. UV imaging has great potential for in vitro drug dissolution testing...

  15. Optical microscopy as a comparative analytical technique for single-particle dissolution studies.

    Science.gov (United States)

    Svanbäck, Sami; Ehlers, Henrik; Yliruusi, Jouko

    2014-07-20

    Novel, simple and cost effective methods are needed to replace advanced chemical analytical techniques, in small-scale dissolution studies. Optical microscopy of individual particles could provide such a method. The aim of the present work was to investigate and verify the applicability of optical microscopy as an analytical technique for drug dissolution studies. The evaluation was performed by comparing image and chemical analysis data of individual dissolving particles. It was shown that the data obtained by image analysis and UV-spectrophotometry produced practically identical dissolution curves, with average similarity and difference factors above 82 and below 4, respectively. The relative standard deviation for image analysis data, of the studied particle size range, varied between 1.9% and 3.8%. Consequently, it is proposed that image analysis can be used, on its own, as a viable analytical technique in single-particle dissolution studies. The possibility for significant reductions in sample preparation, operational cost, time and substance consumption gives optical detection a clear advantage over chemical analytical methods. Thus, image analysis could be an ideal and universal analytical technique for rapid small-scale dissolution studies. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Efavirenz Dissolution Enhancement I: Co-Micronization

    Directory of Open Access Journals (Sweden)

    Helvécio Vinícius Antunes Rocha

    2012-12-01

    Full Text Available AIDS constitutes one of the most serious infectious diseases, representing a major public health priority. Efavirenz (EFV, one of the most widely used drugs for this pathology, belongs to the Class II of the Biopharmaceutics Classification System for drugs with very poor water solubility. To improve EFV’s dissolution profile, changes can be made to the physical properties of the drug that do not lead to any accompanying molecular modifications. Therefore, the study objective was to develop and characterize systems with efavirenz able to improve its dissolution, which were co-processed with sodium lauryl sulfate (SLS and polyvinylpyrrolidone (PVP. The technique used was co-micronization. Three different drug:excipient ratios were tested for each of the two carriers. The drug dispersion dissolution results showed significant improvement for all the co-processed samples in comparison to non-processed material and corresponding physical mixtures. The dissolution profiles obtained for dispersion with co-micronized SLS samples proved superior to those of co-micronized PVP, with the proportion (1:0.25 proving the optimal mixture. The improvements may be explained by the hypothesis that formation of a hydrophilic layer on the surface of the micronized drug increases the wettability of the system formed, corroborated by characterization results indicating no loss of crystallinity and an absence of interaction at the molecular level.

  17. Applying green analytical chemistry for rapid analysis of drugs: Adding health to pharmaceutical industry

    Directory of Open Access Journals (Sweden)

    Nazrul Haq

    2017-02-01

    Full Text Available Green RP-HPLC method for a rapid analysis of olmesartan medoxomil (OLM in bulk drugs, self-microemulsifying drug delivery system (SMEDDS and marketed tablets was developed and validated in the present investigation. The chromatographic identification was achieved on Lichrosphere 250 × 4.0 mm RP C8 column having a 5 μm packing as a stationary phase using a combination of green solvents ethyl acetate:ethanol (50:50% v/v as a mobile phase, at a flow rate of 1.0 mL/min with UV detection at 250 nm. The proposed method was validated for linearity, selectivity, accuracy, precision, reproducibility, robustness, sensitivity and specificity. The utility of the proposed method was verified by an assay of OLM in SMEDDS and commercial tablets. The proposed method was found to be selective, precise, reproducible, accurate, robust, sensitive and specific. The amount of OLM in SMEDDS and commercial tablets was found to be 101.25% and 98.67% respectively. The proposed method successfully resolved OLM peak in the presence of its degradation products which indicated stability-indicating property of the proposed method. These results indicated that the proposed method can be successfully employed for a routine analysis of OLM in bulk drugs and commercial formulations.

  18. Calcite Dissolution Kinetics

    Science.gov (United States)

    Berelson, W.; Subhas, A.; Dong, S.; Naviaux, J.; Adkins, J. F.

    2016-12-01

    A geological buffer for high atmospheric CO2 concentrations is neutralization via reaction with CaCO3. We have been studying the dissolution kinetics of carbonate minerals using labeled 13C calcite and Picarro-based measurements of 13C enrichments in solution DIC. This methodology has greatly facilitated our investigation of dissolution kinetics as a function of water carbonate chemistry, temperature and pressure. One can adjust the saturation state Omega by changing the ion activity product (e.g. adjusting carbonate ion concentration), or by changing the solubility product (e.g. adjusting temperature or pressure). The canonical formulation of dissolution rate vs. omega has been refined (Subhas et al. 2015) and shows distinct non-linear behavior near equilibrium and rates in sea water of 1-3 e-6 g/cm2day at omega = 0.8. Carbonic anhydrase (CA), an enzyme that catalyzes the hydration of dissolved CO2 to carbonic acid, was shown (in concentrations rate at low degrees of undersaturation by >500x. This result points to the importance of carbonic acid in enhancing dissolution at low degrees of undersaturation. CA activity and abundance in nature must be considered regarding the role it plays in catalyzing dissolution. We also have been investigating the role of temperature on dissolution kinetics. An increase of 16C yields an order of magnitude increase in dissolution rate. Temperature (and P) also change Omega critical, the saturation state where dissolution rates change substantially. Increasing pressure (achieved in a pressure reaction chamber we built) also shifts Omega critical closer to equilibrium and small pressure increases have large impact on dissolution kinetics. Dissolution rates are enhanced by an order of magnitude for a change in pressure of 1500 psi relative to the dissolution rate achieved by water chemistry effects alone for an omega of 0.8. We've shown that the thermodynamic determination of saturation state does not adequately describe the kinetics

  19. Real time PCR for the rapid identification and drug susceptibility of Mycobacteria present in Bronchial washings

    Directory of Open Access Journals (Sweden)

    Thilini Piushani Keerthirathne

    2016-10-01

    Full Text Available Abstract Background Mycobacteria have a spectrum of virulence and different susceptibilities to antibiotics. Distinguishing mycobacterial species is vital as patients with non-tuberculous mycobacterial (NTM infections present clinical features that are similar to those of patients with tuberculosis. Thus, rapid differentiation of Mycobacterium tuberculosis complex from NTM is critical to administer appropriate treatment. Hence the aim of the study was to rapid identification of mycobacterial species present in bronchial washings using multiplex real time Polymerase Chain Reaction (PCR and to determine the drug susceptibility in identified mycobacterial species. Methods Sputum smear negative bronchoscopy specimens (n = 150 were collected for a period of one year, from patients attending the General Hospital Kandy, Sri Lanka. The specimens were processed with modified Petroff’s method and were cultured on Löwenstein– Jensen medium. DNA, extracted from the mycobacterial isolates were subjected to a SYBR green mediated real time multiplex, PCR assay with primers specific for the M. tuberculosis complex, M. avium complex, M. chelonae-M.abscessus group and M. fortuitum group. DNA sequencing was performed for the species confirmation, by targeting the 16S rRNA gene and the drug susceptibility testing was performed for the molecularly identified isolates of M. tuberculosis and NTM. Results The optimized SYBR Green mediated multiplex real-time PCR assay was able to identify the presence of genus Mycobacterium in 25 out of 26 AFB positive isolates, two M. tuberculosis complex, three M. avium complex and two isolates belonging to M. chelonae-M. abscessus group. DNA sequencing confirmed the presence of M. tuberculosis, M. chelonae-M. abscessus, M. intracellulare, M. avium, Rhodococcus sp. and M. celatum. Remaining isolates were identified as Mycobacterium sp. All the NTM isolates were sensitive to amikacin and seven were resistant to ciproflaxacin

  20. Drug-Related Hyponatremic Encephalopathy: Rapid Clinical Response Averts Life-Threatening Acute Cerebral Edema.

    Science.gov (United States)

    Siegel, Arthur J; Forte, Sophie S; Bhatti, Nasir A; Gelda, Steven E

    2016-03-09

    Drug-induced hyponatremia characteristically presents with subtle psychomotor symptoms due to its slow onset, which permits compensatory volume adjustment to hypo-osmolality in the central nervous system. Due mainly to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), this condition readily resolves following discontinuation of the responsible pharmacological agent. Here, we present an unusual case of life-threatening encephalopathy due to adverse drug-related effects, in which a rapid clinical response facilitated emergent treatment to avert life-threatening acute cerebral edema. A 63-year-old woman with refractory depression was admitted for inpatient psychiatric care with a normal physical examination and laboratory values, including a serum sodium [Na+] of 144 mEq/L. She had a grand mal seizure and became unresponsive on the fourth day of treatment with the dual serotonin and norepinephrine reuptake inhibitor [SNRI] duloxetine while being continued on a thiazide-containing diuretic for a hypertensive disorder. Emergent infusion of intravenous hypertonic (3%) saline was initiated after determination of a serum sodium [Na+] of 103 mEq/L with a urine osmolality of 314 mOsm/kg H20 and urine [Na+] of 12 mEq/L. Correction of hyposmolality in accordance with current guidelines resulted in progressive improvement over several days, and she returned to her baseline mental status. Seizures with life-threatening hyponatremic encephalopathy in this case likely resulted from co-occurring SIADH and sodium depletion due to duloxetine and hydrochlorothiazide, respectively. A rapid clinical response expedited diagnosis and emergent treatment to reverse life-threatening acute cerebral edema and facilitate a full recovery without neurological complications.

  1. Formulation self nano emulsifying drug delivery system glimepiride using oleic acid as oil phase

    Directory of Open Access Journals (Sweden)

    Sani Ega Priani

    2017-12-01

    Full Text Available Glimepiride is a third generation sulphonylurea antidiabetic drug. Glimepiride is poorly water soluble drug that may cause poor dissolution and unpredicted bioavailability. Self nanoemulsifying drug delivery systems (SNEDDS have become a popular formulation option as nanocarriers for poorly water-soluble drugs. The objective of this research was to develop SNEDDS formulation of glimepiride to improve oral dissolution and bioavailability. Glimepiride SNEDDS was formulated using oleic acid as oil phase, tween 80 as surfactant, and transcutol as co-surfactant due to their higher solubilization effect. The formulated SNEDDS were evaluated for % transmittance, dispersibility, thermodynamic stability, dissolution, globule size and morphology analysis. The results showed that the glimepiride SNEDDS was rapidly formed clear emulsion and stabile based on thermodynamic test. Transmission electron microscopy demonstrated the spherical droplets morphology in nanometer range. The globule average diameter size was 45 nm. The SNEDDS formulation significantly increase dissolution of glimepiride compared with pure drug.

  2. Modeling of Dissolution Effects on Waterflooding

    DEFF Research Database (Denmark)

    Alexeev, Artem; Shapiro, Alexander; Thomsen, Kaj

    2015-01-01

    reaction rates) may exhibit rapid increase of porosity and permeability near the inlet probably indicating a formation of high permeable channels (wormholes). Water saturation in the zone of dissolution increases due to an increase in the bulk volume accessible for the injected fluid. Volumetric non...

  3. Ego-Dissolution and Psychedelics: Validation of the Ego-Dissolution Inventory (EDI).

    Science.gov (United States)

    Nour, Matthew M; Evans, Lisa; Nutt, David; Carhart-Harris, Robin L

    2016-01-01

    The experience of a compromised sense of "self", termed ego-dissolution, is a key feature of the psychedelic experience. This study aimed to validate the Ego-Dissolution Inventory (EDI), a new 8-item self-report scale designed to measure ego-dissolution. Additionally, we aimed to investigate the specificity of the relationship between psychedelics and ego-dissolution. Sixteen items relating to altered ego-consciousness were included in an internet questionnaire; eight relating to the experience of ego-dissolution (comprising the EDI), and eight relating to the antithetical experience of increased self-assuredness, termed ego-inflation. Items were rated using a visual analog scale. Participants answered the questionnaire for experiences with classical psychedelic drugs, cocaine and/or alcohol. They also answered the seven questions from the Mystical Experiences Questionnaire (MEQ) relating to the experience of unity with one's surroundings. Six hundred and ninety-one participants completed the questionnaire, providing data for 1828 drug experiences (1043 psychedelics, 377 cocaine, 408 alcohol). Exploratory factor analysis demonstrated that the eight EDI items loaded exclusively onto a single common factor, which was orthogonal to a second factor comprised of the items relating to ego-inflation (rho = -0.110), demonstrating discriminant validity. The EDI correlated strongly with the MEQ-derived measure of unitive experience (rho = 0.735), demonstrating convergent validity. EDI internal consistency was excellent (Cronbach's alpha 0.93). Three analyses confirmed the specificity of ego-dissolution for experiences occasioned by psychedelic drugs. Firstly, EDI score correlated with drug-dose for psychedelic drugs (rho = 0.371), but not for cocaine (rho = 0.115) or alcohol (rho = -0.055). Secondly, the linear regression line relating the subjective intensity of the experience to ego-dissolution was significantly steeper for psychedelics (unstandardized regression

  4. Development and validation of dissolution test for Metoprolol ...

    African Journals Online (AJOL)

    GREGO

    2007-03-02

    Mar 2, 2007 ... Dissolution test for sustained release capsules of Metoprolol 125 mg was developed and validated according to FDA and ICH guidelines. Metoprolol coated pellets were coated with microcrystalline wax and glyceryl distearate for slow release of drug. The dissolution method which uses USP apparatus I.

  5. Biomimetic Dissolution: A Tool to Predict Amorphous Solid Dispersion Performance.

    Science.gov (United States)

    Puppolo, Michael M; Hughey, Justin R; Dillon, Traciann; Storey, David; Jansen-Varnum, Susan

    2017-11-01

    The presented study describes the development of a membrane permeation non-sink dissolution method that can provide analysis of complete drug speciation and emulate the in vivo performance of poorly water-soluble Biopharmaceutical Classification System class II compounds. The designed membrane permeation methodology permits evaluation of free/dissolved/unbound drug from amorphous solid dispersion formulations with the use of a two-cell apparatus, biorelevant dissolution media, and a biomimetic polymer membrane. It offers insight into oral drug dissolution, permeation, and absorption. Amorphous solid dispersions of felodipine were prepared by hot melt extrusion and spray drying techniques and evaluated for in vitro performance. Prior to ranking performance of extruded and spray-dried felodipine solid dispersions, optimization of the dissolution methodology was performed for parameters such as agitation rate, membrane type, and membrane pore size. The particle size and zeta potential were analyzed during dissolution experiments to understand drug/polymer speciation and supersaturation sustainment of felodipine solid dispersions. Bland-Altman analysis was performed to measure the agreement or equivalence between dissolution profiles acquired using polymer membranes and porcine intestines and to establish the biomimetic nature of the treated polymer membranes. The utility of the membrane permeation dissolution methodology is seen during the evaluation of felodipine solid dispersions produced by spray drying and hot melt extrusion. The membrane permeation dissolution methodology can suggest formulation performance and be employed as a screening tool for selection of candidates to move forward to pharmacokinetic studies. Furthermore, the presented model is a cost-effective technique.

  6. Physicochemical characterization and dissolution properties of ...

    African Journals Online (AJOL)

    Physicochemical characterization and dissolution properties of binary systems of pyrimethamine and 2- hydroxypropyl-β-cyclodextrin. ... (PYR), a drug effective against protozoan parasites, such as Toxoplasma gondii and Plasmodium falciparum, is poorly water soluble and exhibits marked variation in oral bioavailability.

  7. Variable-focus microscopy and UV surface dissolution imaging as complementary techniques in intrinsic dissolution rate determination

    DEFF Research Database (Denmark)

    Ward, Adam; Walton, Karl; Box, Karl

    2017-01-01

    This work reports a novel approach to the assessment of the surface properties of compacts used in Surface Dissolution Imaging (SDI). SDI is useful for determining intrinsic dissolution rate (IDR), an important parameter in early stage drug development. Surface topography, post-compaction and pos...

  8. A comparative study of the dissolution characteristics of capsule and tablet dosage forms of melt granulations of paracetamol--diluent effects.

    Science.gov (United States)

    Uhumwangho, Michael U; Okor, Roland S

    2007-01-01

    The dissolution characteristics of melt granulations of paracetamol in capsule and tablet dosage form were compared to determine whether the dissolution characteristics of the granules can be actualized by formulating them as rapidly disintegrating tablets. The term melt granulation refers here to the wax-matrix granules that were formed by triturating the drug powder (paracetamol) with a melted carnauba wax. The matrix granules were admixed with diluents (lactose, alpha-cellulose or microcrystalline cellulose) also in granular form to prevent size separation during encapsulation or tableting. The granules were filled into hard gelatin capsules (mean content weight, 500 +/- 6.2 mg) or tableted (mean weight 500 +/- 5.1 mg, and tensile strength 1.36 +/- 0.2 to 1.7 +/- 0.3 MN/m2). The capsules and tablets were subjected to disintegration and in vitro dissolution tests. The dissolution data were analyzed on the basis of zero, first order rate kinetics and Higuchi square root of time relationship. The results showed that the dissolution profiles were generally consistent with a first order rate kinetics (r = 0.95). The first order dissolution rate constants of capsules and tablets of the matrix granules only (without diluents) were 0.31 +/- 0.02 min(-1) and 0.20 +/- 0.03 min(-1), respectively, indicating faster dissolution from the capsules. Therefore, the dissolution characteristics of the matrix particles were not intact after tableting. Addition of diluents to the capsule formulations had no effect on dissolution rates, whereas in the tablets, dissolution rates increased. For instance, inclusion of a diluent up to 50% w/w in the tablets increased the dissolution rate constants to 0.34 +/- 0.04 min(-1) (lactose), 0.42 +/- 0.02 min(-1) (alpha-cellulose), and 0.46 +/- 0.03 min(-1) (microcrystalline cellulose). Thus, alpha-cellulose and microcrystalline cellulose produced greater enhancer effect on the tablet dissolution rates compared to lactose. Both the capsules and

  9. Treatment of fevers prior to introducing rapid diagnostic tests for malaria in registered drug shops in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K.; Lal, Sham; Cundill, Bonnie

    2013-01-01

    shops on presenting symptoms, the consultation process, treatment received, and malaria diagnoses. Malaria diagnosis made by drug shop vendors were confirmed by the study team through microscopy examination of a blood slide to ascertain whether appropriate treatment was received. RESULTS: Among febrile......BACKGROUND: Since drug shops play an important role in treatment of fever, introducing rapid diagnostic tests (RDTs) for malaria at drug shops may have the potential of targeting anti-malarial drugs to those with malaria parasites and improve rational drug use. As part of a cluster randomized trial...... to examine impact on appropriate treatment of malaria in drug shops in Uganda and adherence to current malaria treatment policy guidelines, a survey was conducted to estimate baseline prevalence of, and factors associated with, appropriate treatment of malaria to enable effective design and implementation...

  10. Factors Affecting the Dissolution of Indomethacin Solid Dispersions.

    Science.gov (United States)

    Zhang, Wei; Zhang, Chen-Ning; He, Yue; Duan, Ban-Yan; Yang, Guang-Yi; Ma, Wei-Dong; Zhang, Yong-Hong

    2017-11-01

    The aim of this study was to investigate the influence of factors such as carrier type, drug/carrier ratio, binary carriers, and preparation method on the dissolution of an insoluble drug, indomethacin (IM), under supersaturation conditions. Using a solvent evaporation (SE) method, poloxamer 188 and PVP K30 showed better dissolution among the selected carriers. Furthermore, as the ratio of carriers increased (drug/carrier ratio from 1:0.5 to 1:2), the dissolution rate increased especially in almost two times poloxamer 188 solid dispersions (SDs), while the reverse results were observed for PVP K30 SDs. For the binary carrier SD, a lower dissolution was found. Under hot melt extrusion (HME), the dissolution of poloxamer 188 SD and PVP K30 SD was 0.83- and 0.94-folds lower than that using SE, respectively, while the binary carrier SD showed the best dissolution. For poloxamer 188 SDs, the drug's crystal form changed when using SE, while no crystal form change was observed using HME. IM was amorphous in PVP K30 SDs prepared by both methods. For binary carrier systems, amorphous and crystalline drugs coexisted in SD using SE, and negligible amorphous IM was in SD using HME. This study indicated that a higher amorphous proportion in SD did not correlate with higher dissolution rate, and other factors, such as carrier type, particle size, and density, were also critical.

  11. Dissolution Model of Multiple Species: Leaching of Highly Soluble Minerals

    Science.gov (United States)

    Moreno, Luis; Ordóñez, Javier I.; Cisternas, Luis A.

    2017-06-01

    Dissolution of multi-species from a solid matrix is widely extended in different processes such as leaching of minerals; however, its modeling is often focused on a single species. A model for the simultaneous dissolution of soluble species was developed, which considers different solubilities and dissolution rates and considers that particle collapses when the rapidly soluble species is depleted. The collapsed matter is formed by inert material and a fraction of the soluble species with lower dissolution rate that has not dissolved yet. The model is applied to the leaching of a water-soluble mineral (caliche) with two soluble species dissolving simultaneously with different rates. Measured outlet concentrations of nitrate and magnesium were used to validate the model. Results showed that the model reproduced adequately the leaching of species with rapid and intermediate dissolution rate. Effect of the operating and kinetic parameters on the leaching process is also shown using the actual conditions of heap leaching for caliche mineral.

  12. Evaluation of rapid alternative methods for drug susceptibility testing in clinical isolates of Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Luciano Mengatto

    2006-08-01

    Full Text Available A study was carried out to compare the performance of a commercial method (MGIT and four inexpensive drug susceptibility methods: nitrate reductase assay (NRA, microscopic observation drug susceptibility (MODS assay, MTT test, and broth microdilution method (BMM. A total of 64 clinical isolates of Mycobacterium tuberculosis were studied. The Lowenstein-Jensen proportion method (PM was used as gold standard. MGIT, NRA, MODS, and MTT results were available on an average of less than 10 days, whereas BMM results could be reported in about 20 days. Most of the evaluated tests showed excellent performance for isoniazid and rifampicin, with sensitivity and specificity values > 90%. With most of the assays, sensitivity for ethambutol was low (62-87% whereas for streptomycin, sensitivity values ranged from 84 to 100%; NRA-discrepancies were associated with cultures with a low proportion of EMB-resistant organisms while most discrepancies with quantitative tests (MMT and BMM were seen with isolates whose minimal inhibitory concentrations fell close the cutoff. MGIT is reliable but still expensive. NRA is the most inexpensive and easiest method to perform without changing the organization of the routine PM laboratory performance. While MODS, MTT, and BMM, have the disadvantage from the point of view of biosafety, they offer the possibility of detecting partial resistant strains. This study shows a very good level of agreement of the four low-cost methods compared to the PM for rapid detection of isoniazid, rifampicin and streptomycin resistance (Kappa values > 0.8; more standardization is needed for ethambutol.

  13. Veterinary drug residues in meat: Concerns and rapid methods for detection.

    Science.gov (United States)

    Reig, Milagro; Toldrá, Fidel

    2008-01-01

    The use of substances having hormonal or thyreostatic action as well as β-agonists is banned in the European Union. However, sometimes forbidden drugs may be added to feeds for illegal administration to farm animals for promoting increased muscle development or increased water retention and thus obtain an economical benefit. The result is a fraudulent overweight of meat but, what is worse, residues of these substances may remain in meat and may pose a real threat to the consumer either through exposure to the residues, transfer of antibiotic resistance or allergy risk. This has exerted a great concern among European consumers. The control of the absence of these forbidden substances in animal foods and feeds is regulated in the European Union by Directive96/23/EC on measures to monitor certain substances and residues in live animals and animal products. Analytical methodology, including criteria for identification and confirmation, for the monitoring of compliance was also given in Decisions 93/256/EEC and 93/257/EEC. More recently, Decision 2002/657/EC provided rules for the analytical methods to be used in testing of official samples. A crucial step is the screening of veterinary drug residues in live animals, feeds and animal products in view of the remarkable number of samples and large variety of residues to be analysed. In recent years, different rapid methods having easy performance, high sensitivity and high throughput have been proposed and are being extensively used. These methods as well as other new methods are reviewed in this manuscript.

  14. [Preparation and in vitro dissolution of magnolol solid dispersion].

    Science.gov (United States)

    Tang, Lan; Qiu, Shuai-Bo; Wu, Lan; Lv, Long-Fei; Lv, Hui-Xia; Shan, Wei-Guang

    2016-02-01

    In this study, solid dispersion system of magnolol in croscarmellose sodium was prepared by using the solvent evaporation method, in order to increase the drug dissolution. And its dissolution behavior, stability and physical characteristics were studied. The solid dispersion was prepared with magnolol and croscarmellose sodium, with the proportion of 1∶5, the in vitro dissolution of magnolol solid dispersion was up to 80.66% at 120 min, which was 6.9 times of magnolol. The results of DSC (differential scanning calorimetry), IR (infra-red) spectrum and SEM (scanning electron microscopy) showed that magnolol existed in solid dispersion in an amorphous form. After an accelerated stability test for six months, the drug dissolution and content in magnolol solid dispersion showed no significant change. So the solid dispersion prepared with croscarmellose sodium as the carrier can remarkably improve the stability and dissolution of magnolol. Copyright© by the Chinese Pharmaceutical Association.

  15. Evaluation of a biphasic in vitro dissolution test for estimating the bioavailability of carbamazepine polymorphic forms.

    Science.gov (United States)

    Deng, Jia; Staufenbiel, Sven; Bodmeier, Roland

    2017-07-15

    The purpose of this study was to discriminate three crystal forms of carbamazepine (a BCS II drug) by in vitro dissolution testing and to correlate in vitro data with published in vivo data. A biphasic dissolution system (phosphate buffer pH6.8 and octanol) was used to evaluate the dissolution of the three polymorphic forms and to compare it with conventional single phase dissolution tests performed under sink and non-sink conditions. Similar dissolution profiles of three polymorphic forms were observed in the conventional dissolution test under sink conditions. Although a difference in dissolution was seen in the single phase dissolution test under non-sink conditions as well as in the aqueous phase of the biphasic test, little relevance for in vivo data was observed. In contrast, the biphasic dissolution system could discriminate between the different polymorphic forms in the octanol phase with a ranking of form III>form I>dihydrate form. This was in agreement with the in vivo performance. The dissolved drug available for oral absorption, which was dominated by dissolution and solution-mediated phase transformation, could be reflected in the biphasic dissolution test. Moreover, a good correlation was established between in vitro dissolution in the octanol phase of the biphasic test and in vivo pharmacokinetic data (R(2)=0.99). The biphasic dissolution method is a valuable tool to discriminate between different crystal forms in the formulations of poorly soluble drugs. Copyright © 2017. Published by Elsevier B.V.

  16. Jarosite dissolution rates in perchlorate brine

    Science.gov (United States)

    Legett, Carey; Pritchett, Brittany N.; Elwood Madden, Andrew S.; Phillips-Lander, Charity M.; Elwood Madden, Megan E.

    2018-02-01

    Perchlorate salts and the ferric sulfate mineral jarosite have been detected at multiple locations on Mars by both landed instruments and orbiting spectrometers. Many perchlorate brines have eutectic temperatures Mars surface conditions. Therefore, jarosite-bearing rocks and sediments may have been altered by perchlorate brines. Here we measured jarosite dissolution rates in 2 M sodium perchlorate brine as well as dilute water at 298 K to determine the effects of perchlorate anions on jarosite dissolution rates and potential reaction products. We developed a simple method for determining aqueous iron concentrations in high salinity perchlorate solutions using ultraviolet-visible spectrophotometry that eliminates the risk of rapid oxidation reactions during analyses. Jarosite dissolution rates in 2 M perchlorate brine determined by iron release rate (2.87 × 10-12 ±0.85 × 10-12 mol m-2 s-1) were slightly slower than the jarosite dissolution rate measured in ultrapure (18.2 MΩ cm-1) water (5.06 × 10-12 mol m-2 s-1) using identical methods. No additional secondary phases were observed in XRD analyses of the reaction products. The observed decrease in dissolution rate may be due to lower activity of water (ɑH2O = 0.9) in the 2 M NaClO4 brine compared with ultrapure water (ɑH2O = 1). This suggests that the perchlorate anion does not facilitate iron release, unlike chloride anions which accelerated Fe release rates in previously reported jarosite and hematite dissolution experiments. Since dissolution rates are slower in perchlorate-rich solutions, jarosite is expected to persist longer in perchlorate brines than in dilute waters or chloride-rich brines. Therefore, if perchlorate brines dominate aqueous fluids on the surface of Mars, jarosite may remain preserved over extended periods of time, despite active aqueous processes.

  17. Acceptability of rapid oral fluid HIV testing among male injection drug users in Taiwan, 1997 and 2007.

    Science.gov (United States)

    Lyu, Shu-Yu; Morisky, Donald E; Yeh, Ching-Ying; Twu, Shiing-Jer; Peng, Eugene Yu-Chang; Malow, Robert M

    2011-04-01

    Rapid oral fluid HIV testing (rapid oral testing) is in the process of being adapted in Taiwan and elsewhere given its advantages over prior HIV testing methods. To guide this process, we examined the acceptability of rapid oral testing at two time points (i.e., 1997 and 2007) among one of the highest risk populations, male injection drug users (IDUs). For this purpose, an anonymous self-administered survey was completed by HIV-negative IDUs involved in the criminal justice system in 1997 (N (1)=137 parolees) and 2007 (N (2)=106 prisoners). A social marketing model helped guide the design of our questionnaire to assess the acceptability of rapid oral testing. This included assessing a new product, across four marketing dimensions: product, price, promotion, and place. Results revealed that in both 1997 and 2007, over 90% indicated that rapid oral testing would be highly acceptable, particularly if the cost was under US$6, and that a pharmacy would be the most appropriate and accessible venue for selling the rapid oral testing kits. The vast majority of survey respondents believed that the cost of rapid oral testing should be federally subsidized and that television and newspaper advertisements would be the most effective media to advertise for rapid oral testing. Both the 1997 and 2007 surveys suggested that rapid oral HIV testing would be particularly accepted in Taiwan by IDUs after release from the criminal justice system.

  18. Rapid detection of drug resistance and mutational patterns of extensively drug-resistant strains by a novel GenoType® MTBDRsl assay.

    Science.gov (United States)

    Singh, A K; Maurya, A K; Kant, S; Umrao, J; Kushwaha, R A S; Nag, V L; Dhole, T N

    2013-01-01

    The emergence of extensively drug-resistant tuberculosis (XDR-TB) is a major concern in the India. The burden of XDR-TB is increasing due to inadequate monitoring, lack of proper diagnosis, and treatment. The GenoType ® Mycobacterium tuberculosis drug resistance second line (MTBDRsl) assay is a novel line probe assay used for the rapid detection of mutational patterns conferring resistance to XDR-TB. The aim of this study was to study the rapid detection of drug resistance and mutational patterns of the XDR-TB by a novel GenoType ® MTBDRsl assay. We evaluated 98 multidrug-resistant (MDR) M. tuberculosis isolates for second line drugs susceptibility testing by 1% proportion method (BacT/ALERT 3D system) and GenoType ® MTBDRsl assay for rapid detection of conferring drug resistance to XDR-TB. A total of seven (17.4%) were identified as XDR-TB by using standard phenotypic method. The concordance between phenotypic and GenoType ® MTBDRsl assay was 91.7-100% for different antibiotics. The sensitivity and specificity of the MTBDRsl assay were 100% and 100% for aminoglycosides; 100% and 100% for fluoroquinolones; 91.7% and 100% for ethambutol. The most frequent mutations and patterns were gyrA MUT1 (A90V) in seven (41.2%) and gyrA + WT1-3 + MUT1 in four (23.5%); rrs MUT1 (A1401G) in 11 (64.7%), and rrs WT1-2 + MUT1 in eight (47.1%); and embB MUT1B (M306V) in 11 (64.7%) strains. These data suggest that the GenoType ® MTBDRsl assay is rapid, novel test for detection of resistance to second line anti-tubercular drugs. This assay provides additional information about the frequency and mutational patterns responsible for XDR-TB resistance.

  19. Loco-regional cancer drug therapy: present approaches and rapidly reversible hydrophobization (RRH) of therapeutic agents as the future direction.

    Science.gov (United States)

    Budker, Vladimir G; Monahan, Sean D; Subbotin, Vladimir M

    2014-12-01

    Insufficient drug uptake by solid tumors remains the major problem for systemic chemotherapy. Many studies have demonstrated anticancer drug effects to be dose-dependent, although dose-escalation studies have resulted in limited survival benefit with increased systemic toxicities. One solution to this has been the idea of loco-regional drug treatments, which offer dramatically higher drug concentrations in tumor tissues while minimizing systemic toxicity. Although loco-regional delivery has been most prominent in cancers of the liver, soft tissues and serosal peritoneal malignancies, survival benefits are very far from desirable. This review discusses the evolution of loco-regional treatments, the present approaches and offers rapidly reversible hydrophobization of drugs as the new future direction. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Rapid assessment of drug use and sexual HIV risk patterns among ...

    African Journals Online (AJOL)

    This exploratory study examines the links between drug use and high-risk sexual practices and HIV in vulnerable drug-using populations in South Africa, including commercial sex workers (CSWs), men who have sex with men (MSM), injecting drug users (IDUs) and non-injecting drug users who are not CSWs or MSM ...

  1. Improving dissolution and oral bioavailability of pranlukast hemihydrate by particle surface modification with surfactants and homogenization

    Directory of Open Access Journals (Sweden)

    Ha ES

    2015-06-01

    Full Text Available Eun-Sol Ha,1 In-hwan Baek,2 Jin-Wook Yoo,1 Yunjin Jung,1 Min-Soo Kim1 1College of Pharmacy, Pusan National University, 2College of Pharmacy, Kyungsung University, Busan, Republic of Korea Abstract: The present study was carried out to develop an oral formulation of pranlukast hemihydrate with improved dissolution and oral bioavailability using a surface-modified microparticle. Based on solubility measurements, surface-modified pranlukast hemihydrate microparticles were manufactured using the spray-drying method with hydroxypropylmethyl cellulose, sucrose laurate, and water and without the use of an organic solvent. The hydrophilicity of the surface-modified pranlukast hemihydrate microparticle increased, leading to enhanced dissolution and oral bioavailability of pranlukast hemihydrate without a change in crystallinity. The surface-modified microparticles with an hydroxypropylmethyl cellulose/sucrose laurate ratio of 1:2 showed rapid dissolution of up to 85% within 30 minutes in dissolution medium (pH 6.8 and oral bioavailability higher than that of the commercial product, with approximately 2.5-fold and 3.9-fold increases in area under the curve (AUC0→12 h and peak plasma concentration, respectively. Therefore, the surface-modified microparticle is an effective oral drug delivery system for the poorly water-soluble therapeutic pranlukast hemihydrate. Keywords: solubility, wettability, sucrose laurate, cellulose

  2. Formulation design of a highly hygroscopic drug (pyridostigmine bromide) for its hygroscopic character improvement and investigation of in vitro/in vivo dissolution properties.

    Science.gov (United States)

    Huang, Yuh-Tyng; Tsai, Tong-Rong; Cheng, Chun-Jen; Cham, Thau-Ming; Lai, Tsun-Fwu; Chuo, Wen-Ho

    2007-04-01

    Pyridostigmine bromide (PB) sustained-release (SR) pellets were developed by extrusion-spheronization and fluid-bed methods using Taguchi experimental and 2(3) full factorial design. In vitro studies, the 2(3) full factorial design was utilized to search for the optimal SR pellets with specific release rate at different time intervals (release percent of 2, 6, 12, and 24 hr were 6.24, 33.48, 75.18, and 95.26%, respectively) which followed a zero-order mechanism (n=0.93). The results of moisture absorption by Karl Fischer has shown the optimum SR pellets at 25 degrees C/60% RH, 30 degrees C/65% RH, and 40 degrees C/75% RH chambers from 1 hr-4 weeks, attributing that the moisture absorption was not significantly increased. In the in vivo study, the results of the bioavailability data showed the Tmax (from 0.65+/-0.082 hr-4.82+/-2.12 hr) and AUC0-30 hr (from 734.88+/-230.68 ng/mL.hr-1454.86+/-319.28 ng/mL.hr) were prolonged and increased, as well as Cmax (from 251.87+/-27.51 ng/mL-115.08+/-14.87 ng/mL) was decreased for optimum SR-PB pellets when compared with commercial immediate-release (IR) tablets. Furthermore, a good linear regression relationship (r=0.9943) was observed between the fraction dissolution and fraction absorption for the optimum SR pellets. In this study, the formulation design not only improved the hygroscopic character of PB but also achieved the SR effect.

  3. Simultaneous UV Imaging and Raman Spectroscopy for the Measurement of Solvent-Mediated Phase Transformations During Dissolution Testing

    DEFF Research Database (Denmark)

    Ostergaard, Jesper; Wu, Jian; Naelapää, Kaisa

    2014-01-01

    The current work reports the simultaneous use of UV imaging and Raman spectroscopy for detailed characterization of drug dissolution behavior including solid-state phase transformations during dissolution. The dissolution of drug substances from compacts of sodium naproxen in 0.1 HCl as well...

  4. The effect of rapid detoxification method with Naltrexone on drug abuse quitting in drug abusers referred to Khorramabad Psychiatric hospital during the first half of the year 2005

    Directory of Open Access Journals (Sweden)

    hedayat Nazari

    2009-03-01

    Full Text Available Background: About 8 percent of Iranian adult population are illicit drug abusers. Affected persons grow more each day. Ominous consequences such as divorce, prostitution, murder and other crimes and infectious diseases such as AIDS and hepatitis take place following drug abuse, as well as a loss equall to 29% of national income for our country. Traditional treatment methods wasted too much time and cost. professional inpatient clinics are not adequate for admission of all care seekers. Rapid detoxification methods are supposed to be better alternatives. Materials and Methods: 140 male drug abusers in two matched groups were assessed from March to September, 2005. They used heroin or opium. Both groups were scheduled for detoxification and were closely observed for 3 months thereafter. First group received Clonidine, Benzodiazepine and Naltrexone besides symptom relieving modalities in first 4 days of treatment. Naltrexone was continued in maintenance dose for one month. Second group received Methadone for one month. Results: Clients age was between 18 to 73 years, with mean age 34 years old. Their intelligence quotients were above the lower limit of normal range. There was no significant difference according to these parameters between two groups. Success rate in rapid detoxification group was 55 % and in Methadone group was 50 %. Relapse in rapid detoxification method occurred less frequent and slower (45 % vs. 50%. In Naltrexone group, better success rate was due to less duration of drug abuse and heroin dependency. In Methadone group, therapy had better results in patients with longer drug abuse history and opium addiction. There was no significant difference between success rate and either drug kind or job, marital status or education level. The most serious adverse effect in both groups was hypotension (10% in Naltrexone and 5 % in Methadone groups.

  5. Comparative Genomic Analysis of Rapid Evolution of an Extreme-Drug-Resistant Acinetobacter baumannii Clone

    Science.gov (United States)

    Tan, Sean Yang-Yi; Chua, Song Lin; Liu, Yang; Høiby, Niels; Andersen, Leif Percival; Givskov, Michael; Song, Zhijun; Yang, Liang

    2013-01-01

    The emergence of extreme-drug-resistant (EDR) bacterial strains in hospital and nonhospital clinical settings is a big and growing public health threat. Understanding the antibiotic resistance mechanisms at the genomic levels can facilitate the development of next-generation agents. Here, comparative genomics has been employed to analyze the rapid evolution of an EDR Acinetobacter baumannii clone from the intensive care unit (ICU) of Rigshospitalet at Copenhagen. Two resistant A. baumannii strains, 48055 and 53264, were sequentially isolated from two individuals who had been admitted to ICU within a 1-month interval. Multilocus sequence typing indicates that these two isolates belonged to ST208. The A. baumannii 53264 strain gained colistin resistance compared with the 48055 strain and became an EDR strain. Genome sequencing indicates that A. baumannii 53264 and 48055 have almost identical genomes—61 single-nucleotide polymorphisms (SNPs) were found between them. The A. baumannii 53264 strain was assembled into 130 contigs, with a total length of 3,976,592 bp with 38.93% GC content. The A. baumannii 48055 strain was assembled into 135 contigs, with a total length of 4,049,562 bp with 39.00% GC content. Genome comparisons showed that this A. baumannii clone is classified as an International clone II strain and has 94% synteny with the A. baumannii ACICU strain. The ResFinder server identified a total of 14 antibiotic resistance genes in the A. baumannii clone. Proteomic analyses revealed that a putative porin protein was down-regulated when A. baumannii 53264 was exposed to antimicrobials, which may reduce the entry of antibiotics into the bacterial cell. PMID:23538992

  6. Rapid expansion of intravitreal drug injection procedures, 2000 to 2008: a population-based analysis.

    Science.gov (United States)

    Campbell, Robert J; Bronskill, Susan E; Bell, Chaim M; Paterson, J Michael; Whitehead, Marlo; Gill, Sudeep S

    2010-03-01

    To evaluate patterns of care for age-related macular degeneration following the introduction of vascular endothelial growth factor inhibitors. Using a population-based retrospective design, we studied monthly fee claims for intravitreal injections submitted to the Ontario Health Insurance Plan between January 1, 2000, and March 30, 2008, and linked procedures to the physicians who performed them. This database records physician services provided as part of universal health care insurance coverage in Ontario, Canada. This program covers all residents of Ontario, which had an average population of 12.1 million during the study period. Following regulatory approval of bevacizumab for colorectal cancer in 2005, off-label use of this drug for the treatment of retinal disease, particularly age-related macular degeneration, became increasingly common. The rate of intravitreal injections in Ontario rapidly grew 8-fold, and this growth preceded the availability of ranibizumab by more than a year. Moreover, in 2007, more than 50% of intravitreal injections in Ontario were performed by 3% of ophthalmologists. The development of vascular endothelial growth factor inhibitors has revolutionized the treatment of age-related macular degeneration. To our knowledge, this study is the first to quantify the dramatic uptake of these treatments at a population level. Our findings also suggest that off-label injection of bevacizumab was highly prevalent in Ontario. Serial intravitreal injections requiring direct physician administration and the concentration of injection procedures in the hands of a small number of ophthalmologists have the potential to affect services for other vision-threatening conditions.

  7. Protein tethering enables rapid and label-free SERS platform for screening drugs of abuse (Conference Presentation)

    Science.gov (United States)

    Siddhanta, Soumik; Wróbel, Maciej S.; Barman, Ishan

    2017-02-01

    A quick, cost-effective method for detection of drugs of abuse in biological fluids would be of great value in healthcare, law enforcement, and home testing applications. The alarming rise in narcotics abuse has led to considerable focus on developing potent and versatile analytical tools that can address this societal problem. While laboratory testing plays a key role in the current detection of drug misuse and the evaluation of patients with drug induced intoxication, these typically require expensive reagents and trained personnel, and may take hours to complete. Thus, a significant unmet need is to engineer a facile method that can rapidly detect drugs with little sample preparation, especially the bound fraction that is typically dominant in the blood stream. Here we report an approach that combines the exquisite sensitivity of surface enhanced Raman spectroscopy (SERS) and a facile protein tethering mechanism to reliably detect four different classes of drugs, barbiturate, benzodiazepine, amphetamine and benzoylecgonine. The proposed approach harnesses the reliable and specific attachment of proteins to both drugs and nanoparticle to facilitate the enhancement of spectral markers that are sensitive to the presence of the drugs. In conjunction with chemometric tools, we have shown the ability to quantify these drugs lower than levels achievable by existing clinical immunoassays. Through molecular docking simulations, we also probe the mechanistic underpinnings of the protein tethering approach, opening the door to detection of a broad class of narcotics in biological fluids within a few minutes as well as for groundwater analysis and toxin detection.

  8. Rapid antimicrobial susceptibility test for identification of new therapeutics and drug combinations against multidrug-resistant bacteria

    Science.gov (United States)

    Sun, Wei; Weingarten, Rebecca A; Xu, Miao; Southall, Noel; Dai, Sheng; Shinn, Paul; Sanderson, Philip E; Williamson, Peter R; Frank, Karen M; Zheng, Wei

    2016-01-01

    Current antimicrobial susceptibility testing has limited screening capability for identifying empirical antibiotic combinations to treat severe bacterial infections with multidrug-resistant (MDR) organisms. We developed a new antimicrobial susceptibility assay using automated ultra-high-throughput screen technology in combination with a simple bacterial growth assay. A rapid screening of 5170 approved drugs and other compounds identified 25 compounds with activities against MDR Klebsiella pneumoniae. To further improve the efficacy and reduce the effective drug concentrations, we applied a targeted drug combination approach that integrates drugs' clinical antimicrobial susceptibility breakpoints, achievable plasma concentrations, clinical toxicities and mechanisms of action to identify optimal drug combinations. Three sets of three-drug combinations were identified with broad-spectrum activities against 10 MDR clinical isolates including K. pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Citrobacter freundii, Enterobacter cloacae and Escherichia coli. Colistin–auranofin–ceftazidime and colistin–auranofin–rifabutin suppressed >80% growth of all 10 MDR strains; while rifabutin–colistin–imipenem inhibited >75% of these strains except two Acinetobacter baumannii isolates. The results demonstrate this new assay has potential as a real-time method to identify new drugs and effective drug combinations to combat severe clinical infections with MDR organisms. PMID:27826141

  9. Insight into Flufenamic Acid Cocrystal Dissolution in the Presence of a Polymer in Solution: from Single Crystal to Powder Dissolution.

    Science.gov (United States)

    Guo, Minshan; Wang, Ke; Qiao, Ning; Fábián, László; Sadiq, Ghazala; Li, Mingzhong

    2017-11-10

    Effects of three polymers, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and copolymer of vinylpyrrolidone/vinyl acetate (PVP-VA), on the dissolution behavior of the cocrystals of flufenamic acid with theophylline (FFA-TP CO) and nicotinamide (FFA-NIC CO) were investigated at multiple length scales. At the molecular level, the interactions of crystal surfaces with a polymer were analyzed by observing etching pattern changes using atomic force microscopy. At the macroscopic scale, dissolution rates of particular faces of a single crystal were determined by measurement of the physical retreat velocities of the faces using optical light microscopy. In the bulk experiments, the FFA concentration in a dissolution medium in the absence or presence of a polymer was measured under both sink and nonsink conditions. It has been found that the dissolution mechanisms of FFA-TP CO are controlled by the defect sites of the crystal surface and by precipitation of the parent drug FFA as individual crystals in the bulk fluid. In contrast, the dissolution mechanisms of FFA-NIC CO are controlled by surface layer removal and by a surface precipitation mechanism, where the parent drug FFA precipitates directly onto the surface of the dissolving cocrystals. Through controlling the dissolution environment by predissolving a polymer, PVP or PVP-VA, which can interact with the crystal surface to alter its dissolution properties, improved solubility, and dissolution rates of FFA-TP CO and FFA-NIC CO have been demonstrated.

  10. Controlled Dissolution of Griseofulvin Solid Dispersions from Electrosprayed Enteric Polymer Micromatrix Particles: Physicochemical Characterization and in Vitro Evaluation.

    Science.gov (United States)

    Roine, Jorma; Kaasalainen, Martti; Peurla, Markus; Correia, Alexandra; Araújo, Francisca; Santos, Hélder A; Murtomaa, Matti; Salonen, Jarno

    2015-07-06

    The oral bioavailability of a poorly water-soluble drug is often inadequate for the desired therapeutic effect. The bioavailability can be improved by enhancing the physicochemical properties of the drug (e.g., dissolution rate, permeation across the gastrointestinal tract). Other approach include shielding the drug from the gastric metabolism and targeted drug release to obtain optimal drug absorption. In this study, a poorly water-soluble model drug, griseofulvin, was encapsulated as disordered solid dispersions into Eudragit L 100-55 enteric polymer micromatrix particles, which were produced by electrospraying. Similar micromatrix particles were also produced with griseofulvin-loaded thermally oxidized mesoporous silicon (TOPSi) nanoparticles dispersed to the polymer micromatrices. The in vitro drug dissolution at pH 1.2 and 6.8, and permeation at pH 7.4 across Caco-2/HT29 cell monolayers from the micromatrix particles, were investigated. The micromatrix particles were found to be gastro-resistant, while at pH 6.8 the griseofulvin was released very rapidly in a fast-dissolving form. Compared to free griseofulvin, the permeability of encapsulated griseofulvin across the intestinal cell monolayers was greatly improved, particularly for the TOPSi-doped micromatrix particles. The griseofulvin solid dispersions were stable during storage for 6 months at accelerated conditions. Overall, the method developed here could prove to be a useful oral drug delivery solution for improving the bioavailability of poorly water-soluble or otherwise problematic drugs.

  11. A novel high throughput method to investigate polymer dissolution.

    Science.gov (United States)

    Zhang, Ying; Mallapragada, Surya K; Narasimhan, Balaji

    2010-02-16

    The dissolution behavior of polystyrene (PS) in biodiesel was studied by developing a novel high throughput approach based on Fourier-transform infrared (FTIR) microscopy. A multiwell device for high throughput dissolution testing was fabricated using a photolithographic rapid prototyping method. The dissolution of PS films in each well was tracked by following the characteristic IR band of PS and the effect of PS molecular weight and temperature on the dissolution rate was simultaneously investigated. The results were validated with conventional gravimetric methods. The high throughput method can be extended to evaluate the dissolution profiles of a large number of samples, or to simultaneously investigate the effect of variables such as polydispersity, crystallinity, and mixed solvents. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. ENHANCEMENT OF SOLUBILITY AND DISSOLUTION PROPERTY OF GRISEOFULVIN BY NANOCRYSTALLIZATION

    OpenAIRE

    Phanchaxari M Dandagi; Sumit Kaushik; Shaktish Telsang

    2011-01-01

    The aim of this study was to develop the formulation of griseofulvin by nanocrystallization for the enhancement of solubility and dissolution property of drug. In the present study the area of interest are drugs belonging to class II of BCS classification. Nanocrystal is a new carrier free colloidal drug delivery system with particle size ranging from 100-1000 nm, and is considered as a viable drug delivery strategy to develop the poorly soluble drugs. In the present work an attempt was made ...

  13. Rapid, automated, nonradiometric susceptibility testing of Mycobacterium tuberculosis complex to four first-line antituberculous drugs used in standard short-course chemotherapy

    DEFF Research Database (Denmark)

    Johansen, Isik Somuncu; Thomsen, Vibeke Østergaard; Marjamäki, Merja

    2004-01-01

    The increasing prevalence of drug-resistant tuberculosis necessitates rapid and accurate susceptibility testing. The nonradiometric BACTEC Mycobacteria Growth Indicator Tube 960 (MGIT) system for susceptibility testing was evaluated on 222 clinical Mycobacterium tuberculosis complex isolates...... MGIT system is a rapid and reliable alternative for susceptibility testing of M. tuberculosis complex to first-line drugs....

  14. Carboxylesterase 1A2 encoding gene with increased transcription and potential rapid drug metabolism in Asian populations

    DEFF Research Database (Denmark)

    Rasmussen, Henrik Berg; Madsen, Majbritt Busk; Lyauk, Yassine Kamal

    2017-01-01

    The carboxylesterase 1 gene (CES1) encodes a hydrolase implicated in the metabolism of commonly used drugs. CES1A2, a hybrid of CES1 and a CES1-like pseudogene, has a promoter that is weak in most individuals. However, some individuals harbor a promoter haplotype of this gene with two overlapping...... Sp1 sites that confer significantly increased transcription potentially leading to rapid drug metabolism. This CES1A2 haplotype has previously been reported to be common among Asians. Using polymerase chain reaction followed by sequencing, the present study examined variation in the promoter and 5...

  15. Dissolution Enhancement of Rosuvastatin Calcium by Liquisolid Compact Technique

    Directory of Open Access Journals (Sweden)

    V. J. Kapure

    2013-01-01

    Full Text Available In present investigation liquisolid compact technique is investigated as a tool for enhanced dissolution of poorly water-soluble drug Rosuvastatin calcium (RVT. The model drug RVT, a HMG-Co A reductase inhibitor was formulated in form of directly compressed tablets and liquisolid compacts; and studied for in-vitro release characteristics at different dissolution conditions. In this technique, liquid medications of water insoluble drugs in non-volatile liquid vehicles can be converted into acceptably flowing and compressible powders. Formulated systems were assessed for precompression parameters like flow properties of liquisolid system, Fourior transform infra red spectra (FTIR analysis, X-ray powder diffraction (XRPD, differential scanning calorimetry (DSC, and post compression parameters like content uniformity, weight variation, hardness and friability, disintegration test, wetting time, in vitro dissolution studies, effect of dissolution volume on drug release rate, and estimation of fraction of molecularly dispersed drug in liquid medication. As liquisolid compacts demonstrated significantly higher drug release rates, we lead to conclusion that it could be a promising strategy in improving the dissolution of poor water soluble drugs and formulating immediate release solid dosage forms.

  16. Teste de dissolução para avaliação de liberação de glibenclamida em comprimidos Glibenclamide dissolution test for drug release evaluation in tablets

    Directory of Open Access Journals (Sweden)

    Christiane Gino Colu Nery

    2007-09-01

    Full Text Available A glibenclamida (GLIB ou gliburida, é um hipoglicemiante oral de segunda geração, da classe das sulfoniluréias, usado sob a forma de comprimidos para tratamento do diabetes mellitus. Variações no tratamento podem ocorrer, devido à baixa solubilidade do fármaco em comprimidos. A comparação de várias formulações de comprimidos piloto com comprimidos do medicamento referência (Daonil®, glibenclamida 5 mg comprimidos, Aventis Pharma Ltda. foi avaliada por meio do desenvolvimento de um teste de dissolução sem adição de solventes orgânicos ou tensoativos no meio, que mostrou ser discriminativo para as diferentes formulações farmacêuticas propostas. A quantificação de GLIB foi realizada por meio de cromatografia líquida de alta eficiência em fase reversa (CLAE-FR, método previamente validado. A partir de vários ensaios de perfil de dissolução testados comparativamente àquele de comprimidos do medicamento referência, verificou-se o potencial de determinada formulação proposta (f1 4,04 and f2 69,35 como candidata a medicamento genérico no mercado brasileiro.Glibenclamide (GLIB or glyburide, a second-generation hypoglycemic agent is used per oral as tablets for the treatment of diabetes mellitus. Much variabilility in the treatment may occur because of the low drug aqueous solubility in tablets dosage forms. This work reports the comparison of several pilot formulation batches with the commercial reference drug dosage form (Daonil®, glibenclamide 5 mg per tablet, Aventis Pharma Ltda.. A feasible dissolution test, developed with no use of organic solvents or surfactants in the medium, showed to be discriminative regarding to different formulations tested. GLIB quantitation was performed by a previously validated reverse-phase high performance liquid chromatography (RP-HPLC. Among several dissolution profiles compared with that of a commercial reference, a potential for a generic candidate was evident (f1 4.04 and f2 69

  17. Determinants of marriage dissolution

    Science.gov (United States)

    Rahim, Mohd Amirul Rafiq Abu; Shafie, Siti Aishah Mohd; Hadi, Az'lina Abdul; Razali, Nornadiah Mohd; Azid @ Maarof, Nur Niswah Naslina

    2015-10-01

    Nowadays, the number of divorce cases among Muslim couples is very worrisome whereby the total cases reported in 2013 increased by half of the total cases reported in the previous year. The questions on the true key factors of dissolution of marriage continue to arise. Thus, the objective of this study is to reveal the factors that contribute to the dissolution of marriage. A total of 181 cases and ten potential determinants were included in this study. The potential determinants considered were age at marriage of husband and wife, educational level of husband and wife, employment status of husband and wife, income of husband and wife, the number of children and the presence at a counseling session. Logistic regression analysis was used to analyze the data. The findings revealed that four determinants, namely the income of husband and wife, number of children and the presence at a counselling session were significant in predicting the likelihood of divorce among Muslim couples.

  18. Development and Validation of Discriminating and Biorelevant Dissolution Test for Lornoxicam Tablets

    Science.gov (United States)

    Anumolu, P. D.; Sunitha, G.; Bindu, S. Hima; Satheshbabu, P. R.; Subrahmanyam, C. V. S.

    2015-01-01

    The establishment of biorelevant and discriminating dissolution procedure for drug products with limited water solubility is a useful technique for qualitative forecasting of the in vivo behavior of formulations. It also characterizes the drug product performance in pharmaceutical development. Lornoxicam, a BCS class-II drug is a nonsteroidal antiinflammatory drug of the oxicam class, has no official dissolution media available in the literature. The objective of present work was to develop and validate a discriminating and biorelevant dissolution test for lornoxicam tablet dosage forms. To quantify the lornoxicam in dissolution samples, UV spectrophotometric method was developed using 0.01M sodium hydroxide solution as solvent at λma×376 nm. After evaluation of saturation solubility, dissolution, sink conditions and stability of lornoxicam bulk drug in different pH solutions and biorelevant media, the dissolution method was optimized using USP paddle type apparatus at 50 rpm rotation speed and 500 ml simulated intestinal fluid as discriminating and biorelevant dissolution medium. The similarity factor (f2) were investigated for formulations with changes in composition and manufacturing variations, values revealed that dissolution method having discriminating power and method was validated as per standard guidelines. The proposed dissolution method can be effectively applied for routine quality control in vitro dissolution studies of lornoxicam in tablets and helpful to pharmacopoeias. PMID:26180277

  19. A rapid ex vivo tissue model for optimising drug detection and ionisation in MALDI imaging studies.

    Science.gov (United States)

    Huber, K; Aichler, M; Sun, N; Buck, A; Li, Z; Fernandez, I E; Hauck, S M; Zitzelsberger, H; Eickelberg, O; Janssen, K P; Keller, U; Walch, A

    2014-10-01

    The aim of this study was to establish an ex vivo model for a faster optimisation of sample preparation procedures, for example matrix choice, in matrix-assisted laser desorption/ionisation (MALDI) drug imaging studies. The ionisation properties of four drugs, afatinib, erlotinib, irinotecan and pirfenidone, were determined in an ex vivo tissue experiment by spotting decreasing dilution series onto liver sections. Hereby, the drug signals were distinctly detectable using different matrix compounds, which allowed the selection of the optimal matrix for each drug. The analysis of afatinib and erlotinib yielded high drug signals with α-cyano-4-hydroxycinnamic acid matrix, whereas 2,3-dihydroxybenzoic acid was identified as optimal matrix for irinotecan and pirfenidone detection. Our method was validated by a MALDI drug imaging approach of in vivo treated mouse tissue resulting in corresponding findings, indicating the spotting method as an appropriate approach to determine the matrix of choice. The present study shows the accordance between the detection of ex vivo spotted drugs and in vivo administered drugs by MALDI-TOF and MALDI-FT-ICR imaging, which has not been demonstrated so far. Our data suggest the ex vivo tissue spotting method as an easy and reliable model to optimise MALDI imaging measurements and to predict drug detection in tissue sections derived from treated mice prior to the recruitment of laboratory animals, which helps to save animals, time and costs.

  20. Rapid antimicrobial susceptibility test for identification of new therapeutics and drug combinations against multidrug-resistant bacteria

    OpenAIRE

    Sun, Wei; Weingarten, Rebecca A; Xu, Miao; Southall, Noel; Dai, Sheng; Shinn, Paul; Sanderson, Philip E; Williamson, Peter R; Frank, Karen M; Zheng, Wei

    2016-01-01

    Current antimicrobial susceptibility testing has limited screening capability for identifying empirical antibiotic combinations to treat severe bacterial infections with multidrug-resistant (MDR) organisms. We developed a new antimicrobial susceptibility assay using automated ultra-high-throughput screen technology in combination with a simple bacterial growth assay. A rapid screening of 5170 approved drugs and other compounds identified 25 compounds with activities against MDR Klebsiella pne...

  1. Rapid detection of drug resistance and mutational patterns of extensively drug-resistant strains by a novel GenoType® MTBDRsl assay

    Directory of Open Access Journals (Sweden)

    A K Singh

    2013-01-01

    Full Text Available Background: The emergence of extensively drug-resistant tuberculosis (XDR-TB is a major concern in the India. The burden of XDR-TB is increasing due to inadequate monitoring, lack of proper diagnosis, and treatment. The GenoType ® Mycobacterium tuberculosis drug resistance second line (MTBDRsl assay is a novel line probe assay used for the rapid detection of mutational patterns conferring resistance to XDR-TB. Aim: The aim of this study was to study the rapid detection of drug resistance and mutational patterns of the XDR-TB by a novel GenoType ® MTBDRsl assay. Materials and Methods: We evaluated 98 multidrug-resistant (MDR M. tuberculosis isolates for second line drugs susceptibility testing by 1% proportion method (BacT/ALERT 3D system and GenoType ® MTBDRsl assay for rapid detection of conferring drug resistance to XDR-TB. Results: A total of seven (17.4% were identified as XDR-TB by using standard phenotypic method. The concordance between phenotypic and GenoType ® MTBDRsl assay was 91.7-100% for different antibiotics. The sensitivity and specificity of the MTBDRsl assay were 100% and 100% for aminoglycosides; 100% and 100% for fluoroquinolones; 91.7% and 100% for ethambutol. The most frequent mutations and patterns were gyrA MUT1 (A90V in seven (41.2% and gyrA + WT1-3 + MUT1 in four (23.5%; rrs MUT1 (A1401G in 11 (64.7%, and rrs WT1-2 + MUT1 in eight (47.1%; and embB MUT1B (M306V in 11 (64.7% strains. Conclusions: These data suggest that the GenoType ® MTBDRsl assay is rapid, novel test for detection of resistance to second line anti-tubercular drugs. This assay provides additional information about the frequency and mutational patterns responsible for XDR-TB resistance.

  2. Reflectometric monitoring of the dissolution process of thin polymeric films.

    Science.gov (United States)

    Laitinen, Riikka; Räty, Jukka; Korhonen, Kristiina; Ketolainen, Jarkko; Peiponen, Kai-Erik

    2017-05-15

    Pharmaceutical thin films are versatile drug-delivery platforms i.e. allowing transdermal, oral, sublingual and buccal administration. However, dissolution testing of thin films is challenging since the commonly used dissolution tests for conventional dosage forms correspond rather poorly to the physiological conditions at the site of administration. Here we introduce a traditional optical reflection method for monitoring the dissolution behavior of thin polymeric films. The substances, e.g. drug molecules, released from the film generate an increase in the refractive index in the liquid medium which can be detected by reflectance monitoring. Thin EUDRAGIT(®) RL PO poly(ethyl acrylate-co-methyl methacrylate-co trimethylammonioethyl methacrylate chloride) (RLPO) films containing the model drug perphenazine (PPZ) were prepared by spraying on a glass substrate. The glass substrates were placed inside the flow cell in the reflectometer which was then filled with phosphate buffer solution. Dissolution was monitored by measuring the reflectance of the buffer liquid. The method was able to detect the distinctive dissolution characteristics of different film formulations and measured relatively small drug concentrations. In conclusion, it was demonstrated that a traditional optical reflection method can provide valuable information about the dissolution characteristics of thin polymeric films in low liquid volume surroundings. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Physicochemical characterization and dissolution properties of ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-04-20

    Apr 20, 2009 ... inclusion complex and a stability constant value of 914 M-1. Solubility and dissolution ... the co-evaporated and freeze-dried systems indicated strong drug amorphization and/or inclusion of. PYR in the CD cavities. .... 50 mg of PYR, to 5 ml simulated gastric fluid (without enzyme) pH. 1.2 [containing 2.0 g/L ...

  4. Short communication. Challenges relating to comparison of flavonoid glycosides dissolution profiles from Sutherlandia frutescens products.

    Science.gov (United States)

    Mbamalu, Oluchi N; Syce, James; Samsodien, Halima

    2017-03-01

    Unlike the case of conventional drug formulations, dissolution tests have hitherto not been required for herbal medicinal products commercially available in South Africa. This study investigated dissolution of the South African Sutherlandia frutescens using selected flavonoid glycosides as marker compounds. Dissolution of markers was assessed in three dissolution media at pH 1.2, 4.5 and 6.8, and samples were analysed using a validated HPLC method. The dissolution profile of each marker varied for the different materials investigated. All three media utilised showed differences in flavonoid glycoside dissolution between the S. frutescens products evaluated, with f2 values dissolution from any two of the materials. Dissolution of S. frutescens materials could thus be characterised using the markers in all the media tested. This tool may be employed in the future for comparison of orally administered S. frutescens products, provided between- batch variability is evaluated and found less than between-sample variability.

  5. Avaliação do perfil de dissolução de comprimidos de ciprofloxacino 250 mg comercializados como similares no Brasil Dissolution profile evaluation of ciprofloxacin 250 mg tablets marketed as similar drugs in Brazil

    Directory of Open Access Journals (Sweden)

    Nilson Oliveira Gonçalves Pita

    2004-09-01

    Full Text Available O presente trabalho avaliou, in vitro, oito especialidades farmacêuticas contendo ciprofloxacino (250 mg, sendo o produto C, o medicamento referência (Cipro® fabricado pela Bayer® S.A. e A, B, D, E, F, G e H medicamentos considerados similares. Além do teste de dissolução preconizado pela Farmacopéia americana, foi traçado o perfil de dissolução de cada amostra a partir do qual foram calculados parâmetros de eficiência de dissolução (ED. O preço máximo ao consumidor também foi levantado, para que fosse possível compará-lo com o desempenho dos produtos. Os resultados obtidos demonstram que todas as amostras atendem aos critérios especificados pelo teste de dissolução descrito na USP 24 ed., mas somente os produtos B, C, E e H foram aprovados no primeiro estágio (S1. Após tratamento estatístico empregando-se ANOVA e teste de Tukey, para os valores de eficiência de dissolução, notou-se que os produtos A e D, B e C, B e E e C e H são semelhantes quanto à liberação do fármaco in vitro. Entretanto, os produtos que mostraram melhor desempenho quanto à liberação de ciprofloxacino in vitro não são os mesmos que se apresentam como melhor opção de custo ao consumidor.The present study has assessed, in vitro, eight pharmaceutical brands containing ciprofloxacin (250 mg. The product C is the reference drug (Cipro® - Bayer® S/A and A, B, D, E, F, G and H are similar drugs. The following physicochemical tests have been carried out: dissolution test and dissolution profile, from which dissolution efficiency (DE have been calculate. The maximum price for consumer has also been obtained, in order that it was possible to compare it with the performance of the products. The results show that all the produts comply with USP specifications, but only the products, B, C, E and H have been approved on the first stage (S1. After statistic treatment, by applying ANOVA and Tukey test for DE values, it has been noted that the

  6. Rapid analysis of the interactions between drugs and human serum albumin (HSA) using high-performance affinity chromatography (HPAC).

    Science.gov (United States)

    Kim, Hee Seung; Wainer, Irving W

    2008-07-01

    This study used a combination of zonal elution and frontal affinity chromatography on immobilized human serum albumin (HSA) high-performance affinity chromatography (HPAC) column to examine the association constants of various compounds that have been studied by equilibrium dialysis or ultra filtration. A standard plot was generated from retention factors of reference compounds using zonal elution chromatography against association constants of reference compounds using frontal affinity chromatography. The linear relationship was established (r2=0.9993) between retention factors and association constants of reference compounds. This standard plot was later used for rapid determination of association constants of various drugs which show low to medium binding affinity to HSA. Association constants of those drugs from this study were compared to that of more generally used methods (i.e., equilibrium dialysis or ultra filtration) from literature and resulted in a relatively high correlation (r2=0.945) value. This combination of zonal elution and frontal affinity chromatography method for determining association constants showed several advantages against traditional methods. Depending on drugs of interest, an association constant of drug to HSA can be measured as fast as 1.5 min. Other notable advantages include an ease of automation and its ability to distinguish association constants of chiral compounds at the same time. The same approach could be used for studying interaction of other drugs and proteins and should further improve overall drug screening process.

  7. Rapid Detection and Identification of Overdose Drugs in Saliva by Surface-Enhanced Raman Scattering Using Fused Gold Colloids

    Directory of Open Access Journals (Sweden)

    Frank Inscore

    2011-07-01

    Full Text Available The number of drug-related emergency room visits in the United States doubled from 2004 to 2009 to 4.6 million. Consequently there is a critical need to rapidly identify the offending drug(s, so that the appropriate medical care can be administered. In an effort to meet this need we have been investigating the ability of surface-enhanced Raman spectroscopy (SERS to detect and identify numerous drugs in saliva at ng/mL concentrations within 10 minutes. Identification is provided by matching measured spectra to a SERS library comprised of over 150 different drugs, each of which possess a unique spectrum. Trace detection is provided by fused gold colloids trapped within a porous glass matrix that generate SERS. Speed is provided by a syringe-driven sample system that uses a solid-phase extraction capillary combined with a SERS-active capillary in series. Spectral collection is provided by a portable Raman analyzer. Here we describe successful measurement of representative illicit, prescribed, and over-the-counter drugs by SERS, and 50 ng/mL cocaine in saliva as part of a focused study.

  8. Efavirenz Dissolution Enhancement IV-Antisolvent Nanocrystallization by Sonication, Physical Stability, and Dissolution.

    Science.gov (United States)

    Sartori, Gabriela Julianelly; Prado, Livia Deris; Rocha, Helvécio Vinícius Antunes

    2017-11-01

    Efavirenz is a fundamental drug in the HIV therapy; however, it has a low bioavailability due to low water solubility. Particle nanonization should enhance its dissolution and therefore its bioavailability. Nanocrystallization is a promising technique for preparing drug nanocrystals. A solution containing efavirenz (EFV) and methanol was added to an aqueous solution of particle stabilizers, under sonication. The adequate polymer stabilizer and its concentration and drug load were evaluated. Particle size and zeta potential of suspensions were measured. Nanosuspensions were freeze-dried and the resulting powder was characterized by some techniques, with special attention to dissolution. Particle size and zeta potential analysis showed that HMPC and PVP were the most suitable polymers. All samples prepared with these stabilizers had nanosized particles and proper zeta potential; however, sedimentation and particle growth were detected with Turbiscan™. Time-related destabilization occurred when the lowest polymer concentration of 20% was used. SEM analysis of the dried powder shows film formation for suspensions with 40% of polymer and particle aggregation in samples with less polymer. Dissolution profiles of samples were higher than EFV raw material, although the lower the polymer concentration, the higher the dissolution.

  9. Adenovirus-vectored drug-vaccine duo as a rapid-response tool for conferring seamless protection against influenza.

    Directory of Open Access Journals (Sweden)

    Jianfeng Zhang

    Full Text Available Few other diseases exert such a huge toll of suffering as influenza. We report here that intranasal (i.n. administration of E1/E3-defective (ΔE1E3 adenovirus serotype 5 (Ad5 particles rapidly induced an anti-influenza state as a means of prophylactic therapy which persisted for several weeks in mice. By encoding an influenza virus (IFV hemagglutinin (HA HA1 domain, an Ad5-HA1 vector conferred rapid protection as a prophylactic drug followed by elicitation of sustained protective immunity as a vaccine for inducing seamless protection against influenza as a drug-vaccine duo (DVD in a single package. Since Ad5 particles induce a complex web of host responses, which could arrest influenza by activating a specific arm of innate immunity to impede IFV growth in the airway, it is conceivable that this multi-pronged influenza DVD may escape the fate of drug resistance that impairs the current influenza drugs.

  10. Solubility limits on radionuclide dissolution

    Energy Technology Data Exchange (ETDEWEB)

    Kerrisk, J.F.

    1984-12-31

    This paper examines the effects of solubility in limiting dissolution rates of a number of important radionuclides from spent fuel and high-level waste. Two simple dissolution models were used for calculations that would be characteristics of a Yucca Mountain repository. A saturation-limited dissolution model, in which the water flowing through the repository is assumed to be saturated with each waste element, is very conservative in that it overestimates dissolution rates. A diffusion-limited dissolution model, in which element-dissolution rates are limited by diffusion of waste elements into water flowing past the waste, is more realistic, but it is subject to some uncertainty at this time. Dissolution rates of some elements (Pu, Am, Sn, Th, Zr, Sm) are always limited by solubility. Dissolution rates of other elements (Cs, Tc, Np, Sr, C, I) are never solubility limited; their release would be limited by dissolution of the bulk waste form. Still other elements (U, Cm, Ni, Ra) show solubility-limited dissolution under some conditions. 9 references, 3 tables.

  11. Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs - Toxicity Evaluation of Homeopathic Drugs Using Zebrafish Embryo Model -

    Directory of Open Access Journals (Sweden)

    Himanshu R Gupta

    2016-12-01

    exposure times used in this study. The embryonic zebrafish model is recommended as a well-established method for rapidly assessing the toxicity of homeopathic drugs.

  12. Rapid identification of drug-type strains in Cannabis sativa using loop-mediated isothermal amplification assay.

    Science.gov (United States)

    Kitamura, Masashi; Aragane, Masako; Nakamura, Kou; Watanabe, Kazuhito; Sasaki, Yohei

    2017-01-01

    In Cannabis sativa L., tetrahydrocannabinol (THC) is the primary psychoactive compound and exists as the carboxylated form, tetrahydrocannabinolic acid (THCA). C. sativa is divided into two strains based on THCA content-THCA-rich (drug-type) strains and THCA-poor (fiber-type) strains. Both strains are prohibited by law in many countries including Japan, whereas the drug-type strains are regulated in Canada and some European countries. As the two strains cannot be discriminated by morphological analysis, a simple method for identifying the drug-type strains is required for quality control in legal cultivation and forensic investigation. We have developed a novel loop-mediated isothermal amplification (LAMP) assay for identifying the drug-type strains of C. sativa. We designed two selective LAMP primer sets for on-site or laboratory use, which target the drug-type THCA synthase gene. The LAMP assay was accomplished within approximately 40 min. The assay showed high specificity for the drug-type strains and its sensitivity was the same as or higher than that of conventional polymerase chain reaction. We also showed the effectiveness of melting curve analysis that was conducted after the LAMP assay. The melting temperature values of the drug-type strains corresponded to those of the cloned drug-type THCA synthase gene, and were clearly different from those of the cloned fiber-type THCA synthase gene. Moreover, the LAMP assay with simple sample preparation could be accomplished within 1 h from sample treatment to identification without the need for special devices or techniques. Our rapid, sensitive, specific, and simple assay is expected to be applicable to laboratory and on-site detection.

  13. Introducing rapid diagnostic tests for malaria into registered drug shops in Uganda: lessons learned and policy implications.

    Science.gov (United States)

    Mbonye, Anthony K; Clarke, Sîan E; Lal, Sham; Chandler, Clare I; Hutchinson, Eleanor; Hansen, Kristian S; Magnussen, Pascal

    2015-11-14

    Malaria is a major public health problem in Uganda and the current policy recommends introduction of rapid diagnostic tests for malaria (RDTs) to facilitate effective case management. However, provision of RDTs in drug shops potentially raises a new set of issues, such as adherence to RDTs results, management of severe illnesses, referral of patients, and relationship with caretakers. The main objective of the study was to examine the impact of introducing RDTs in registered drug shops in Uganda and document lessons and policy implications for future scale-up of malaria control in the private health sector. A cluster-randomized trial introducing RDTs into registered drug shops was implemented in central Uganda from October 2010 to July 2012. An evaluation was undertaken to assess the impact and the processes involved with the introduction of RDTs into drug shops, the lessons learned and policy implications. Introducing RDTs into drug shops was feasible. To scale-up this intervention however, drug shop practices need to be regulated since the registration process was not clear, supervision was inadequate and record keeping was poor. Although initially it was anticipated that introducing a new practice of record keeping would be cumbersome, but at evaluation this was not found to be a constraint. This presents an important lesson for introducing health management information system into drug shops. Involving stakeholders, especially the district health team, in the design was important for ownership and sustainability. The involvement of village health teams in community sensitization to the new malaria treatment and diagnosis policy was a success and this strategy is recommended for future interventions. Introducing RDTs into drug shops was feasible and it increased appropriate treatment of malaria with artemisinin-based combination therapy. It is anticipated that the lessons presented will help better implementation of similar interventions in the private sector.

  14. Coherent anti-Stokes Raman Scattering (CARS) Microscopy Visualizes Pharmaceutical Tablets During Dissolution

    NARCIS (Netherlands)

    Fussell, A.L.; Kleinebudde, P.; Herek, Jennifer Lynn; Strachan, C.J.; Offerhaus, Herman L.

    2014-01-01

    Traditional pharmaceutical dissolution tests determine the amount of drug dissolved over time by measuring drug content in the dissolution medium. This method provides little direct information about what is happening on the surface of the dissolving tablet. As the tablet surface composition and

  15. Strongly enhanced dissolution rate of fenofibrate solid dispersion tablets by incorporation of superdisintegrants

    NARCIS (Netherlands)

    Srinarong, P.; Faber, J.H.; Visser, M.R.; Hinrichs, W.L.J.; Frijlink, H.W.

    2009-01-01

    In this study, it was shown that the incorporation of superdisintegrants in solid dispersion tablets containing a high drug load can strongly enhance the dissolution rate of the highly lipophilic drug fenofibrate. In addition, the dissolution rate was more increased when the superdisintegrant was

  16. Application of lean manufacturing concepts to drug discovery: rapid analogue library synthesis.

    Science.gov (United States)

    Weller, Harold N; Nirschl, David S; Petrillo, Edward W; Poss, Michael A; Andres, Charles J; Cavallaro, Cullen L; Echols, Martin M; Grant-Young, Katherine A; Houston, John G; Miller, Arthur V; Swann, R Thomas

    2006-01-01

    The application of parallel synthesis to lead optimization programs in drug discovery has been an ongoing challenge since the first reports of library synthesis. A number of approaches to the application of parallel array synthesis to lead optimization have been attempted over the years, ranging from widespread deployment by (and support of) individual medicinal chemists to centralization as a service by an expert core team. This manuscript describes our experience with the latter approach, which was undertaken as part of a larger initiative to optimize drug discovery. In particular, we highlight how concepts taken from the manufacturing sector can be applied to drug discovery and parallel synthesis to improve the timeliness and thus the impact of arrays on drug discovery.

  17. Development and validation of a dissolution test for diltiazem hydrochloride in immediate release capsules

    Directory of Open Access Journals (Sweden)

    Taciane Ferreira Mendonça

    2011-01-01

    Full Text Available This work describes the development and validation of a dissolution test for 60 mg of diltiazem hydrochloride in immediate release capsules. The best dissolution in vitro profile was achieved using potassium phosphate buffer at pH 6.8 as the dissolution medium and paddle as the apparatus at 50 rpm. The drug concentrations in the dissolution media were determined by UV spectrophotometry and HPLC and a statistical analysis revealed that there were significant differences between HPLC and spectrophotometry. This study illustrates the importance of an official method for the dissolution test, since there is no official monograph for diltiazem hydrochloride in capsules.

  18. Drug-Related Hyponatremic Encephalopathy: Rapid Clinical Response Averts Life-Threatening Acute Cerebral Edema

    OpenAIRE

    Siegel, Arthur J; Forte, Sophie S.; Bhatti, Nasir A.; Gelda, Steven E.

    2016-01-01

    Patient: Female, 63 Final Diagnosis: Drug-induced hyponatremic encephalopathy Symptoms: Seizures ? coma Medication: Hypertonic 3% saline infusion Clinical Procedure: ? Specialty: Internal Medicine Objective: Unusual clinical course Background: Drug-induced hyponatremia characteristically presents with subtle psychomotor symptoms due to its slow onset, which permits compensatory volume adjustment to hypo-osmolality in the central nervous system. Due mainly to the syndrome of inappropriate anti...

  19. Surface-stress sensors for rapid and ultrasensitive detection of active free drugs in human serum

    Science.gov (United States)

    Ndieyira, Joseph W.; Kappeler, Natascha; Logan, Stephen; Cooper, Matthew A.; Abell, Chris; McKendry, Rachel A.; Aeppli, Gabriel

    2014-03-01

    There is a growing appreciation that mechanical signals can be as important as chemical and electrical signals in biology. To include such signals in a systems biology description for understanding pathobiology and developing therapies, quantitative experiments on how solution-phase and surface chemistry together produce biologically relevant mechanical signals are needed. Because of the appearance of drug-resistant hospital `superbugs', there is currently great interest in the destruction of bacteria by bound drug-target complexes that stress bacterial cell membranes. Here, we use nanomechanical cantilevers as surface-stress sensors, together with equilibrium theory, to describe quantitatively the mechanical response of a surface receptor to different antibiotics in the presence of competing ligands in solution. The antibiotics examined are the standard, Food and Drug Administration-approved drug of last resort, vancomycin, and the yet-to-be approved oritavancin, which shows promise for controlling vancomycin-resistant infections. The work reveals variations among strong and weak competing ligands, such as proteins in human serum, that determine dosages in drug therapies. The findings further enhance our understanding of the biophysical mode of action of the antibiotics and will help develop better treatments, including choice of drugs as well as dosages, against pathogens.

  20. Three-dimensional simulations of fracture dissolution

    Science.gov (United States)

    Starchenko, Vitaliy; Marra, Cameron J.; Ladd, Anthony J. C.

    2016-09-01

    Numerical studies of fracture dissolution are frequently based on two-dimensional models, where the fracture geometry is represented by an aperture field h(x,y). However, it is known that such models can break down when the spatial variations in aperture are rapid or large in amplitude; for example, in a rough fracture or when instabilities in the dissolution front develop into pronounced channels (or wormholes). Here we report a finite-volume implementation of a three-dimensional reactive transport model using the OpenFOAM® toolkit. Extensions to the OpenFOAM source code have been developed which displace and then relax the mesh in response to variations in the surface concentration; up to 100-fold increases in fracture aperture are possible without remeshing. Our code has simulated field-scale fractures with physical dimensions of about 10 m. We report simulations of smooth fractures, with small, well-controlled perturbations in fracture aperture introduced at the inlet. This allows for systematic convergence studies and for detailed comparisons with results from a two-dimensional model. Initially, the fracture aperture develops similarly in both models, but as local inhomogeneities develop the results start to diverge. We investigate numerically the onset of instabilities in the dissolution of fractures with small random variations in the initial aperture field. Our results show that elliptical cross sections, which are characteristic of karstic conduits, can develop very rapidly, on time scales of 10-20 years in calcite rocks.

  1. A high throughput solubility assay for drug discovery using microscale shake-flask and rapid UHPLC-UV-CLND quantification.

    Science.gov (United States)

    Lin, Baiwei; Pease, Joseph H

    2016-04-15

    The rapid determination of key physical properties of lead compounds is essential to the drug discovery process. Solubility is one of the most important properties since good solubility is needed not only for obtaining reliable in vitro and in vivo assay results in early discovery but also to ensure sufficient concentration of the drug being in circulation to get the desired therapeutic exposure at the target of interest. In order for medicinal chemists to tune solubility of lead compounds, a rapid assay is needed to provide solubility data that is accurate and predictive so that it can be reliably used for designing the next generation of compounds with improved properties. To ensure speed and data quality, we developed a high throughput solubility assay that utilizes a single calibration UHPLC-UV-CLND method and a 24h shake-flask format for rapid quantification. A set of 46 model compounds was used to demonstrate that the method is accurate, reproducible and predictive. Here we present development of the assay, including evaluation of quantification method, filtration membranes, equilibrium times, DMSO concentrations, and buffer conditions. A comparison of thermodynamic solubility results to our high throughput 24h shake-flask solubility assay results is also discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Prospective multicentre evaluation of the direct nitrate reductase assay for the rapid detection of extensively drug-resistant tuberculosis.

    Science.gov (United States)

    Martin, Anandi; Imperiale, Belen; Ravolonandriana, Pascaline; Coban, Ahmet Yilmaz; Akgunes, Alper; Ikram, Aamer; Satti, Luqman; Odoun, Mathieu; Pandey, Pooja; Mishra, Manvi; Affolabi, Dissou; Singh, Urvashi; Rasolofo, Voahangy; Morcillo, Nora; Vandamme, Peter; Palomino, Juan Carlos

    2014-02-01

    To perform a multicentre study evaluating the performance of the direct nitrate reductase assay (NRA) for the detection of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in sputum samples. The study was conducted in six laboratories performing tuberculosis diagnosis that were located in six different countries. The NRA was performed directly on sputum samples in parallel with the reference method used at each site. Detection of resistance was performed for rifampicin, isoniazid, ofloxacin and kanamycin. Excellent agreement was obtained for all drugs tested at the majority of sites. The accuracy was 93.7%-100% for rifampicin, 88.2%-100% for isoniazid, 94.6%-100% for ofloxacin and 100% for kanamycin. The majority of NRA results were available at day 21 for sites 1, 2 and 5. Site 3 had a turnaround time of 13.9 days, at site 4 it was 18.4 days and at site 6 it was 16.2 days. The contamination rate ranged between 2.5% and 12%. Rapid detection of drug resistance by the direct NRA on sputum smear-positive samples was accurate and easy to implement in clinical diagnostic laboratories, making it a good alternative for rapid screening for MDR and XDR tuberculosis.

  3. Comparative Genomic Analysis of Rapid Evolution of an Extreme-Drug-Resistant Acinetobacter baumannii Clone

    DEFF Research Database (Denmark)

    Tan, Sean Yang-Yi; Chua, Song Lin; Liu, Yang

    2013-01-01

    , comparative genomics has been employed to analyze the rapid evolution of an EDR Acinetobacter baumannii clone from the intensive care unit (ICU) of Rigshospitalet at Copenhagen. Two resistant A. baumannii strains, 48055 and 53264, were sequentially isolated from two individuals who had been admitted to ICU...

  4. Chemical imaging of Oral Solid Dosage Forms and Changes upon Dissolution Using Coherent Anti-Stokes Raman Scattering Microscopy

    NARCIS (Netherlands)

    Windbergs, Maike; Jurna, M.; Offerhaus, Herman L.; Herek, Jennifer Lynn; Kleinebudde, Peter; Strachan, Clare J.

    2009-01-01

    Dissolution testing is a crucial part of pharmaceutical dosage form investigations and is generally performed by analyzing the concentration of the released drug in a defined volume of flowing dissolution medium. As solid-state properties of the components affect dissolution behavior to a large and

  5. Rhabdomyolysis in MDMA intoxication : A rapid and underestimated killer. "clean" Ecstasy, a safe party drug?

    NARCIS (Netherlands)

    Eede, Herve Vanden; Montenij, Leon J.; Touw, Daan J.; Norris, Elizabeth M.

    Background: Ecstasy is a popular drug among young adults. It is often thought to be safe. The dose of methylenedioxymethamphetamine (MDMA) in a tablet of Ecstasy varies greatly, and there is also a difference in individual response to a dose of MDMA. Objectives: To increase the awareness of

  6. Direct nitrate reductase assay versus microscopic observation drug susceptibility test for rapid detection of MDR-TB in Uganda.

    Directory of Open Access Journals (Sweden)

    Freddie Bwanga

    Full Text Available The most common method for detection of drug resistant (DR TB in resource-limited settings (RLSs is indirect susceptibility testing on Lowenstein-Jensen medium (LJ which is very time consuming with results available only after 2-3 months. Effective therapy of DR TB is therefore markedly delayed and patients can transmit resistant strains. Rapid and accurate tests suitable for RLSs in the diagnosis of DR TB are thus highly needed. In this study we compared two direct techniques--Nitrate Reductase Assay (NRA and Microscopic Observation Drug Susceptibility (MODS for rapid detection of MDR-TB in a high burden RLS. The sensitivity, specificity, and proportion of interpretable results were studied. Smear positive sputum was collected from 245 consecutive re-treatment TB patients attending a TB clinic in Kampala, Uganda. Samples were processed at the national reference laboratory and tested for susceptibility to rifampicin and isoniazid with direct NRA, direct MODS and the indirect LJ proportion method as reference. A total of 229 specimens were confirmed as M. tuberculosis, of these interpretable results were obtained in 217 (95% with either the NRA or MODS. Sensitivity, specificity and kappa agreement for MDR-TB diagnosis was 97%, 98% and 0.93 with the NRA; and 87%, 95% and 0.78 with the MODS, respectively. The median time to results was 10, 7 and 64 days with NRA, MODS and the reference technique, respectively. The cost of laboratory supplies per sample was low, around 5 USD, for the rapid tests. The direct NRA and MODS offered rapid detection of resistance almost eight weeks earlier than with the reference method. In the study settings, the direct NRA was highly sensitive and specific. We consider it to have a strong potential for timely detection of MDR-TB in RLS.

  7. In vitro dissolution of proton-pump inhibitor products intended for paediatric and geriatric use in physiological bicarbonate buffer.

    Science.gov (United States)

    Liu, Fang; Shokrollahi, Honaz

    2015-05-15

    Proton-pump inhibitor (PPI) products based on enteric coated multiparticulates are design to meet the needs of patients who cannot swallow tablets such as children and older adults. Enteric coated PPI preparations exhibit delays in in vivo absorption and onset of antisecretory effects, which is not reflected by the rapid in vitro dissolution in compendial pH 6.8 phosphate buffer commonly used for assessment of these products. A more representative and physiological medium, pH 6.8 mHanks bicarbonate buffer, was used in this study to evaluate the in vitro dissolution of enteric coated multiparticulate-based PPI products. Commercially available omeprazole, lansoprazole and esomeprazole products were subject to dissolution tests using USP-II apparatus in pH 4.5 phosphate buffer saline for 45 min (acid stage) followed by pH 6.8 phosphate buffer or pH 6.8 mHanks bicarbonate buffer. In pH 6.8 phosphate buffer, all nine tested products displayed rapid and comparable dissolution profiles meeting the pharmacopeia requirements for delayed release preparations. In pH 6.8 mHanks buffer, drug release was delayed and failed the pharmacopeia requirements from most enteric coated preparations. Despite that the same enteric polymer, methacrylic acid-ethyl acrylate copolymer (1:1), was applied to all commercial multiparticulate-based products, marked differences were observed between dissolution profiles of these preparations. The use of pH 6.8 physiological bicarbonate (mHanks) buffer can serve as a useful tool to provide realistic and discriminative in vitro release assessment of enteric coated PPI preparations and to assist rational formulation development of these products. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Evaluation of GenoType® MTBDRplus assay for rapid detection of drug susceptibility testing of multi-drug resistance tuberculosis in Northern India.

    Science.gov (United States)

    Maurya, Anand Kumar; Umrao, Jyoti; Singh, Amresh Kumar; Kant, Surya; Kushwaha, Ram Awadh Singh; Dhole, Tapan N

    2013-01-01

    The problem of multi-drug resistance tuberculosis (MDR-TB) is growing in several hotspots throughout the world. Rapid and accurate diagnosis of MDR-TB is crucial to facilitate early treatment and to reduce its spread in the community. The aim of the present study was to evaluate the new, novel GenoType® MTBDRplus assay for rapid detection of drug susceptibility testing (DST) of MDR-TB cases in Northern India. A total of 550 specimens were collected from highly suspected drug resistant from pulmonary and extra-pulmonary TB cases. All the specimens were processed by Ziehl- Neelsen staining, culture, differentiation by the GenoType® CM assay, first line DST using BacT/ALERT 3D system and GenoType® MTBDRplus assay. The concordance of the GenoType® MTBDRplus assay was calculated in comparison with conventional DST results. Overall the sensitivity for detection of rifampicin, isoniazid and MDR-TB resistance by GenoType® MTBDRplus assay was 98.0%, 98.4% and 98.2% respectively. Out of 55 MDR-TB strains, 45 (81.8%), 52 (94.5%) and 17 (30.9%) strains showed mutation in rpoB, katG and inhA genes respectively (P < 0.05). The most prominent mutations in rpoB, katG and inhA genes were; 37 (67.3%) in S531L, 52 (94.5%) in S315T1 and 11 (20%) in C15T regions respectively (P < 0.05). Our study demonstrated a high concordance between the GenoType® MTBDRplus assay resistance patterns and those were observed by conventional DST with good sensitivity, specificity with short turnaround times and to control new cases of MDR-TB in countries with a high prevalence of MDR-TB.

  9. An Implantable MEMS Drug Delivery Device for Rapid Delivery in Ambulatory Emergency Care

    Science.gov (United States)

    2009-06-01

    vol. 32, pp. 377-379, 2000. I. Singer and H. L. Edmonds, "Head-up tilt testing predicts syncope during ventricular tachycardia in implantable... pulse through it, as has been demonstrated in the past (Maloney, 2005). The limitations of this solution are: the significant increase in current to...H. Brem, M. J. Cima, and R. Langer, "Multi- pulse drug delivery from a resorbable polymeric microchip device," Nature Materials, vol. 2, pp. 767-772

  10. Development of dissolution test method for a telmisartan/amlodipine besylate combination using synchronous derivative spectrofluorimetry

    Directory of Open Access Journals (Sweden)

    Panikumar Durga Anumolu

    2014-04-01

    Full Text Available The dissolution process is considered an important in vitro tool to evaluate product quality and drug release behavior. Single dissolution methods for the analysis of combined dosage forms are preferred to simplify quality control testing. The objective of the present work was to develop and validate a single dissolution test for a telmisartan (TEL and amlodipine besylate (AML combined tablet dosage form. The sink conditions, stability and specificity of both drugs in different dissolution media were tested to choose a discriminatory dissolution method, which uses an USP type-II apparatus with a paddle rotating at 75 rpm, with 900 mL of simulated gastric fluid (SGF without enzymes as the dissolution medium. This dissolution methodology provided good dissolution profiles for both TEL and AML and was able to discriminate changes in the composition and manufacturing process. To quantify both drugs simultaneously, a synchronous first derivative spectrofluorimetric method was developed and validated. Drug release was analyzed by a fluorimetric method at 458 nm and 675 nm for AML and TEL, respectively. The dissolution method was validated as per ICH guidance.

  11. Dissolution of materials in artificial skin surface film liquids.

    Science.gov (United States)

    Stefaniak, Aleksandr B; Harvey, Christopher J

    2006-12-01

    The dissolution of chemical constituents from jewelry, textiles, cosmetics, drugs, industrial chemicals, and particles in direct and prolonged contact with human skin is often assessed in vitro using artificial skin surface film liquids (SSFL). To provide meaningful results, the composition of artificial SSFL should accurately mimic human sweat and sebum, and the conditions of the in vitro test system should accurately reflect in vivo skin conditions. We summarized the reported composition of human SSFL and compared it to 45 different formulations of artificial sweat and 18 formulations of artificial sebum (studies published from 1940 to 2005). Conditions of in vitro dissolution test systems were reviewed and compared to in vivo skin conditions. The concentrations of individual constituents and pH of artificial sweat and concentrations of artificial sebum constituents are not always within ranges reported for human SSFL. Nearly all artificial SSFL lack many of the constituents in human SSFL. To develop a comprehensive model SSFL, we propose a standard SSFL, modified from the two best published sweat and sebum formulations. Little is known concerning the influence of test system conditions on dissolution, including SSFL temperature, container material composition, agitation, and physicochemical properties of the test article on dissolution. Thus, both a need and an opportunity exist for standardizing the composition of artificial SSFL and in vitro dissolution test methodologies. To standardize in vitro dissolution test systems, we recommend: maintaining artificial SSFL at a biologically relevant temperature appropriate to the human activity being modeled, carefully selecting test and sample storage containers to avoid bias in dissolution measurements, accounting for friction between a test article and skin in a biologically plausible manner, and physicochemical characterization of the test article or material to better understand mechanisms of dissolution and

  12. Comparative dissolution testing of paracetamol commercial tablet dosage forms.

    Science.gov (United States)

    Ozkan, Y; Ozalp, Y; Savaşer, A; Ozkan, S A

    2000-01-01

    Dissolution can best be described as a tool that can provide valuable information about the availability of a drug product. In this study, nine different paracetamol tablet dosage forms available on the Turkish Drug Market have been investigated and physical controls were realized. Paddle and rotating basket apparatus methods were applied to all the formulations. In order to evaluate the dissolution rates, five different kinetics have been studied and the best fitting kinetics was found to be the Hixson-Crowell kinetics. It was found that all the preparations are in accordance with the Pharmacopeia standards.

  13. Has introduction of rapid drug susceptibility testing at diagnosis impacted treatment outcomes among previously treated tuberculosis patients in Gujarat, India?

    Science.gov (United States)

    Dave, Paresh; Vadera, Bhavin; Kumar, Ajay M V; Chinnakali, Palanivel; Modi, Bhavesh; Solanki, Rajesh; Patel, Pranav; Patel, Prakash; Pujara, Kirit; Nimavat, Pankaj; Shah, Amar; Bharaswadkar, Sandeep; Rade, Kiran; Parmar, Malik; Nair, Sreenivas Achuthan

    2015-01-01

    Revised National TB Control Programme (RNTCP) in India recommends that all previously-treated TB (PT) patients are offered drug susceptibility testing (DST) at diagnosis, using rapid diagnostics and screened out for rifampicin resistance before being treated with standardized, eight-month, retreatment regimen. This is intended to improve the early diagnosis of rifampicin resistance and its appropriate management and improve the treatment outcomes among the rest of the patients. In this state-wide study from Gujarat, India, we assess proportion of PT patients underwent rapid DST at diagnosis and the impact of this intervention on their treatment outcomes. This is a retrospective cohort study involving review of electronic patient-records maintained routinely under RNTCP. All PT patients registered for treatment in Gujarat during January-June 2013 were included. Information on DST and treatment outcomes were extracted from 'presumptive DR-TB patient register' and TB treatment register respectively. We performed a multivariate analysis to assess if getting tested is independently associated with unfavourable outcomes (death, loss-to-follow-up, failure, transfer out). Of 5,829 PT patients, 5306(91%) were tested for drug susceptibility with rapid diagnostics. Overall, 71% (4,113) TB patients were successfully treated - 72% among tested versus 60% among non-tested. Patients who did not get tested at diagnosis had a 34% higher risk of unsuccessful outcomes as compared to those who got tested (aRR - 1.34; 95% CI 1.20-1.50) after adjusting for age, sex, HIV status and type of TB. Unfavourable outcomes (particularly failure and switched to category IV) were higher among INH-resistant patients (39%) as compared to INH-sensitive (29%). Offering DST at diagnosis improved the treatment outcomes among PT patients. However, even among tested, treatment outcomes remained suboptimal and were related to INH resistance and high loss-to-follow-up. These need to be addressed urgently

  14. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2015-08-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  15. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2014-05-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  16. Desorption electrospray ionisation mass spectrometry: A rapid screening tool for veterinary drug preparations and forensic samples from hormone crime investigations

    Energy Technology Data Exchange (ETDEWEB)

    Nielen, M.W.F. [RIKILT Institute of Food Safety, P.O. Box 230, 6700 AE Wageningen (Netherlands); Wageningen University, Laboratory of Organic Chemistry, Dreijenplein 8, 6703 HB Wageningen (Netherlands)], E-mail: michel.nielen@wur.nl; Hooijerink, H. [RIKILT Institute of Food Safety, P.O. Box 230, 6700 AE Wageningen (Netherlands); Claassen, F.C. [Wageningen University, Laboratory of Organic Chemistry, Dreijenplein 8, 6703 HB Wageningen (Netherlands); Engelen, M.C. van [RIKILT Institute of Food Safety, P.O. Box 230, 6700 AE Wageningen (Netherlands); Beek, T.A. van [Wageningen University, Laboratory of Organic Chemistry, Dreijenplein 8, 6703 HB Wageningen (Netherlands)

    2009-04-01

    Hormone and veterinary drug screening and forensics can benefit from the recent developments in desorption electrospray ionisation (DESI) mass spectrometry (MS). In this work the feasibility of DESI application has been studied. Using a linear ion trap or quadrupole time-of-flight (TOF) MS instrument both full-scan and data-dependent collision-induced dissociation MS{sup n} spectra were acquired in seconds without sample preparation. Preliminary data are presented for the rapid screening of (pro)hormone supplement samples, an illegal steroid cocktail and forensic samples from veterinary drug investigations. The potential of this DESI approach is clearly demonstrated since compounds observed could be independently confirmed by liquid chromatography/TOFMS with accurate mass measurement, and/or proton nuclear magnetic resonance spectroscopy. Specific concerns related to false-positive and false-negative findings due to limitations in quantification and memory-effects are briefly discussed. It is envisaged that DESI will achieve a prominent role in hormone and veterinary drug analysis in the near future.

  17. Enhanced dissolution of meloxicam from orodispersible tablets prepared by different methods

    Directory of Open Access Journals (Sweden)

    Ahmed Abd Elbary

    2012-12-01

    Full Text Available The objective of this study was formulation, development and evaluation of meloxicam orodispersible tablets. ODTs were prepared by two methods including sublimation technique where different subliming agents like camphor, menthol and thymol were used with Ac-Di-Sol as a superdisintegrant. Each subliming agent was used in three different concentrations (5, 10 and 15% w/w. Tablets were first prepared and later exposed to vacuum. Meloxicam ODTs were also prepared by freeze-drying an aqueous dispersion of meloxicam containing a matrix former, a sugar alcohol, and a collapse protectant. In addition, different disintegration accelerators were tested (each in 1% w/v including PVP K25, PVP K90, PEG 6000, PEG 4000, PEG 400, tween 80 and tween 20. The prepared ODTs from two methods were evaluated for weight variation, thickness, drug content, friability, hardness, wetting time, in vitro disintegration time and in vitro dissolution study. The best formulation was subjected to stability testing for 3 months at temperatures 40 °C and 75% relative humidity and at 60 °C. All formulations showed disintegration time ranging from 1 to 46 s. All the prepared formulae complied with the pharmacopoeial requirements of the drug contents. T17 gave the best in vitro disintegration and dissolution results. ODT formula T17 has shown no appreciable changes with respect to physical characters, meloxicam content and dissolution profiles when stored at elevated temperatures. In conclusion the results of this work suggest that orodispersible tablets of meloxicam with rapid disintegration time, fast drug release and good hardness can be efficiently and successfully formulated by employing freeze drying and sublimation methods.

  18. Development of in situ ion selective sensors for dissolution

    Energy Technology Data Exchange (ETDEWEB)

    Bohets, Hugo [Antwerp University, Chemistry Department, Groenenborgerlaan 171, B-2020 Antwerpen (Belgium); Vanhoutte, Koen [Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse (Belgium); De Maesschalck, Roy [Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse (Belgium); Cockaerts, Paul [Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse (Belgium); Vissers, Bert [Antwerp University, Chemistry Department, Groenenborgerlaan 171, B-2020 Antwerpen (Belgium); Nagels, Luc J. [Antwerp University, Chemistry Department, Groenenborgerlaan 171, B-2020 Antwerpen (Belgium)]. E-mail: luc.nagels@ua.ac.be

    2007-01-02

    The dissolution of formulations of the drugs dapoxetine, paliperidone, cinnarizine, tetrazepam, mebeverine, loperamide, galantamine and ibuprofen was studied by an in-line potentiometric measurement system. The transpose of a Nikolskii-Eisenman type function performed the conversion of potential to percentage of dissolution. A novel gradient membrane electrode was developed especially for dissolution, varying continuously in composition from an ionically conducting rubber phase to an electronically conducting solid state PVC/graphite composite. The gradient part had a thickness of 200 {mu}m. The electrodes life span exceeded 6 months. An ion exchange procedure was used to prepare them for one specific drug. This enabled us to use one universal electrode built to measure a wide array of drugs. The system parameters such as accuracy, reproducibility and linearity were presented with the data obtained for the drug dapoxetine. In dissolution, accurate measurements were possible from 10{sup -9} to 10{sup -3} M concentrations, for high log P drugs. The effect of t {sub 90} response times on the measurement error was estimated. The t {sub 90} response times of the electrodes were concentration dependent, and varied between 50 and 10 s for, respectively, 10{sup -6} and 10{sup -3} M concentrations. Potential drift was studied in detail. The measurements performed with these electrodes showed an accuracy of 1%, and inter- and intra electrode variabilities of 0.6 and 1.7%, respectively. The electrodes were successfully applied in colloidal media containing suspended matter, typically formed during dissolution of tablets. The advantages and pitfalls of potentiometry over the presently used techniques for dissolution testing are discussed.

  19. Elongation of fibers from highly viscous dextran solutions enables fabrication of rapidly dissolving drug carrying fabrics.

    Science.gov (United States)

    Frampton, John P; Lai, David; Lounds, Maxwell; Chung, Kyeongwoon; Kim, Jinsang; Mansfield, John F; Takayama, Shuichi

    2015-01-28

    A simple method is presented for forming thread-like fibers from highly viscous dextran solutions. Based on the cohesive and adhesive forces between a dextran solution and the substrate to which it is applied, multiple fibers of approximately 10 μm in diameter can be elongated simultaneously. These fibers can be woven into multiple layers to produce fabrics of varying fiber orientations and mechanical properties. Various bioactive agents can be incorporated into the dextran solution prior to fiber formation, including hemostatic and antibiotic agents. Fabrics containing thrombin are capable of coagulating human platelet poor plasma in vitro. Fabrics containing antibiotics are capable of suppressing bacterial growth in a disk diffusion assay. These data suggest that this new material composed entirely of dextran has promise as a drug delivery component in wound dressings. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Rapid evolution of virulence and drug resistance in the emerging zoonotic pathogen Streptococcus suis.

    Directory of Open Access Journals (Sweden)

    Matthew T G Holden

    2009-07-01

    Full Text Available Streptococcus suis is a zoonotic pathogen that infects pigs and can occasionally cause serious infections in humans. S. suis infections occur sporadically in human Europe and North America, but a recent major outbreak has been described in China with high levels of mortality. The mechanisms of S. suis pathogenesis in humans and pigs are poorly understood.The sequencing of whole genomes of S. suis isolates provides opportunities to investigate the genetic basis of infection. Here we describe whole genome sequences of three S. suis strains from the same lineage: one from European pigs, and two from human cases from China and Vietnam. Comparative genomic analysis was used to investigate the variability of these strains. S. suis is phylogenetically distinct from other Streptococcus species for which genome sequences are currently available. Accordingly, approximately 40% of the approximately 2 Mb genome is unique in comparison to other Streptococcus species. Finer genomic comparisons within the species showed a high level of sequence conservation; virtually all of the genome is common to the S. suis strains. The only exceptions are three approximately 90 kb regions, present in the two isolates from humans, composed of integrative conjugative elements and transposons. Carried in these regions are coding sequences associated with drug resistance. In addition, small-scale sequence variation has generated pseudogenes in putative virulence and colonization factors.The genomic inventories of genetically related S. suis strains, isolated from distinct hosts and diseases, exhibit high levels of conservation. However, the genomes provide evidence that horizontal gene transfer has contributed to the evolution of drug resistance.

  1. Rapid evolution of virulence and drug resistance in the emerging zoonotic pathogen Streptococcus suis.

    Science.gov (United States)

    Holden, Matthew T G; Hauser, Heidi; Sanders, Mandy; Ngo, Thi Hoa; Cherevach, Inna; Cronin, Ann; Goodhead, Ian; Mungall, Karen; Quail, Michael A; Price, Claire; Rabbinowitsch, Ester; Sharp, Sarah; Croucher, Nicholas J; Chieu, Tran Bich; Mai, Nguyen Thi Hoang; Diep, To Song; Chinh, Nguyen Tran; Kehoe, Michael; Leigh, James A; Ward, Philip N; Dowson, Christopher G; Whatmore, Adrian M; Chanter, Neil; Iversen, Pernille; Gottschalk, Marcelo; Slater, Josh D; Smith, Hilde E; Spratt, Brian G; Xu, Jianguo; Ye, Changyun; Bentley, Stephen; Barrell, Barclay G; Schultsz, Constance; Maskell, Duncan J; Parkhill, Julian

    2009-07-15

    Streptococcus suis is a zoonotic pathogen that infects pigs and can occasionally cause serious infections in humans. S. suis infections occur sporadically in human Europe and North America, but a recent major outbreak has been described in China with high levels of mortality. The mechanisms of S. suis pathogenesis in humans and pigs are poorly understood. The sequencing of whole genomes of S. suis isolates provides opportunities to investigate the genetic basis of infection. Here we describe whole genome sequences of three S. suis strains from the same lineage: one from European pigs, and two from human cases from China and Vietnam. Comparative genomic analysis was used to investigate the variability of these strains. S. suis is phylogenetically distinct from other Streptococcus species for which genome sequences are currently available. Accordingly, approximately 40% of the approximately 2 Mb genome is unique in comparison to other Streptococcus species. Finer genomic comparisons within the species showed a high level of sequence conservation; virtually all of the genome is common to the S. suis strains. The only exceptions are three approximately 90 kb regions, present in the two isolates from humans, composed of integrative conjugative elements and transposons. Carried in these regions are coding sequences associated with drug resistance. In addition, small-scale sequence variation has generated pseudogenes in putative virulence and colonization factors. The genomic inventories of genetically related S. suis strains, isolated from distinct hosts and diseases, exhibit high levels of conservation. However, the genomes provide evidence that horizontal gene transfer has contributed to the evolution of drug resistance.

  2. Rapid analysis of interaction between six drugs and β2 -adrenergic receptor by injection amount-dependent method.

    Science.gov (United States)

    Zeng, Kaizhu; Wang, Jing; Sun, Zhenyu; Li, Qian; Liao, Sha; Zhao, Xinfeng; Zheng, Xiaohui

    2017-06-01

    Drug-protein interaction analysis has become a considerable topic in life science which includes clarifying protein functions, explaining drug action mechanisms and uncovering novel drug candidates. This work was to determine the association constants (KA ) of six drugs to β2 -adrenergic receptor by injection amount-dependent method using stationary phase containing the immobilized receptor. The values of KA were calculated to be (25.85 ± 0.035) × 104  m-1 for clorprenaline, (42.51 ± 0.054) × 104  m-1 for clenbuterol, (6.67 ± 0.008) × 104  m-1 for terbutaline, (33.99 ± 0.025) × 104  m-1 for tulobuterol, (7.59 ± 0.011) × 104  m-1 for salbutamol and (78.52 ± 0.087) × 104  m-1 for bambuterol. This rank order agreed well with the data determined by zonal elution, frontal analysis and nonlinear chromatography, even using different batches of β2 -AR column. A good correlation was found between the association constants by the current method and radio-ligand binding assay. Our data indicates that the injection amount-dependent method is a powerful alternative for rapid analysis of ligand-receptor interactions. Copyright © 2016 John Wiley & Sons, Ltd.

  3. Rapid synthesis of hybrids and hollow PdO nanostructures by controlled in situ dissolution of a ZnO nanorod template: insights into the formation mechanism and thermal stability

    Science.gov (United States)

    Kundu, Subhajit; Ravishankar, N.

    2016-01-01

    Hollow nanomaterials have attracted a lot of interest by virtue of their wide range of applications that arise primarily due to their unique architecture. A common strategy to synthesize hollow nanomaterials is by nucleation of the shell material over a preformed core and subsequent dissolution of the core in the second step. Herein an ultrafast, microwave route has been demonstrated, to synthesize PdO nanotubes in a single step using ZnO as a sacrificial template. The mechanism of the nanotube formation has been investigated in detail using control experiments. By tuning the starting ratio of PdCl2 : ZnO, hollow to hybrid PdO nanostructures could be obtained using the same method. Conversion of the PdO to Pd nanotubes has been shown by simple NaBH4 treatment. The thermal stability of the PdO nanotubes has been studied. The insights presented here are general and applicable for the synthesis of hybrids/hollow structures in other systems as well.Hollow nanomaterials have attracted a lot of interest by virtue of their wide range of applications that arise primarily due to their unique architecture. A common strategy to synthesize hollow nanomaterials is by nucleation of the shell material over a preformed core and subsequent dissolution of the core in the second step. Herein an ultrafast, microwave route has been demonstrated, to synthesize PdO nanotubes in a single step using ZnO as a sacrificial template. The mechanism of the nanotube formation has been investigated in detail using control experiments. By tuning the starting ratio of PdCl2 : ZnO, hollow to hybrid PdO nanostructures could be obtained using the same method. Conversion of the PdO to Pd nanotubes has been shown by simple NaBH4 treatment. The thermal stability of the PdO nanotubes has been studied. The insights presented here are general and applicable for the synthesis of hybrids/hollow structures in other systems as well. Electronic supplementary information (ESI) available: Details of experiments

  4. Introducing rapid diagnostic tests for malaria into drug shops in Uganda: design and implementation of a cluster randomized trial.

    Science.gov (United States)

    Mbonye, Anthony K; Magnussen, Pascal; Chandler, Clare I R; Hansen, Kristian S; Lal, Sham; Cundill, Bonnie; Lynch, Caroline A; Clarke, Siân E

    2014-07-29

    An intervention was designed to introduce rapid diagnostics tests for malaria (mRDTs) into registered drug shops in Uganda to encourage rational and appropriate treatment of malaria with artemisinin-based combination therapy (ACT). We conducted participatory training of drug shop vendors and implemented supporting interventions to orientate local communities (patients) and the public sector (health facility staff and district officials) to the behavioral changes in diagnosis, treatment and referral being introduced in drug shops. The intervention was designed to be evaluated through a cluster randomized trial. In this paper, we present detailed design, implementation and evaluation experiences in order to help inform future studies of a complex nature. Three preparatory studies (formative, baseline and willingness-to-pay) were conducted to explore perceptions on diagnosis and treatment of malaria at drug shops, and affordable prices for mRDTs and ACTs in order to inform the design of the intervention and implementation modalities. The intervention required careful design with the intention to be acceptable, sustainable and effective. Critical components of intervention were: community sensitization and creating awareness, training of drug shop vendors to diagnose malaria with mRDTs, treat and refer customers to formal health facilities, giving pre-referral rectal artesunate and improved record-keeping. The primary outcome was the proportion of patients receiving appropriately-targeted treatment with ACT, evaluated against microscopy on a research blood slide. Introducing mRDTs in drug shops may seem simple, but our experience of intervention design, conduct and evaluation showed this to be a complex process requiring multiple interventions and evaluation components drawing from a combination of epidemiological, social science and health economics methodologies. The trial was conducted in phases sequenced such that each benefited from the other. The main challenges

  5. Neurophysiological basis of rapid eye movement sleep behavior disorder: informing future drug development

    Directory of Open Access Journals (Sweden)

    Jennum P

    2016-04-01

    Full Text Available Poul Jennum, Julie AE Christensen, Marielle Zoetmulder Department of Clinical Neurophysiology, Faculty of Health Sciences, Danish Center for Sleep Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Abstract: Rapid eye movement (REM sleep behavior disorder (RBD is a parasomnia characterized by a history of recurrent nocturnal dream enactment behavior and loss of skeletal muscle atonia and increased phasic muscle activity during REM sleep: REM sleep without atonia. RBD and associated comorbidities have recently been identified as one of the most specific and potentially sensitive risk factors for later development of any of the alpha-synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, and other atypical parkinsonian syndromes. Several other sleep-related abnormalities have recently been identified in patients with RBD/Parkinson’s disease who experience abnormalities in sleep electroencephalographic frequencies, sleep–wake transitions, wake and sleep stability, occurrence and morphology of sleep spindles, and electrooculography measures. These findings suggest a gradual involvement of the brainstem and other structures, which is in line with the gradual involvement known in these disorders. We propose that these findings may help identify biomarkers of individuals at high risk of subsequent conversion to parkinsonism. Keywords: motor control, brain stem, hypothalamus, hypocretin

  6. Rapid detection of drugs of abuse in saliva using surface enhanced Raman spectroscopy and microfluidics.

    Science.gov (United States)

    Andreou, Chrysafis; Hoonejani, Mehran R; Barmi, Meysam R; Moskovits, Martin; Meinhart, Carl D

    2013-08-27

    We present a microfluidic device that detects trace concentrations of drugs of abuse in saliva within minutes using surface-enhanced Raman spectroscopy (SERS). Its operation is demonstrated using methamphetamine. The detection scheme exploits concentration gradients of chemicals, fostered by the laminar flow in the device, to control the interactions between the analyte, silver nanoparticles (Ag-NPs), and a salt. Also, since all species interact while advecting downstream, the relevant reaction coordinates occur with respect to the position in the channel. The system was designed to allow the analyte first to diffuse into the side stream containing the Ag-NPs, on which it is allowed to adsorb, before salt ions are introduced, causing the Ag-NPs to aggregate, and so creating species with strong SERS signal. The device allows partial separation via diffusion of the analyte from the complex mixture. Also, the reproducible salt-induced NP aggregation decouples the aggregation reaction (necessary for strong SERS) from the analyte concentration or charge. This method enables the creation of a region where detection of the analyte of interest via SERS is optimal, and dramatically extends the classes of molecules and quality of signals that can be measured using SERS, compared to bulk solution methods. The spatial distribution of the SERS signals was used to map the degree of nanoparticle aggregation and species diffusion in the channel, which, together with numerical simulations, was used to describe the kinetics of the colloid aggregation reaction, and to determine the optimal location in the channel for SERS interrogation.

  7. Rapid synthesis of hybrids and hollow PdO nanostructures by controlled in situ dissolution of a ZnO nanorod template: insights into the formation mechanism and thermal stability.

    Science.gov (United States)

    Kundu, Subhajit; Ravishankar, N

    2016-01-21

    Hollow nanomaterials have attracted a lot of interest by virtue of their wide range of applications that arise primarily due to their unique architecture. A common strategy to synthesize hollow nanomaterials is by nucleation of the shell material over a preformed core and subsequent dissolution of the core in the second step. Herein an ultrafast, microwave route has been demonstrated, to synthesize PdO nanotubes in a single step using ZnO as a sacrificial template. The mechanism of the nanotube formation has been investigated in detail using control experiments. By tuning the starting ratio of PdCl2 : ZnO, hollow to hybrid PdO nanostructures could be obtained using the same method. Conversion of the PdO to Pd nanotubes has been shown by simple NaBH4 treatment. The thermal stability of the PdO nanotubes has been studied. The insights presented here are general and applicable for the synthesis of hybrids/hollow structures in other systems as well.

  8. Errors in reporting on dissolution research: methodological and statistical implications.

    Science.gov (United States)

    Jasińska-Stroschein, Magdalena; Kurczewska, Urszula; Orszulak-Michalak, Daria

    2017-02-01

    In vitro dissolution testing provides useful information at clinical and preclinical stages of the drug development process. The study includes pharmaceutical papers on dissolution research published in Polish journals between 2010 and 2015. They were analyzed with regard to information provided by authors about chosen methods, performed validation, statistical reporting or assumptions used to properly compare release profiles considering the present guideline documents addressed to dissolution methodology and its validation. Of all the papers included in the study, 23.86% presented at least one set of validation parameters, 63.64% gave the results of the weight uniformity test, 55.68% content determination, 97.73% dissolution testing conditions, and 50% discussed a comparison of release profiles. The assumptions for methods used to compare dissolution profiles were discussed in 6.82% of papers. By means of example analyses, we demonstrate that the outcome can be influenced by the violation of several assumptions or selection of an improper method to compare dissolution profiles. A clearer description of the procedures would undoubtedly increase the quality of papers in this area.

  9. Modeling of the dissolution of a pharmaceutical compound

    Science.gov (United States)

    Mangin, D.; Garcia, E.; Gerard, S.; Hoff, C.; Klein, J. P.; Veesler, S.

    2006-01-01

    This paper analyses the phenomena encountered in the dissolution of a powder composed by drug crystals using the complementarity between the experimental and numerical approach. A macroscopic model based on the population balance equation was developed to describe dissolution experiments. The population balance equation was discretized and solved with the method of classes. The experiments were performed in a perfectly mixed vessel. Different initial masses of solid particles were introduced. The size distribution of the initial particles was measured by image analysis to take into account the particle anisotropy. For each experiment, the evolution of the concentration during the dissolution process was followed by conductimetry. The concentration measurements show an acceleration of the overall dissolution kinetics at the beginning of the dissolution process, although the undersaturation decreases. This particular behavior suggests that the aggregated powder is first disaggregated under the effect of stirring. The introduction of a fragmentation mechanism in our model has allowed a correct description of the concentration profiles. Intrinsic dissolution kinetics was found to be controlled by mass transfer.

  10. The use of recently described ionisation techniques for the rapid analysis of some common drugs and samples of biological origin.

    Science.gov (United States)

    Williams, Jonathan P; Patel, Vibhuti J; Holland, Richard; Scrivens, James H

    2006-01-01

    Three ionisation techniques that require no sample preparation or extraction prior to mass analysis have been used for the rapid analysis of pharmaceutical tablets and ointments. These methods were (i) the novel direct analysis in real time (DART), (ii) desorption electrospray ionisation (DESI), and (iii) desorption atmospheric pressure chemical ionisation (DAPCI). The performance of the three techniques was investigated for a number of common drugs. Significant differences between these approaches were observed. For compounds of moderate to low polarity DAPCI produced more effective ionisation. Accurate DESI and DAPCI tandem mass spectra were obtained and these greatly enhance the selectivity and information content of the experiment. The detection from human skin of the active ingredients from ointments is reported together with the detection of ibuprofen metabolites in human urine. Copyright 2006 John Wiley & Sons, Ltd.

  11. The shell dissolution of various empty hard capsules.

    Science.gov (United States)

    Chiwele, I; Jones, B E; Podczeck, F

    2000-07-01

    The shell dissolution properties of gelatine, gelatine/polyethylene glycol (PEG) and hydroxypropyl methylcellulose (HPMC) capsules were studied as a function of temperature, dissolution medium, and after different storage conditions. In any dissolution medium with a pH below or equal to 5.8, HPMC capsule shells dissolved rapidly, and there was no difference in the time in which dissolution occurred in the tested temperature interval of 10 to 55 degrees C. Gelatine and gelatine/PEG capsule shells, generally, did not dissolve at temperatures below 30 degrees C. The shell dissolution time of all capsules tested was prolonged and more variable in mixed phosphate buffer pH = 6.8. The addition of enzymes (pepsin, pancreatin) to any dissolution medium was found not to enhance the differences between the different types of capsules investigated. In practical terms, the results indicated that capsule formulations should not be taken with drinks from the carbonated Cola-type. Gelatine containing capsules should preferably be administered with a warm drink, whereas HPMC capsules could be given with cold or warm drinks. The latter type of capsules should also be preferred for preparations to be taken in the fasted state. A short storage of gelatine containing capsules under hot humid tropical conditions appeared not to alter the dissolution properties of the shells, and changes in disintegration times and dissolution times of formulations filled in such capsules might be a reflection of changes of the powders incorporated rather than of the capsule shells. However, a short storage of HPMC capsules under such conditions appeared to influence the capsule shell matrix.

  12. Dissolution Threats and Legislative Bargaining

    DEFF Research Database (Denmark)

    Becher, Michael; Christiansen, Flemming Juul

    2015-01-01

    Chief executives in many parliamentary democracies have the power to dissolve the legislature. Despite a well-developed literature on the endogenous timing of parliamentary elections, political scientists know remarkably little about the strategic use of dissolution power to influence policymakin......, are important determinants of the use and effectiveness of dissolution threats in policymaking. Analyzing an original time-series data set from a multiparty parliamentary democracy, we find evidence in line with key empirical implications of the model....

  13. Dissolution of peripheral arterial thrombi by ultrasound.

    Science.gov (United States)

    Ariani, M; Fishbein, M C; Chae, J S; Sadeghi, H; Michael, A D; Dubin, S B; Siegel, R J

    1991-10-01

    We have previously shown that continuous-wave ultrasound can rapidly dissolve human thrombi in vitro, with 99% of all residual particles measuring less than 10 microns in diameter. To assess the effects of pulsed-wave ultrasound energy on whole blood clots, 1) in vitro studies were preformed to assess precisely the rates of clot disruption and to quantify particulate size, and 2) in vivo studies were performed to assess the efficacy and safety of catheter-delivered ultrasound for intra-arterial thrombus dissolution. In vitro, we studied 50 samples of human whole blood clots and using an 89-cm-long wire probe, applied pulse-wave energies from 8 to 23 W. The corresponding peak-to-peak tip displacement range was 63.5 - 102 microns. We studied arterial thrombosis in vivo in 21 canine superficial femoral arteries. To produce an acute thrombosis, 200 units of thrombin followed by 2 ml of 72-hour-old autologous clot were injected into a 5-7-cm segment of femoral artery and left to coagulate for 2 hours. Ultrasound energy was intermittently applied at a frequency of 20 kHz with a prototype ultrasound wire ensheathed in a catheter and directed to clots by fluoroscopy. In nine cases, angioscopic guidance was used to put the probe into direct contact with the intra-arterial thromboses. In vitro clot dissolution times were inversely related to the ultrasound power output (r = 0.95). All in vivo canine thromboses were disrupted in 4 minutes or less. All successful recanalizations were confirmed by angiography and in nine cases by angioscopy as well. Angioscopy demonstrated that probe activation caused rapid clot disruption. Histological studies of the vessels showed no evidence of thermal or cavitation injury, occlusive distal embolization, or perforation. Our findings in this experimental canine model suggest that ultrasound clot dissolution has the potential to be an effective and safe alternative to current treatment modalities for peripheral arterial thrombosis.

  14. Anomalous dissolution behaviour of tablets prepared from sugar glass-based solid dispersions

    NARCIS (Netherlands)

    Van Drooge, D.J.; Hinrichs, W.L.J.; Frijlink, H.W.

    2004-01-01

    In this study, anomalous dissolution behaviour of tablets consisting of sugar glass dispersions was investigated. The poorly aqueous soluble diazepam was used as a lipophilic model drug. The release of diazepam and sugar carrier was determined to study the mechanisms governing dissolution behaviour.

  15. Modelos in vitro para determinação da absorção de fármacos e previsão da relação dissolução/absorção In vitro models for the determination of drug absorption and a prediction of dissolution/absorption relationships

    Directory of Open Access Journals (Sweden)

    Jacqueline de Souza

    2007-12-01

    Full Text Available Fármacos contidos em formas farmacêuticas sólidas devem ter adequada solubilidade aquosa e permeabilidade intestinal para serem absorvidos após administração oral. A velocidade e a extensão com as quais um fármaco é absorvido podem variar devido às suas características físico-químicas e fatores relacionados à desintegração e dissolução. Segundo o Sistema de Classificação Biofarmacêutica (SCB, a dissolução e a permeação intestinal do fármaco podem limitar a absorção e, conseqüentemente, a ação terapêutica. Este trabalho objetiva discutir dados da literatura referentes à previsão da relação entre a dissolução de fármacos e sua absorção empregando sistemas in vitro. Para avaliar a permeação in vitro são discutidos modelos com tecidos e segmentos intestinais, vesículas extraídas de membranas e cultura de células. Na literatura existem estudos de permeabilidade utilizando células Caco-2, TC-7, 2/4/A1, MDCK e MDCK-MDR1. As células Caco-2 são extraídas de adenocarcinoma de c��lon humano que, em cultura celular, se diferenciam em enterócitos, podendo ser acopladas a sistemas de dissolução. Estas técnicas representam importante ferramenta para estudos de dissolução/permeação, porém, ainda são limitadas e não conseguem reproduzir adequadamente os mecanismos de transporte ativo.Drugs contained in a solid pharmaceutical form should be adequately water soluble and permeable, into the intestine in order to be effectively absorbed after oral adminis-tration. The speed and extent at which a drug is absorbed can vary due to its physicochemical characteristics and factors related to disintegration and dissolution of the drug. According to Biopharmaceutical Drug System Classification (BSC, the dissolution and the intestinal permeation of a drug can limit the absorption and, consequently, the therapeutic action of that drug. This article focuses on data concerning the predictability of dissolution

  16. Fast mouse PK (Fast PK): a rapid screening method to increase pharmacokinetic throughput in pre-clinical drug discovery.

    Science.gov (United States)

    Reddy, Jitendar; Madishetti, Sreedhar; Vachaspati, Prakash R

    2012-09-29

    We describe a rapid screening methodology for performing pharmacokinetic (PK) studies in mice called Fast PK. In this Fast PK method, two mice were used per compound and four blood samples were collected from each mouse. The sampling times were staggered (sparse sampling) between the two mice, thus yielding complete PK profile in singlicate across eight time points. The plasma PK parameters from Fast PK were comparable to that obtained from conventional PK methods. This method has been used to rapidly screen compounds in the early stages of drug discovery and about 600 compounds have been profiled in the last 3 years, which has resulted in reduction in the usage of mice by 800 per year in compliance with the 3R principles of animal ethics. In addition, this Fast PK method can also help in evaluating the PK parameters from the same set of animals used in safety/toxicology/efficacy studies without the need for satellite groups. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Polypyrrole solid phase microextraction: A new approach to rapid sample preparation for the monitoring of antibiotic drugs

    Energy Technology Data Exchange (ETDEWEB)

    Szultka, Malgorzata [Department of Environmental Chemistry and Bioanalytics, Faculty of Chemistry, Nicolaus, Copernicus University, Gagarin 7, 87-100 Torun (Poland); Kegler, Ricarda [Institute of Clinical Pharmacology, University of Rostock, Schillingallee 70, D-18057 Rostock (Germany); Fuchs, Patricia [Department of Anaesthesia and Intensive Care, University of Rostock, Schillingallee 35, D-18057 Rostock (Germany); Olszowy, Pawel [Department of Environmental Chemistry and Bioanalytics, Faculty of Chemistry, Nicolaus, Copernicus University, Gagarin 7, 87-100 Torun (Poland); Miekisch, Wolfram; Schubert, Jochen K. [Department of Anaesthesia and Intensive Care, University of Rostock, Schillingallee 35, D-18057 Rostock (Germany); Buszewski, Boguslaw [Department of Environmental Chemistry and Bioanalytics, Faculty of Chemistry, Nicolaus, Copernicus University, Gagarin 7, 87-100 Torun (Poland); Mundkowski, Ralf G., E-mail: ralf.mundkowski@med.uni-rostock.de [Institute of Clinical Pharmacology, University of Rostock, Schillingallee 70, D-18057 Rostock (Germany)

    2010-05-14

    Simple or even rapid bioanalytical methods are rare, since they generally involve complicated, time-consuming sample preparation from the biological matrices like LLE or SPE. SPME provides a promising approach to overcome these limitations. The full potential of this innovative technique for medical diagnostics, pharmacotherapy or biochemistry has not been tapped yet. In-house manufactured SPME probes with polypyrrole (PPy) coating were evaluated using three antibiotics of high clinical relevance - linezolid, daptomycin, and moxifloxacin - from PBS, plasma, and whole blood. The PPy coating was characterised by scanning electron microscopy. Influences of pH, inorganic salt, and blood anticoagulants were studied for optimum performance. Extraction yields were determined from stagnant media as well as re-circulating human blood using the heart-and-lung machine model system. The PPy-SPME fibres showed high extraction yields, particularly regarding linezolid. The reproducibility of the method was optimised to achieve RSDs of 9% or 17% and 7% for SPME from stagnant or re-circulating blood using fresh and re-used fibres, respectively. The PPy-SPME approach was demonstrated to meet the requirements of therapeutic monitoring of the drugs tested, even from re-circulating blood at physiological flow rates. SPME represents a rapid and simple dual-step procedure with potency to significantly reduce the effort and expenditure of complicated sample preparations in biomedical analysis.

  18. 12 CFR 546.4 - Voluntary dissolution.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Voluntary dissolution. 546.4 Section 546.4... ASSOCIATIONS-MERGER, DISSOLUTION, REORGANIZATION, AND CONVERSION § 546.4 Voluntary dissolution. A Federal savings association's board of directors may propose a plan for dissolution of the association. The plan...

  19. Evaluation of a dynamic dissolution/permeation model

    DEFF Research Database (Denmark)

    Sironi, Daniel; Christensen, Mette; Rosenberg, Jörg

    2017-01-01

    Combined dissolution/permeation testing is gaining increasing attention as an in vitro tool for predictive performance ranking of enabling oral formulations. The current aim was to study how in vitro drug permeation evolves under conditions, where the donor concentration is changing (non-steady s...

  20. Effect of Different Crystallization Techniques on the Dissolution ...

    African Journals Online (AJOL)

    Methods: Ketoprofen crystals were prepared by various crystallization technique including spherical agglomeration (SA), spray drying (SD), freeze drying (FD) and ... The solubility of FD crystals in water increased almost fivefold to 0.0926 mg/ml compared with that of the drug (0.0172 mg/ml), while the dissolution rates of the ...

  1. Investigation of the Dissolution Profile of Gliclazide Modified-Release Tablets Using Different Apparatuses and Dissolution Conditions.

    Science.gov (United States)

    Skripnik, K K S; Riekes, M K; Pezzini, B R; Cardoso, S G; Stulzer, H K

    2017-07-01

    In the absence of an official dissolution method for modified-release tablets of gliclazide, dissolution parameters, such as apparatuses (1, 2, and 3), rotation speeds, pH, and composition of the dissolution medium were investigated. The results show that although the drug presents a pH-mediated solubility (pH 7.0 > 6.8 > 6.4 > 6.0 > 5.5 > 4.5), the in vitro release of the studied tablets was not dependent on this parameter, despite of the apparatus tested. On the other hand, the rotation speed demonstrated a greater influence (100 rpm >50 rpm). Using similar hydrodynamic conditions, the three different apparatuses were compared in pH 6.8 and provided the following trend: apparatus 1 at 100 rpm >2 at 50 rpm ≈3 at 10 dpm. As a complete, but slow release is expected from modified-release formulations, apparatus 2, in phosphate buffer pH 6.8 and 100 rpm, were selected as the optimized dissolution method. In comparison to apparatus 1 under the same conditions, the paddle avoids the stickiness of formulation excipients at the mesh of the basket, which could prejudice the release of gliclazide. Results obtained with biorelevant medium through the developed dissolution method were similar to the buffer solution pH 6.8. The application of the optimized method as a quality control test between two different brands of gliclazide modified-release tablets showed that both dissolution profiles were considered similar by the similarity factor (f2 = 51.8). The investigation of these dissolution profiles indicated a dissolution kinetic following first-order model.

  2. Unexpected differences in dissolution behavior of tablets prepared from solid dispersions with a surfactant physically mixed or incorporated

    NARCIS (Netherlands)

    de Waard, H.; Hinrichs, W.L.J.; Visser, M.R.; Bologna, C.; Frijlink, H.W.

    2008-01-01

    In a previous study, it was shown that the incorporation of poorly soluble drugs (BCS class II) in sugar glasses could largely increase the drug's dissolution rate [van Drooge, D.J., Hinrichs, W.L.J., Frijlink, H.W., 20041). Anomalous dissolution behaviour of tablets prepared from sugar glass-based

  3. A superior preparation method for daidzein-hydroxypropyl-β-cyclodextrin complexes with improved solubility and dissolution: Supercritical fluid process

    Directory of Open Access Journals (Sweden)

    Pan Hao

    2017-03-01

    Full Text Available Advantages of the supercritical fluid (SCF process compared to the conventional solution stirring method (CSSM in the preparation of daidzein-hydroxypropyl-β-cyclodextrin (HPβCD complexes were investigated. Formation of daidzein/ HPβCD inclusion complexes was confirmed by Fourier transformed-infrared spectroscopy (FTIR, differential scanning calorimetry (DSC, X-ray diffraction (XRD and scanning electron microscopy (SEM. Particle size, inclusion yield, drug solubility and dissolution of daidzein/HPβCD complexes were evaluated. Compared to CSSM, the SCF process resulted in higher inclusion yield and higher solubility. Also, extended dissolution of daidzein from the SCF processed HPβCD inclusion complexes was observed, with only 22.94 % released in 45 min, compared to its rapid release from those prepared by CSSM, with 98.25 % drug release in 15 min. This extended release of daidzein from SCF prepared inclusion complexes was necessary to avoid drug precipitation and improve drug solubilisation in the gastrointestinal tract. The results showed that the SCF process is a superior preparation method for daidzein-hydroxypropyl-β-cyclodextrin complexes.

  4. In Vivo Predictive Dissolution: Comparing the Effect of Bicarbonate and Phosphate Buffer on the Dissolution of Weak Acids and Weak Bases.

    Science.gov (United States)

    Krieg, Brian J; Taghavi, Seyed Mohammad; Amidon, Gordon L; Amidon, Gregory E

    2015-09-01

    Bicarbonate is the main buffer in the small intestine and it is well known that buffer properties such as pKa can affect the dissolution rate of ionizable drugs. However, bicarbonate buffer is complicated to work with experimentally. Finding a suitable substitute for bicarbonate buffer may provide a way to perform more physiologically relevant dissolution tests. The dissolution of weak acid and weak base drugs was conducted in bicarbonate and phosphate buffer using rotating disk dissolution methodology. Experimental results were compared with the predicted results using the film model approach of (Mooney K, Mintun M, Himmelstein K, Stella V. 1981. J Pharm Sci 70(1):22-32) based on equilibrium assumptions as well as a model accounting for the slow hydration reaction, CO2 + H2 O → H2 CO3 . Assuming carbonic acid is irreversible in the dehydration direction: CO2 + H2 O ← H2 CO3 , the transport analysis can accurately predict rotating disk dissolution of weak acid and weak base drugs in bicarbonate buffer. The predictions show that matching the dissolution of weak acid and weak base drugs in phosphate and bicarbonate buffer is possible. The phosphate buffer concentration necessary to match physiologically relevant bicarbonate buffer [e.g., 10.5 mM (HCO3 (-) ), pH = 6.5] is typically in the range of 1-25 mM and is very dependent upon drug solubility and pKa . © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  5. Microenvironmental pH measurement during sodium naproxenate dissolution in acidic medium by UV/vis imaging

    DEFF Research Database (Denmark)

    Ostergaard, Jesper; Jensen, Henrik; Larsen, Susan W

    2014-01-01

    Variable dissolution from sodium salts of drugs containing a carboxylic acid group after passing the acidic environment of the stomach may affect oral bioavailability. The aim of the present proof of concept study was to investigate pH effects in relation to the dissolution of sodium naproxenate...... in 0.01M hydrochloric acid. For this purpose a UV/vis imaging-based approach capable of measuring microenvironmental pH in the vicinity of the solid drug compact as well as monitoring drug dissolution was developed. Using a pH indicating dye real-time spatially resolved measurement of pH was achieved....... Sodium naproxenate, can significantly alter the local pH of the dissolution medium, is eventually neutralized and precipitates as the acidic species naproxen. The developed approach is considered useful for detailed studies of pH dependent dissolution phenomena in dissolution testing....

  6. Designing and comparison study of rapid detection methods of resistance to injectable drugs in clinical strains of Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Fatemeh Salehi

    2012-01-01

    Full Text Available Introduction: In this study, some molecular methods were designed for rapid detection of resistance to kanamycin and amikacin.Materials and methods: Among 120 clinical isolates of mycobacterium tuberculosis, 70 strains were selected for evaluation of possible mutations. A PCR-RFLP method was designed for detection of wild type (using enzyme ajii and mutant from (BstFNI enzyme of the isolates. Furthermore, allele specific method (as PCR was designed for detection mutations in codons 1401 and 1402 gene rrs. Some selected isolates were sequenced.Results: In PCR-RFLP method, among the 70 strains examined by BstFNI enzyme, could detect 17 mutant strains among 24 phenotypicaly resistant and 44 non-mutant isolates from 46 susceptible isolates. The sensitivity of this method was %70.83 and specificity was %95.65 on the other hand, 12 mutant from 20 resistant strains and 29 non-mutant strains from 32 susceptible strains were detected by AjiI enzyme. The sensitivity and specificity of this method was 60 and %90.62, respectively. In MAS PCR, 3 mutants from 6 resistant strains and 12 non-mutants from 17 resistant strains were detected. The sensitivity of this method was 50 and specificity was 70.58. Results of sequencing method confirmed the results of molecular methods.Discussion and conclusion: PCR-RFLP method by BstFNI enzyme was the best method for rapid detection of Mycobacterium tuberculosis resistant to second-line injectable drugs and was recommended for routine use.

  7. Monitoring the hydrolyzation of aspirin during the dissolution testing for aspirin delayed-release tablets with a fiber-optic dissolution system

    Directory of Open Access Journals (Sweden)

    Yan Wang

    2012-10-01

    Full Text Available The purpose of this study was to investigate the hydrolyzation of aspirin during the process of dissolution testing for aspirin delayed-release tablets. Hydrolysis product of salicylic acid can result in adverse effects and affect the determination of dissolution rate assaying. In this study, the technique of differential spectra was employed, which made it possible to monitor the dissolution testing in situ. The results showed that the hydrolyzation of aspirin made the percentage of salicylic acid exceed the limit of free salicylic acid (4.0, and the hydrolyzation may affect the quality detection of aspirin delayed-release tablets. Keywords: Aspirin delayed-release tablets, Drug dissolution test, Fiber-optic dissolution system, UV–vis spectrum

  8. Solubility and dissolution enhancement strategies: current understanding and recent trends.

    Science.gov (United States)

    Jain, Shashank; Patel, Niketkumar; Lin, Senshang

    2015-06-01

    Identification of lead compounds with higher molecular weight and lower aqueous solubility has become increasingly prevalent with the advent of high throughput screening. Poor aqueous solubility of these lipophilic compounds can drastically affect the dissolution rate and subsequently the drug absorbed in the systemic circulation, imposing a significant burden of time and money during drug development process. Various pre-formulation and formulation strategies have been applied in the past that can improve the aqueous solubility of lipophilic compounds by manipulating either the crystal lattice properties or the activity coefficient of a solute in solution or both, if possible. However, despite various strategies available in the armor of formulation scientist, solubility issue still remains an overriding problem in the drug development process. It is perhaps due to the insufficient conceptual understanding of solubility and dissolution phenomenon that hinders the judgment in selecting suitable strategy for improving aqueous solubility and/or dissolution rate. This article, therefore, focuses on (i) revisiting the theoretical and mathematical concepts associated with solubility and dissolution, (ii) their application in making rationale decision for selecting suitable pre-formulation and formulation strategies and (iii) the relevant research performed in this field in past decade.

  9. Dissolution of anionic surfactant mesophases.

    Science.gov (United States)

    Poulos, Andreas S; Jones, Christopher S; Cabral, João T

    2017-08-09

    Linear and circular solvent penetration experiments are used to study the dissolution of anionic SLE3S surfactant mesophases in water. We show that a lamellar (Lα) phase in contact with water will transit through a series of cubic, hexagonal, and micellar phase bands with sharp interfaces identified from their optical textures. In both linear and circular geometries, the kinetics of front propagation and eventual dissolution are well described by diffusive penetration of water, and a simple model applies to both geometries, with a different effective diffusion coefficient for water Df as the only fitting parameter. Finally, we show a surprising variation of dissolution rates with initial surfactant concentration that can be well explained by assuming that the driving force for solvent penetration is the osmotic pressure difference between neat water and the aqueous fraction of the mesophase that is highly concentrated in surfactant counterions.

  10. Actor bonds after relationship dissolution

    DEFF Research Database (Denmark)

    Skaates, Maria Anne

    2000-01-01

    Most of the presented papers at the 1st NoRD Workshop can be classified as belonging to the business marketing approach to relationship dissolution. Two papers were conceptual, and the remaining six were empirical studies. The first conceptual study by Skaates (2000) focuses on the nature...... of the actor bonds that remain after a business relationship has ended. The study suggests that an interdisciplinary approach would provide a richer understanding of the phenomenon; this could be achieved by using e.g. Bourdieu's sociological concepts in dissolution research....

  11. Country-wide surveillance of molecular markers of antimalarial drug resistance in Senegal by use of positive Malaria Rapid Diagnostic Tests

    DEFF Research Database (Denmark)

    Ndiaye, Magatte; Sow, Doudou; Nag, Sidsel

    2017-01-01

    of drug resistance. Therefore, surveillance of drug resistance in the malaria parasites is essential. The objective of this pilot study was to test the feasibility of routinely sampled malaria rapid diagnostic tests (RDTs) at a national scale to assess the temporal changes in the molecular profiles...... of antimalarial drug resistance markers of Plasmodium falciparum parasites. Overall, 9,549 positive malaria RDTs were collected from 14 health facilities across the country. A limited random set of RDTs were analyzed regarding Pfcrt gene polymorphisms at codon 72-76. Overall, a high but varied prevalence (> 50...

  12. The Influence of Milling on the Dissolution Performance of Simvastatin

    Directory of Open Access Journals (Sweden)

    Thomas Rades

    2010-12-01

    Full Text Available Particle size reduction is a simple means to enhance the dissolution rate of poorly water soluble BCS-class II and IV drugs. However, the major drawback of this process is the possible introduction of process induced disorder. Drugs with different molecular arrangements may exhibit altered properties such as solubility and dissolution rate and, therefore, process induced solid state modifications need to be monitored. The aim of this study was two-fold: firstly, to investigate the dissolution rates of milled and unmilled simvastatin; and secondly, to screen for the main milling factors, as well as factor interactions in a dry ball milling process using simvastatin as model drug, and to optimize the milling procedure with regard to the opposing responses particle size and process induced disorder by application of a central composite face centered design. Particle size was assessed by scanning electron microscopy (SEM and image analysis. Process induced disorder was determined by partial least squares (PLS regression modeling of respective X-ray powder diffractograms (XRPD and Raman spectra. Valid and significant quadratic models were built. The investigated milling factors were milling frequency, milling time and ball quantity at a set drug load, out of which milling frequency was found to be the most important factor for particle size as well as process induced disorder. Milling frequency and milling time exhibited an interaction effect on the responses. The optimum milling settings using the maximum number of milling balls (60 balls with 4 mm diameter was determined to be at a milling frequency of 21 Hz and a milling time of 36 min with a resulting primary particle size of 1.4 μm and a process induced disorder of 6.1% (assessed by Raman spectroscopy and 8.4% (assessed by XRPD, at a set optimization limit of < 2 μm for particle size and < 10% for process induced disorder. This optimum was tested experimentally and the process induced disorder

  13. Estonian and Russian Federation amoxicillin formulations: a comparative study of in vitro dissolution.

    Science.gov (United States)

    Bronnikova, O; Matto, V; Meos, A

    2008-06-01

    The in vitro dissolution properties were compared for four different formulations from the Estonian drug market and four from the Russian Federation drug market. Seven of the eight formulations tested released at least 75% or 80% amoxicillin during 30- or 90-min dissolution tests (37 degrees C, purified water, 75 rpm), respectively. One marketed Russian Federation formulation released 74% amoxicillin over a 90-min period. The present study shows that, in general, the in vitro dissolution properties of the Russian Federation amoxicillin formulations are, with some minor exceptions, comparable to those of the Estonian formulations. Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.

  14. Improvement of dissolution rate of indomethacin by inkjet printing

    DEFF Research Database (Denmark)

    Wickström, Henrika; Palo, Mirja; Rijckaert, Karen

    2015-01-01

    The aim of this study was to prepare printable inks of the poorly water soluble drug indomethacin (IMC), fabricate printed systems with flexible doses and investigate the effect of ink excipients on the printability, dissolution rate and the solid state properties of the drug. A piezoelectric...... inkjet printer was used to print 1×1cm2 squares onto a paper substrate and an impermeable transparency film. l-arginine (ARG) and polyvinylpyrrolidone (PVP) were used as additional formulation excipients. Accurately dosed samples were generated as a result of the ink and droplet formation optimization....... Increased dissolution rate was obtained for all formulations. The formulation with IMC and ARG printed on transparency film resulted in a co-amorphous system. The solid state characteristics of the printed drug on porous paper substrates were not possible to determine due to strong interference from...

  15. Griseofulvin micronization and dissolution rate improvement by supercritical assisted atomization.

    Science.gov (United States)

    Reverchon, E; Della Porta, G; Spada, A; Antonacci, A

    2004-11-01

    Supercritical assisted atomization (SAA) was used to micronize griseofulvin (GF), selected as a model compound, to verify the performance of this innovative process. SAA is based on the solubilization of supercritical carbon dioxide in a liquid solution containing the drug. The ternary mixture is then sprayed through a nozzle and microparticles are formed as a consequence of the enhanced atomization. Precipitation temperature and drug concentration in the liquid solution were studied to evaluate their influence on morphology and size of precipitated particles. A good particle size control was obtained and GF spherical particles with mean diameters ranging from 0.5 to 2.5 microm were produced with a narrow particle size distribution. Processed GF was characterized by high-performance liquid chromatography-UV/vis, headspace-gas chromatography-flame ionization detection, differential scanning calorimetry, BET and X-ray analyses. No drug degradation was observed and a solvent residue (acetone) less than 800 ppm was measured. GF microparticles showed good stability and surface areas ranging from about 4 to 6 m(2) g(-1); moreover, the micronized drug retained the crystalline habit. GF capsules were formulated with starch and used to compare the dissolution rate of SAA-processed and conventional jet-milled drug. A faster dissolution and a better reproducibility of the dissolution profile were observed for SAA-processed GF.

  16. Dissolution of cemented carbide powders in artificial sweat: implications for cobalt sensitization and contact dermatitis.

    Science.gov (United States)

    Stefaniak, Aleksandr B; Harvey, Christopher J; Virji, M Abbas; Day, Gregory A

    2010-10-06

    Skin exposure to cobalt-containing materials can cause systemic immune sensitization and upon repeat contact, elicitation of allergic contact dermatitis (ACD). Data on cobalt dissolution rates are needed to calculate uptake through skin and for development of models to understand risk of sensitization or dermatitis. The purpose of this research was to measure the dissolution kinetics of feedstock and process-sampled powders encountered in the production of hard metal alloys using artificial sweat. The physicochemical properties of each material were characterized prior to evaluation of dissolution behavior. Variations in artificial sweat solvent pH and chemistry were used to understand critical factors in dissolution. Dissolution of cobalt, tungsten, and tungsten carbide was often biphasic with the initial rapid phase being up to three orders of magnitude faster than the latter long-term phase. Artificial sweat pH did not influence dissolution of cobalt or tungsten carbide. Solvent composition had little influence on observed dissolution rates; however, vitamin E suppressed the dissolution of cobalt and tungsten carbide from sintered particles obtained from a chamfer grinder. There was no effect of particle size on dissolution of feedstock cobalt, tungsten, tungsten carbide, and admixture powders. Particle physicochemical properties influenced observed dissolution rates with more cobalt and tungsten carbide dissolving from chamfer grinder particles compared to the feedstock powders or admixture powder. Calculations using the observed dissolution rates revealed that skin exposure concentrations were similar to concentrations known to induce cobalt sensitization and elicit ACD. Observed dissolution rates for cobalt in artificial sweat indicate that dermal uptake may be sufficient to induce cobalt sensitization and allergic dermatitis.

  17. A novel off-center paddle impeller (OPI) dissolution testing system for reproducible dissolution testing of solid dosage forms.

    Science.gov (United States)

    Wang, Yimin; Armenante, Piero M

    2012-02-01

    Dissolution testing is routinely conducted in the pharmaceutical industry to provide in vitro drug release information for quality control purposes. The most common dissolution testing system for solid dosage forms is the United States Pharmacopeia (USP) Dissolution Testing Apparatus 2. This apparatus is very sensitive to the initial location of the tablet, which cannot be controlled because the tablet is dropped into the vessel at the beginning of the test and it may rest at random locations at the vessel's bottom. In this work, a modified Apparatus 2 in which the impeller was placed 8 mm off center in the vessel was designed and tested. This new design was termed "OPI" for "off-center paddle impeller." Dissolution tests were conducted with the OPI apparatus for nine different tablet locations using both disintegrating tablets (prednisone) and nondisintegrating tablets (salicylic acid). The dissolution profiles in the OPI apparatus were largely independent of the tablet location at the vessel's bottom, whereas those obtained in the Standard System generated statistically different profiles depending on the tablet location. The newly proposed OPI system can effectively eliminate artifacts generated by random settling of the tablet at the vessel's bottom, thus making the test more robust. Copyright © 2011 Wiley Periodicals, Inc.

  18. Major reduction in anti-malarial drug consumption in Senegal after nation-wide introduction of malaria rapid diagnostic tests.

    Directory of Open Access Journals (Sweden)

    Sylla Thiam

    Full Text Available BACKGROUND: While WHO recently recommended universal parasitological confirmation of suspected malaria prior to treatment, debate has continued as to whether wide-scale use of rapid diagnostic tests (RDTs can achieve this goal. Adherence of health service personnel to RDT results has been poor in some settings, with little impact on anti-malarial drug consumption. The Senegal national malaria control programme introduced universal parasite-based diagnosis using malaria RDTs from late 2007 in all public health facilities. This paper assesses the impact of this programme on anti-malarial drug consumption and disease reporting. METHODS AND FINDINGS: Nationally-collated programme data from 2007 to 2009 including malaria diagnostic outcomes, prescription of artemisinin-based combination therapy (ACT and consumption of RDTs in public health facilities, were reviewed and compared. Against a marked seasonal variation in all-cause out-patient visits, non-malarial fever and confirmed malaria, parasite-based diagnosis increased nationally from 3.9% of reported malaria-like febrile illness to 86.0% over a 3 year period. The prescription of ACT dropped throughout this period from 72.9% of malaria-like febrile illness to 31.5%, reaching close equivalence to confirmed malaria (29.9% of 584,873 suspect fever cases. An estimated 516,576 courses of inappropriate ACT prescription were averted. CONCLUSIONS: The data indicate high adherence of anti-malarial prescribing practice to RDT results after an initial run-in period. The large reduction in ACT consumption enabled by the move from symptom-based to parasite-based diagnosis demonstrates that effective roll-out and use of malaria RDTs is achievable on a national scale through well planned and structured implementation. While more detailed information on management of parasite-negative cases is required at point of care level to assess overall cost-benefits to the health sector, considerable cost-savings were

  19. Major reduction in anti-malarial drug consumption in Senegal after nation-wide introduction of malaria rapid diagnostic tests.

    Science.gov (United States)

    Thiam, Sylla; Thior, Moussa; Faye, Babacar; Ndiop, Médoune; Diouf, Mamadou Lamine; Diouf, Mame Birame; Diallo, Ibrahima; Fall, Fatou Ba; Ndiaye, Jean Louis; Albertini, Audrey; Lee, Evan; Jorgensen, Pernille; Gaye, Oumar; Bell, David

    2011-04-06

    While WHO recently recommended universal parasitological confirmation of suspected malaria prior to treatment, debate has continued as to whether wide-scale use of rapid diagnostic tests (RDTs) can achieve this goal. Adherence of health service personnel to RDT results has been poor in some settings, with little impact on anti-malarial drug consumption. The Senegal national malaria control programme introduced universal parasite-based diagnosis using malaria RDTs from late 2007 in all public health facilities. This paper assesses the impact of this programme on anti-malarial drug consumption and disease reporting. Nationally-collated programme data from 2007 to 2009 including malaria diagnostic outcomes, prescription of artemisinin-based combination therapy (ACT) and consumption of RDTs in public health facilities, were reviewed and compared. Against a marked seasonal variation in all-cause out-patient visits, non-malarial fever and confirmed malaria, parasite-based diagnosis increased nationally from 3.9% of reported malaria-like febrile illness to 86.0% over a 3 year period. The prescription of ACT dropped throughout this period from 72.9% of malaria-like febrile illness to 31.5%, reaching close equivalence to confirmed malaria (29.9% of 584,873 suspect fever cases). An estimated 516,576 courses of inappropriate ACT prescription were averted. The data indicate high adherence of anti-malarial prescribing practice to RDT results after an initial run-in period. The large reduction in ACT consumption enabled by the move from symptom-based to parasite-based diagnosis demonstrates that effective roll-out and use of malaria RDTs is achievable on a national scale through well planned and structured implementation. While more detailed information on management of parasite-negative cases is required at point of care level to assess overall cost-benefits to the health sector, considerable cost-savings were achieved in ACT procurement. Programmes need to be allowed

  20. Drug release, preclinical and clinical pharmacokinetics relationships of alginate pellets prepared by melt technology.

    Science.gov (United States)

    Bose, Anirbandeep; Harjoh, Nurulaini; Pal, Tapan Kumar; Dan, Shubhasis; Wong, Tin Wui

    2016-01-01

    Alginate pellets prepared by the aqueous agglomeration technique experience fast drug dissolution due to the porous pre-formed calcium alginate microstructure. This study investigated in vitro drug release, preclinical and clinical pharmacokinetics relationships of intestinal-specific calcium acetate-alginate pellets against calcium-free and calcium carbonate-alginate pellets. Alginate pellets were prepared by solvent-free melt pelletization instead of aqueous agglomeration technique using chlorpheniramine maleate as model drug. A fast in situ calcium acetate dissolution in pellets resulted in rapid pellet breakup, soluble Ca(2+) crosslinking of alginate fragments and drug dissolution retardation at pH 1.2, which were not found in other pellet types. The preclinical drug absorption rate was lower with calcium acetate loaded than calcium-free alginate pellets. In human subjects, however, the extent and the rate of drug absorption were higher from calcium acetate-loaded pellets than calcium-free alginate pellets. The fine, dispersible and weakly gastric mucoadhesive calcium alginate pellets underwent fast human gastrointestinal transit. They released the drug at a greater rate than calcium-free pellets in the intestine, thereby promoting drug bioavailability. Calcium acetate was required as a disintegrant more than as a crosslinking agent clinically to promote pellet fragmentation, fast gastrointestinal transit and drug release in intestinal medium, and intestinal-specific drug bioavailability.

  1. Pectin-HPMC E15LV Vs pH sensitive polymer coating films for delayed drug delivery to colon: a comparison of two dissolution models to assess colonic targeting performance in-vitro

    OpenAIRE

    A. Maria John Newton; L Prabakaran; Jayaveera, K.N.

    2012-01-01

    Summary.The study was designed to evaluate the in vitro dissolution characteristics comparatively between pH sensitive polymer coated tablets and natural polymer coated tablets in a various simulated fluids (pH values 1.2, 6, 6.8, 7.2, 5). The fabricated Mesalamine tablets were coated with pectin-HPMC(Hydroxy propyl methyl cellulose) E15LV (FC1-FC5) in combination and with Eudragit L100 ( FC6-FC10)separately. Different buffer conditions were chosen to mimic the pH changes of the terminal part...

  2. Artemisinin-Polyvinylpyrrolidone Composites Prepared by Evaporative Precipitation of Nanosuspension for Dissolution Enhancement.

    Science.gov (United States)

    Kakran, M; Sahoo, N G; Li, L; Judeh, Z; Panda, P

    2011-01-01

    Nanoparticles of a poorly water-soluble anti-malarial drug, artemisinin (ART), and its composite particles with a hydrophilic polymer, polyvinylpyrrolidone (PVP), were synthesized using a nanofabrication method called the evaporative precipitation of nanosuspension (EPN). ART nanoparticles and ART/PVP composite particles containing ART nanoparticles coated with PVP were successfully prepared with the aim of improving the dissolution rate of ART. The effect of polymer concentration on the physical and morphological properties, and dissolution rate of the EPN-prepared ART/PVP composite particles was investigated. The crystallinity of ART nanoparticles decreased with increasing polymer concentration, as suggested by the differential scanning calorimetry and X-ray diffraction studies. The phase solubility studies revealed an AL-type of curve, indicating a linear increase in the drug solubility with PVP concentration. The dissolution of the ART nanoparticles and ART/PVP composite particles markedly increased as compared to that of the original ART powder due to lower particle size and reduced crystallinity of the drug particles. The percent dissolution efficiency (DE), relative dissolution (RD), t 75% and similarity factor (f 2) were calculated for the statistical analysis. Various mathematical models, viz., zero-order, first-order, Korsemeyer-Peppas and Higuchi, were applied to fit the experimental drug-dissolution data and diffusion was found to be the drug release mechanism.

  3. Development of Itraconazole Liquisolid Compact: Effect of Polyvinylpyrrolidone on the Dissolution Properties.

    Science.gov (United States)

    Gong, Wei; Wang, Yuli; Sun, Lei; Yang, Jiahui; Shan, Li; Yang, Meiyan; Gao, Chunsheng

    2016-01-01

    The aim of this work was to utilize the liquisolid technique to enhance dissolution of itraconazole (ITZ). Liquisolid tablets of ITZ were formulated by using N-methyl-2-pyrrolidone as liquid vehicle, polyvinylpyrrolidone (PVP) as a precipitation inhibitor and magnesium aluminometasilicate Neusilin® as a carrier and coating material. The effect of PVP level on stability of liquid medication, physicomechnanical properties and dissolution rate of liquisolid compacts was studied in detail. The crystallinity of formulated drug and the interaction between excipients were examined by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). All the liquisolid tablets showed higher drug dissolution rates than the conventional, directly compressed tablets. The flowability of liquisolid powders was slightly improved as the proportion of PVP in ITZ-NMP mixture increased. Moreover, the stability of liquid medication and wetting ability of liquisolid tablets were improved by PVP. The presence of low amount of PVP (≤ 1%) in liquisolid formulation could enhance dissolution of ITZ liquisolid tablets, whereas the percentage of PVP over 5% decreased the dissolution of ITZ from liquisolid tablets. Both DSC and XRPD suggested reduction or loss of ITZ crystallinity upon liquisolid formulations indicating that the drug was almost solubilized and molecularly dispersed with excipients within the liquisolid matrix. It could be shown that increased solubility, wetting properties and surface area available for dissolution contributed to the improvement of the dissolution of ITZ from liquisolid tablets.

  4. Mebeverine-loaded electrospun nanofibers: physicochemical characterization and dissolution studies.

    Science.gov (United States)

    Illangakoon, Upulitha Eranka; Nazir, Tahir; Williams, Gareth R; Chatterton, Nicholas P

    2014-01-01

    Both fast dissolving and sustained release drug delivery systems (DDSs) comprising mebeverine hydrochloride (MB-HCl) embedded in either povidone (PVP) K60 or Eudragit(®) L 100-55 nanofibers have been prepared by electrospinning. The fibers are found to have cylindrical morphologies with smooth surfaces, except at high drug loadings that appear to induce surface roughness (PVP) or fragmentation (Eudragit). There is a general increase in fiber diameter with drug loading. Differential scanning calorimetry and X-ray diffraction demonstrate that the drug exists in an amorphous state in the fibers. Infrared spectroscopy data indicate that the drug has good compatibility with the polymer, whereas nuclear magnetic resonance spectroscopy and high-performance liquid chromatography analyses confirmed that the MB-HCl was not degraded during the spinning process. In vitro dissolution tests of the PVP fiber mats show them to dissolve within 10 s, an improved dissolution profile over the pure drug. The Eudragit fibers show pH-dependent drug release profiles, with only very limited release at pH 2.0 but sustained release over approximately 8 h at pH 6.8. The Eudragit nanofibers have the potential to be developed as oral DDSs for localized drug release in the intestinal tract, whereas the PVP materials may find the application as buccal delivery systems or suppositories. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

  5. 25 CFR 11.606 - Dissolution proceedings.

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Dissolution proceedings. 11.606 Section 11.606 Indians... ORDER CODE Domestic Relations § 11.606 Dissolution proceedings. (a) Either or both parties to the marriage may initiate dissolution proceedings. (b) If a proceeding is commenced by one of the parties, the...

  6. Childbearing and Dissolution of the Second Marriage.

    Science.gov (United States)

    Wineberg, Howard

    1992-01-01

    Examined relationship between childbearing and dissolution of second marriage among 713 white women. Women who gave birth in second marriage had significantly reduced probability of dissolution. Childbearing prior to remarriage was associated with increased risk of dissolution in first five years of remarriage. Other results suggest bringing…

  7. Preparation, characterization, and dissolution studies of naproxen solid dispersions using polyethylene glycol 6000 and labrafil M2130

    Directory of Open Access Journals (Sweden)

    Jafar Akbari

    2015-06-01

    Full Text Available Naproxen is a poor water soluble, non-steroidal analgesic and anti-inflammatory drug. The enhancement of oral bioavailability of poor water soluble drugs remains one of the most challenging aspects of drug development. Although salt formation, solubilization and particle size reduction have commonly been used to increase dissolution rate and thereby oral absorption and bioavailability of low water soluble drugs, there are practical limitation of these techniques. However, the most attractive option for increasing the release rate is improvement of solubility through formulation approaches. In this study, solid dispersions (SD of naproxen were prepared by hot melt method using various ratios of drug to polymers (PEG6000 separately and characterized for physical appearance, FTIR, DSC, X-Ray crystallography, and in-vitro dissolution studies. The influence of several amounts of Labrafil M2130 was also studied. FTIR study revealed that drug was stable in SDs, and great state of amorphous formed particles was proofed by DSC analysis. The in vitro dissolution studies were carried using USP type II (paddle dissolution apparatus at medium (pH 1.5. Solubility of naproxen from SDs was increased in dissolution media. The prepared dispersion showed increase in the dissolution rate of naproxen comparing to that of physical mixtures of drug and polymers and pure drug. Percent of drug released in 60 minutes was 23.92% for pure naproxen witch is increased in SDs and reached to100% for best formulations of PEG6000 and labrafil based SDs respectively, considering ratio of drug to polymers.It is concluded that dissolution of the naproxen could be improved by the solid dispersion. Although physical mixtures have increased the rate of dissolution, dissolution shows faster release from SDs which would therefore be due to formation of amorphous particles through the hot melt process which was also revealed by DSC analysis and XRD.

  8. Lyophilic matrix method for dissolution and release studies of nanoscale particles.

    Science.gov (United States)

    Pessi, Jenni; Svanbäck, Sami; Lassila, Ilkka; Hæggström, Edward; Yliruusi, Jouko

    2017-10-25

    We introduce a system with a lyophilic matrix to aid dissolution studies of powders and particulate systems. This lyophilic matrix method (LM method) is based on the ability to discriminate between non-dissolved particles and the dissolved species. In the LM method the test substance is embedded in a thin lyophilic core-shell matrix. This permits rapid contact with the dissolution medium while minimizing dispersion of non-dissolved particles without presenting a substantial diffusion barrier. The method produces realistic dissolution and release results for particulate systems, especially those featuring nanoscale particles. By minimizing method-induced effects on the dissolution profile of nanopowders, the LM method overcomes shortcomings associated with current dissolution tests. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Fabrication and characterization of a rapid prototyped tissue engineering scaffold with embedded multicomponent matrix for controlled drug release

    DEFF Research Database (Denmark)

    Chen, Muwan; Le, Dang Q S; Hein, San

    2012-01-01

    showed that the scaffold was osteoinductive. The drug-release kinetics was investigated by loading doxorubicin into the scaffold. The scaffolds comprising nanoclay released up to 45% of the drug for up to 2 months, while the scaffold without nanoclay released 95% of the drug within 4 days. Therefore...

  10. Simultaneous Rapid Determination of the Solubility and Diffusion Coefficients of a Poorly Water-Soluble Drug Based on a Novel UV Imaging System.

    Science.gov (United States)

    Lu, Yan; Li, Mingzhong

    2016-01-01

    The solubility and diffusion coefficient are two of the most important physicochemical properties of a drug compound. In practice, both have been measured separately, which is time consuming. This work utilizes a novel technique of UV imaging to determine the solubility and diffusion coefficients of poorly water-soluble drugs simultaneously. A 2-step optimal method is proposed to determine the solubility and diffusion coefficients of a poorly water-soluble pharmaceutical substance based on the Fick's second law of diffusion and UV imaging measurements. Experimental results demonstrate that the proposed method can be used to determine the solubility and diffusion coefficients of a drug with reasonable accuracy, indicating that UV imaging may provide a new opportunity to accurately measure the solubility and diffusion coefficients of a poorly water-soluble drug simultaneously and rapidly. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  11. Unravelling the relationship between degree of disorder and the dissolution behavior of milled glibenclamide

    DEFF Research Database (Denmark)

    Mah, Pei T; Laaksonen, Timo; Rades, Thomas

    2014-01-01

    Milling is an attractive method to prepare amorphous formulations as it does not require the use of solvents and is suitable for thermolabile drugs. One of the key critical quality attributes of milled amorphous formulations is their dissolution behavior. However, there are limited studies...... that have investigated the relationship between degree of disorder induced by milling and dissolution behavior. The main aim of this study was to identify the analytical technique used to characterize degree of disorder that correlates best with the recrystallization behavior during dissolution of milled...... glibenclamide samples. Solid state and surface changes during dissolution of milled glibenclamide samples were monitored in order to elucidate the processes that influence the dissolution behavior of milled glibenclamide samples. Glibenclamide was ball milled for different durations and analyzed using X...

  12. Rapid confirmatory analysis of non-steroidal anti-inflammatory drugs in bovine milk by rapid resolution liquid chromatography tandem mass spectrometry.

    Science.gov (United States)

    Dowling, Geraldine; Gallo, Pasquale; Malone, Edward; Regan, Liam

    2009-11-13

    A rapid method has been developed to analyse carprofen (CPF), diclofenac (DCF), mefenamic acid (MFN), niflumic acid (NIFLU), naproxen (NAP), oxyphenylbutazone (OXYPHEN), phenylbutazone (PBZ) and suxibuzone (SUXI) residues in bovine milk. Milk samples are extracted with acetonitrile and sample extracts were purified on Evolute ABN solid phase extraction cartridges. Aliquots were analysed by rapid resolution liquid chromatography tandem mass spectrometry (RRLC-MS/MS) with a runtime of 6.5 min. The method was validated in bovine milk, according to the criteria defined in Commission Decision 2002/657/EC. CCalpha values of 0.46, 1.08, 0.92, 1.26, 1.29, 2.12, 0.55 and 2.86 ng mL(-1) were determined for CPF, DCF, MFN, NIFLU, NAP, OXYPHEN, PBZ and SUXI, respectively. CCbeta values of 0.79, 1.85, 1.56, 2.15, 2.19, 3.62, 0.94 and 4.87 ng mL(-1) were determined for CPF, DCF, MFN, NIFLU, NAP, OXYPHEN, PBZ and SUXI, respectively. The measurement uncertainty of the method was estimated at 9, 28, 28, 45, 46, 45, 10 and 39% for CPF, DCF, MFN, NIFLU, NAP, OXYPHEN, PBZ and SUXI. Fortifying bovine milk samples (n=18) in three separate assays, show the accuracy of the method to be between 82 and 108%. The precision of the method, expressed as RSD values for the within-lab reproducibility at the three levels of fortification (5, 7.5 and 10 ng mL(-1)) was less than 16%, respectively. The advantage of the method is that low ng mL(-1) levels can be detected and quantitatively confirmed rapidly in milk and that 3 batches of samples can be analysed within a single day using RRLC-MS/MS with a runtime of 6.5 min.

  13. Dissolution test for glibenclamide tablets

    Directory of Open Access Journals (Sweden)

    Elisabeth Aparecida dos Santos Gianotto

    2007-10-01

    Full Text Available The aim of this work is to develop and validate a dissolution test for glibenclamide tablets. Optimal conditions to carry out the dissolution test are 500 mL of phosphate buffer at pH 8.0, paddles at 75 rpm stirring speed, time test set to 60 min and using equipment with six vessels. The derivative UV spectrophotometric method for determination of glibenclamide released was developed, validated and compared with the HPLC method. The UVDS method presents linearity (r² = 0.9999 in the concentration range of 5-14 µg/mL. Precision and recoveries were 0.42% and 100.25%, respectively. The method was applied to three products commercially available on the Brazilian market.

  14. Dissolution Kinetics of Alumina Calcine

    Energy Technology Data Exchange (ETDEWEB)

    Batcheller, Thomas Aquinas

    2001-09-01

    Dissolution kinetics of alumina type non-radioactive calcine was investigated as part of ongoing research that addresses permanent disposal of Idaho High Level Waste (HLW). Calcine waste was produced from the processing of nuclear fuel at the Idaho Nuclear Technology and Engineering Center (INTEC). Acidic radioactive raffinates were solidified at ~500°C in a fluidized bed reactor to form the dry granular calcine material. Several Waste Management alternatives for the calcine are presented in the Idaho High Level Waste Draft EIS. The Separations Alternative addresses the processing of the calcine so that the HLW is ready for removal to a national geological repository by the year 2035. Calcine dissolution is the key front-end unit operation for the separations alternative.

  15. After adoption: dissolution or permanence?

    Science.gov (United States)

    Festinger, Trudy

    2002-01-01

    Results are presented on the whereabouts of 516 adopted children, based on a random sample of children adopted from placement in New York City in 1996. Data from interviews with adoptive parents were augmented by information from adoption subsidy records and state child tracking files, as well as interviews with caregivers of children whose adoptive parents were deceased. There were few dissolutions, but postadoption service needs were many.

  16. Fully validated method for rapid and simultaneous measurement of six antiepileptic drugs in serum and plasma using ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry.

    Science.gov (United States)

    Kuhn, Joachim; Knabbe, Cornelius

    2013-06-15

    Therapeutic drug monitoring (TDM) may be very useful in the clinical management of antiepileptic drug therapy for multiple reasons, such as individual variability, metabolism, genetic factors or drug-drug or drug-food interactions. In addition, TDM is helpful to study the variation in pharmacokinetics that occurs between individuals. Here, we describe a rapid assay using ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry to measure the antiepileptic drugs lacosamide, lamotrigine, levetiracetam, primidone, topiramate, and zonisamide. After the addition of internal standards (ISs) and protein precipitation of serum or plasma, 1 μl of sample was separated on a 2.1×50 mm reverse phase column (Waters, Acquity UPLC BEH Phenyl, 1.7 μm). Analytes were then ionized and detected by electrospray ionization mass spectrometry with multiple reaction monitoring. Runtime was 2.5 min per injection. Matrix effects were investigated by systematical ion suppression and in-source fragmentation experiments. The calibration curves of the 6 antiepileptic drugs were linear over the working range between 0.05 and 50 mg/L (r>0.99). The limit of detection (LOD) was measured in the assay. The intraassay and interassay coefficients of variation for all compounds were 1.0 mg/L). Mean recoveries were between 87.8 and 98.6% for all drugs. There were no significant ion suppressions detected at the elution times of the analytes. The mean differences between serum and heparinized plasma values were less than 6% for the 6 antiepileptic drugs. All drugs were stable in serum at -20°C, 4°C, and even at RT for at least 1 month. In summary, a specific and sensitive stable isotope dilution UPLC-MS/MS method was developed and validated for routine clinical monitoring of lacosamide, lamotrigine, levetiracetam, primidone, topiramate, and zonisamide. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Development and characterization of solid dispersion of piroxicam for improvement of dissolution rate using hydrophilic carriers

    Directory of Open Access Journals (Sweden)

    Mohammad Barzegar-jalali

    2014-09-01

    Full Text Available Introduction: The main objective of this study was preparation and characterization of solid dispersion of piroxicam to enhance its dissolution rate. Methods: Solid dispersion formulations with different carriers including crospovidone, microcrystalline cellulose and Elaeagnus angustifolia fruit powder and with different drug: carrier ratios were prepared employing cogrinding method. Dissolution study of the piroxicam powders, physical mixtures and solid dispersions was performed in simulated gastric fluid and simulated intestinal fluid using USP Apparatus type II. The physical characterization of formulations were analyzed using powder X ray diffraction (PXRD, particle size analyzer and differential scanning calorimetry (DSC. Interactions between the drug and carriers were evaluated by Fourier transform infrared (FT-IR spectroscopic method. Results: It was revealed that all of three carriers increase the dissolution rate of piroxicam from physical mixtures and especially in solid dispersions compared to piroxicam pure and treated powders. PXRD and DSC results were confirmed the reduction of crystalline form of piroxicam. FT-IR analysis did not show any physicochemical interaction between drug and carriers in the solid dispersion formulations. Conclusion: Dissolution rate was dependent on the type and ratio of drug: carrier as well as pH of dissolution medium. Dissolution data of formulations were fitted well in to the linear Weibull as well as non-linear logistic and a suggested models.

  18. Development and Validation of New Discriminative Dissolution Method for Carvedilol Tablets

    Science.gov (United States)

    Raju, V.; Murthy, K. V. R.

    2011-01-01

    The objective of the present study was to develop and validate a discriminative dissolution method for evaluation of carvedilol tablets. Different conditions such as type of dissolution medium, volume of dissolution medium and rotation speed of paddle were evaluated. The best in vitro dissolution profile was obtained using Apparatus II (paddle), 50 rpm, 900 ml of pH 6.8 phosphate buffer as dissolution medium. The drug release was evaluated by high-performance liquid chromatographic method. The dissolution method was validated according to current ICH and FDA guidelines using parameters such as the specificity, accuracy, precision and stability were evaluated and obtained results were within the acceptable range. The comparison of the obtained dissolution profiles of three different products were investigated using ANOVA-based, model-dependent and model-independent methods, results showed that there is significant difference between the products. The dissolution test developed and validated was adequate for its higher discriminative capacity in differentiating the release characteristics of the products tested and could be applied for development and quality control of carvedilol tablets. PMID:22923865

  19. Hydrogen production from the dissolution of nano zero valent iron and its effect on anaerobic digestion.

    Science.gov (United States)

    Huang, Yu-Xi; Guo, Jialiang; Zhang, Chunyang; Hu, Zhiqiang

    2016-01-01

    Nano zero valent iron (NZVI) has shown inhibition on methanogenesis in anaerobic digestion due to its reductive decomposition of cell membrane. The inhibition was accompanied by the accumulation of hydrogen gas due to rapid NZVI dissolution. It is not clear whether and how rapid hydrogen release from NZVI dissolution directly affects anaerobic digestion. In this study, the hydrogen release kinetics from NZVI (average size = 55 ± 11 nm) dissolution in deionized water under anaerobic conditions was first evaluated. The first-order NZVI dissolution rate constant was 2.62 ± 0.26 h(-1) with its half-life of 0.26 ± 0.03 h. Two sets of anaerobic digestion experiments (i.e., in the presence of glucose or without any substrate but at different anaerobic sludge concentrations) were performed to study the impact of H2 release from rapid NZVI dissolution, in which H2 was generated in a separate water bottle containing NZVI (i.e., ex situ H2 or externally supplied from NZVI dissolution) before hydrogen gas was introduced to anaerobic digestion. The results showed that the H2 partial pressure in the headspace of the digestion bottle reached as high as 0.27 atm due to rapid NZVI dissolution, resulting in temporary inhibition of methane production. Nevertheless, the 5-d cumulative methane volume in the group with ex situ H2 production due to NZVI dissolution was actually higher than that of control, suggesting NZVI inhibition on methanogenesis is solely due to the reductive decomposition of cell membrane after direct contact with NZVI. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Enhanced dissolution of sildenafil citrate as dry foam tablets.

    Science.gov (United States)

    Sawatdee, Somchai; Atipairin, Apichart; Sae Yoon, Attawadee; Srichana, Teerapol; Changsan, Narumon

    2017-01-30

    Dry foam formulation technology is alternative approach to enhance dissolution of the drug. Sildenafil citrate was suspended in sodium dodecyl sulfate solution and adding a mixture of maltodextrin and mannitol as diluent to form a paste. Sildenafil citrate paste was passed through a nozzle spray bottle to obtain smooth foam. The homogeneous foam was dried in a vacuum oven and sieved to obtain dry foam granules. The granules were mixed with croscarmellose sodium, magnesium stearate and compressed into tablet. All formulations were evaluated for their physicochemical properties and dissolution profiles. All the tested excipients were compatible with sildenafil citrate by both differential scanning calorimetry (DSC) and infrared (IR) analysis. There are no X-ray diffraction (XRD) peaks representing crystals of sildenafil citrate observed form dry foam formulations. The hardness of tablets was about 5 kg, friability test <1% with a disintegration time <5 min. The sildenafil citrate dry foam tablet had higher dissolution rate in 0.1 N HCl in comparison with commercial sildenafil citrate tablet, sildenafil citrate prepared by direct compression and wet granulation method. Sildenafil citrate dry foam tablet with the high-level composition of surfactant, water and diluent showed enhanced dissolution rate than that of the lower-level composition of these excipients. This formulation was stable under accelerated conditions for at least 6 months.

  1. Rapid determination of yunaconitine and related alkaloids in aconites and aconite-containing drugs by ultra high-performance liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Song, Long; Zhang, Hong; Liu, Xin; Zhao, Zhi-Li; Chen, Shi-Lin; Wang, Zheng-Tao; Xu, Hong-Xi

    2012-12-01

    Yunaconitine (YAC) is a toxic aconite alkaloid that is considered to be a hidden aconite poison since it is frequently found in body fluids from aconite poisoning patients, but has not been well studied in commonly used herbal drugs. In this paper, a rapid and sensitive ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) detection combined with microwave-assisted extraction (MAE) was developed for high throughput simultaneous determination of YAC and six other toxic aconite alkaloids in 31 samples of crude, processed aconites and aconite-containing drugs. The optimized method showed excellent linearity, precision, accuracy and recovery for all target compounds with short run time. YAC was detected in some samples with contents from 0.015 to 10.41 mg/g. This is the first report on the determination of YAC in Radix Aconiti, Radix Aconiti Kusnezoffii and aconite-containing drugs. This newly developed method facilitates the rapid screening of YAC and related toxic aconite alkaloids and allows YAC to be used as a chemical marker for the quality control of aconites and aconite-containing drugs. Copyright © 2012 John Wiley & Sons, Ltd.

  2. Latent variable modeling to analyze the effects of process parameters on the dissolution of paracetamol tablet

    OpenAIRE

    Sun, Fei; Xu, Bing; Zhang, Yi; Dai, Shengyun; Shi, Xinyuan; Qiao, Yanjiang

    2016-01-01

    The dissolution is one of the critical quality attributes (CQAs) of oral solid dosage forms because it relates to the absorption of drug. In this paper, the influence of raw materials, granules and process parameters on the dissolution of paracetamol tablet was analyzed using latent variable modeling methods. The variability in raw materials and granules was understood based on the principle component analysis (PCA), respectively. A multi-block partial least squares (MBPLS) model was used to ...

  3. A quantitative high-resolution genetic profile rapidly identifies sequence determinants of hepatitis C viral fitness and drug sensitivity.

    Directory of Open Access Journals (Sweden)

    Hangfei Qi

    2014-04-01

    Full Text Available Widely used chemical genetic screens have greatly facilitated the identification of many antiviral agents. However, the regions of interaction and inhibitory mechanisms of many therapeutic candidates have yet to be elucidated. Previous chemical screens identified Daclatasvir (BMS-790052 as a potent nonstructural protein 5A (NS5A inhibitor for Hepatitis C virus (HCV infection with an unclear inhibitory mechanism. Here we have developed a quantitative high-resolution genetic (qHRG approach to systematically map the drug-protein interactions between Daclatasvir and NS5A and profile genetic barriers to Daclatasvir resistance. We implemented saturation mutagenesis in combination with next-generation sequencing technology to systematically quantify the effect of every possible amino acid substitution in the drug-targeted region (domain IA of NS5A on replication fitness and sensitivity to Daclatasvir. This enabled determination of the residues governing drug-protein interactions. The relative fitness and drug sensitivity profiles also provide a comprehensive reference of the genetic barriers for all possible single amino acid changes during viral evolution, which we utilized to predict clinical outcomes using mathematical models. We envision that this high-resolution profiling methodology will be useful for next-generation drug development to select drugs with higher fitness costs to resistance, and also for informing the rational use of drugs based on viral variant spectra from patients.

  4. Rapid in situ detection of street samples of drugs of abuse on textile substrates using microRaman spectroscopy

    Science.gov (United States)

    Ali, Esam M. A.; Edwards, Howell G. M.; Scowen, Ian J.

    2011-10-01

    Trace amounts of street samples of cocaine hydrochloride and N-methyl-3,4-methylenedioxy-amphetamine (MDMA) on natural and synthetic textiles were successfully detected in situ using confocal Raman microscopy. The presence of some excipient bands in the spectra of the drugs did not prevent the unambiguous identification of the drugs. Raman spectra of the drugs were readily obtained without significant interference from the fibre substrates. Interfering bands arising from the fibre natural or synthetic polymer structure and/or dye molecules did not overlap with the characteristic Raman bands of the drugs. If needed, interfering bands could be successfully removed by spectral subtraction. Also, Raman spectra could be acquired from drug particles trapped between the fibres of highly fluorescent textile specimens. The total acquisition time of the spectra of the drug particles was 90 s accomplished non-destructively and without detachment from their substrates. Sample preparation was not required and spectra of the drugs could be obtained non-invasively preserving the integrity of the evidential material for further analysis.

  5. Original research paper. A superior preparation method for daidzein-hydroxypropyl-β-cyclodextrin complexes with improved solubility and dissolution: Supercritical fluid process.

    Science.gov (United States)

    Pan, Hao; Wang, Han-Bing; Yu, Yi-Bin; Cheng, Bing-Chao; Wang, Xiao-Yu; Li, Ying

    2017-03-01

    Advantages of the supercritical fluid (SCF) process compared to the conventional solution stirring method (CSSM) in the preparation of daidzein-hydroxypropyl-β-cyclodextrin (HPβCD) complexes were investigated. Formation of daidzein/ HPβCD inclusion complexes was confirmed by Fourier transformed-infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM). Particle size, inclusion yield, drug solubility and dissolution of daidzein/HPβCD complexes were evaluated. Compared to CSSM, the SCF process resulted in higher inclusion yield and higher solubility. Also, extended dissolution of daidzein from the SCF processed HPβCD inclusion complexes was observed, with only 22.94 % released in 45 min, compared to its rapid release from those prepared by CSSM, with 98.25 % drug release in 15 min. This extended release of daidzein from SCF prepared inclusion complexes was necessary to avoid drug precipitation and improve drug solubilisation in the gastrointestinal tract. The results showed that the SCF process is a superior preparation method for daidzein-hydroxypropyl-β-cyclodextrin complexes.

  6. Solid phospholipid nano-particles: investigations into formulation and dissolution properties of griseofulvin.

    Science.gov (United States)

    Brinkmann-Trettenes, Ulla; Bauer-Brandl, Annette

    2014-06-05

    Solid phospholipid (PL) nanoparticles with griseofulvin (GRIS) as a model drug were prepared by co-spray drying. Their dissolution properties were compared with formulations containing the physical blends of the native crystalline drug and excipient materials, and physical blends of the spray dried materials. Co-spray drying was performed from ethanol+water solutions (80+20) using Büchi Nano Spray Dryer B-90. Dissolution profiles in phosphate buffer (PBS), simulated intestinal fluids (fasted state simulated intestinal fluid (FaSSIF)) and pancreatin containing media (PAN) were studied. It was found that the influence of PL on the dissolution profile was affected by both the solid state of the drug formulation and the dissolution medium: the co-SD formulations showed the fastest release in all media. The amount of GRIS dissolved after 5h increases by a factor of 7 for the co SD as compared to physical blend of native materials in PBS, and a factor of 4 in FaSSIF respectively. Surprisingly, in contrast to PBS, dissolution rate in FaSSIF decreased with increasing the PL content. All the pancreatin containing media showed a decrease in dissolution rate and extent independently of the processing methods due to an incompatibility between GRIS and PAN. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Evaluation of paracetamol suppositories by a pharmacopoeial dissolution test--comments on methodology.

    Science.gov (United States)

    Janicki, S; Sznitowska, M; Zebrowska, W; Gabiga, H; Kupiec, M

    2001-09-01

    Ph.Eur. and BP have introduced a dissolution apparatus for suppositories. Suitability of the apparatus for quality control of paracetamol suppositories was evaluated and the effect of experimental conditions on dissolution profiles was studied. Paracetamol suppositories containing 80-500 mg of the drug, on fatty base, were obtained from four manufacturers (A, B, C, D). The diffusion cell was modified by incorporation of an in-built thermoprobe and large difference (up to 1.7 degrees C) between temperature in the water-bath and in the dissolution chamber was observed. This effect was avoided by increasing the length of tubing immersed in the thermostat at the inlet of the cell. The most reproducible results were observed for A and C suppositories, however from suppository C the total dose of paracetamol was released after 3.5-4.5 h while the release from suppository A was slow with only 40-87% of the total dose liberated during 6 h. Suppositories B did not melt at 37 degrees C and less than 5% of the drug was released. Fast release was observed after melting when the temperature was elevated to 39.5 degrees C. The results demonstrate clearly that essentially complete melting of a suppository in the dissolution chamber is required for an appropriate dissolution of paracetamol in vitro. Disintegration time, softening time, drop point and particle size of the suspended drug were measured and the relevance of these parameters for dissolution behaviour of the preparations was discussed.

  8. Human tooth enamel dissolution in citric acid as a function of degree of saturation and pH

    Energy Technology Data Exchange (ETDEWEB)

    Barbour, Michele Emily

    2002-07-01

    There is increasing concern among the dental community regarding the damage caused to teeth by the acids in soft drinks. Enamel dissolution in acidic solution can be reduced by addition of calcium and/or phosphate salts to increase the degree of saturation with respect to hydroxyapatite (DS{sub HA}), or by an increase in pH. In soft drinks, however, both of these approaches are associated with a reduced taste quality. The separate effects of each parameter are not known. In the work presented here, enamel dissolution was studied in citric acid solutions with compositions typical of soft drinks. Nanoindentation and atomic force microscopy (AFM) were used to investigate very early stages of enamel dissolution, with typical exposure times of 30-600 s. Preliminary investigations of the application of SIMS, ESEM and XPS to enamel dissolution studies are also reported. The individual effects of DS{sub HA}, pH and calcium and phosphate concentrations on enamel dissolution have been investigated. It was shown that there exists a threshold condition defined by calcium and phosphate concentrations and pH, below which there is considerable dissolution and a rapid dependence of dissolution rate on DS{sub HA}, and above which little or no discernible dissolution takes place. This threshold condition corresponds to a considerably undersaturated solution (DS{sub HA} {approx_equal} 0.1). However, contrary to assumptions in many enamel dissolution models in the literature, DS{sub HA} is not sufficient to predict the dissolution rate and the individual calcium and phosphate concentrations are also important. The dependence of enamel dissolution on pH is comparatively minor, with only a small change in dissolution rate for a change in pH. In terms of soft drink modification, it has been shown here that DS{sub HA} adjustment can be used to greatly reduce the rate of enamel dissolution, and that a concurrent change in pH may be superfluous. (author)

  9. General class of multiparticulate dissolution models.

    Science.gov (United States)

    Pedersen, P V; Brown, K F

    1977-10-01

    The dissolution of multiparticulate systems under sink and nonsink conditions can be described rigorously according to a generally applicable formula on the basis of the single-particle dissolution model and the initial particle distribution. The kinetic model for log-normal systems dissolving under sink conditions is extended to nonsink conditions as a specific example. The equation presented describes a general class of multiparticulate models for various values of the dispersion parameter and the dissolution capacity coefficient.

  10. Magnetically optimized SERS assay for rapid detection of trace drug-related biomarkers in saliva and fingerprints.

    Science.gov (United States)

    Yang, Tianxi; Guo, Xiaoyu; Wang, Hui; Fu, Shuyue; Wen, Ying; Yang, Haifeng

    2015-06-15

    New developments in the fields of human healthcare and social security call for the exploration of an easy and on-field method to detect drug-related biomarkers. In this paper, Au nanoparticles dotted magnetic nanocomposites (AMN) modified with inositol hexakisphosphate (IP6) were used as surface-enhanced Raman scattering (SERS) substrate to quickly monitor trace drug-related biomarkers in saliva and to on-site screen a trace drug biomarker in fingerprints. Due to inducing with an external magnet, such substrate presented a huge SERS activity, which has met the sensitivity requirement for assay to detect the drug biomarkers in saliva from the U.S. Substance Abuse and Mental Health Services Administration, and also the limit of detection for drug biomarker in fingerprint reached 100 nM. In addition, this AMN-based SERS assay was successfully conducted using a portable Raman spectrometer, which could be used to on-site and accurately differentiate between the smokers and drug addicts in near future. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. A multi-site validation in India of the line probe assay for the rapid diagnosis of multi-drug resistant tuberculosis directly from sputum specimens.

    Science.gov (United States)

    Raizada, Neeraj; Sachdeva, K S; Chauhan, D S; Malhotra, Bharti; Reddy, Kishore; Dave, P V; Mundade, Yamuna; Patel, Pranav; Ramachandran, Ranjani; Das, Ram; Solanki, Rajesh; Wares, Douglas Fraser; Sahu, Suvanand; O'Brien, Rick; Paramasivan, C N; Dewan, Puneet K

    2014-01-01

    Rifampicin (R) and isoniazid (H) are key first-line anti-tuberculosis drugs. Failure to detect resistance to these two drugs early results in treatment failure and poor clinical outcomes. The study purpose was to validate the use of the GenoType MTBDRplus line probe assay (LPA) to detect resistance to R and H in Mycobacterium tuberculosis strains directly from smear-positive sputum samples in India. Smear positive sputum specimens from 320 patients were subjected to LPA and results compared against those from conventional Lowenstein Jensen (LJ) culture and drug susceptibility testing (C&DST). All specimens with discordant R DST results were subjected to either sequencing of the rpoB gene and/or repeat DST on liquid culture (MGIT 960) at a National Reference Laboratory. Significantly higher proportion of interpretable results were observed with LPA compared to LJ C&DST (94% vs. 80%, p-value turnaround testing time, including specimen transportation time, on LPA was 11 days as compared with 89 days for LJ C&DST. LPA proved highly accurate in the rapid detection of R resistance. The reduction in time to diagnosis may potentially enable earlier commencement of the appropriate drug therapy, leading to some reduction of transmission of drug-resistant strains.

  12. Preparation of multilocation reduction-sensitive core crosslinked folate-PEG-coated micelles for rapid release of doxorubicin and tariquidar to overcome drug resistance

    Science.gov (United States)

    Yi, Xiaoqing; Zhao, Dan; Zhang, Quan; Xu, Jiaqi; Yuan, Gongdao; Zhuo, Renxi; Li, Feng

    2017-02-01

    Herein, we prepared folate-targeting core crosslinked polymeric micelles (CCL/FA) containing multiple disulfide bonds located at the interface and core of the micelles to co-deliver doxorubicin (DOX) and the P-glycoprotein (P-gp) inhibitor tariquidar (TQR) for reversing drug resistance. The stability and redox-responsive behavior of the CCL/FA micelles was evaluated through the changes in morphology, molecular weight and hydrodynamic size. On the one hand, the micelles possessed good stability, which led to the suppression of drug release from the CCL micelles in the physiological environment. On the other hand, under reductive conditions, the CCL micelles collapsed rapidly and accelerated drug release markedly. In vitro cytotoxicity measurements, combined with confocal laser scanning microscopy (CLSM) and flow cytometry, confirmed that the dual-drug-loaded micelles exhibited obviously higher cytotoxicity to MCF-7/ADR-resistant cells than free DOX · HCl, single-drug loaded CCL micelles and nontargeted CCL micelles. The results imply that co-delivering DOX and TQR by CCL/FA micelles may be a promising way of overcoming multidrug resistance in tumor treatments.

  13. Dissolution of minerals and hydrometallurgical processes

    Science.gov (United States)

    Habashi, Fathi

    1983-08-01

    Physical, chemical, electrochemical, and electrolytic processes involved in the dissolution of minerals in aqueous solutions are identified and characterized. Their importance to hydrometallurgy is outlined.

  14. Development and Characterisation of Ursolic Acid Nanocrystals Without Stabiliser Having Improved Dissolution Rate and In Vitro Anticancer Activity

    National Research Council Canada - National Science Library

    Song, Ju; Wang, Yancai; Song, Yuelin; Chan, Hokman; Bi, Chao; Yang, Xiao; Yan, Ru; Wang, Yitao; Zheng, Ying

    2014-01-01

    Ursolic acid (UA), which is a natural pentacyclic triterpenoid, has the potential to be developed as an anticancer drug, whereas its poor aqueous solubility and dissolution rate limit its clinical application...

  15. Willingness-to-pay for a rapid malaria diagnostic test and artemisinin-based combination therapy from private drug shops in Mukono District, Uganda.

    Science.gov (United States)

    Hansen, Kristian Schultz; Pedrazzoli, Debora; Mbonye, Anthony; Clarke, Sian; Cundill, Bonnie; Magnussen, Pascal; Yeung, Shunmay

    2013-03-01

    In Uganda, as in many parts of Africa, the majority of the population seek treatment for malaria in drug shops as their first point of care; however, parasitological diagnosis is not usually offered in these outlets. Rapid diagnostic tests (RDTs) for malaria have attracted interest in recent years as a tool to improve malaria diagnosis, since they have proved accurate and easy to perform with minimal training. Although RDTs could feasibly be performed by drug shop vendors, it is not known how much customers would be willing to pay for an RDT if offered in these settings. We conducted a contingent valuation survey among drug shop customers in Mukono District, Uganda. Exit interviews were undertaken with customers aged 15 years and above after leaving a drug shop having purchased an antimalarial and/or paracetamol. The bidding game technique was used to elicit the willingness-to-pay (WTP) for an RDT and a course of artemisinin-based combination therapy (ACT) with and without RDT confirmation. Factors associated with WTP were investigated using linear regression. The geometric mean WTP for an RDT was US$0.53, US$1.82 for a course of ACT and US$2.05 for a course of ACT after a positive RDT. Factors strongly associated with a higher WTP for these commodities included having a higher socio-economic status, no fever/malaria in the household in the past 2 weeks and if a malaria diagnosis had been obtained from a qualified health worker prior to visiting the drug shop. The findings further suggest that the WTP for an RDT and a course of ACT among drug shop customers is considerably lower than prevailing and estimated end-user prices for these commodities. Increasing the uptake of ACTs in drug shops and restricting the sale of ACTs to parasitologically confirmed malaria will therefore require additional measures.

  16. Tailor-Made pH-Responsive Poly(choline phosphate) Prodrug as a Drug Delivery System for Rapid Cellular Internalization.

    Science.gov (United States)

    Wang, Wenliang; Wang, Bo; Ma, Xiaojing; Liu, Sanrong; Shang, Xudong; Yu, Xifei

    2016-06-13

    Rapid cellular uptake and efficient drug release in tumor cells are two of the major challenges for cancer therapy. Herein, we designed and synthesized a novel pH-responsive polymer-drug conjugate system poly(2-(methacryloyloxy)ethyl choline phosphate)-b-poly(2-methoxy-2-oxoethyl methacrylate-hydrazide-doxorubicin) (PCP-Dox) to overcome these two challenges simultaneously. It has been proved that PCP-Dox can be easily and rapidly internalized by various cancer cells due to the strong interaction between multivalent choline phosphate (CP) groups and cell membranes. Furthermore, Dox, linked to the polymer carrier via acid-labile hydrazone bond, can be released from carriers due to the increased acidity in lysosome/endosome (pH 5.0-5.5) after the polymer prodrug was internalized into the cancer cells. The cell viability assay demonstrated that this novel polymer prodrug has shown enhanced cytotoxicity in various cancer cells, indicating its great potential as a new drug delivery system for cancer therapy.

  17. Use of peak decay analysis and affinity microcolumns containing silica monoliths for rapid determination of drug-protein dissociation rates.

    Science.gov (United States)

    Yoo, Michelle J; Hage, David S

    2011-04-15

    This report examined the use of silica monoliths in affinity microcolumns containing human serum albumin (HSA) to measure the dissociation rates for various drugs from this protein. Immobilized HSA and control monolith columns with dimensions of 1 mm × 4.6 mm i.d. were prepared for this work and used with a noncompetitive peak decay method. Several drugs known to bind HSA were examined, such as warfarin, diazepam, imipramine, acetohexamide, and tolbutamide. Items that were studied and optimized in this method included the sample volume, sample concentration, and elution flow rate. It was found that flow rates up to 10 mL/min could be used in this approach. Work with HSA silica monoliths at these high flow rates made it possible to provide dissociation rate constants for drugs such as warfarin in less than 40s. The dissociation rate constants that were measured gave good agreement with values reported in the literature or that had been obtained with other solutes that had similar binding affinities for HSA. This approach is a general one that should be useful in examining the dissociation of other drugs from HSA and in providing a high-throughput method for screening drug-protein interactions. Copyright © 2010 Elsevier B.V. All rights reserved.

  18. Calcite dissolution rate spectra measured by in situ digital holographic microscopy.

    Science.gov (United States)

    Brand, Alexander S; Feng, Pan; Bullard, Jeffrey W

    2017-09-01

    Digital holographic microscopy in reflection mode is used to track in situ, real-time nanoscale topography evolution of cleaved (104) calcite surfaces exposed to flowing or static deionized water. The method captures full-field holograms of the surface at frame rates of up to 12.5 s(-1). Numerical reconstruction provides 3D surface topography with vertical resolution of a few nanometers and enables measurement of time-dependent local dissolution fluxes. A statistical distribution, or spectrum, of dissolution rates is generated by sampling multiple area domains on multiple crystals. The data show, as has been demonstrated by Fischer et al. (2012), that dissolution is most fully described by a rate spectrum, although the modal dissolution rate agrees well with published mean dissolution rates (e.g., 0.1 µmol m(-2) s(-1) to 0.3 µmol m(-2) s(-1)). Rhombohedral etch pits and other morphological features resulting from rapid local dissolution appear at different times and are heterogeneously distributed across the surface and through the depth. This makes the distribution in rates measured on a single crystal dependent both on the sample observation field size and on time, even at nominally constant undersaturation. Statistical analysis of the inherent noise in the DHM measurements indicates that the technique is robust and that it likely can be applied to quantify and interpret rate spectra for the dissolution or growth of other minerals.

  19. Mechanistic analysis of solute transport in an in vitro physiological two-phase dissolution apparatus

    Science.gov (United States)

    Mudie, Deanna M.; Shi, Yi; Ping, Haili; Gao, Ping; Amidon, Gordon L.; Amidon, Gregory E.

    2015-01-01

    In vitro dissolution methodologies that adequately capture the oral bioperformance of solid dosage forms are critical tools needed to aid formulation development. Such methodologies must encompass important physiological parameters and be designed with drug properties in mind. Two-phase dissolution apparatuses, which contain an aqueous phase in which the drug dissolves (representing the dissolution/solubility component) and an organic phase into which the drug partitions (representing the absorption component), have the potential to provide meaningful predictions of in vivo oral bioperformance for some BCS II, and possibly some BCS IV drug products. Before such an apparatus can be evaluated properly, it is important to understand the kinetics of drug substance partitioning from the aqueous to the organic medium. A mass transport analysis was performed of the kinetics of partitioning of drug substance solutions from the aqueous to the organic phase of a two-phase dissolution apparatus. Major assumptions include pseudo-steady-state conditions, a dilute aqueous solution and diffusion-controlled transport. Input parameters can be measured or estimated a priori. This paper presents the theory and derivation of our analysis, compares it with a recent kinetic approach, and demonstrates its effectiveness in predicting in vitro partitioning profiles of three BCS II weak acids in four different in vitro two-phase dissolution apparatuses. Very importantly, the paper discusses how a two-phase apparatus can be scaled to reflect in vivo absorption kinetics and for which drug substances the two-phase dissolution systems may be appropriate tools for measuring oral bioperformance. PMID:22847296

  20. The influence of milling on the dissolution performance of simvastatin

    DEFF Research Database (Denmark)

    Zimper, Ulrike; Aaltonen, Jaakko; Krauel-Goellner, Karen

    2012-01-01

    , as well as factor interactions in a dry ball milling process using simvastatin as model drug, and to optimize the milling procedure with regard to the opposing responses particle size and process induced disorder by application of a central composite face centered design. Particle size was assessed...... properties such as solubility and dissolution rate and, therefore, process induced solid state modifications need to be monitored. The aim of this study was two-fold: firstly, to investigate the dissolution rates of milled and unmilled simvastatin; and secondly, to screen for the main milling factors...... by scanning electron microscopy (SEM) and image analysis. Process induced disorder was determined by partial least squares (PLS) regression modeling of respective X-ray powder diffractograms (XRPD) and Raman spectra. Valid and significant quadratic models were built. The investigated milling factors were...

  1. Investigation of Deteriorated Dissolution of Amorphous Itraconazole: Description of Incompatibility with Magnesium Stearate and Possible Solutions.

    Science.gov (United States)

    Démuth, B; Galata, D L; Szabó, E; Nagy, B; Farkas, A; Balogh, A; Hirsch, E; Pataki, H; Rapi, Z; Bezúr, L; Vigh, T; Verreck, G; Szalay, Z; Demeter, Á; Marosi, G; Nagy, Z K

    2017-11-06

    Disadvantageous crystallization phenomenon of amorphous itraconazole (ITR) occurring in the course of dissolution process was investigated in this work. A perfectly amorphous form (solid dispersion) of the drug was generated by the electroblowing method (with vinylpyrrolidone-vinyl acetate copolymer), and the obtained fibers were formulated into tablets. Incomplete dissolution of the tablets was noticed under the circumstances of the standard dissolution test, after which a precipitated material could be filtered. The filtrate consisted of ITR and stearic acid since no magnesium content was detectable in it. In parallel with dissolution, ITR forms an insoluble associate, stabilized by hydrogen bonding, with stearic acid deriving from magnesium stearate. This is why dissolution curves do not have the plateaus at 100%. Two ways are viable to tackle this issue: change the lubricant (with sodium stearyl fumarate >95% dissolution can be accomplished) or alter the polymer in the solid dispersion to a type being able to form hydrogen bonds with ITR (e.g., hydroxypropyl methylcellulose). This work draws attention to one possible phenomenon that can lead to a deterioration of originally good dissolution of an amorphous solid dispersion.

  2. Use of bicarbonate buffer systems for dissolution characterization of enteric-coated proton pump inhibitor tablets.

    Science.gov (United States)

    Shibata, Hiroko; Yoshida, Hiroyuki; Izutsu, Ken-Ichi; Goda, Yukihiro

    2016-04-01

    The aim of this study was to assess the effects of buffer systems (bicarbonate or phosphate at different concentrations) on the in vitro dissolution profiles of commercially available enteric-coated tablets. In vitro dissolution tests were conducted using an USP apparatus II on 12 enteric-coated omeprazole and rabeprazole tablets, including innovator and generic formulations in phosphate buffers, bicarbonate buffers and a media modified Hanks (mHanks) buffer. Both omeprazole and rabeprazole tablets showed similar dissolution profiles among products in the compendial phosphate buffer system. However, there were large differences between products in dissolution lag time in mHanks buffer and bicarbonate buffers. All formulations showed longer dissolution lag times at lower concentrations of bicarbonate or phosphate buffers. The dissolution rank order of each formulation differed between mHanks buffer and bicarbonate buffers. A rabeprazole formulation coated with a methacrylic acid copolymer showed the shortest lag time in the high concentration bicarbonate buffer, suggesting varied responses depending on the coating layer and buffer components. Use of multiple dissolution media during in vitro testing, including high concentration bicarbonate buffer, would contribute to the efficient design of enteric-coated drug formulations. © 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology.

  3. Physical characterization and dissolution performance assessment of Etravirine solid dispersions prepared by spray drying process.

    Science.gov (United States)

    Kommavarapu, Pavan; Maruthapillai, Arthanareeswari; Palanisamy, Kamaraj; Koya, Ravi Teja

    2016-11-01

    The aim of the current exertion was to prepare Solid Dispersion of Etravirine by Spray drying technique to enhance aqueous solubility and dissolution rate. Solid dispersions (SD) of Etravirine were prepared using Copovidone and Povidone-Copovidone in dichloromethane and physical properties were characterized by Scanning electron microscopy (SEM), X-Ray diffractometry (PXRD), Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC). SD's were evaluated for equilibrium solubility and in vitro drug release profile by dissolution testing. The diffraction and thermal patterns of solid dispersions indicated the conversion of crystalline Etravirine to amorphous form. The solubility of drug in SD's was appreciably more when evaluated against physical mixtures and intact Etravirine. Drug release characteristics were evaluated in three different media at different pH and found that drug release kinetic was best described by weibull mathematical model. Mean dissolution time (MDT) and Dissolution efficiency (DE %) in different media were evaluated for SDs. Statistical evaluation of dissolution data using Analysis Of Variance (ANOVA) single factor and t-Test: Paired Two Sample for Means was applied for better understanding and evaluation.

  4. Comparison of Dissolution Similarity Assessment Methods for Products with Large Variations: f2 Statistics and Model-Independent Multivariate Confidence Region Procedure for Dissolution Profiles of Multiple Oral Products.

    Science.gov (United States)

    Yoshida, Hiroyuki; Shibata, Hiroko; Izutsu, Ken-Ichi; Goda, Yukihiro

    2017-01-01

    The current Japanese Ministry of Health Labour and Welfare (MHLW)'s Guideline for Bioequivalence Studies of Generic Products uses averaged dissolution rates for the assessment of dissolution similarity between test and reference formulations. This study clarifies how the application of model-independent multivariate confidence region procedure (Method B), described in the European Medical Agency and U.S. Food and Drug Administration guidelines, affects similarity outcomes obtained empirically from dissolution profiles with large variations in individual dissolution rates. Sixty-one datasets of dissolution profiles for immediate release, oral generic, and corresponding innovator products that showed large variation in individual dissolution rates in generic products were assessed on their similarity by using the f2 statistics defined in the MHLW guidelines (MHLW f2 method) and two different Method B procedures, including a bootstrap method applied with f2 statistics (BS method) and a multivariate analysis method using the Mahalanobis distance (MV method). The MHLW f2 and BS methods provided similar dissolution similarities between reference and generic products. Although a small difference in the similarity assessment may be due to the decrease in the lower confidence interval for expected f2 values derived from the large variation in individual dissolution rates, the MV method provided results different from those obtained through MHLW f2 and BS methods. Analysis of actual dissolution data for products with large individual variations would provide valuable information towards an enhanced understanding of these methods and their possible incorporation in the MHLW guidelines.

  5. The effect of surfactants on the dissolution behavior of amorphous formulations

    DEFF Research Database (Denmark)

    Mah, Pei T; Peltonen, Leena; Novakovic, Dunja

    2016-01-01

    in detail. The main aim of this study was to investigate the effect of surfactant on the dissolution behavior of neat amorphous drug and binary polymer based solid dispersion. Indomethacin was used as the model drug and the surfactants studied were polysorbate 80 and poloxamer 407. The presence...... of surfactants (alone or in combination with polymers) in the buffer was detrimental to the dissolution of neat amorphous indomethacin, suggesting that the surfactants promoted the crystallization of neat amorphous indomethacin. In contrast, the presence of surfactants (0.01% w/v) in the buffer resulted...... studies of neat amorphous drugs requires prudent consideration. The design of amorphous formulations with optimal dissolution performance requires the appropriate selection of a combination of excipients and consideration of the method of introducing the excipients....

  6. The protease inhibitors ritonavir and saquinavir influence lipid metabolism: a pig model for the rapid evaluation of new drugs

    DEFF Research Database (Denmark)

    Petersen, E.; Mu, Huiling; Porsgaard, Trine

    2010-01-01

    Background: Studies of the effects of antiretroviral drugs on lipid metabolism are limited by the availability of suitable models. We have thus developed an animal model utilising Gottingen mini-pigs. The normal lipid metabolism of mini-pigs closely reflects that of humans and they are expected t...

  7. Rapid determination of furosemide in drug and blood plasma of wrestlers by a carboxyl-MWCNT sensor.

    Science.gov (United States)

    Heidarimoghadam, Rashid; Farmany, Abbas

    2016-01-01

    A novel method is developed for the quantification of furosemide in biological fluids. The method is based on the electro-reduction of Zn(II)-furosemide complex at carboxyl-MWCNT modified glassy carbon electrode. It is shown that, in Britton-Robinson buffer (pH5.7) the reduction peak of Zn(II)-furosemide complex formed at -1.0 V (versus, Ag/AgCl). The increment of current signal obtained from the reduction peak current of the Zn(II)-furosemide complex was rectilinear with furosemide concentration in the range of 0.03 to 140.0 μg ml(-1), with a detection limit of 0.007 μg ml(-1). The drug recovery ranged between 97.8% and 100.8% and the mean drug recovery was 98.89%. The accuracies (relative error% and RSD%) were less than 15% and are acceptable according to the US FDA guideline for bioanalytical method validation. The sensor was used for quantification of furosemide in drug and biological fluid samples. The data of drug analysis were compared with the standard method. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. DISSOLUTION OF LANTHANUM FLUORIDE PRECIPITATES

    Science.gov (United States)

    Fries, B.A.

    1959-11-10

    A plutonium separatory ore concentration procedure involving the use of a fluoride type of carrier is presented. An improvement is given in the derivation step in the process for plutonium recovery by carrier precipitation of plutonium values from solution with a lanthanum fluoride carrier precipitate and subsequent derivation from the resulting plutonium bearing carrier precipitate of an aqueous acidic plutonium-containing solution. The carrier precipitate is contacted with a concentrated aqueous solution of potassium carbonate to effect dissolution therein of at least a part of the precipitate, including the plutonium values. Any remaining precipitate is separated from the resulting solution and dissolves in an aqueous solution containing at least 20% by weight of potassium carbonate. The reacting solutions are combined, and an alkali metal hydroxide added to a concentration of at least 2N to precipitate lanthanum hydroxide concomitantly carrying plutonium values.

  9. Willingness-to-pay for a rapid malaria diagnostic test and artemisinin-based combination therapy from private drug shops in Mukono district, Uganda

    DEFF Research Database (Denmark)

    Hansen, Kristian Schultz; Pedrazzoli, Debora; Mbonye, Anthony

    2013-01-01

    In Uganda, as in many parts of Africa, the majority of the population seek treatment for malaria in drug shops as their first point of care; however, parasitological diagnosis is not usually offered in these outlets. Rapid diagnostic tests (RDTs) for malaria have attracted interest in recent years...... and a course of artemisinin-based combination therapy (ACT) with and without RDT confirmation. Factors associated with WTP were investigated using linear regression. The geometric mean WTP for an RDT was US$0.53, US$1.82 for a course of ACT and US$2.05 for a course of ACT after a positive RDT. Factors strongly...

  10. Toward an In Vivo Dissolution Methodology: A Comparison of Phosphate and Bicarbonate Buffers

    Science.gov (United States)

    Sheng, Jennifer J.; McNamara, Daniel P.; Amidon, Gordon L.

    2011-01-01

    Purpose To evaluate the difference between the pharmaceutical phosphate buffers and the gastrointestinal bicarbonates in dissolution of ketoprofen and indomethacin, to illustrate the dependence of buffer differential on biopharmaceutical properties of BCS II weak acids, and to recommend phosphate buffers equivalent to bicarbonates. Methods The intrinsic dissolution rates of, ketoprofen and indomethacin, were experimentally measured using rotating disk method at 37°C in USP SIF/FaSSIF and various concentrations of bicarbonates. Theoretical models including an improved reaction plane model and a film model were applied to estimate the surrogate phosphate buffers equivalent to the bicarbonates. Results Experimental results show that the intrinsic dissolution rates of ketoprofen and indomethacin, in USP and FaSSIF phosphate buffers are 1.5–3.0 times of that in the 15 mM bicarbonates. Theoretical analysis demonstrates that the buffer differential is largely dependent on the drug pKa and secondly on solubility, and weakly dependent on the drug diffusivity. Further, in accordance with the drug pKa, solubility and diffusivity, simple phosphate surrogate was proposed to match an average bicarbonate value (15 mM) of the upper gastrointestinal region. Specifically, phosphate buffers of 13–15 mM and 3–4 mM were recommended for ketoprofen and indomethacin, respectively. For both ketoprofen and indomethacin, the intrinsic dissolution using the phosphate surrogate buffers closely approximated the 15 mM bicarbonate buffer. Conclusions This work demonstrates the substantial difference between pharmaceutical phosphates and physiological bicarbonates in determining the drug intrinsic dissolution rates of BCS II weak acids, such as ketoprofen and indomethacin. Surrogate phosphates were recommended in order to closely reflect the in vivo dissolution of ketoprofen and indomethacin in gastrointestinal bicarbonates, which has significant implications for defining buffer systems for

  11. Emotional and Cognitive Coping in Relationship Dissolution

    Science.gov (United States)

    Wrape, Elizabeth R.; Jenkins, Sharon Rae; Callahan, Jennifer L.; Nowlin, Rachel B.

    2016-01-01

    Dissolution of a romantic relationship can adversely affect functioning among college students and represents one primary reason for seeking campus counseling. This study examined the associations among common coping strategies and distress following relationship dissolution. Avoidance and repetitive negative thinking (RNT) were significantly…

  12. CALCIUM CARBONATE DISSOLUTION RATE IN LIMESTONE CONTACTORS

    Science.gov (United States)

    The rate of carbonate mineral dissolution from limestone was studied using a rotating disk apparatus and samples of limestone of varied composition. The purpose of this study was to determine the effect of limestone composition on the kinetics of carbonate mineral dissolution. Th...

  13. Numerical modelling of multicomponent LNAPL dissolution kinetics ...

    Indian Academy of Sciences (India)

    During the initial phase, the dissolution rate of a soluble compound is very high due to the high concentration gradient, and as dissolution progresses, its effective solubility decreases with change in mole fraction. At higher pore volumes, the mole fractions of lower solubility fractions increase which can result in higher ...

  14. Dissolution kinetics of paracetamol single crystals.

    Science.gov (United States)

    Prasad, Korlakunte V R; Ristic, Radoljub I; Sheen, David B; Sherwood, John N

    2002-05-15

    The dissolution anisotropy of paracetamol crystals grown in the presence and absence of the molecularly similar additive, p-acetoxyacetanilide (PAA) was studied under controlled conditions using a single crystal dissolution method in undersaturated aqueous solutions. Linear dissolution rates were determined for all the major habit faces by measuring their movement (regression) with time in a flow cell using a microscope. The rates of dissolution of particular faces of the pure material were distinctly different in crystals of different morphology grown at different supersaturations. The dissolution rates of [001] and [110] faces of crystals grown in the presence of PAA (6.02% w/w in solution) are higher than those of pure paracetamol. The results correlate with the distribution of strain in the crystal and support the concept that integral strain increases the solubility and hence the dissolution rate of the material. The mechanism of the dissolution process at the [001], [201;] and [110] faces was defined using optical microscopy and X-ray topography. At all undersaturations above 1% the dissolution studies yielded well developed, structurally oriented, etch pits on both [001] and [201;] faces while on the [110] face rough shallow etch pits were observed. On all three faces, this etch-pitting was considerably more widespread than the dislocation content of the sector and probably reflects a 2-dimensional nucleation process rather than a dislocation controlled mechanism.

  15. A rapid and low-cost microscopic observation drug susceptibility assay for detecting TB and MDR-TB among individuals infected by HIV in South India

    Directory of Open Access Journals (Sweden)

    S Solomon

    2013-01-01

    Full Text Available Background: The converging epidemics of HIV and tuberculosis (TB pose one of the greatest public health challenges of our time. Rapid diagnosis of TB is essential in view of its infectious nature, high burden of cases, and emergence of drug resistance. Objective: The purpose of this present study was to evaluate the feasibility of implementing the microscopic observation drug susceptibility (MODS assay, a novel assay for the diagnosis of TB and multi-drug-resistant tuberculosis (MDR-TB directly from sputum specimens, in the Indian setting. Materials and Methods: This study involved a cross-sectional, blinded assessment of the MODS assay on 1036 suspected cases of pulmonary TB in HIV-positive and HIV-negative patients against the radiometric method, BD-BACTEC TB 460 system. Results: Overall, the sensitivity, specificity, positive predictive value, and negative predictive value of the MODS assay in detecting MTB among TB suspected patients were 89.1%, 99.1%, 94.2%, 95.8%, respectively. In addition, in the diagnosis of drug-resistant TB, the MODS assay was 84.2% sensitive for those specimens reporting MDR, 87% sensitivity for those specimens reporting INH mono-resistance, and 100% sensitive for specimens reporting RIF mono-resistance. The median time to detection of TB in the MODS assay versus BACTEC was 9 versus 21 days (P < 0.001. Conclusion: Costing 5 to 10 times lesser than the automated culture methods, the MODS assay has the potential clinical utility as a simple and rapid method. It could be effectively used as an alternative method for diagnosing TB and detection of MDR-TB in a timely and affordable way in resource-limited settings.

  16. Make and break - Facile synthesis of cocrystals and comprehensive dissolution studies

    Science.gov (United States)

    Batzdorf, L.; Zientek, N.; Rump, D.; Fischer, F.; Maiwald, M.; Emmerling, F.

    2017-04-01

    Mechanochemistry is increasingly used as a 'green alternative' for synthesizing various materials including pharmaceutical cocrystals. Herein, we present the mechanochemical synthesis of three new cocrystals containing the API carbamazepine (cocrystals CBZ:Indometacin 1:1, CBZ:Benzamide 1:1, and CBZ:Nifedipine 1:1). The mechanochemical reaction was investigated in situ documenting a fast and complete reaction within one minute. Online NMR spectroscopy proved the direct influence of the dissolution behaviour of the coformers to the dissolution behaviour of the API carbamazepine. The dissolution behaviour of the organic cocrystals is compared to the behaviour of the pure drug indicating a general applicability of this approach for detailed cocrystal dissolution studies.

  17. Haste Makes Waste: The Interplay Between Dissolution and Precipitation of Supersaturating Formulations.

    Science.gov (United States)

    Sun, Dajun D; Lee, Ping I

    2015-11-01

    Contrary to the early philosophy of supersaturating formulation design for oral solid dosage forms, current evidence shows that an exceedingly high rate of supersaturation generation could result in a suboptimal in vitro dissolution profile and subsequently could reduce the in vivo oral bioavailability of amorphous solid dispersions. In this commentary, we outline recent research efforts on the specific effects of the rate and extent of supersaturation generation on the overall kinetic solubility profiles of supersaturating formulations. Additional insights into an appropriate definition of sink versus nonsink dissolution conditions and the solubility advantage of amorphous pharmaceuticals are also highlighted. The interplay between dissolution and precipitation kinetics should be carefully considered in designing a suitable supersaturating formulation to best improve the dissolution behavior and oral bioavailability of poorly water-soluble drugs.

  18. The effect of selected water-soluble excipients on the dissolution of paracetamol and Ibuprofen.

    Science.gov (United States)

    Shaw, Lance R; Irwin, William J; Grattan, Tim J; Conway, Barbara R

    2005-07-01

    The purpose of this investigation was to study the dissolution behavior of paracetamol and ibuprofen in the presence of a range of selected potential excipients. First, a pH-solubility profile was generated for both drugs, and the effect of changing hydrodynamic conditions on the intrinsic dissolution rate was investigated. It was established that both drugs dissolved according to the diffusion-layer model. Paracetamol solubility (approximately 20.3 mg mL(-1)) did not vary from pH 1.2-8.0, corresponding to the in vivo range in the gastrointestinal tract. Ibuprofen had an intrinsic solubility of approximately 0.06 mg mL(-1), and pK(a) was calculated as 4.4. Second, the effects of selected potential excipients (lactose, potassium bicarbonate, sodium bicarbonate, sodium chloride, and tartaric acid) were evaluated by measuring the effect of the inclusion of each additive in the dissolution medium on drug solubility, drug intrinsic dissolution rate, and solution viscosity. The results were evaluated using the diffusion-layer model, and it was determined that for paracetamol, the collected data fitted the model for all the excipients studied. For ibuprofen, it was found that there were differences between the excipients that raised the solution pH above the pK(a) to those that did not. For the excipients raising the pH above the pK(a), the effect on intrinsic dissolution rate was not as high as that expected from the change in drug solubility. It was postulated that this might be due to lack of penetration of the excipient into the drug boundary layer microenvironment. Formulators may calculate the effect of adding an excipient based on solubility increases but may not find the dissolution rate improvement expected.

  19. Enhanced performance large volume dissolution-DNP

    DEFF Research Database (Denmark)

    Bowen, Sean; Ardenkjær-Larsen, Jan Henrik

    2014-01-01

    A systematic study of the performance of the dissolution process in dissolution-DNP is presented. A relatively simple set of modifications is made to the standard Hypersense dissolution system to enable polarization of large volume samples. These consist of a large volume sample cup along...... with supporting modifications to the dissolution head and related components. Additional modifications were made to support the mapping of the temperature/pressure space of the dissolution process as well as enabling the use of large volumes of solvent and improving the robustness of the system. No loss...... of polarization was observed as sample size was increased to the 1g capacity of the large volume cup and for a dilution factor as low as 1:10....

  20. Accelerated dissolution of iron oxides in ice

    Directory of Open Access Journals (Sweden)

    D. Jeong

    2012-11-01

    Full Text Available Iron dissolution from mineral dusts and soil particles is vital as a source of bioavailable iron in various environmental media. In this work, the dissolution of iron oxide particles trapped in ice was investigated as a new pathway of iron supply. The dissolution experiments were carried out in the absence and presence of various organic complexing ligands under dark condition. In acidic pH conditions (pH 2, 3, and 4, the dissolution of iron oxides was greatly enhanced in the ice phase compared to that in water. The dissolved iron was mainly in the ferric form, which indicates that the dissolution is not a reductive process. The extent of dissolved iron was greatly affected by the kind of organic complexing ligands and the surface area of iron oxides. The iron dissolution was most pronounced with high surface area iron oxides and in the presence of strong iron binding ligands. The enhanced dissolution of iron oxides in ice is mainly ascribed to the "freeze concentration effect", which concentrates iron oxide particles, organic ligands, and protons in the liquid like ice grain boundary region and accelerates the dissolution of iron oxides. The ice-enhanced dissolution effect gradually decreased when decreasing the freezing temperature from −10 to −196 °C, which implies that the presence and formation of the liquid-like ice grain boundary region play a critical role. The proposed phenomenon of enhanced dissolution of iron oxides in ice may provide a new pathway of bioavailable iron production. The frozen atmospheric ice with iron-containing dust particles in the upper atmosphere thaws upon descending and may provide bioavailable iron upon deposition onto the ocean surface.

  1. Modulation of solubility and dissolution of furosemide by preparation of phospholipid complex

    Directory of Open Access Journals (Sweden)

    Mona Semalty

    2014-01-01

    Full Text Available Aim: The aim of this study is to improve the solubility and dissolution of furosemide (a potent high ceiling diuretic used for the treatment of hypertension and a Class IV drug that is low solubility and low permeability drug as per the Biopharmaceutical Classification System by preparing its phospholipid complexes or pharmacosomes. Materials and Methods: Furosemide was complexed with phosphatidylcholine in four different molar ratios (1:1, 1:2, 1:3 and 1:4 by conventional solvent-evaporation technique. The pharmacosomes prepared were evaluated for drug content, solubility, X-ray powder diffraction (XRPD and in-vitro dissolution study. Results: Pharmacosomes of furosemide showed high drug content ranging from 88.30% to 100%. XRPD studies confirmed the formation of phospholipid complex and the amorphization of drug in the complex. The water solubility was found to be increased up to six-fold in the complexes. The octanol solubility also increased in the complexes indicating the probable increase in permeability. The in-vitro dissolution profile of the prepared complexes was found to be much better than furosemide. Conclusion: It was concluded that the phospholipid complexes can be effectively used for improving the solubility, dissolution, permeability and hence the bioavailability of furosemide like Class IV drugs.

  2. Rapid generation of drug-resistance alleles at endogenous loci using CRISPR-Cas9 indel mutagenesis.

    Directory of Open Access Journals (Sweden)

    Jonathan J Ipsaro

    Full Text Available Genetic alterations conferring resistance to the effects of chemical inhibitors are valuable tools for validating on-target effects in cells. Unfortunately, for many therapeutic targets such alleles are not available. To address this issue, we evaluated whether CRISPR-Cas9-mediated insertion/deletion (indel mutagenesis can produce drug-resistance alleles at endogenous loci. This method takes advantage of the heterogeneous in-frame alleles produced following Cas9-mediated DNA cleavage, which we show can generate rare alleles that confer resistance to the growth-arrest caused by chemical inhibitors. We used this approach to identify novel resistance alleles of two lysine methyltransferases, DOT1L and EZH2, which are each essential for the growth of MLL-fusion leukemia cells. We biochemically characterized the DOT1L mutation, showing that it is significantly more active than the wild-type enzyme. These findings validate the on-target anti-leukemia activities of existing DOT1L and EZH2 inhibitors and reveal a simple method for deriving drug-resistance alleles for novel targets, which may have utility during early stages of drug development.

  3. Physical solid-state properties and dissolution of sustained-release matrices of polyvinylacetate.

    Science.gov (United States)

    Gonzalez Novoa, Gelsys Ananay; Heinämäki, Jyrki; Mirza, Sabir; Antikainen, Osmo; Colarte, Antonio Iraizoz; Paz, Alberto Suzarte; Yliruusi, Jouko

    2005-02-01

    Solid-state compatibility and in vitro dissolution of direct-compressed sustained-release matrices of polyvinylacetate (PVAc) and polyvinylpyrrolidone (PVP) containing ibuprofen as a model drug were studied. Polyvinylalcohol (PVA) was used as an alternative water-soluble polymer to PVP. Differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) were used for characterizing solid-state polymer-polymer and drug-polymer interactions. The mechanical treatment for preparing physical mixtures of polyvinyl polymers and the drug (i.e. simple blending or stressed cogrinding) was shown not to affect the physical state of the drug and the polymers. With the drug-polymer mixtures the endothermic effect due to drug melting was always evident, but a considerable modification of the melting point of the drug in physical binary mixtures (drug:PVP) was observed, suggesting some interaction between the two. On the other hand, the lack of a significant shift of the melting endothermic peak of the drug in physical tertiary drug-polymer mixtures revealed no evidence of solid-state interaction between the drug and the present polymers. Sustained-release dissolution profiles were achieved from the direct-compressed matrices made from powder mixtures of the drug and PVAc combined with PVP, and the proportion of PVAc in the mixture clearly altered the drug release profiles in vitro. The drug release from the present matrix systems is controlled by both diffusion of the drug through the hydrate matrix and the erosion of the matrix itself.

  4. Zero crossing and ratio spectra derivative spectrophotometry for the dissolution tests of amlodipine and perindopril in their fixed dose formulations

    Directory of Open Access Journals (Sweden)

    Maczka Paulina

    2014-06-01

    Full Text Available Dissolution tests of amlodipine and perindopril from their fixed dose formulations were performed in 900 mL of phosphate buffer of pH 5.5 at 37°C using the paddle apparatus. Then, two simple and rapid derivative spectrophotometric methods were used for the quantitative measurements of amlodipine and perindopril. The first method was zero crossing first derivative spectrophotometry in which measuring of amplitudes at 253 nm for amlodipine and 229 nm for perindopril were used. The second method was ratio derivative spectrophotometry in which spectra of amlodipine over the linearity range were divided by one selected standard spectrum of perindopril and then amplitudes at 242 nm were measured. Similarly, spectra of perindopril were divided by one selected standard spectrum of amlodipine and then amplitudes at 298 nm were measured. Both of the methods were validated to meet official requirements and were demonstrated to be selective, precise and accurate. Since there is no official monograph for these drugs in binary formulations, the dissolution tests and quantification procedure presented here can be used as a quality control test for amlodipine and perindopril in respective dosage forms.

  5. A multi-site validation in India of the line probe assay for the rapid diagnosis of multi-drug resistant tuberculosis directly from sputum specimens.

    Directory of Open Access Journals (Sweden)

    Neeraj Raizada

    Full Text Available Rifampicin (R and isoniazid (H are key first-line anti-tuberculosis drugs. Failure to detect resistance to these two drugs early results in treatment failure and poor clinical outcomes. The study purpose was to validate the use of the GenoType MTBDRplus line probe assay (LPA to detect resistance to R and H in Mycobacterium tuberculosis strains directly from smear-positive sputum samples in India.Smear positive sputum specimens from 320 patients were subjected to LPA and results compared against those from conventional Lowenstein Jensen (LJ culture and drug susceptibility testing (C&DST. All specimens with discordant R DST results were subjected to either sequencing of the rpoB gene and/or repeat DST on liquid culture (MGIT 960 at a National Reference Laboratory.Significantly higher proportion of interpretable results were observed with LPA compared to LJ C&DST (94% vs. 80%, p-value <0.01. A total of 248 patients had both LJ and LPA DST results available; 232 (93.5% had concordant R DST results. Among the 16 discordant R DST results, 13 (81% were resolved in agreement with LPA results. Final LPA performance characteristics were sensitivity 96% (CI: 90%-98%, specificity 99% (CI: 95%-99%, positive predictive value 99% (CI: 95%-99%, and negative predictive value 95% (CI: 89%-98%. The median turnaround testing time, including specimen transportation time, on LPA was 11 days as compared with 89 days for LJ C&DST.LPA proved highly accurate in the rapid detection of R resistance. The reduction in time to diagnosis may potentially enable earlier commencement of the appropriate drug therapy, leading to some reduction of transmission of drug-resistant strains.

  6. Multicentre laboratory validation of the colorimetric redox indicator (CRI) assay for the rapid detection of extensively drug-resistant (XDR) Mycobacterium tuberculosis.

    Science.gov (United States)

    Martin, Anandi; Paasch, Fabienne; Docx, Sven; Fissette, Krista; Imperiale, Belen; Ribón, Wellman; González, Liliana Andrea; Werngren, Jim; Engström, Anna; Skenders, Girts; Juréen, Pontus; Hoffner, Sven; Del Portillo, Patricia; Morcillo, Nora; Palomino, Juan Carlos

    2011-04-01

    To perform a multicentre study to evaluate the performance of the colorimetric redox indicator (CRI) assay and to establish the MICs and critical concentrations of rifampicin, isoniazid, ofloxacin, kanamycin and capreomycin. The study was carried out in two phases. Phase I determined the MIC of each drug. Phase II established critical concentrations for the five drugs tested by the CRI assay compared with the conventional proportion method. Phase I: a strain was considered resistant by the CRI assay if the MIC was ≥0.5 mg/L for rifampicin, ≥0.25 mg/L for isoniazid, ≥4.0 mg/L for ofloxacin and ≥5.0 mg/L for kanamycin and capreomycin. Sensitivity was 99.1% for isoniazid and 100% for the other drugs and specificity was 97.9% for capreomycin and 100% for the other drugs. Phase II: the critical concentration was 0.5 mg/L for rifampicin, 0.25 mg/L for isoniazid, 2.0 mg/L for ofloxacin and 2.5 mg/L for kanamycin and capreomycin giving an overall accuracy of 98.4%, 96.6%, 96.7%, 98.3% and 90%, respectively. Results demonstrate that the CRI assay is an accurate method for the rapid detection of XDR Mycobacterium tuberculosis. The CRI assay is faster than the conventional drug susceptibility testing method using solid medium, has the same turnaround time as the BACTEC MGIT 960 system, but is less expensive, and could be an adequate method for low-income countries.

  7. The influence of lung surfactant liquid crystalline nanostructures on respiratory drug delivery.

    Science.gov (United States)

    Das, Shyamal C; Stewart, Peter J

    2016-12-05

    The respiratory route increasingly has been used for both local and systemic drug delivery. Although drug is absorbed rapidly after respiratory delivery, the role of lung surfactant in drug delivery is not well understood. The human lung contains only around 15mL of surface lining fluid spread over ∼100m2 surface. The fluid contains lung surfactant at a concentration of 8-24mg/kg/body weight; the lung surfactant which is lipo-protein in nature can form different liquid crystalline nanostructures. After a brief overview of the anatomy of respiratory system, the review has focused on the current understanding of lung surface lining fluid, lung surfactants and their composition and possible self-assembled nanostructures. The role of lung surfactant in drug delivery and drug dissolution has been briefly considered. Lung surfactant may form different liquid crystalline phases which can have an active role in drug delivery. The hypotheses developed in this review focuses on the potential roles of surface epithelial fluid containing liquid crystalline nanostructures in defining the dissolution mechanism and rate. The hypotheses also focus an understanding how liquid crystalline nanostructures can be used to control dissolution rate and how the nanostructures might be changed to influence delivery and induce toxicity. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. A novel microdialysis-dissolution/permeation system for testing oral dosage forms: A proof-of-concept study.

    Science.gov (United States)

    Fong, Sophia Yui Kau; Poulsen, Jessie; Brandl, Martin; Bauer-Brandl, Annette

    2017-01-01

    A novel microdialysis-dissolution/permeation (M-D/P) system was developed for the biopharmaceutical assessment of oral drug formulations. This system consists of a side-by-side diffusion chamber, a microdialysis unit fixed within the dissolution chamber for continuous sampling, and a biomimetic Permeapad® as the intestinal barrier. In the M-D/P system, the concentration of the molecularly dissolved drug (with MWCO dissolution compartment (representing the gastrointestinal tract) while the concentration of the permeated drug was measured in the acceptor compartment (representing the blood). The kinetics of both the dissolution process and the permeation process were simultaneously quantified under circumstances that mimic physiological conditions. For the current proof-of-concept study, hydrocortisone (HCS) in the form of slowly dissolving solvate crystals and buffer and the biorelevant fasted state simulated intestinal fluids (FaSSIF), were employed as the model drug and dissolution media, respectively. The applicability of the M-D/P system to dissolution and permeation profiling of HCS in buffer and in FaSSIF has been successfully demonstrated. Compared to the conventional direct sampling method (using filter of 0.1-0.45μm), sampling by the M-D/P system exhibited distinct advantages, including (1) showing minimal disturbance of the permeation process, (2) differentiating "molecularly" dissolved drugs from "apparently" dissolved drugs during dissolution of HCS in FaSSIF, and (3) being less laborious and having better sampling temporal resolution. M-D/P system appeared to be a promising, simple and routine tool that allows for the researchers' intensive comprehension of the interplay of dissolution and permeation thus helping for better oral formulation screening and as an ultimate goal, for better dosage forms assessment. Copyright © 2016. Published by Elsevier B.V.

  9. Preparation and dissolution characteristics of griseofulvin solid dispersions with saccharides.

    Science.gov (United States)

    Saito, Masataka; Ugajin, Takashi; Nozawa, Yasuo; Sadzuka, Yasuyuki; Miyagishima, Atsuo; Sonobe, Takashi

    2002-12-05

    To improve the solubility of poorly water-soluble drugs, we studied physical characteristics of griseofulvin (GF) solid dispersions with saccharides as the dispersion carrier using a roll mixing method. In all carriers tested, roll mixtures of GF and saccharides gradually became amorphous, and the solubility of GF increased. The solubility of GF was higher in the mixtures with higher molecular weight carriers such as corn starch and processed starch. The dissolution of GF was markedly improved by the GF-Britishgum roll mixture. The initial dissolution rate of these mixtures was 170-fold higher than GF alone. The surface tension of carrier aqueous solutions was low in the processed starch with branched sugar chains. The initial dissolution rate of GF in physical mixtures was correlated with the surface tension of carrier aqueous solutions. The stability of the amorphous state of GF at a high humidity was maintained in the mixtures with carriers with a high molecular weight. These results indicated that the solubility of GF was markedly improved in the roll mixtures. It was suggested that the saccharides with a high molecular weight are useful carriers for solid dispersions.

  10. Evaluation of a Miniaturized Rotating Disk Apparatus for In Vitro Dissolution Rate Measurements in Aqueous Media : Correlation of In Vitro Dissolution Rate with Apparent Solubility

    OpenAIRE

    Persson, Anita M.

    2010-01-01

    The general aim of this thesis was to evaluate a newly designed and constructed miniaturized rotating disk apparatus for in vitro dissolution rate measurements of different drug substances from all of the classes in the Biopharmaceutical Classification System (BCS). The new equipment is based on a low volume flow-through cell of Plexiglas, a gold plated magnetic bar and a special designed press. The disk of drug substance (approx. 5 mg) is placed eccentrically in the bar. Rotation speeds were...

  11. Dissolution of steel slags in aqueous media.

    Science.gov (United States)

    Yadav, Shashikant; Mehra, Anurag

    2017-07-01

    Steel slag is a major industrial waste in steel industries, and its dissolution behavior in water needs to be characterized in the larger context of its potential use as an agent for sequestering CO2. For this purpose, a small closed system batch reactor was used to conduct the dissolution of steel slags in an aqueous medium under various dissolution conditions. In this study, two different types of steel slags were procured from steel plants in India, having diverse structural features, mineralogical compositions, and particle sizes. The experiment was performed at different temperatures for 240 h of dissolution at atmospheric pressure. The dissolution rates of major and minor slag elements were quantified through liquid-phase elemental analysis using an inductively coupled plasma atomic emission spectroscopy at different time intervals. Advanced analytical techniques such as field emission gun-scanning electron microscope, energy-dispersive X-ray, BET, and XRD were also used to analyze mineralogical and structural changes in the slag particles. High dissolution of slags was observed irrespective of the particle size distribution, which suggests high carbonation potential. Concentrations of toxic heavy metals in the leachate were far below maximum acceptable limits. Thus, the present study investigates the dissolution behavior of different mineral ions of steel slag in aqueous media in light of its potential application in CO2 sequestration.

  12. Rapid wide-scope screening of drugs of abuse, prescription drugs with potential for abuse and their metabolites in influent and effluent urban wastewater by ultrahigh pressure liquid chromatography-quadrupole-time-of-flight-mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Hernandez, Felix, E-mail: felix.hernandez@qfa.uji.es [Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat s/n, E-12071 Castellon (Spain); Bijlsma, Lubertus, E-mail: bijlsma@guest.uji.es [Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat s/n, E-12071 Castellon (Spain); Sancho, Juan V.; Diaz, Ramon; Ibanez, Maria [Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat s/n, E-12071 Castellon (Spain)

    2011-01-17

    This work illustrates the potential of hybrid quadrupole-time-of-flight mass spectrometry (QTOF MS) coupled to ultrahigh pressure liquid chromatography (UHPLC) to investigate the presence of drugs of abuse in wastewater. After solid-phase extraction with Oasis MCX cartridges, seventy-six illicit drugs, prescription drugs with potential for abuse, and metabolites were investigated in the samples by TOF MS using electrospray interface under positive ionization mode, with MS data acquired over an m/z range of 50-1000 Da. For 11 compounds, reference standards were available, and experimental data (e.g., retention time and fragmentation data) could be obtained, facilitating a more confident identification. The use of a QTOF instrument enabled the simultaneous application of two acquisition functions with different collision energies: a low energy (LE) function, where none or poor fragmentation took place, and a high energy (HE) function, where fragmentation in the collision cell was promoted. This approach, known as MS{sup E}, enabled the simultaneous acquisition of full-spectrum accurate mass data of both protonated molecules and fragment ions in a single injection, providing relevant information that facilitates the rapid detection and reliable identification of these emerging contaminants in the sample matrices analyzed. In addition, isomeric compounds, like the opiates, morphine and norcodeine, could be discriminated by their specific fragments observed in HE TOF MS spectra, without the need of reference standards. UHPLC-QTOF MS was proven to be a powerful and efficient technique for rapid wide-scope screening and identification of many relevant drugs in complex matrices, such as influent and effluent urban wastewater.

  13. DISSOLUTION PROPERTIES AND KINETIC STUDY OF SULFADIMIDINE AND TRIMETHOPRIM TABLETS CONTAINING FOUR DIFFERENT SUPERDISINTEGRANTS.

    Science.gov (United States)

    Zimmer, Łukasz; Kasperek, Regina; Poleszak, Ewa

    2015-01-01

    The objective of this study was to evaluate and compare the effect of four superdisintegrants such as croscarmellose sodium (Ac-Di-Sol), crospovidone (Kollidon CL and with smaller particle sizes Kollidon CL-F), sodium starch glycolate (Explotab) in combination with β-lactose and microcrystalline cellulose (Avicel PH-102) as base excipients exhibiting properties of directly compressed tablets and increasing the disintegration and the dissolution rate of sulfadimidine sodium (SDD-Na) and trimethoprim (TMP). All tablets were prepared by direct compression method and superdisintegrants were used at 2% for all formulations. The tablets were evaluated with regard to uniformity of weight, hardness, friability, drug content, disintegration time and dissolution properties. Dissolution properties such as t50% and t80% (time to release 50 and 80% of drug), DP3045 (percent of drug dissolved in 30 and 45 min) and the dissolution rate constant value (K) were considered in comparing the dissolution results. The results showed that crospovidone (Kollidon CL) provides the shortest disintegration time and the fastest rate of dissolution for both TMP and SDD-Na. The kinetic study of the dissolution data reveals that in vitro release profiles of TMP and SDD-Na can be best explained by first order model or by Higuchi model. The obtained data were plotted into Korsmeyer-Peppas equation to find out the confirmed diffusion mechanism. For TMP release, the values of the release exponent are beyond the limits of Korsmeyer model, so-called, power law. For SDD-Na release, exponent values are characteristic for anomalous transport (non-Fickian) or the value of the release exponent is beyond the limits of Korsmeyer model.

  14. A microstructural study of sleep instability in drug-naive patients with schizophrenia and healthy controls: sleep spindles, rapid eye movements, and muscle atonia.

    Science.gov (United States)

    Guénolé, Fabian; Chevrier, Elyse; Stip, Emmanuel; Godbout, Roger

    2014-05-01

    This study aimed at characterizing the functional stability of sleep in schizophrenia by quantifying dissociated stages of sleep (DSS), and to explore their correlation with psychopathology. The sleep of 10 first-break, drug-naive young adults with schizophrenia and 10 controls was recorded. Four basic DSS patterns were scored: 1) the transitional EEG-mixed intermediate stage (EMIS); 2) Rapid-eye-movement (REM) sleep without rapid eye movement (RSWR); 3) REM sleep without atonia (RSWA); and 4) non-REM sleep with rapid eye movements. An intermediate sleep (IS) score was calculated by summing EMIS and RSWR scores, and the durations of intra-REM sleep periods IS (IRSPIS) and IS scored "at the expense" of REM sleep (ISERS) were determined. Patients were administered the Brief Psychiatric Rating Scale (BPRS) at the time of recording. Proportions of each DSS variables over total sleep time and proportions of IRSPIS and ISERS over REM sleep duration were compared between patients and controls. Correlation coefficients between DSS variables and BPRS total scores were calculated. The proportion of total DSS did not differ between patients and controls. Among DSS subtypes, RSWA was significantly increased in patients while other comparisons showed no significant differences. Significant positive correlations were found between BPRS scores and proportions of DSS, IS, RSWR, IRSPIS and ISERS over total sleep and REM sleep durations. These results demonstrate the functional instability of REM sleep in first-break, drug naive young adults with schizophrenia and unveil a pattern reminiscent of REM sleep behavior disorder. The significant correlation suggests that schizophrenia and REM sleep share common neuronal control mechanisms. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Fe-Containing Allophane and Hisingerite Dissolution and Implications for Gale Crater, Mars

    Science.gov (United States)

    Ralston, S. J.; Hausrath, E. M.; Tschauner, O.; Rampe, E. B.; Clark-Hogancamp, J. V.; Christoffersen, R.

    2017-01-01

    The mass-normalized dissolution rates measured in this study demonstrate that hisingerite and Fe-substituted allophane dissolve rapidly, much faster than crystalline phyllosilicates such as nontronite and kaolinite that have similar compositions. In addition, hisingerite dissolves more rapidly than allophane. Future work will focus on measuring dissolution rates at other pH values, so that dissolution rate laws for allophane and hisingerite can be derived. Results will be used to interpret data from Gale Crater. These initial experiments suggest that, if the liquid water present in Gale Crater was highly acidic, it was likely present for only a short time, allowing some amorphous soil-material similar to allophane to persist. Further experiments will enable us to constrain the timescales over which liquid water was present in Gale Crater and provide insight into its pH. This information is essential to assessing the potential habitability of ancient Mars.

  16. Optimization of Sample Preparation and Instrumental Parameters for the Rapid Analysis of Drugs of Abuse in Hair samples by MALDI-MS/MS Imaging

    Science.gov (United States)

    Flinders, Bryn; Beasley, Emma; Verlaan, Ricky M.; Cuypers, Eva; Francese, Simona; Bassindale, Tom; Clench, Malcolm R.; Heeren, Ron M. A.

    2017-08-01

    Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) has been employed to rapidly screen longitudinally sectioned drug user hair samples for cocaine and its metabolites using continuous raster imaging. Optimization of the spatial resolution and raster speed were performed on intact cocaine contaminated hair samples. The optimized settings (100 × 150 μm at 0.24 mm/s) were subsequently used to examine longitudinally sectioned drug user hair samples. The MALDI-MS/MS images showed the distribution of the most abundant cocaine product ion at m/z 182. Using the optimized settings, multiple hair samples obtained from two users were analyzed in approximately 3 h: six times faster than the standard spot-to-spot acquisition method. Quantitation was achieved using longitudinally sectioned control hair samples sprayed with a cocaine dilution series. A multiple reaction monitoring (MRM) experiment was also performed using the `dynamic pixel' imaging method to screen for cocaine and a range of its metabolites, in order to differentiate between contaminated hairs and drug users. Cocaine, benzoylecgonine, and cocaethylene were detectable, in agreement with analyses carried out using the standard LC-MS/MS method. [Figure not available: see fulltext.

  17. Real-time UV imaging identifies the role of pH in insulin dissolution behavior in hydrogel-based subcutaneous tissue surrogate

    DEFF Research Database (Denmark)

    Jensen, Sabrine S; Jensen, Henrik; Cornett, Claus

    2015-01-01

    in the development of new protein drug formulations. Using insulin as a model compound, the aim of this work was to develop a UV imaging-based method to study the real-time dissolution and diffusion behavior of solid protein drugs under stagnant conditions in a hydrogel matrix mimicking the subcutaneous tissue...... in the vicinity of solid protein drug in a hydrogel matrix with the aim of achieving a better understanding of in vivo dissolution processes....

  18. Oral hesperidin-Amorphization and improved dissolution properties by controlled loading onto porous silica.

    Science.gov (United States)

    Wei, Qionghua; Keck, Cornelia M; Müller, Rainer H

    2017-02-25

    The oral bioavailability of poorly soluble drugs can be improved by amorphization generated by loading into the pores of mesoporous particles (pore size 2-50nm). The main mechanisms are increased kinetic saturation solubility and dissolution velocity due to the amorphous drug state and the nano-size of the drug (=increased dissolution pressure). In this study, the maximum achievable drug loading compared to the theoretical drug loading, and the effect of drug loading degree on the dissolution properties (solubility, dissolution velocity) were investigated. Hesperidin was used as the model active (having also practical relevance for e.g. nutraceutical products), loading was performed onto AEROPERL ® 300 Pharma. Degree of successful drug loading could be easily followed by simple light microscopy (=useful tool for formulation optimization), and was in agreement with scanning electron microscopy. Amorphous versus crystalline state was followed by X-ray diffraction and differential scanning calorimetry. Loadings prepared were 28.6wt.%, 54.5wt.% and 60.0wt.%, the maximum theoretical loading was 72.5wt.%. Obviously the maximum drug loading is not achievable, the 54.5wt.% drug loading was the practical maximum with already some minor crystalline hesperidin on the surface. Interestingly, the maximum kinetic saturation solubility was obtained for the 54.5wt.% drug loading (941.74μg/ml in pH 6.8 PBS), versus 408.80μg/ml for the 60.0wt.% drug loading (=overloaded system). The raw drug powder had a thermodynamic solubility of only 18.40μg/ml. The fastest in vitro release was obtained with the 28.6wt.% loaded system, followed by the 54.5wt.% and 60.0wt.% loadings. The dissolution properties (solubility, dissolution velocity) can obviously be influenced by a "controlled loading". This is a simple, cost-effective technological alternative to modulating this property by chemical modification of silica, requiring a new costly regulatory approval of these chemically modified

  19. Dissolution Kinetics of Milled-Silicate Rock Fertilizers in Organic Acid

    Directory of Open Access Journals (Sweden)

    Joko Priyono

    2008-01-01

    Full Text Available A dissolution experiment was carried out to identify the effects of milling condition on dissolution kinetics of silicate rock fertilizers. Initially ground materials (Ø < 250 μm for basalt, dolerite, gneiss, and Ø < 150 μm for K-feldspar were further milled with a ball mill (Spex 8000 under dry and wet conditions for 10, 60, and 120 minutes. The rock powders were dissolved in a mixture of 0.01M acetic-citric acid at a rock powder/solvent ratio of 1/1000, and the solution was agitated continuously on a rotary shaker at 25o C. The concentrations of dissolved Na, K, Ca, Mg, Al, and Si from the milled rocks were determined at intervals from 1 hour up to 56 days. Results indicated that the relationships of quantity of dissolved rock and elemental plant nutrients (Et with time (t were well described by a power equation: Et = Eo + atn with reaction order (n of 0.3 – 0.8. Milling increased quantity of total and individual dissolved element (Et , dissolution rate (Rt, the proportion of rapidly soluble rock or element (Eo, and dissolution constant a. The increases in dissolution due to dry milling were larger than for wet milling. Although further proves should be provided, results of this dissolution experiment clearly indicates that SRFs may be used as multinutrient fertilizers as well as remedial materials for acidic soils; and dry milling may be applied as an appropriate method for manufacturing effective SRFs.

  20. In situ measurement of solvent-mediated phase transformations during dissolution testing

    DEFF Research Database (Denmark)

    Aaltonen, Jaakko; Heinänen, Paula; Peltonen, Leena

    2006-01-01

    ) and measurement of the solid-state form of the dissolving solid (in situ with Raman spectroscopy). The solid phase transformations were also investigated off-line with scanning electron microscopy. TP anhydrate underwent a transformation to TP monohydrate, and NF anhydrate (form beta) to NF monohydrate (form II......In this study, solvent-mediated phase transformations of theophylline (TP) and nitrofurantoin (NF) were measured in a channel flow intrinsic dissolution test system. The test set-up comprised simultaneous measurement of drug concentration in the dissolution medium (with UV-Vis spectrophotometry...... that of NF. The presence of a water absorbing excipient, microcrystalline cellulose, was found to delay the onset of the transformation of TP anhydrate. Combining the measurement of drug concentration in the dissolution medium with the solid phase measurement offers a deeper understanding of the solvent...

  1. Solid-state properties and dissolution behaviour of tablets containing co-amorphous indomethacin-arginine

    DEFF Research Database (Denmark)

    Lenz, Elisabeth; Jensen, Katrine Birgitte Tarp; Blaabjerg, Lasse Ingerslev

    2015-01-01

    Co-amorphous drug formulations provide the possibility to stabilize a drug in its amorphous form by interactions with low molecular weight compounds, e.g. amino acids. Recent studies have shown the feasibility of spray drying as a technique to manufacture co-amorphous indomethacin......–arginine in a larger production scale. In this work, a tablet formulation was developed for a co-amorphous salt, namely spray dried indomethacin–arginine (SD IND–ARG). The effects of compaction pressure on tablet properties, physical stability and dissolution profiles under non-sink conditions were examined....... Dissolution profiles of tablets with SD IND–ARG (TAB SD IND–ARG) were compared to those of tablets containing a physical mixture of crystalline IND and ARG (TAB PM IND–ARG) and to the dissolution of pure spray dried powder. Concerning tableting, the developed formulation allowed for the preparation of tablets...

  2. Formulation and evaluation of a montelukast sodium orally disintegrating tablet with a similar dissolution profile as the marketed product.

    Science.gov (United States)

    Chen, Yong; Feng, Tingting; Li, Yong; Du, Bin; Weng, Weiyu

    2017-03-01

    A major challenge of orally disintegrating tablet (ODT) development is predicting its bioequivalence to its corresponding marketed product. Therefore, comparing ODT dissolution profiles to those of the corresponding marketed product is very important. The objective of this study was to develop a 5.2-mg montelukast sodium (MS) ODT with a similar dissolution profile to that of the marketed chewable tablet. Dissolution profiles were examined in different media to screen each formulation. We found that MS dissolution from ODTs in acidic medium heavily depended on manufacturing methods. All MS ODTs prepared using direct compression rapidly disintegrated in acidic medium. However, dispersed MS powders aggregated into sticky masses, resulting in slow dissolution. In contrast, MS ODTs prepared using wet granulation had much faster dissolution rates in acidic medium with no obvious aggregation. Additionally, the optimized formulation, prepared using wet granulation, displayed similar dissolution profiles to the marketed reference in all four types of media examined (f2 > 50). The in vitro disintegration time of the optimized ODT was 9.5 ± 2.4 s, which meets FDA requirements. In conclusion, the wet granulation preparation method of MS ODTs resulted in a product with equivalent dissolution profiles as those of the marketed product.

  3. Approaches for Establishing Clinically Relevant Dissolution Specifications for Immediate Release Solid Oral Dosage Forms.

    Science.gov (United States)

    Hermans, Andre; Abend, Andreas M; Kesisoglou, Filippos; Flanagan, Talia; Cohen, Michael J; Diaz, Dorys A; Mao, Y; Zhang, Limin; Webster, Gregory K; Lin, Yiqing; Hahn, David A; Coutant, Carrie A; Grady, Haiyan

    2017-11-01

    This manuscript represents the perspective of the Dissolution Analytical Working Group of the IQ Consortium. The intent of this manuscript is to highlight the challenges of, and to provide a recommendation on, the development of clinically relevant dissolution specifications (CRS) for immediate release (IR) solid oral dosage forms. A roadmap toward the development of CRS for IR products containing active ingredients with a non-narrow therapeutic window is discussed, within the context of mechanistic dissolution understanding, supported by in-human pharmacokinetic (PK) data. Two case studies present potential outcomes of following the CRS roadmap and setting dissolution specifications. These cases reveal some benefits and challenges of pursuing CRS with additional PK data, in light of current regulatory positions, including that of the US Food and Drug Administration (FDA), who generally favor this approach, but with the understanding that both industry and regulatory agency perspectives are still evolving in this relatively new field. The CRS roadmap discussed in this manuscript also describes a way to develop clinically relevant dissolution specifications based primarily on dissolution data for batches used in pivotal clinical studies, acknowledging that not all IR product development efforts need to be supported by additional PK studies, albeit with the associated risk of potentially unnecessarily tight manufacturing controls. Recommendations are provided on what stages during the life cycle investment into in vivo studies may be valuable. Finally, the opportunities for CRS within the context of post-approval changes, Modeling and Simulation (M&S), and the application of biowaivers, are briefly discussed.

  4. Dissolution assessment of allopurinol immediate release tablets by near infrared spectroscopy.

    Science.gov (United States)

    Smetiško, Jelena; Miljanić, Snežana

    2017-10-25

    The purpose of this study was to develop a NIR spectroscopic method for assessment of drug dissolution from allopurinol immediate release tablets. Thirty three different batches of allopurinol immediate release tablets containing constant amount of the active ingredient, but varying in excipients content and physical properties were introduced in a PLS calibration model. Correlating allopurinol dissolution reference values measured by the routinely used UV/Vis method, with the data extracted from the NIR spectra, values of correlation coefficient, bias, slope, residual prediction determination and root mean square error of prediction (0.9632, 0.328%, 1.001, 3.58, 3.75%) were evaluated. The obtained values implied that the NIR diffuse reflectance spectroscopy could serve as a faster and simpler alternative to the conventional dissolution procedure, even for the tablets with a very fast dissolution rate (>85% in 15minutes). Apart from the possibility of prediction of the allopurinol dissolution rate, the other multivariate technique, PCA, provided additional data on the non-chemical characteristics of the product, which could not be obtained from the reference dissolution values. Analysis on an independent set of samples confirmed that a difference between the UV/Vis reference method and the proposed NIR method was not significant. According to the presented results, the proposed NIR method may be suitable for practical application in routine analysis and for continuously monitoring the product's chemical and physical properties responsible for expected quality. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Measurement uncertainty of dissolution test of acetaminophen immediate release tablets using Monte Carlo simulations

    Directory of Open Access Journals (Sweden)

    Daniel Cancelli Romero

    2017-10-01

    Full Text Available ABSTRACT Analytical results are widely used to assess batch-by-batch conformity, pharmaceutical equivalence, as well as in the development of drug products. Despite this, few papers describing the measurement uncertainty estimation associated with these results were found in the literature. Here, we described a simple procedure used for estimating measurement uncertainty associated with the dissolution test of acetaminophen tablets. A fractionate factorial design was used to define a mathematical model that explains the amount of acetaminophen dissolved (% as a function of time of dissolution (from 20 to 40 minutes, volume of dissolution media (from 800 to 1000 mL, pH of dissolution media (from 2.0 to 6.8, and rotation speed (from 40 to 60 rpm. Using Monte Carlo simulations, we estimated measurement uncertainty for dissolution test of acetaminophen tablets (95.2 ± 1.0%, with a 95% confidence level. Rotation speed was the most important source of uncertainty, contributing about 96.2% of overall uncertainty. Finally, it is important to note that the uncertainty calculated in this paper reflects the expected uncertainty to the dissolution test, and does not consider variations in the content of acetaminophen.

  6. Low temperature dissolution flowsheet for plutonium metal

    Energy Technology Data Exchange (ETDEWEB)

    Daniel, W. E. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Almond, P. M. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Rudisill, T. S. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2016-05-01

    The H-Canyon flowsheet used to dissolve Pu metal for PuO2 production utilizes boiling HNO3. SRNL was requested to develop a complementary dissolution flowsheet at two reduced temperature ranges. The dissolution and H2 generation rates of Pu metal were investigated using a dissolving solution at ambient temperature (20-30 °C) and for an intermediate temperature of 50-60 °C. Additionally, the testing included an investigation of the dissolution rates and characterization of the off-gas generated from the ambient temperature dissolution of carbon steel cans and the nylon bags that contain the Pu metal when charged to the dissolver.

  7. Corundum dissolution in concentrated sodium hydroxide solution

    Directory of Open Access Journals (Sweden)

    u-sheng Wu

    2016-11-01

    Full Text Available The corundum (α-alumina core has been considered as a suitable candidate for investment casting of hollow, high pressure turbine engine airfoils due to its excellent properties. However, the efficiency of removing alumina cores in concentrated caustic solution cannot meet the needs of industrial production. In this paper, the effects of temperature and initial solution concentration on dissolution of α-alumina were studied by the classical weight-loss method. The fractal kinetic model was developed in order to describe α-alumina dissolution, assuming that the nonporous particles shrank during reaction process. The results show that the dissolution rate increases with increasing reaction temperature and initial solution concentration. Especially, the initial solution concentration has a significant influence on α-alumina dissolution rate at a higher reaction temperature. The activation energies decrease with increasing initial solution concentration, and the chemical reaction is the rate-controlling step.

  8. Status report on dissolution model development

    Energy Technology Data Exchange (ETDEWEB)

    Jackson, D.D.

    1983-07-01

    The computer program PROTOCOL models the dissolution reactions of chemical species in water. It is being developed particularly to study the dissolution of proposed nuclear waste forms and related phases. Experimentally derived leaching rate functions are coupled to thermochemical equilibrium calculations and water flow rates. The program has been developed over a period of years. This report describes improvements that have been done in the past year.

  9. Rapid on-site TLC-SERS detection of four antidiabetes drugs used as adulterants in botanical dietary supplements.

    Science.gov (United States)

    Zhu, Qingxia; Cao, Yongbing; Cao, Yingying; Chai, Yifeng; Lu, Feng

    2014-03-01

    A novel facile method has been established for rapid on-site detection of antidiabetes chemicals used to adulterate botanical dietary supplements (BDS) for diabetes. Analytes and components of pharmaceutical matrices were separated by thin-layer chromatography (TLC) then surface-enhanced Raman spectroscopy (SERS) was used for qualitative identification of trace substances on the HPTLC plate. Optimization and standardization of the experimental conditions, for example the method used for preparation of silver colloids, the mobile phase, and the concentration of colloidal silver, resulted in a very robust and highly sensitive method which enabled successful detection when the amount of adulteration was as low as 0.001 % (w/w). The method was also highly selective, enabling successful identification of some chemicals in extremely complex herbal matrices. The established TLC-SERS method was used for analysis of real BDS used to treat diabetes, and the results obtained were verified by liquid chromatography-triple quadrupole mass spectrometry (LC-MS-MS). The study showed that TLC-SERS could be used for effective separation and detection of four chemicals used to adulterate BDS, and would have good prospects for on-site qualitative screening of BDS for adulterants.

  10. The non-benzodiazepine anxiolytic drug etifoxine causes a rapid, receptor-independent stimulation of neurosteroid biosynthesis.

    Directory of Open Access Journals (Sweden)

    Jean Luc do Rego

    Full Text Available Neurosteroids can modulate the activity of the GABAA receptors, and thus affect anxiety-like behaviors. The non-benzodiazepine anxiolytic compound etifoxine has been shown to increase neurosteroid concentrations in brain tissue but the mode of action of etifoxine on neurosteroid formation has not yet been elucidated. In the present study, we have thus investigated the effect and the mechanism of action of etifoxine on neurosteroid biosynthesis using the frog hypothalamus as an experimental model. Exposure of frog hypothalamic explants to graded concentrations of etifoxine produced a dose-dependent increase in the biosynthesis of 17-hydroxypregnenolone, dehydroepiandrosterone, progesterone and tetrahydroprogesterone, associated with a decrease in the production of dihydroprogesterone. Time-course experiments revealed that a 15-min incubation of hypothalamic explants with etifoxine was sufficient to induce a robust increase in neurosteroid synthesis, suggesting that etifoxine activates steroidogenic enzymes at a post-translational level. Etifoxine-evoked neurosteroid biosynthesis was not affected by the central-type benzodiazepine (CBR receptor antagonist flumazenil, the translocator protein (TSPO antagonist PK11195 or the GABAA receptor antagonist bicuculline. In addition, the stimulatory effects of etifoxine and the triakontatetraneuropeptide TTN, a TSPO agonist, were additive, indicating that these two compounds act through distinct mechanisms. Etifoxine also induced a rapid stimulation of neurosteroid biosynthesis from frog hypothalamus homogenates, a preparation in which membrane receptor signalling is disrupted. In conclusion, the present study demonstrates that etifoxine stimulates neurosteroid production through a membrane receptor-independent mechanism.

  11. Fabrication of novel Si-doped hydroxyapatite/gelatine scaffolds by rapid prototyping for drug delivery and bone regeneration.

    Science.gov (United States)

    Martínez-Vázquez, F J; Cabañas, M V; Paris, J L; Lozano, D; Vallet-Regí, M

    2015-03-01

    Porous 3-D scaffolds consisting of gelatine and Si-doped hydroxyapatite were fabricated at room temperature by rapid prototyping. Microscopic characterization revealed a highly homogeneous structure, showing the pre-designed porosity (macroporosity) and a lesser in-rod porosity (microporosity). The mechanical properties of such scaffolds are close to those of trabecular bone of the same density. The biological behavior of these hybrid scaffolds is greater than that of pure ceramic scaffolds without gelatine, increasing pre-osteoblastic MC3T3-E1 cell differentiation (matrix mineralization and gene expression). Since the fabrication process of these structures was carried out at mild conditions, an antibiotic (vancomycin) was incorporated in the slurry before the extrusion of the structures. The release profile of this antibiotic was measured in phosphate-buffered saline solution by high-performance liquid chromatography and was adjusted to a first-order release kinetics. Vancomycin released from the material was also shown to inhibit bacterial growth in vitro. The implications of these results for bone tissue engineering applications are discussed. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  12. Feasibility of Using Gluconolactone, Trehalose and Hydroxy-Propyl Gamma Cyclodextrin to Enhance Bendroflumethiazide Dissolution Using Lyophilisation and Physical Mixing Techniques

    Directory of Open Access Journals (Sweden)

    Ashraf Saleh

    2018-02-01

    Full Text Available Purpose: Hydrophobic drugs are facing a major challenge in dissolution rate enhancement and solubility in aqueous solutions; therefore, a variety of methods have been used to improve dissolution rate and/or solubility of bendroflumethiazide as a model hydrophobic drug. Methods: In this study, two main methods (physical mixing and lyophilisation were used with gluconolactone, hydroxyl propyl γ-ccyclodextrin, and trehalose to explore this challenge. Bendroflumethiazide, practically insoluble in water, was mixed with one of the three excipients gluconolactone, hydroxyl propyl γ-cyclodextrin, and trehalose in three different ratios 1:1, 1:2, 1:5. To the best of our knowledge, the dissolution of the drug has not been previously enhanced by using either these methods or any of the used excipients. Samples containing drug and each of the excipients were characterized via dissolution testing, Fourier Transform infra-red spectroscopy, differential scanning calorimetry, and scanning electron microscopy. Results: The used methods showed a significant enhancement in dug dissolution rate; physical mixing significantly, p < 0.05, increased the percentage of the drug released with time; for example, bendroflumethiazide dissolution in distilled water was improved from less than 20% to 99.79% within 90 min for physically mixed drug-cyclodextrin 1:5. The lyophilisation process was enhanced and the drug dissolution rate and the highest drug dissolution was achieved for (drug-gluconolactone 1:1 with 98.98% drug release within 90 min. Conclusions: the physical mixing and freeze drying processes significantly increased the percentage of drug release with time.

  13. The Biopharmaceutics Classification System: Subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC

    Science.gov (United States)

    Tsume, Yasuhiro; Mudie, Deanna M.; Langguth, Peter; Amidon, Greg E.; Amidon, Gordon L.

    2014-01-01

    The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences. The classification scheme captures the two most significant factors influencing oral drug absorption; solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given drug and drug product. In this manuscript we propose a simple extension of the BCS classes to include subspecification of acid (a), base (b) and neutral (c) for classes II and IV. Sub-classification for Classes I and III (high solubility drugs as currently defined) is generally not needed except perhaps in border line solubility cases. It is well known that the , pKa physical property of a drug (API) has a significant impact on the aqueous solubility dissolution of drug from the drug product both in vitro and in vivo for BCS Class II and IV acids and bases, and is the basis, we propose for a sub-classification extension of the original BCS classification. This BCS sub-classification is particularly important for in vivo predictive dissolution methodology development due to the complex and variable in vivo environment in the gastrointestinal tract, with its changing pH, buffer capacity, luminal volume, surfactant luminal conditions, permeability profile along the gastrointestinal tract and variable transit and fasted and fed states. We believe this sub-classification is a step toward developing a more science-based mechanistic in vivo predictive dissolution (IPD) methodology. Such a dissolution methodology can be used by development scientists to assess the likelihood of a

  14. Anomalous dissolution behavior of celecoxib in PVP/Isomalt solid dispersions prepared using spray drier.

    Science.gov (United States)

    Ghanavati, Roya; Taheri, Azade; Homayouni, Alireza

    2017-03-01

    Celecoxib is a COX II inhibitor NSAID which is used for joint pains, rheumatoid arthritis and osteoarthritis, however due to its poor water solubility it shows very low oral bioavailability. Using solid dispersion formulations is one of the most promising strategies to increase solubility of poorly water soluble drugs. The purpose of this study is dissolution enhancement of celecoxib by preparation of solid dispersions via spray drying technique using PVP and Isomalt as hydrophilic carriers. Different ratios of celecoxib, Isomalt and PVP K30 (7:3:0, 5:5:0, 3:7:0, 1:9:0 and 3:5:2, 3:2:5) were prepared from 2% hydroalcoholic solutions (70:30 ethanol:water) using spray drier. Particle size analyzing, saturation solubility, SEM, DSC, FT-IR, XRPD and dissolution studies in 0.25% SDS and 0.04M Na3HPO4 mediums were performed. Stability of samples was also studied after a week and a month storage at 75% humidity condition. The results showed that the saturation solubility of celecoxib in solid dispersion samples is 20-30 folds higher than raw celecoxib. Similar results have been shown for dissolution studies. Solid state analyses showed glass solution state of celecoxib in PVP/Isomalt matrixes. FTIR studies exhibited the formation of hydrogen bonding between celecoxib and PVP in these samples. Spray dried celecoxib (amorphous celecoxib) without usage of carrier showed lower dissolution rate compare to its crystalline state (in 0.25% SDS dissolution medium) whilst these results is vise versa in Na3PO4 dissolution medium. Interestingly almost all samples exhibited higher dissolution rate (in 0.25% SDS) after storage in 75% humidity. XRPD analysis demonstrated the crystallization of amorphous celecoxib after 1month storage. In general using PVP K30 and Isomalt as hydrophilic carriers could increase solubility and dissolution rate of celecoxib in solid dispersion formulations. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Rapid in situ repeatable analysis of drugs in powder form using reflectance near-infrared spectroscopy and multivariate calibration.

    Science.gov (United States)

    Melucci, Dora; Monti, Dario; D'Elia, Marcello; Luciano, Giorgio

    2012-01-01

    This study takes the first step toward in situ analysis of powder drugs which does not require any alteration of the samples. A fast, inexpensive analytical method based on reflectance near-infrared (NIR) spectrometry and multivariate calibration was applied. A diode-array fiber-optic portable spectrometer in the 900-1700 nm range was employed. Samples were laboratory-prepared ternary powders (diacetylmorphine, caffeine, and paracetamol). Partial least squares regression was applied. The choice of the standard samples for calibration and validation was performed through a D-optimal experimental design. The explained variance was higher than 90%, and the relative root mean square errors were <2%. The number of principal components (6) was very low when compared with the number of raw variables (356 absorbance values). Response plots showed slopes and intercepts were very close to optimal values. Correlation coefficients ranged between 0.909 and 0.989. The method here proposed proved to be competitive with Fourier transform NIR spectrometry. © 2011 American Academy of Forensic Sciences.

  16. Hydrodynamic, mass transfer, and dissolution effects induced by tablet location during dissolution testing.

    Science.gov (United States)

    Bai, Ge; Armenante, Piero M

    2009-04-01

    Tablets undergoing dissolution in the USP Dissolution Testing Apparatus II are often found at locations on the vessel bottom that are off-center with respect to the dissolution vessel and impeller. A previously validated CFD approach and a novel experimental method were used here to examine the effect of tablet location on strain rates and dissolution rates. Dissolution tests were conducted with non-disintegrating tablets (salicylic acid) and disintegrating tablets (Prednisone) immobilized at different locations along the vessel bottom. CFD was used to predict the velocity profiles and strain rates when the tablets were placed at such locations. A CFD-based model was derived to predict the mass transfer coefficient and dissolution curves, which were then compared to the experimental results. Both non-disintegrating and disintegrating off-center tablets experimentally produced higher dissolution rates than centered tablets. The CFD-predicted strain rate distribution along the bottom was highly not uniform and the predicted strain rates correlated well with the experimental mass transfer coefficients. The proposed CFD-based model predicts mass transfer rates that correlate well with the experimental ones. The exact tablet location has a significant impact on the dissolution profile. The proposed model can satisfactorily predict the mass transfer coefficients and dissolution profiles for non-disintegrating tablets.

  17. Variability of Zinc Oxide Dissolution Rates.

    Science.gov (United States)

    Michaelis, Monika; Fischer, Cornelius; Colombi Ciacchi, Lucio; Luttge, Andreas

    2017-04-18

    Zinc oxide (ZnO) is of widespread use for numerous applications, including many in the cosmetic industry. Thus, ZnO particles are quite likely to enter the environment. ZnO may be harmful because of the release of cytotoxic Zn2+ ions during dissolution reactions. Here, we analyze the dissolution kinetics of the polar zinc-terminated (000-1) and nonpolar (10-10) crystal surfaces in ultrapure water to examine the impact of the crystal defects on dissolution. By using a complementary approach of atomic force microscopy and vertical scanning interferometry, we quantify the difference in reaction rate between the crystal faces, the overall range of rate variability, and the rate components that combine to an overall rate. The mean dissolution rate of the (000-1) crystal surface is more than 4 times that of the (10-10) surface. By using the rate spectrum analysis, we observed an overall dissolution rate variability of more than 1 order of magnitude. The rate components and the range of dissolution rate are important input parameters in reactive transport models for the prediction of potential release of Zn2+ into the environment.

  18. Assessment of solvents for cellulose dissolution.

    Science.gov (United States)

    Ghasemi, Mohammad; Tsianou, Marina; Alexandridis, Paschalis

    2017-03-01

    A necessary step in the processing of biomass is the pretreatment and dissolution of cellulose. A good solvent for cellulose involves high diffusivity, aggressiveness in decrystallization, and capability of disassociating the cellulose chains. However, it is not clear which of these factors and under what conditions should be improved in order to obtain a more effective solvent. To this end, a newly-developed phenomenological model has been applied to assess the controlling mechanism of cellulose dissolution. Among the findings, the cellulose fibers remain crystalline almost to the end of the dissolution process for decrystallization-controlled kinetics. In such solvents, decreasing the fiber crystallinity, e.g., via pretreatment, would result in a considerable increase in the dissolution rate. Such insights improve the understanding of cellulose dissolution and facilitate the selection of more efficient solvents and processing conditions for biomass. Specific examples of solvents are provided where dissolution is limited due to decrystallization or disentanglement. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Effect of particle size on solubility, dissolution rate, and oral bioavailability: evaluation using coenzyme Q10 as naked nanocrystals

    Science.gov (United States)

    Sun, Jiao; Wang, Fan; Sui, Yue; She, Zhennan; Zhai, Wenjun; Wang, Chunling; Deng, Yihui

    2012-01-01

    In this paper work, four naked nanocrystals (size range 80–700 nm) were prepared without any surfactant or polymer using the solvent/nonsolvent method. The effects of particle size on their solubility, dissolution, and oral bioavailability were investigated. Solubility and dissolution testing were performed in three types of dissolution medium, and the studies demonstrated that the equilibrium solubilities of coenzyme Q10 nanocrystals and bulk drugs were not affected by the dissolution media but the kinetic solubilities were. Kinetic solubility curves and changes in particle size distribution were determined and well explained by the proposed solubilization model for the nanocrystals and bulk drugs. The particle size effect on dissolution was clearly influenced by the diffusion coefficients of the various dissolution media, and the dissolution velocity of coenzyme Q10 increased as particle size decreased. The bioavailability of coenzyme Q10 after oral administration in beagle dogs was improved by reducing the particle size. For 700 nm nanocrystals, the AUC0–48 was 4.4-fold greater than that for the coarse suspensions, but a further decrease in particle size from 700 nm to 120 nm did not contribute to improvement in bioavailability until the particle size was reduced to 80 nm, when bioavailability was increased by 7.3-fold. PMID:23166438

  20. Development and Validation of a Dissolution Test Method for ...

    African Journals Online (AJOL)

    Purpose: To develop and validate a dissolution test method for dissolution release of artemether and lumefantrine from tablets. Methods: A single dissolution method for evaluating the in vitro release of artemether and lumefantrine from tablets was developed and validated. The method comprised of a dissolution medium of ...

  1. Enhancing dissolution of domperidone by spray-drying: effect of different storage conditions on stability.

    Science.gov (United States)

    Lee, Jung H; Kim, Min J; Yang, Jaewon; Kim, Kyoung H; Kim, Hye M; Lee, So J; Lee, Dongwon; Khang, Gilson

    2014-03-01

    Domperidone is an antidopaminergic drug that facilitates a function of the digestive smooth muscle. Depending on the Biopharmaceutical Classification System, domperidone is classified as class II with poor solubility and high permeability. Solid dispersions were prepared by spray-drying with a polymer. The characterization of prepared solid dispersions was analyzed by scanning electron microscope, Fourier transform infrared spectroscopy, x-ray diffraction and differential scanning calorimeter. In vitro dissolution behavior was carried out in gastric juice (pH 1.2) and these results were compared with pure domperidone (active pharmaceutical ingredient). The dissolution rate was improved due to the influence of polymers. Stability assays were conducted by the same pre-experiment. Storage conditions of the solid dispersions were as follows: 25°C relative humidity 25% and 65°C relative humidity 80%. In this study, the goal is to improve the dissolution rate of domperidone by solid dispersions and to confirm stability of the prepared solid dispersions. It suggests that the content of polymers added in solid dispersions can affect the dissolution behavior and change dissolution rate of drug.

  2. Improved solubility and dissolution rate of piroxicam using gelucire 44/14 and labrasol.

    Science.gov (United States)

    Karataş, Ayşegül; Yüksel, Nilüfer; Baykara, Tamer

    2005-09-01

    Piroxicam is a nonsteroidal anti-inflammatory drug that is characterized by low solubility-high permeability. The present study was designed to improve the dissolution rate of piroxicam at the physiological pH's through its increased solubility by preparing semi-solid dispersions of drug using Gelucires and Labrasol. These excipients are essentially characterized by their melting points and HLB (hydrophilic-lipophilic balance) values. The dissolution tests of the preparations were performed in the media with different pH's. Differential scanning calorimetry (DSC), were used to examine the interaction between piroxicam and excipients. Gelucire 44/14 and Labrasol at the concentration of 15% w/v in water provided 20- and 50-fold increase in the solubility of piroxicam, respectively. The semi-solid dispersion containing 1/20 of drug/excipient mixture (20% Gelucire 44/14 and 80% Labrasol in w/w) produced the dissolution not less than 85% of piroxicam within 30 min in each dissolution media (simulated gastric fluid (SGF), pH 1.2; phosphate buffers, pH 4.5 and 6.8; and water). DSC analysis of this semi-solid dispersion indicated that there was no chemical reaction between the drug and excipients, and that a solid-state solution of piroxicam with excipient formed.

  3. Moisture-induced amorphous phase separation of amorphous solid dispersions: molecular mechanism, microstructure, and its impact on dissolution performance.

    Science.gov (United States)

    Chen, Huijun; Pui, Yipshu; Liu, Chengyu; Chen, Zhen; Su, Ching-Chiang; Hageman, Michael; Hussain, Munir; Haskell, Roy; Stefanski, Kevin; Foster, Kimberly; Gudmundsson, Olafur; Qian, Feng

    2017-10-26

    Amorphous phase separation (APS) is commonly observed in amorphous solid dispersions (ASD) when exposed to moisture. The objective of this study was to investigate: 1) the phase behavior of amorphous solid dispersions composed of a poorly water-soluble drug with extremely low crystallization propensity, BMS-817399, and PVP, following exposure to different relative humidity (RH), and 2) the impact of phase separation on the intrinsic dissolution rate of amorphous solid dispersion. Drug-polymer interaction was confirmed in ASDs at different drug loading using Infrared (IR) spectroscopy and water vapor sorption analysis. It was found that the drug-polymer interaction could persist at low RH (≤ 75% RH) but was disrupted after exposure to high RH, with the advent of phase separation. Surface morphology and composition of 40/60 ASD at micro-/nano- scale before and after exposure to 95% RH were also compared. It was found that hydrophobic drug enriched on the surface of ASD after phase separation. However, for the 40/60 ASD system, the intrinsic dissolution rate of amorphous drug was hardly affected by the phase behavior of ASD, which may be partially attributed to the low crystallization tendency of amorphous BMS-817399 and high hydrophobicity of ASD. Intrinsic dissolution rate of PVP was decreased resulting from phase separation, leading to a lower concentration in the dissolution medium, but supersaturation maintenance was not anticipated to be altered after phase separation due to the limited ability of PVP to inhibit drug precipitation and prolong the supersaturation of drug in solution. This study indicated that for compounds with low crystallization propensity and high hydrophobicity, the risk of moisture-induced phase separation is high but such phase separation may not have profound impact on the drug dissolution performance of ASDs. Therefore, application of ASD technology on slow crystallizers could incur low risks not only in physical stability, but also in

  4. Evolution of Choice of Solubility and Dissolution Media After Two Decades of Biopharmaceutical Classification System.

    Science.gov (United States)

    Bou-Chacra, Nadia; Melo, Katherine Jasmine Curo; Morales, Ivan Andrés Cordova; Stippler, Erika S; Kesisoglou, Filippos; Yazdanian, Mehran; Löbenberg, Raimar

    2017-07-01

    The introduction of the biopharmaceutics drug classification system (Biopharmaceutics Classification System (BCS)), in 1995, provided a simple way to describe the biopharmaceutics behavior of a drug. Solubility and permeability are among the major parameters, which determine the fraction dose absorbed of a drug substance and consequently its chances to be bioavailable. The purpose of this review is to summarize the evolution of the media used for determining solubility and dissolution and how this can be used in modern drug development. Over the years, physiologically adapted media and buffers were introduced with the intention to better predict the in vivo solubility and dissolution of drug substances. Water, buffer solutions, compendial media, micellar solubilization media, and biorelevant media are reviewed. At this time point, there is no universal medium available which can be used to predict every drug substance's solubility or a drug product's in vivo dissolution behavior. However, there have been many improvements and additions made to media to optimize their in vivo predictability; for example, the current phosphate concentrations in buffers seem to be too high to correlate with the carbonate buffer concentrations in vivo. Biorelevant media were updated to correlate them better with the composition of human intestinal fluids. The BCS was introduced into regulatory sciences as a scientific risk management tool to waive bioequivalence studies under certain conditions. Today's different guidance documents define the dose-solubility ratio differently. As shown for amoxicillin, this can cause more confusion than certainty for globally operating companies. Harmonization of BCS guidelines is highly desirable.

  5. Rapid detection by direct analysis in real time-mass spectrometry (DART-MS) of psychoactive plant drugs of abuse: the case of Mitragyna speciosa aka "Kratom".

    Science.gov (United States)

    Lesiak, Ashton D; Cody, Robert B; Dane, A John; Musah, Rabi A

    2014-09-01

    Mitragyna speciosa, also known commonly as "Kratom" or "Ketum", is a plant with psychoactive properties that have been attributed to the presence of various indole alkaloids such as mitragynine and 7-hydroxymitragynine. M. speciosa use is gaining popularity internationally as a natural and legal alternative to narcotics. As a drug of abuse, its detection and identification are not straightforward, since M. speciosa plant material is not particularly distinctive. Here, we show that direct analysis in real time-mass spectrometry (DART-MS) can be used not only to rapidly identify M. speciosa plant material and distinguish it from other plants, but also to distinguish between M. speciosa plant varieties, based on differences between their chemical profiles. The method is rapid and the analysis expeditious. Plant material such as that found at a crime scene can be analyzed directly with no sample pre-preparation steps. Furthermore, we show that the basis set of principal components that permit characterization of the plant material can be used to positively identify M. speciosa. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. Rapid acquisition and modulation of colistin-resistance by an extensively drug-resistant Acinetobacter baumannii: case report and review of current literature

    Directory of Open Access Journals (Sweden)

    Jari Intra

    2016-10-01

    Full Text Available Acinetobacter baumannii has emerged as a major cause of healthcare-associated infections. It commonly expresses clinical resistance to multiple antimicrobial agents, and hence, it is considered the paradigm of an extensively drug-resistant (XDR bacterium. XDR A. baumannii is a rapidly emerging pathogen, especially in the intensive care unit (ICU, causing nosocomial infections including sepsis, ventilatorassociated pneumonia, meningitis, peritonitis, urinary tract infection, and central venous catheter-related infection. In the present report, we described an in vivo evolution of A. baumannii strain from a colistinsusceptibility to a colistin-resistance state. A 65-year-old male, who suffered a duodenal ulcer, two days after hospitalization and during the stay in ICU, contracted a pneumonia and peritoneal infection by a carbapenem-resistant A. baumannii strain. After a combination treatment with colistin, vancomycin plus imipenem, and within seven days, the pathogen rapidly evolved in seven days to a pandrug-resistant phenotype. As the antimicrobial treatment was stopped, the A. baumannii isolate changed another time its profile to colistin, becoming newly susceptible, showing a very high level of adaptability to external conditions. We also have reviewed here the current literature on this worryingly public health threat.

  7. Discriminative Dissolution Method for Benzoyl Metronidazole Oral Suspension.

    Science.gov (United States)

    da Silva, Aline Santos; da Rosa Silva, Carlos Eduardo; Paula, Fávero Reisdorfer; da Silva, Fabiana Ernestina Barcellos

    2016-06-01

    A dissolution method for benzoyl metronidazole (BMZ) oral suspensions was developed and validated using a high-performance liquid chromatography (HPLC) method. After determination of sink conditions, dissolution profiles were evaluated using different dissolution media and agitation speeds. The sample insertion mode in dissolution media was also evaluated. The best conditions were obtained using a paddle, 50 rpm stirring speed, simulated gastric fluid (without pepsin) as the dissolution medium, and sample insertion by a syringe. These conditions were suitable for providing sink conditions and discriminatory power between different formulations. Through the tested conditions, the results can be considered specific, linear, precise, accurate, and robust. The dissolution profiles of five samples were compared using the similarity factor (f 2) and dissolution efficiency. The dissolution kinetics were evaluated and described by the Weibull model. Whereas there is no monograph for this pharmaceutical formulation, the dissolution method proposed can be considered suitable for quality control and dissolution profile comparison of different commercial formulations.

  8. Combinational approach using solid dispersion and semi-solid matrix technology to enhance in vitro dissolution of telmisartan

    Directory of Open Access Journals (Sweden)

    Syed Faisal Ali

    2016-02-01

    Full Text Available The present investigation was focused to formulate semi-solid capsules (SSCs of hydrophobic drug telmisartan (TLMS by encapsulating semi-solid matrix of its solid dispersion (SD in HPMC capsules. The combinational approach was used to reduce the lag time in drug release and improvise its dissolution. SDs of TLMS was prepared using hot fusion method by varying the combinations of Pluronic-F68, Gelucire 50/13 and Plasdone S630. A total of nine batches (SD1-SD9 were characterized for micromeritic properties, in vitro dissolution behavior and surface characterization. SD4 with 52.43% cumulative drug release (CDR in phosphate buffer, pH 7.4, in 120 min, t50% 44.2 min and DE30min 96.76% was selected for the development of semi-solid capsules. Differential scanning calorimetry of SD4 revealed molecular dispersion of TLMS in Pluronic-F68. SD4 was formulated into SSCs using Gelucire 44/14 and PEG 400 as semi-solid components and PEG 6000 as a suspending agent to achieve reduction in lag time for effective drug dissolution. SSC6 showed maximum in vitro drug dissolution 97.49 % in phosphate buffer, pH 7.4 with in 20 min that was almost a three folds reduction in the time required to achieve similar dissolution by SD. Thus, SSCs present an excellent approach to enhance in vitro dissolution as well as to reduce the lag time of dissolution for poorly water soluble drugs especially to those therapeutic classes that are intended for faster onset of action. Developed approach based on HPMC capsules provided a better alternative to target delivery of telmisartan to the vegetarian population.

  9. Real-Time PCR and High-Resolution Melt Analysis for Rapid Detection of Mycobacterium leprae Drug Resistance Mutations and Strain Types

    Science.gov (United States)

    Li, Wei; Matsuoka, Masanori; Kai, Masanori; Thapa, Pratibha; Khadge, Saraswoti; Hagge, Deanna A.; Brennan, Patrick J.

    2012-01-01

    Drug resistance surveillance and strain typing of Mycobacterium leprae are necessary to investigate ongoing transmission of leprosy in regions of endemicity. To enable wider implementation of these molecular analyses, novel real-time PCR–high-resolution melt (RT-PCR-HRM) assays without allele-specific primers or probes and post-PCR sample handling were developed. For the detection of mutations within drug resistance-determining regions (DRDRs) of folP1, rpoB, and gyrA, targets for dapsone, rifampin, and fluoroquinolones, real-time PCR-HRM assays were developed. Wild-type and drug-resistant mouse footpad-derived strains that included three folP1, two rpoB, and one gyrA mutation types in a reference panel were tested. RT-PCR-HRM correctly distinguished the wild type from the mutant strains. In addition, RT-PCR-HRM analyses aided in recognizing samples with mixed or minor alleles and also a mislabeled sample. When tested in 121 sequence-characterized clinical strains, HRM identified all the folP1 mutants representing two mutation types, including one not within the reference panel. The false positives (PCR inhibition. A second set of RT-PCR-HRM assays for identification of three previously reported single nucleotide polymorphisms (SNPs) that have been used for strain typing were developed and validated in 22 reference and 25 clinical strains. Real-time PCR-HRM is a sensitive, simple, rapid, and high-throughput tool for routine screening known DRDR mutants in new and relapsed cases, SNP typing, and detection of minor mutant alleles in the wild-type background at lower costs than current methods and with the potential for quality control in leprosy investigations. PMID:22170923

  10. Improvement of dissolution and hypoglycemic efficacy of glimepiride by different carriers.

    Science.gov (United States)

    Mohamed, Elham A; Meshali, Mahasen M; Foda, Abdel Monem M; Borg, Thanaa M

    2012-09-01

    Effects of tromethamine (Tris), polyvinylpyrrolidone (PVP-K25), and low molecular weight chitosan (LM-CH) on dissolution and therapeutic efficacy of glimepiride (Gmp) were investigated using physical mixtures (PMs), coground mixtures, coprecipitates (Coppts) or kneaded mixtures (KMs), and compared with drug alone. Fourier transform infrared spectroscopy, differential scanning colorimetry, and X-ray diffractometry were performed to identify any physicochemical interaction with Gmp. Surface morphology was examined via scanning electron microscopy. The results of Gmp in vitro dissolution revealed that it was greatly enhanced by Coppt with Tris or PVP-K25 and KM with LM-CH at a drug to carrier ratio of 1:8. Gmp amorphization by PVP-K25 and LM-CH was a major factor in increasing Gmp dissolution. Being basic, Tris might increase the pH of the microdiffusion layer around Gmp particles improving its dissolution. Formation of water-soluble complexes suggested by solubility study may also explain the enhanced dissolution. Capsules were prepared from Coppts and KM 1:8 drug to carrier binary systems and also with Tris PMs. In vivo, the hypoglycemic efficacy of Gmp capsules in rabbits increased by 1.63-, 1.50-, and 1.46-fold for 1:8 Coppts with Tris or PVP-K25 and KM with LM-CH respectively, compared with Gmp alone. Surprisingly, the response to Tris PM 1:20 capsules was 1.52-fold revealing statistically insignificant difference to that of Tris Coppt 1:8 (1.63 fold). As a conclusion, dissolution enhancement and hypoglycemic potentiation by 1:20 PM of Gmp/Tris, being simple and easy to prepare, may enable development of a reduced-dose and fast-release oral dosage form of Gmp.

  11. In vivo optical coherence tomography imaging of dissolution of hyaluronic acid microneedles in human skin (Conference Presentation)

    Science.gov (United States)

    Song, Seungri; Kim, Jung Dong; Bae, Jung-hyun; Chang, Sooho; Kim, Soocheol; Lee, Hyungsuk; Jeong, Dohyeon; Kim, Hong Kee; Joo, Chulmin

    2017-02-01

    Transdermal drug delivery (TDD) has been recently highlighted as an alternative to oral delivery and hypodermic injections. Among many methods, drug delivery using a microneedle (MN) is one of the promising administration strategies due to its high skin permeability, mininal invasiveness, and ease of injection. In addition, microneedle-based TDD is explored for cosmetic and therapeutic purposes, rapidly developing market of microneedle industry for general population. To date, visualization of microneedles inserted into biological tissue has primarily been performed ex vivo. MRI, CT and ultrasound imaging do not provide sufficient spatial resolution, and optical microscopy is not suitable because of their limited imaging depth; structure of microneedles located in 0.2 1mm into the skin cannot be visulalized. Optical coherence tomography (OCT) is a non-invasive, cross-sectional optical imaging modality for biological tissue with high spatial resolution and acquisition speed. Compared with ultrasound imaging, it exhibits superior spatial resolution (1 10 um) and high sensitivity, while providing an imaging depth of biological tissue down to 1 2 mm. Here, we present in situ imaging and analysis of the penetration and dissolution characteristics of hyaluronic acid based MNs (HA-MN) with various needle heights in human skin in vivo. In contrast to other studies, we measured the actual penetration depths of the HA-MNs by considering the experimentally measured refractive index of HA in the solid state. For the dissolution dynamics of the HA-MNs, time-lapse structural alteration of the MNs could be clearly visualized, and the volumetric changes of the MNs were measured with an image analysis algorithm.

  12. Biorelevant Dissolution Models for a Weak Base To Facilitate Formulation Development and Overcome Reduced Bioavailability Caused by Hypochlordyria or Achlorhydria.

    Science.gov (United States)

    Kou, Dawen; Dwaraknath, Sudharsan; Fischer, Yannick; Nguyen, Daniel; Kim, Myeonghui; Yiu, Hiuwing; Patel, Preeti; Ng, Tania; Mao, Chen; Durk, Matthew; Chinn, Leslie; Winter, Helen; Wigman, Larry; Yehl, Peter

    2017-10-02

    In this study, two dissolution models were developed to achieve in vitro-in vivo relationship for immediate release formulations of Compound-A, a poorly soluble weak base with pH-dependent solubility and low bioavailability in hypochlorhydric and achlorhydric patients. The dissolution models were designed to approximate the hypo-/achlorhydric and normal fasted stomach conditions after a glass of water was ingested with the drug. The dissolution data from the two models were predictive of the relative in vivo bioavailability of various formulations under the same gastric condition, hypo-/achlorhydric or normal. Furthermore, the dissolution data were able to estimate the relative performance under hypo-/achlorhydric and normal fasted conditions for the same formulation. Together, these biorelevant dissolution models facilitated formulation development for Compound-A by identifying the right type and amount of key excipient to enhance bioavailability and mitigate the negative effect of hypo-/achlorhydria due to drug-drug interaction with acid-reducing agents. The dissolution models use readily available USP apparatus 2, and their broader utility can be evaluated on other BCS 2B compounds with reduced bioavailability caused by hypo-/achlorhydria.

  13. Griseofulvin/carrier blends: application of partial least squares (PLS) regression analysis for estimating the factors affecting the dissolution efficiency.

    Science.gov (United States)

    Cutrignelli, Annalisa; Trapani, Adriana; Lopedota, Angela; Franco, Massimo; Mandracchia, Delia; Denora, Nunzio; Laquintana, Valentino; Trapani, Giuseppe

    2011-12-01

    The main aim of the present study was to estimate the carrier characteristics affecting the dissolution efficiency of griseofulvin (Gris) containing blends (BLs) using partial least squares (PLS) regression analysis. These systems were prepared at three different drug/carrier weight ratios (1/5, 1/10, and 1/20) by the solvent evaporation method, a well-established method for preparing solid dispersions (SDs). The carriers used were structurally different including polymers, a polyol, acids, bases and sugars. The BLs were characterised at the solid-state by spectroscopic (Fourier transform infrared spectroscopy), thermoanalytical (differential scanning calorimetry) and X-ray diffraction studies and their dissolution behaviours were quantified in terms of dissolution efficiencies (log DE/DE(Gris)). The correlation between the selected descriptors, including parameters for size, lipophilicity, cohesive energy density, and hydrogen bonding capacity and log DE/DE(Gris) (i.e., DE and DE(Gris) are the dissolution efficiencies of the BLs and the pure drug, respectively) was established by PLS regression analysis. Thus two models characterised by satisfactory coefficient of determination were derived. The generated equations point out that aqueous solubility, density, lipophilic/hydrophilic character, dispersive/polar forces and hydrogen bonding acceptor/donor ability of the carrier are important features for dissolution efficiency enhancement. Finally, it could be concluded that the correlations developed may be used to predict at a semiquantitative level the dissolution behaviour of BLs of other essentially neutral drugs possessing hydrogen bonding acceptor groups only.

  14. Dissolution kinetics of schwertmannite and ferrihydrite in oxidized mine samples and their detection by differential X-ray diffraction (DXRD)

    Energy Technology Data Exchange (ETDEWEB)

    Dold, Bernhard

    2003-10-01

    A dissolution test with 9 natural and synthetic schwertmannite and ferrihydrite samples was performed by reaction with 0.2 M ammonium oxalate at pH 3.0 in the dark. The method was coupled with differential X-ray diffraction (DXRD) to successfully detect schwertmannite at low concentrations in oxidized mine tailings. Rapid dissolution was observed for all schwertmannites (> 94% in 60 min) and natural 2-line ferrihydrites (> 85% in 60 min); however, synthetic 2-line and 6-line ferrihydrite dissolved slower (42 and 16% after 60 min, respectively). The results showed that it was not possible to distinguish between natural schwertmannites and ferrihydrites on the basis of their dissolution kinetics. Modeling of the schwertmannite dissolution curves, examinations of mineral shape by scanning electron microscopy, and Fe/S mole ratios of the dissolved fractions indicated that two different schwertmannite particle morphologies (spherical and web-like) occurred. Collapse of spherical (sea-urchin) schwertmannite aggregates seemed to control the dissolution kinetics according to a shrinking core model. In the case of web-like schwertmannite, dissolution could be modeled with a simple first order equation, and structural SO{sub 4}{sup 2-} may have affected the dissolution kinetics. No relationship was found between ferrihydrite particle shape and dissolution behavior in acid NH{sub 4}-oxalate. A 1-h extraction with 0.2 M NH{sub 4}-oxalate at pH 3.0 in the dark should be adequate to dissolve schwertmannite and natural 2-line ferrihydrite in most samples. In some cases, a fraction of secondary jarosite or goethite may also be dissolved, although at a slower rate. If only schwertmannite is of interest (e.g., determination by DXRD), a 15 min attack should be used to increase selectivity. A truly selective leach of schwertmannite and ferrihydrite should be based on dissolution tests, as a broad variety of dissolution kinetics can be observed in this mineral group.

  15. SPHERICAL CRYSTALLIZATION OF ZALTOPROFEN FOR ENHANCEMENT OF MICROMERITIC PROPERTIES AND DISSOLUTION RATE

    OpenAIRE

    E. Hari Krishna*, V. Ram Mohan Gupta and S. Jyothi

    2012-01-01

    The present work deals with the spherical crystallization process by Spherical agglomeration method applied to Zaltoprofen, a novel NSAID drug. The object of present study was to prepare and characterize the spherical agglomeration of water insoluble non-steroidal anti-inflammatory drug. Zaltoprofen spherical agglomerates prepared with poly ethylene glycol, which is hydrophilic polymer by using simple spherical agglomeration technique for enhancing micromeritic properties and dissolution rate...

  16. Advances in Polymer Design for Enhancing Oral Drug Solubility and Delivery.

    Science.gov (United States)

    Ting, Jeffrey M; Porter, William W; Mecca, Jodi M; Bates, Frank S; Reineke, Theresa M

    2018-01-10

    Synthetic polymers have enabled amorphous solid dispersions (ASDs) to emerge as an oral delivery strategy for overcoming poor drug solubility in aqueous environments. Modern ASD products noninvasively treat a range of chronic diseases (for example, hepatitis C, cystic fibrosis, and HIV). In such formulations, polymeric carriers generate and maintain drug supersaturation upon dissolution, increasing the apparent drug solubility to enhance gastrointestinal barrier absorption and oral bioavailability. In this Review, we outline several approaches in designing polymeric excipients to drive interactions with active pharmaceutical ingredients (APIs) in spray-dried ASDs, highlighting polymer-drug formulation guidelines from industrial and academic perspectives. Special attention is given to new commercial and specialized polymer design strategies that can solubilize highly hydrophobic APIs and suppress the propensity for rapid drug recrystallization. These molecularly customized excipients and hierarchical excipient assemblies are promising toward informing early-stage drug-discovery development and reformulating existing API candidates into potentially lifesaving oral medicines for our growing global population.

  17. Arresting dissolution by interfacial rheology design

    Science.gov (United States)

    Beltramo, Peter J.; Gupta, Manish; Alicke, Alexandra; Liascukiene, Irma; Gunes, Deniz Z.; Baroud, Charles N.; Vermant, Jan

    2017-09-01

    A strategy to halt dissolution of particle-coated air bubbles in water based on interfacial rheology design is presented. Whereas previously a dense monolayer was believed to be required for such an “armored bubble” to resist dissolution, in fact engineering a 2D yield stress interface suffices to achieve such performance at submonolayer particle coverages. We use a suite of interfacial rheology techniques to characterize spherical and ellipsoidal particles at an air-water interface as a function of surface coverage. Bubbles with varying particle coverages are made and their resistance to dissolution evaluated using a microfluidic technique. Whereas a bare bubble only has a single pressure at which a given radius is stable, we find a range of pressures over which bubble dissolution is arrested for armored bubbles. The link between interfacial rheology and macroscopic dissolution of ˜ 100 μm bubbles coated with ˜ 1 μm particles is presented and discussed. The generic design rationale is confirmed by using nonspherical particles, which develop significant yield stress at even lower surface coverages. Hence, it can be applied to successfully inhibit Ostwald ripening in a multitude of foam and emulsion applications.

  18. Investigation into the dissolution rate increase on storage of Wellbutrin SR 100 mg tablets.

    Science.gov (United States)

    Wells, Mickey L; Williams, Sandra O; Sanftleben, Ronald A; Balik, Samuel B; Evans, Barry A

    2010-03-01

    The Food and Drug Administration (FDA) approved the New Drug Application for Wellbutrin sustained release (SR) 100 mg tablets on October 4, 1996. However, by 1998, the FDA expressed concern about the stability of this drug product based on an increase in the dissolution profile on storage. Data submitted in the annual report showed that this drug product could not meet the expiry of 18 months at the International Committee on Harmonization storage condition of 25 degrees C/60% relative humidity. The FDA mandated a 12-month expiry and GlaxoWellcome tightened this further by instituting an expiry of 9 months. The FDA also requested a long-term solution to the stability of Wellbutrin SR 100 mg tablets. Investigations via colloidal solutions revealed that the dissolution rate increase on storage occurred due to acid hydrolysis of the release controlling polymer. This drug product was successfully reformulated by slowing the initial dissolution rate and having an increased ratio of release controlling polymer to acid stabilizer. The reformulation used the same ingredients and manufacturing unit processes as the original formulation. The reformulated drug product was approved by the FDA on October 11, 2000 with an 18-month shelf-life. The shelf-life was extended to 36 months in an annual update to the FDA on December 1, 2005.

  19. Amorphous is not always better—A dissolution study on solid state forms of carbamazepine

    DEFF Research Database (Denmark)

    Jensen, Linda G.; Skautrup, Frederik B.; Müllertz, Anette

    2017-01-01

    state forms of carbamazepine, crystalline or amorphous drug, with or without either polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC) and glass solutions of the drug with both polymers (2:1, 4:1 and 10:1 (w/w) drug-to-polymer ratio) were tested with respect to their dissolution behaviour...... in a biorelevant gastric medium (for 30 min) and subsequently in intestinal conditions (for 2 h). Carbamazepine form III in the absence of polymer dissolved to a drug concentration of 540 μg/ml, but the concentration decreased after around 70 min due to precipitation of the dihydrate form, and reached 436 μg....../ml after 2.5 h dissolution testing. The presence of PVP led to a similar dissolution profile with a slightly earlier onset of decrease in drug concentration, while in the presence of HPMC no decline in dissolved drug concentration was observed. Surprisingly, amorphous carbamazepine did not result in any...

  20. Discrimination and quantification of two isomeric antineoplastic drugs by rapid and non-invasive analytical control using a handheld Raman spectrometer.

    Science.gov (United States)

    Lê, L M M; Tfayli, A; Zhou, J; Prognon, P; Baillet-Guffroy, A; Caudron, E

    2016-12-01

    Raman spectroscopy is a rapid, non-destructive and non-invasive method that is a promising tool for real-time analytical control of drug concentrations. This study evaluated a handheld Raman device to discriminate and quantify two isomeric drugs used to treat cancer. Doxorubicin (DOXO) and epirubicin (EPIR) samples were analyzed at therapeutic concentrations from 0.1 to 2mg/mL (n=90) and 0.08-2mg/mL (n=90) by non-invasive measurements using a portable Raman spectrometer. The discrimination of these two molecules was demonstrated for all concentrations (n=180) by qualitative analysis using partial least square discriminant analysis (PLS-DA) with 100% classification accuracy, sensitivity and specificity and 0% error rate. For each molecule, quantitative analyses were performed using PLS regression. The validity of the model was evaluated using root mean square error of cross validation (RMSECV) and prediction (RMSEP) that furnished 0.05 and 0.02mg/mL for DOXO and 0.17 and 0.16mg/mL for EPIR after pretreatment optimization. Based on the accuracy profile, the linearity range was from 1.256 to 2.000mg/mL for DOXO (R2=0.9988) and from 0.553 to 2.000mg/Ml for EPIR (R2=0.9240) and repeatability (CV% max of 1.8% for DOXO and 3.2% for EPIR) and intermediate precision (CV% max of 2.8% for DOXO and 4.5% for EPIR) were both acceptable. Despite the narrow validated concentration range for quantitative analysis, this study shows the potential of a handheld Raman spectrometer coupled to chemometric approaches for real-time quantification of cytotoxic drugs, as well for discriminating between two drugs with similar UV absorption profiles. Finally, the use of a handheld spectrometer with the possibility of a direct measurement of substances in containers is a potentially valuable tool for combining patient safety with security of healthcare workers. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Impact of processing methods on the dissolution of artemether from two non-ordered mesoporous silicas.

    Science.gov (United States)

    Tahir, Hira; Shahzad, Yasser; Waters, Laura J; Hussain, Talib; Yousaf, Abid Mehmood; Mahmood, Tariq; Sheikh, Rizwan

    2017-11-21

    Poor aqueous solubility is often linked with a poor dissolution rate and ultimately, limited bioavailability of pharmaceutical compounds. This study describes the application of mesoporous materials (Syloid 244 and Syloid AL1) in improving the dissolution rate of a drug with poor aqueous solubility, namely artemether, utilising different processing methods including physical mixing, co-grinding and solid dispersions prepared by solvent evaporation and the lyophilisation technique. The prepared formulations were extensively characterised for their solid-state properties and the drug release attributes were studied. Differential scanning calorimetry and X-ray diffraction confirmed conversion of crystalline artemether into a disordered and amorphous form, whilst no intermolecular interactions were detected between artemether and silica. Both silica grades enhanced the dissolution rate of artemether in comparison with drug alone, for example from 17.43% (±0.87%) to 71.55% (±3.57%) after 120mins with lyophilisation and Syloid 244 at a 1:3 ratio. This enhancement was also dependant on the choice of processing method, for example, co-ground and lyophilised formulations prepared with Syloid 244 at 1:3 ratio produced the most extensive dissolution, thus endorsing the importance of materials as well as choice of formulation method. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Atypical effects of incorporated surfactants on stability and dissolution properties of amorphous polymeric dispersions.

    Science.gov (United States)

    Al-Obaidi, Hisham; Lawrence, M Jayne; Buckton, Graham

    2016-11-01

    To understand the impact of ionic and non-ionic surfactants on the dissolution and stability properties of amorphous polymeric dispersions using griseofulvin (GF) as a model for poorly soluble drugs. Solid dispersions of the poorly water-soluble drug, griseofulvin (GF) and the polymers, poly(vinylpyrrolidone) (PVP) and poly(2-hydroxypropyl methacrylate) (PHPMA), have been prepared by spray drying and bead milling and the effect of the ionic and non-ionic surfactants, namely sodium dodecyl sulphate (SDS) and Tween-80, on the physico-chemical properties of the solid dispersions studied. The X-ra