Drug-Drug/Drug-Excipient Compatibility Studies on Curcumin using Non-Thermal Methods

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Moorthi Chidambaram

2014-05-01

Full Text Available Purpose: Curcumin is a hydrophobic polyphenol isolated from dried rhizome of turmeric. Clinical usefulness of curcumin in the treatment of cancer is limited due to poor aqueous solubility, hydrolytic degradation, metabolism, and poor oral bioavailability. To overcome these limitations, we proposed to fabricate curcumin-piperine, curcumin-quercetin and curcumin-silibinin loaded polymeric nanoformulation. However, unfavourable combinations of drug-drug and drug-excipient may result in interaction and rises the safety concern. Hence, the present study was aimed to assess the interaction of curcumin with excipients used in nanoformulations. Methods: Isothermal stress testing method was used to assess the compatibility of drug-drug/drug-excipient. Results: The combination of curcumin-piperine, curcumin-quercetin, curcumin-silibinin and the combination of other excipients with curcumin, piperine, quercetin and silibinin have not shown any significant physical and chemical instability. Conclusion: The study concludes that the curcumin, piperine, quercetin and silibinin is compatible with each other and with other excipients.

Risk evaluation of impurities in topical excipients: The acetol case

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Jente Boonen

2014-10-01

Full Text Available Pharmaceutical excipients for topical use may contain impurities, which are often neglected from a toxicity qualification viewpoint. The possible impurities in the most frequently used topical excipients were evaluated in-silico for their toxicity hazard. Acetol, an impurity likely present in different topical pharmaceutical excipients such as propylene glycol and glycerol, was withheld for the evaluation of its health risk after dermal exposure.An ex-vivo in-vitro permeation study using human skin in a Franz Diffusion Cell set-up and GC as quantification methodology showed a significant skin penetration with an overall Kp value of 1.82×10−3 cm/h. Using these data, limit specifications after application of a dermal pharmaceutical product were estimated. Based on the TTC approach of Cramer class I substances, i.e. 1800 µg/(day∙person, the toxicity-qualified specification limits of acetol in topical excipients were calculated to be 90 µg/mL and 180 µg/mL for propylene glycol and glycerol, respectively.It is concluded that setting specification limits for impurities within a quality-by-design approach requires a case-by-case evaluation as demonstrated here with acetol. Keywords: Acetol, Impurity, Excipients, Transdermal penetration, Specification limits

Development of Coprocessed Chitin-Calcium Carbonate as Multifunctional Tablet Excipient for Direct Compression.

Science.gov (United States)

Chaheen, Mohammad; Sanchez-Ballester, Noelia M; Bataille, Bernard; Yassine, Ahmad; Belamie, Emmanuel; Sharkawi, Tahmer

2018-04-24

Owing to the increasing interest in multifunctional excipients for tableting, coprocessing of individual excipients is regularly used to produce excipients of improved multifunctionality superior to individual excipients or their physical mix. The use of chitin as an excipient in tablet formulation is limited because of certain drawbacks such as poor flowability and low true density. The objective of this work is to improve these properties through coprocessing of chitin with calcium carbonate (CaCO 3 ) by precipitating CaCO 3 on chitin particles using different methods. In addition, optimization of the coprocessed chitin was carried out to improve the excipient's properties. Physicochemical (CaCO 3 content, true density, X-ray diffraction, infrared spectroscopy, and scanning electron microscopy) and functional testing (swelling force, flowability, tensile strength, deformation mechanism, and disintegration time) were used to characterize the coprocessed product. Results showed that the calcite CaCO 3 polymorph is precipitated on the chitin surface and that it interacts with chitin at carbonyl- and amide-group level. In addition, the coprocessed excipient has an improved true density and powder flowability, with CaCO 3 forming single layer on the chitin particles surface. Tableting studies showed that the coprocessed powder exhibited an intermediate deformation behavior between CaCO 3 (most brittle) and chitin (most plastic). Tablets showed acceptable tensile strength and rapid disintegration (2-4 s). These results show the potential use of coprocessed chitin-CaCO 3 as a multifunctional excipient for fast disintegration of tablets produced by direct compression. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Formulation and evaluation of antipsoriatic gel using natural excipients

OpenAIRE

Raghupatruni Jhansi Laxmi; R. Karthikeyan; P. Srinivasa Babu; R.V.V. Narendra Babu

2013-01-01

Objective: To develop topical gel formulations of Psoralen using natural excipients to minimize the side effects of synthetic drugs. Methods: The Psoralen gel formulations were prepared using different natural gums and polymers. The physicochemical compatibility between Psoralen and other excipients was confirmed by using Fourier transform infrared spectroscopy. All prepared gel formulations were evaluated for drug content uniformity, viscosity, pH, and stability. The release of psoralen f...

Investigation of drug-excipient compatibility using rheological and thermal tools

Science.gov (United States)

Trivedi, Maitri R.

HYPOTHESIS: We plan to investigate a different approach to evaluate drug-excipient physical compatibility using rheological and thermal tools as opposed to commonly used chemical techniques in pharmaceutical industry. This approach offers practical solutions to routinely associated problems arising with API's and commonly used hydrates forms of excipients. ABSTRACT: Drug-Excipient compatibility studies are an important aspect of pre-formulation and formulation development in pharmaceutical research and development. Various approaches have been used in pharmaceutical industry including use of thermal analysis and quantitative assessment of drug-excipient mixtures after keeping the samples under stress environment depending upon the type of formulation. In an attempt to provide better understanding of such compatibility aspect of excipients with different properties of API, various rheological and thermal studies were conducted on binary mixtures of excipients which exist in different hydrates. Dibasic Calcium Phosphate (DCP, anhydrous and dihydrate forms) and Lactose (Lac, anhydrous and monohydrate) were selected with cohesive API's (Acetaminophen and Aspirin). Binary mixtures of DCP and Lac were prepared by addition of 0% w/w to 50% w/w of the API into each powder blend. Rheological and thermal aspects were considered using different approaches such as powder rheometer, rotational shear cell and traditional rheometery approaches like angle of repose (AOR), hausner's ratio (HR) and cares index (CI). Thermal analysis was conducted using modulated differential scanning calorimetry (MDSC) and thermal effusivity. The data suggested that the powder rheometer showed distinctive understanding in the flowability behavior of binary mixtures with addition of increasing proportion of API's than traditional approaches. Thermal approaches revealed the potential interaction of water of crystallization DCP-D with the API (APAP) while such interactions were absent in DCP-A, while

CONDITIONING MICROBIAL PRODUCTS CONTAINING NITROGEN FIXING BACTERIA WITH DIFFERENT SOLID EXCIPIENTS

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VINTILĂ T.

2007-01-01

Full Text Available The stability in real time of two strains of Rhizobium (Rhizobium meliloti andRhizobium japonicum mixed with different excipients was evaluated during a6-months period. The excipients studied were: peat, peat and calciumcarbonate, zeolite, and ceramic. Liquid cultures and excipients mixtures weredried (12-14% humidity, sealed in plastic bags and preserved at +4oC. Thecells were activated periodically by suspending aliquots from dry products in0.9% saline solution. The viability of Rhizobium cells was evaluated bycultivation of diluted suspensions in YMA plates. The number of viable cells isdecreasing during drying in all cases, increase in the first month of storage,and remains constant or decrease very slowly during storage for all obtaineddry products containing rhizobia mixed with solid dry excipients. The highestnumber of viable cells at the end of the experiment was obtained in ceramicwith Rhizobium japonicum (8x105 cells/gram, and the lowest number ofviable cells was obtained in zeolite with Rhizobium meliloti (1,1x103cells/gram.

Miniaturized approach for excipient selection during the development of oral solid dosage form

DEFF Research Database (Denmark)

Raijada, Dharaben Kaushikkumar; Müllertz, Anette; Cornett, Claus

2014-01-01

The present study introduces a miniaturized high-throughput platform to understand the influence of excipients on the performance of oral solid dosage forms during early drug development. Wet massing of binary mixtures of the model drug (sodium naproxen) and representative excipients was followed...... for excipient selection and for early-stage performance testing of active pharmaceutical ingredient intended for oral solid dosage form. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:900-908, 2014....

CONDITIONING MICROBIAL PRODUCTS CONTAINING NITROGEN FIXING BACTERIA WITH DIFFERENT SOLID EXCIPIENTS

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DANIELA VINTILĂ

2007-05-01

Full Text Available The stability in real time of two strains of Rhizobium (Rhizobium meliloti and Rhizobium japonicum mixed with different excipients was evaluated during a 6- months period. The excipients studied were: peat, peat and calcium carbonate, zeolite, and ceramic. Liquid cultures and excipients mixtures were dried (12-14% humidity, sealed in plastic bags and preserved at +4oC. The cells were activated periodically by suspending aliquots from dry products in 0.9% saline solution. The viability of Rhizobium cells was evaluated by cultivation of diluted suspensions in YMA plates. The number of viable cells is decreasing during drying in all cases, increase in the first month of storage, and remains constant or decrease very slowly during storage for all obtained dry products containing rhizobia mixed with solid dry excipients. The highest number of viable cells at the end of the experiment was obtained in ceramic with Rhizobium japonicum (8x105 cells/gram, and the lowest number of viable cells was obtained in zeolite with Rhizobium meliloti (1,1x103 cells/gram.

Microbicide excipients can greatly increase susceptibility to genital herpes transmission in the mouse

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Sun Mianmian

2010-11-01

Full Text Available Abstract Background Several active ingredients proposed as vaginal microbicides have been shown paradoxically to increase susceptibility to infection in mouse genital herpes (HSV-2 vaginal susceptibility models and in clinical trials. In addition, "inactive ingredients" (or excipients used in topical products to formulate and deliver the active ingredient might also cause epithelial toxicities that increase viral susceptibility. However, excipients have not previously been tested in susceptibility models. Methods Excipients commonly used in topical products were formulated in a non-toxic vehicle (the "HEC universal placebo", or other formulations as specified. Twelve hours after exposure to the excipient or a control treatment, mice were challenged with a vaginal dose of HSV-2, and three days later were assessed for infection by vaginal lavage culture to assess susceptibility. Results The following excipients markedly increased susceptibility to HSV-2 after a single exposure: 5% glycerol monolaurate (GML formulated in K-Y® Warming Jelly, 5% GML as a colloidal suspension in phosphate buffered saline, K-Y Warming Jelly alone, and both of its humectant/solvent ingredients (neat propylene glycol and neat PEG-8. For excipients formulated in the HEC vehicle, 30% glycerin significantly increased susceptibility, and a trend toward increased HSV-2 susceptibility was observed after 10% glycerin, and 0.1% disodium EDTA, but not after 0.0186% disodium EDTA. The following excipients did not increase susceptibility: 10% propylene glycol, 0.18%, methylparaben plus 0.02% propylparaben, and 1% benzyl alcohol. Conclusions As reported with other surfactants, the surfactant/emulsifier GML markedly increased susceptibility to HSV-2. Glycerin at 30% significantly increased susceptibility, and, undiluted propylene glycol and PEG-8 greatly increased susceptibility.

Applications of Polymers as Pharmaceutical Excipients in Solid Oral Dosage Forms.

Science.gov (United States)

Debotton, Nir; Dahan, Arik

2017-01-01

Over the last few decades, polymers have been extensively used as pharmaceutical excipients in drug delivery systems. Pharmaceutical polymers evolved from being simply used as gelatin shells comprising capsule to offering great formulation advantages including enabling controlled/slow release and specific targeting of drugs to the site(s) of action (the "magic bullets" concept), hence hold a significant clinical promise. Oral administration of solid dosage forms (e.g., tablets and capsules) is the most common and convenient route of drug administration. When formulating challenging molecules into solid oral dosage forms, polymeric pharmaceutical excipients permit masking undesired physicochemical properties of drugs and consequently, altering their pharmacokinetic profiles to improve the therapeutic effect. As a result, the number of synthetic and natural polymers available commercially as pharmaceutical excipients has increased dramatically, offering potential solutions to various difficulties. For instance, the different polymers may allow increased solubility, swellability, viscosity, biodegradability, advanced coatings, pH dependency, mucodhesion, and inhibition of crystallization. The aim of this article is to provide a wide angle prospect of the different uses of pharmaceutical polymers in solid oral dosage forms. The various types of polymeric excipients are presented, and their distinctive role in oral drug delivery is emphasized. The comprehensive know-how provided in this article may allow scientists to use these polymeric excipients rationally, to fully exploit their different features and potential influence on drug delivery, with the overall aim of making better drug products. © 2016 Wiley Periodicals, Inc.

Safe excipient exposure in neonates and small children - protocol for the SEEN project

DEFF Research Database (Denmark)

Valeur, Kristine Svinning; Hertel, Steen Axel; Lundstrøm, Kaare Engell

2017-01-01

INTRODUCTION: The pharmacokinetics of excipients in neonates differs from that of older children. In a recent pan--European survey, two thirds of neonates received at least one potentially harmful excipient, such as ethanol and benzoates. The content of sweeteners varied by route of administration...... (more common by enteral than parenteral route), and regional differences were revealed. The survey did not identify if the content of excipients was more pronounced in medications prescribed for specific medical diseases, e.g. more common in cardiovascular conditions than lung diseases. Furthermore......, the quantitative amount of e.g. ethanol in the multi-medicated neonate has not been investigated. The aim of the present study was to quantify the total amount of excipients administered to poly-medicated neonatal and paediatric patients during hospitalisation; and to investigate if any particular medical diseases...

Safe excipient exposure in neonates and small children - protocol for the SEEN project

DEFF Research Database (Denmark)

Valeur, Kristine Svinning; Hertel, Steen Axel; Lundstrøm, Kaare Engell

2017-01-01

INTRODUCTION: The pharmacokinetics of excipients in neonates differs from that of older children. In a recent pan--European survey, two thirds of neonates received at least one potentially harmful excipient, such as ethanol and benzoates. The content of sweeteners varied by route of administration...... are treated with potentially harmful excipients. METHODS: This is a retrospective cohort study based on chart-audit on multi-medicated patients ≤ 5 years of age treated at the Rigshospitalet, Denmark. Preparations with ethanol, propylene glycol, benzyl alcohol, parabens, acesulfame p, aspartame, glycerol...

Novel nano-cellulose excipient for generating non-Newtonian droplets for targeted nasal drug delivery.

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Young, Paul M; Traini, Daniela; Ong, Hui Xin; Granieri, Angelo; Zhu, Bing; Scalia, Santo; Song, Jie; Spicer, Patrick T

2017-10-01

Thickening polymers have been used as excipients in nasal formulations to avoid nasal run-off (nasal drip) post-administration. However, increasing the viscosity of the formulation can have a negative impact on the quality of the aerosols generated. Therefore, the study aims to investigate the use of a novel smart nano-cellulose excipient to generate suitable droplets for nasal drug delivery that simultaneously has only marginally increased viscosity while still reducing nasal drips. Nasal sprays containing nano-cellulose at different concentrations were investigated for the additive's potential as an excipient. The formulations were characterized for their rheological and aerosol properties. This was then compared to conventional nasal spray formulation containing the single-component hydroxyl-propyl methyl cellulose (HPMC) viscosity enhancing excipient. The HPMC-containing nasal formulations behave in a Newtonian manner while the nano-cellulose formulations have a yield stress and shear-thinning properties. At higher excipient concentrations and shear rates, the nano-cellulose solutions have significantly lower viscosities compared to the HPMC solution, resulting in improved droplet formation when actuated through conventional nasal spray. Nano-cellulose materials could potentially be used as a suitable excipient for nasal drug delivery, producing consistent aerosol droplet size, and enhanced residence time within the nasal cavity with reduced run-offs compared to conventional polymer thickeners.

Regulatory Notes on Impact of Excipients on Drug Products and the Maillard Reaction.

Science.gov (United States)

Chowdhury, Dipak K; Sarker, Haripada; Schwartz, Paul

2018-02-01

In general, it is an important criterion that excipients remain inert throughout the shelf life of the formulated pharmaceutical product. However, depending on the functionality in chemical structure of active drug and excipients, they may undergo interaction. The well-known Maillard reaction occurs between a primary amine with lactose at high temperature to produce brown pigments. The reactivity of Maillard reaction may vary depending on the concentration as well as other conditions. Commercially, there are products where the active pharmaceutical ingredient is a primary amine and contains less than 75% lactose along with inactive excipients. This product does not show Maillard reaction during its shelf life of around 2 years at ambient conditions. However, when the same type of product contains more than 95 % lactose as an excipient, then there is a possibility of interactions though it is not visible in the initial year. Therefore, this regulatory note discusses involvement of different factors of a known drug-excipient interactions with case studies and provides an overview on how the concentration of lactose in the pharmaceutical product is important in addition to temperature and moisture in Maillard reaction.

"The Effect of Hydroxyl Containing Tablet Excipients on the Adhesive Duration of Some Mucoadhesive Polymers "

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Seyed Alireza Mortazavi

2004-06-01

Full Text Available In order to investigate the effect of hydroxyl group containing tablet excipients on the duration of adhesion of mucoadhesive polymers, discs containing Carbopol 934 (C934, polycarbophil (PC, sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose (HPMC, tragacanth (trag. and sodium alginate (Na alg., either alone or in the presence of various amounts of excipients were prepared. The duration of adhesion of the prepared discs were determined in pH 7.0 phosphate buffer at 37°C. All the excipients examined reduced the duration of adhesion and the relative durability of the polymer containing discs. HPMC discs despite showing the longest duration of mucoadhesion, suffered the greatest reduction in adhesive properties in the presence of excipients which were examined. Following HPMC, Na alg. and then trag. discs showed the greatest sensitivity to the presence of excipients. The least reduction in the duration of adhesion was observed with PC and C934. Among the excipients tested, spray-dried lactose produced the greatest reduction in the duration of adhesion, followed by polyethylene glycol 6000 and pregelatinized starch. The smallest reduction in the adhesive properties of the test polymers was due to talc powder. Hence, it seems that addition of the tablet excipients adversely reduce the adhesive properties of mucoadhesive dosage forms, which should be carefully considered during their formulation.

Excipient Usage Technical Risk Assessment for Generic Solid Dose Products

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Ajay Babu Pazhayattil

2017-09-01

Full Text Available This paper proposes an assessment methodology for solid dose generic small molecule drug products. It addresses the ‘usage of the excipient’ portion of the trinomial by utilizing the systematic approach of Risk Identification, Risk Analysis and Risk Evaluation as per ICH Q9 Quality Risk Management outlined for developing risk control strategies. The assessment and maintenance of excipient risk profile is essential to minimize any potential risk associated to excipients impacting patients.

Chitin and Chitosan as Direct Compression Excipients in Pharmaceutical Applications

Science.gov (United States)

Badwan, Adnan A.; Rashid, Iyad; Al Omari, Mahmoud M.H.; Darras, Fouad H.

2015-01-01

Despite the numerous uses of chitin and chitosan as new functional materials of high potential in various fields, they are still behind several directly compressible excipients already dominating pharmaceutical applications. There are, however, new attempts to exploit chitin and chitosan in co-processing techniques that provide a product with potential to act as a direct compression (DC) excipient. This review outlines the compression properties of chitin and chitosan in the context of DC pharmaceutical applications. PMID:25810109

Chitin and Chitosan as Direct Compression Excipients in Pharmaceutical Applications

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Adnan A. Badwan

2015-03-01

Full Text Available Despite the numerous uses of chitin and chitosan as new functional materials of high potential in various fields, they are still behind several directly compressible excipients already dominating pharmaceutical applications. There are, however, new attempts to exploit chitin and chitosan in co-processing techniques that provide a product with potential to act as a direct compression (DC excipient. This review outlines the compression properties of chitin and chitosan in the context of DC pharmaceutical applications.

Improving oral bioavailability of resveratrol by a UDP-glucuronosyltransferase inhibitory excipient-based self-microemulsion.

Science.gov (United States)

Yang, Fei-Fei; Zhou, Jing; Hu, Xiao; Cong, Zhao-Qing; Liu, Chun-Yu; Pan, Rui-Le; Chang, Qi; Liu, Xin-Min; Liao, Yong-Hong

2018-03-01

Self-microemulsifying (SME) drug delivery system has been developed to increase oral bioavailabilities, and inhibitory excipients are capable of improving oral bioavailability by inhibiting enzyme mediated intestinal metabolism. However, the potential of enzyme inhibitory excipients containing SME in boosting resveratrol bioavailability remains largely uninvestigated. In this study, we set out to prepare SME-1 with UGT inhibitory excipients (excipients without inhibitory activities named SME-2 as control) to increase the bioavailability of RES by inhibiting intestinal metabolism. Results demonstrated that similar physicochemical properties such as size, polydistribution index and in vitro release, cellular uptake and permeability in Caco-2 cells as well as in vivo lymphatic distribution between inhibitory SME-1 and non-inhibitory SME-2 were observed. In vivo study demonstrated that the molar ratios of RES-G/RES were 7.25±0.48 and 5.06±2.42 for free drug and SME-2, respectively, and the molar ratio decreased to 0.36±0.10 in SME-1 group. Pharmacokinetic study confirmed that the inhibitory excipients containing SME demonstrated potential in increasing bioavailability of RES from 6.5% for the free RES and 12.9% for SME-2 to 76.1% in SME-1 through modulating the glucuronidation by UGT inhibitory excipients. Copyright © 2018 Elsevier B.V. All rights reserved.

Characterization of low crystallinity cellulose as a direct compression excipient: Effects of physicochemical properties of cellulose excipients on their tabletting characteristics

Science.gov (United States)

Kothari, Sanjeev Hukmichand

A scale-up method for the preparation of a new excipient, low crystallinity powder cellulose (LCPC), was established. Physicochemical characterization of a series of LCPC materials was performed, and compared to the physicochemical properties of commercially existing cellulose excipients, microcrystalline cellulose (AvicelsRTM) and powdered celluloses (Solka Flocs RTM). Low crystallinity cellulose powders had high amorphous contents (>50%) and a low degree of polymerization (2 kg), typically showed low yield pressures (200 MPa), and intermediate compactability (250--600 MPa2) values. Mechanical characterization of the three types of cellulose materials, and the statistical models obtained for the results, indicated that a high porosity (>810%), a high average of amorphous content (>40%) and moisture content (>4%), and a low degree of polymerization (disintegration times (5 to 90 seconds) for LCPC tablets at low as well as high solid fractions suggest the high affinity of these materials to water, due to their high amorphous contents that expose a larger number of hydroxyl groups to water, compared to the more crystalline materials, such as microcrystalline celluloses, the tablets of which showed extremely long disintegration times (24 to 6000 seconds). The physicochemical and mechanical characterization of low crystallinity cellulose suggests it to be a promising direct compression excipient for immediate release tablet formulations.

Interactions and incompatibilities of pharmaceutical excipients with active pharmaceutical ingredients: a comprehensive review

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Sonali S. Bharate

2010-09-01

Full Text Available Studies of active drug/excipient compatibility represent an important phase in the preformulation stage of the development of all dosage forms. The potential physical and chemical interactions between drugs and excipients can affect the chemical nature, the stability and bioavailability of drugs and, consequently, their therapeutic efficacy and safety. The present review covers the literature reports of interaction and incompatibilities of commonly used pharmaceutical excipients with different active pharmaceutical ingredients in solid dosage forms. Examples of active drug/excipient interactions, such as transacylation, the Maillard browning reaction, acid base reactions and physical changes are discussed for different active pharmaceutical ingredients belonging to different therapeutic categories viz antiviral, anti-inflammatory, antidiabetic, antihypertensive, anti-convulsant, antibiotic, bronchodialator, antimalarial, antiemetic, antiamoebic, antipsychotic, antidepressant, anticancer, anticoagulant and sedative/hypnotic drugs and vitamins. Once the solid-state reactions of a pharmaceutical system are understood, the necessary steps can be taken to avoid reactivity and improve the stability of drug substances and products.

Preparation and characterization of cross-linked excipient of coprocessed xanthan gum-acacia gum as matrix for sustained release tablets

Science.gov (United States)

Surini, Silvia; Wati, Dina Risma; Syahdi, Rezi Riadhi

2018-02-01

Sustained release tablet is solid dosage form which is designed to release drugs slowly in the body. This research was intended to prepare and characterize the cross-linked excipients of co-processed xanthan gum-acacia gum (CL-Co-XGGA) as matrices for sustained release tablets with gliclazide as a model drug. CL-Co-XGGA excipients were cross-linked materials of co-processed excipients of xanthan gum-acacia gum (Co-XGGA) using sodium trimetaphosphate. Co-processed excipients of xanthan gum-acacia gum were prepared in the ratio of each excipient 1:2, 1:1 and 2:1. Co-XGGA and CL-Co-XGGA excipients were characterized physically, chemically and functionally. Then, the sustained release (SR) tablets were formulated by wet granulation method using CL-Co-XGGA excipients as matrices. Also, the dissolution study of the gliclazide SR tablets was carried out in phosphate buffer medium pH 7,4 containing sodium lauryl sulphate 0.2% for 12 hours. The results showed that the degree of substitution (DS) of CL-Co-XGGA 1:2, 1:1, 2:1 excipients were respectively 0.067, 0.082 and 0.08. Besides that, the excipients gel strengths were 14.03, 17.27 and 20,70 gF, respectively. The cross-linked excipients had improved flow properties and swelling capability compared to the Co-XGGA excipients. The results of the gliclazide SR tablets evaluations showed that all tablets were passed all tablet requirements. Moreover, the gliclazide release from SR tablets F1 - F6 revealed the sustained release profile, which was following zero order kinetics (F1, F2, F3, F6) and Higuchi kinetics (F4 and F5). It could be concluded that the obtained CL-Co-XGGA excipients might be used as matrices for sustained release tablets and could retard drug release up to 8 until 32 hours.

Effect of Reprocessing and Excipient Characteristics on Ibuprofen ...

African Journals Online (AJOL)

Methods: The effect of excipient type, technology and reprocessing on flow, compressibility and compactibility was ... granulation technology is used, the ... powders improve particle size distribution, .... 8.04 (Stat-Easy Inc., Minneapolis, USA).

A high throughput platform for understanding the influence of excipients on physical and chemical stability

DEFF Research Database (Denmark)

Raijada, Dhara; Cornett, Claus; Rantanen, Jukka

2013-01-01

The present study puts forward a miniaturized high-throughput platform to understand influence of excipient selection and processing on the stability of a given drug compound. Four model drugs (sodium naproxen, theophylline, amlodipine besylate and nitrofurantoin) and ten different excipients were...... for chemical degradation. The proposed high-throughput platform can be used during early drug development to simulate typical processing induced stress in a small scale and to understand possible phase transformation behaviour and influence of excipients on this....

Dissolution of ibuprofen enantiomers from coprecipitates and suspensions containing chiral excipients.

Science.gov (United States)

Janjikhel, R K; Adeyeye, C M

1999-01-01

The purpose of this research was to evaluate the stereospecific interaction of ibuprofen with chiral excipients such as hydroxypropyl-beta-cyclodextrin (HPCD), tartaric acid, sucrose, hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), and a nonchiral excipient, citric acid. Coprecipitates of ibuprofen were prepared in molar ratios ranging between 1:0.5 and 1:10 by a solvent evaporation method and characterized using x-ray diffraction, Fourier-transform infrared (FTIR) spectroscopy, and dissolution testing. Phase solubility studies of ibuprofen were carried out by adding excess amount of ibuprofen to aqueous excipient solutions of varying concentrations. Interaction was studied in suspensions of ibuprofen with HPMC, MC, and sucrose stored at room temperature and 60 degrees C for 12 weeks. Solubility of ibuprofen in HPCD solutions increased 10-fold, whereas solubility decreased in the tartaric and citric acid solutions, a result of decreased pH with increased amount of the acids in which ibuprofen (pKa 4.8) is less soluble. Phase solubility diagrams of ibuprofen in aqueous HPCD, citric acid, and tartaric acid solutions showed no stereospecific differences in solubility of the two enantiomers. X-ray diffraction studies showed that ibuprofen exists in a crystalline form at low ibuprofen-to-excipient ratios, whereas at the higher ratios, it exists in an amorphous form. FTIR spectroscopy for HPCD coprecipitates showed a shift of the carbonyl stretching band of ibuprofen to a higher wavelength with a markedly decreased intensity, probably because of a breakdown in the intermolecular hydrogen bonding with ibuprofen and restriction of the drug molecule in the HPCD cavity, respectively. Dissolution profiles of the coprecipitates demonstrated higher dissolution rates than those of pure ibuprofen. The presence of chiral excipients did not appear to cause stereoselective release of the drug from the coprecipitates and the suspensions.

Cytotoxicity of Different Excipients on RPMI 2650 Human Nasal Epithelial Cells

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Tamás Horváth

2016-05-01

Full Text Available The nasal route receives a great deal of attention as a non-invasive method for the systemic administration of drugs. For nasal delivery, specific formulations containing excipients are used. Because of the sensitive respiratory mucosa, not only the active ingredients, but also additives need to be tested in appropriate models for toxicity. The aim of the study was to measure the cytotoxicity of six pharmaceutical excipients, which could help to reach larger residence time, better permeability, and increased solubility dissolution rate. The following excipients were investigated on RPMI 2650 human nasal septum tumor epithelial cells: β-d-mannitol, sodium hyaluronate, α and β-cyclodextrin, polyvinyl alcohol and methylcellulose. 3-(4,5-dimethyltiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT dye conversion assay and real-time impedance analysis were used to investigate cytotoxicity. No excipient showed toxicity at 0.3% (w/v concentration or below while 1% concentration a significantly reduced metabolic activity was measured by MTT assay for methylcellulose and cyclodextrins. Using impedance measurements, only β-cyclodextrin (1% was toxic to cells. Mannitol at 1% concentration had a barrier opening effect on epithelial cells, but caused no cellular damage. Based on the results, all additives at 0.3%, sodium hyaluronate and polyvinyl alcohol at 1% concentrations can be safely used for nasal formulations.

Polyoxylglycerides and glycerides: effects of manufacturing parameters on API stability, excipient functionality and processing.

Science.gov (United States)

Jannin, Vincent; Rodier, Jean-David; Musakhanian, Jasmine

2014-05-15

Lipid-based formulations are a viable option to address modern drug delivery challenges such as increasing the oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs), or sustaining the drug release of molecules intended for chronic diseases. Esters of fatty acids and glycerol (glycerides) and polyethylene-glycols (polyoxylglycerides) are two main classes of lipid-based excipients used by oral, dermal, rectal, vaginal or parenteral routes. These lipid-based materials are more and more commonly used in pharmaceutical drug products but there is still a lack of understanding of how the manufacturing processes, processing aids, or additives can impact the chemical stability of APIs within the drug product. In that regard, this review summarizes the key parameters to look at when formulating with lipid-based excipients in order to anticipate a possible impact on drug stability or variation of excipient functionality. The introduction presents the chemistry of natural lipids, fatty acids and their properties in relation to the extraction and refinement processes. Then, the key parameters during the manufacturing process influencing the quality of lipid-based excipients are provided. Finally, their critical characteristics are discussed in relation with their intended functionality and ability to interact with APIs and others excipients within the formulation. Copyright © 2014. Published by Elsevier B.V.

EPR response characterization of drugs excipients for applying in accident dosimetry

International Nuclear Information System (INIS)

Marczewski, Barbara S.; Rodrigues Junior, Orlando; Galante, Ocimar L.; Costa, Zelia M. da; Campos, Leticia L.

2002-01-01

Some drugs are widely used by the population and can be employed to dose retrospective. The carbohydrates (saccharides), commonly used as excipients in the pharmaceutical industry, produce a quantity of free radicals after gamma irradiation, making them useful for dosimetry in emergency or accident situations that imply in dose evaluation from the materials found nearly or in contact with victims. In general, EPR signal from pulverized pills of some drugs are very complex due to the variety of components in the formulation. Because of this fact, some pharmaceutical excipients identified in the pill composition were also analysed by EPR spectrometry. On the counter drugs were studied: Cebion glucose, AAS, Aspirina, Conmel, Lacto-Purga and sugar substitutive ZeroCal. The excipients were: lactose, amide, anhydrous glucose and magnesium stearate. In some samples the number of radicals produced increased with the dose, showing a linear response for a dose range of interest and an adequate sensibility for dosimetry in accident cases

Surface acidity and solid-state compatibility of excipients with an acid-sensitive API: case study of atorvastatin calcium.

Science.gov (United States)

Govindarajan, Ramprakash; Landis, Margaret; Hancock, Bruno; Gatlin, Larry A; Suryanarayanan, Raj; Shalaev, Evgenyi Y

2015-04-01

The objectives of this study were to measure the apparent surface acidity of common excipients and to correlate the acidity with the chemical stability of an acid-sensitive active pharmaceutical ingredient (API) in binary API-excipient powder mixtures. The acidity of 26 solid excipients was determined by two methods, (i) by measuring the pH of their suspensions or solutions and (ii) the pH equivalent (pHeq) measured via ionization of probe molecules deposited on the surface of the excipients. The chemical stability of an API, atorvastatin calcium (AC), in mixtures with the excipients was evaluated by monitoring the appearance of an acid-induced degradant, atorvastatin lactone, under accelerated storage conditions. The extent of lactone formation in AC-excipient mixtures was presented as a function of either solution/suspension pH or pHeq. No lactone formation was observed in mixtures with excipients having pHeq > 6, while the lactone levels were pronounced (> 0.6% after 6 weeks at 50°C/20% RH) with excipients exhibiting pHeq 6, 3-6, and < 3) were consistent with the reported solution pH-stability profile of AC. In contrast to the pHeq scale, lactone formation did not show any clear trend when plotted as a function of the suspension/solution pH. Two mechanisms to explain the discrepancy between the suspension/solution pH and the chemical stability data were discussed. Acidic excipients, which are expected to be incompatible with an acid-sensitive API, were identified based on pHeq measurements. The incompatibility prediction was confirmed in the chemical stability tests using AC as an example of an acid-sensitive API.

Influence of excipients on characteristics and release profiles of poly(ε-caprolactone) microspheres containing immunoglobulin G

Energy Technology Data Exchange (ETDEWEB)

Erdemli, Özge [Department of Engineering Sciences, Middle East Technical University, Ankara (Turkey); Keskin, Dilek [Department of Engineering Sciences, Middle East Technical University, Ankara (Turkey); Biomaterials and Tissue Engineering Center of Excellence, Middle East Technical University, Ankara (Turkey); Tezcaner, Ayşen, E-mail: tezcaner@metu.edu.tr [Department of Engineering Sciences, Middle East Technical University, Ankara (Turkey); Biomaterials and Tissue Engineering Center of Excellence, Middle East Technical University, Ankara (Turkey)

2015-03-01

Protein instability during microencapsulation has been one of the major drawbacks of protein delivery systems. In this study, the effects of various excipients (poly vinyl alcohol, glucose, starch, heparin) on the stability of encapsulated human immunoglobulin G (IgG) in poly(ε-caprolactone) (PCL) microspheres and on microsphere characteristics were investigated before and after γ-sterilization. Microspheres formulated without any excipients and with glucose had a mean particle size around 3–4 μm whereas the mean particle sizes of other microspheres were around 5–6 μm. Use of PVA significantly increased the IgG-loading and encapsulation efficiency of microspheres. After γ-irradiation, IgG stability was mostly maintained in the microspheres with excipients compared to microspheres without any excipients. According to the μBCA results, microspheres without any excipient showed a high initial burst release as well as a fast release profile among all groups. Presence of PVA decreased the loss in the activity of IgG released before (completely retained after 6 h and 15.69% loss after 7 days) and after γ-irradiation (26.04% loss and 52.39% loss after 6 h and 7 days, respectively). The stabilization effect of PVA on the retention of the activity of released IgG was found more efficient compared to other groups formulated with carbohydrates. - Highlights: • Good excipient provides retention of protein stability during microencapsulation. • PVA was more effective on retention of the IgG stability compared to carbohydrates. • Starch was not an appropriate excipient for the retention of IgG stability.

Co-Processed Chitin-Mannitol as a New Excipient for Oro-Dispersible Tablets

Directory of Open Access Journals (Sweden)

Nidal Daraghmeh

2015-03-01

Full Text Available This study describes the preparation, characterization and performance of a novel excipient for use in oro-dispersible tablets (ODT. The excipient (Cop–CM consists of chitin and mannitol. The excipient with optimal physicochemical properties was obtained at a chitin: mannitol ratio of 2:8 (w/w and produced by roll compaction (RC. Differential scanning calorimetry (DSC, Fourier transform-Infrared (FT-IR, X-ray powder diffraction (XRPD and scanning electron microscope (SEM techniques were used to characterize Cop–CM, in addition to characterization of its powder and ODT dosage form. The effect of particle size distribution of Cop–CM was investigated and found to have no significant influence on the overall tablet physical properties. The compressibility parameter (a for Cop–CM was calculated from a Kawakita plot and found to be higher (0.661 than that of mannitol (0.576 due to the presence of the highly compressible chitin (0.818. Montelukast sodium and domperidone ODTs produced, using Cop–CM, displayed excellent physicochemical properties. The exceptional binding, fast wetting and superdisintegration properties of Cop–CM, in comparison with commercially available co-processed ODT excipients, results in a unique multifunctional base which can successfully be used in the formulation of oro-dispersible and fast immediate release tablets.

Modulation of the wettability of excipients by surfactant and its impacts on the disintegration and release of tablets.

Science.gov (United States)

Yang, Baixue; Xu, Lu; Wang, Qiuxiao; Li, Sanming

2016-12-01

To investigate the modulation of the wettability of excipients by different types of surfactants and its impacts on the disintegration of tablets and drug release. The critical micelle concentration (CMC) of surfactants, including sodium dodecyl sulfate (SDS), sodium dodecyl benzene sulfonate (SDBS), dodecyl trimethyl ammonium bromide (DTAB), cetyltrimethyl ammonium bromide (CTAB) and polysorbate (Tween-20 and Tween-80), was obtained using the platinum ring method. Contact angles of surfactant solutions on the excipient compacts and double-distilled water on the mixture of surfactant and the other excipient (magnesium stearate (MgSt) or sodium alginate (SA)) were measured by the sessile drop technique. Besides, surface free energy of excipients was calculated by the Owens method. Finally, the disintegration of tablets and in vitro dissolution testing were performed according to the method described in USP. The wettability of excipients could be enhanced to different extent with low concentration of surfactant solutions and maintained stable basically after CMC. For MgSt (hydrophobic excipient), the shorter the hydrophobic chain (C 12 , including SDS and DTAB), the better the wettability with the addition of surfactant in the formulation, leading to the shorter disintegration time of tablets and higher drug release rate. In contrast, the wettability of SA (hydrophilic excipient) was reduced by adding surfactant, resulting in the longer disintegration time of tablets and lower release rate. The modulation of the wetting of pharmaceutical excipients by surfactant had changed the disintegration time of tablets and drug release rate to a greater extent.

Screening of several excipients for direct compression of tablets: A new perspective based on functional properties

Directory of Open Access Journals (Sweden)

John Rojas

2013-01-01

Full Text Available Excipients are widely used to formulate solid drug forms by direct compression. However, the powderforming and tableting properties of these excipients are affected by the presence of lubricants and active ingredients. In this study, a screening methodology was employed to test the performance of an excipient for direct compression. The effects of three lubricants (magnesium stearate, stearic acid and talc on the compressibility and compaction of these excipients were assessed by the compressibility index and lubricant sensitivity ratio, respectively. Likewise, the dilution potential in blends with a poorly compactible drug such as acetaminophen was also assessed. Finally, the elastic recovery of tablets was evaluated five days after production. All lubricants increased the compressibility of these excipients and improved their flowability. However, hydrophobic lubricants such as magnesium stearate had a marked negative effect on compactibility, especially in plastic-deforming and more regularlyshaped materials with a smooth surface such as Starch 1500. Alginic acid, rice and cassava starches had the largest elastic recovery (>5%, indicating a tendency to cap. Moreover, highly plastic deforming materials such as sorbitol and polyvinylpyrrolidone (PVP-K30 exhibited the best dilution potential (~10%, whereas alginic acid showed a very high value (~70%. In terms of performance, sorbitol, PVP-K30, Avicel PH-101, sodium alginate and pregelatinized starch were the most appropriate excipients for the direct compression of drugs.

The Effect of Excipients on the Permeability of BCS Class III Compounds and Implications for Biowaivers.

Science.gov (United States)

Parr, Alan; Hidalgo, Ismael J; Bode, Chris; Brown, William; Yazdanian, Mehran; Gonzalez, Mario A; Sagawa, Kazuko; Miller, Kevin; Jiang, Wenlei; Stippler, Erika S

2016-01-01

Currently, the FDA allows biowaivers for Class I (high solubility and high permeability) and Class III (high solubility and low permeability) compounds of the Biopharmaceutics Classification System (BCS). Scientific evidence should be provided to support biowaivers for BCS Class I and Class III (high solubility and low permeability) compounds. Data on the effects of excipients on drug permeability are needed to demonstrate that commonly used excipients do not affect the permeability of BCS Class III compounds, which would support the application of biowaivers to Class III compounds. This study was designed to generate such data by assessing the permeability of four BCS Class III compounds and one Class I compound in the presence and absence of five commonly used excipients. The permeability of each of the compounds was assessed, at three to five concentrations, with each excipient in two different models: Caco-2 cell monolayers, and in situ rat intestinal perfusion. No substantial increases in the permeability of any of the compounds were observed in the presence of any of the tested excipients in either of the models, with the exception of disruption of Caco-2 cell monolayer integrity by sodium lauryl sulfate at 0.1 mg/ml and higher. The results suggest that the absorption of these four BCS Class III compounds would not be greatly affected by the tested excipients. This may have implications in supporting biowaivers for BCS Class III compounds in general.

A method to evaluate the effect of contact with excipients on the surface crystallization of amorphous drugs.

Science.gov (United States)

Zhang, Si-Wei; Yu, Lian; Huang, Jun; Hussain, Munir A; Derdour, Lotfi; Qian, Feng; de Villiers, Melgardt M

2014-12-01

Amorphous drugs are used to improve the solubility, dissolution, and bioavailability of drugs. However, these metastable forms of drugs can transform into more stable, less soluble, crystalline counterparts. This study reports a method for evaluating the effect of commonly used excipients on the surface crystallization of amorphous drugs and its application to two model amorphous compounds, nifedipine and indomethacin. In this method, amorphous samples of the drugs were covered by excipients and stored in controlled environments. An inverted light microscope was used to measure in real time the rates of surface crystal nucleation and growth. For nifedipine, vacuum-dried microcrystalline cellulose and lactose monohydrate increased the nucleation rate of the β polymorph from two to five times when samples were stored in a desiccator, while D-mannitol and magnesium stearate increased the nucleation rate 50 times. At 50% relative humidity, the nucleation rates were further increased, suggesting that moisture played an important role in the crystallization caused by the excipients. The effect of excipients on the crystal growth rate was not significant, suggesting that contact with excipients influences the physical stability of amorphous nifedipine mainly through the effect on crystal nucleation. This effect seems to be drug specific because for two polymorphs of indomethacin, no significant change in the nucleation rate was observed under the excipients.

Boosting the bioavailability of hydrophobic nutrients, vitamins, and nutraceuticals in natural products using excipient emulsions.

Science.gov (United States)

McClements, David Julian; Saliva-Trujillo, Laura; Zhang, Ruojie; Zhang, Zipei; Zou, Liqiang; Yao, Mingfei; Xiao, Hang

2016-10-01

Many highly hydrophobic bioactives, such as non-polar nutrients, nutraceuticals, and vitamins, have a relatively low or variable oral bioavailability. The poor bioavailability profile of these bioactives may be due to limited bioaccessibility, poor absorption, and/or chemical transformation within the gastrointestinal tract (GIT). The bioavailability of hydrophobic bioactives can be improved using specially designed oil-in-water emulsions consisting of lipid droplets dispersed within an aqueous phase. The bioactives may be isolated from their natural environment and then incorporated into the lipid phase of emulsion-based delivery systems. Alternatively, the bioactives may be left in their natural environment (e.g., fruits or vegetables), and then ingested with emulsion-based excipient systems. An excipient emulsion may have no inherent health benefits itself, but it boosts the biological activity of bioactive ingredients co-ingested with it by altering their bioaccessibility, absorption, and/or chemical transformation. This review discusses the design and fabrication of excipient emulsions, and gives some examples of recent research that demonstrates their potential efficacy for improving the bioavailability of hydrophobic bioactives. The concept of excipient emulsions could be used to formulate emulsion-based food products (such as excipient sauces, dressings, dips, creams, or yogurts) specifically designed to increase the bioavailability of bioactive agents in natural foods, such as fruits and vegetables. Copyright © 2015 Elsevier Ltd. All rights reserved.

The relationship between the particle properties, mechanical behavior, and surface roughness of some pharmaceutical excipient compacts

International Nuclear Information System (INIS)

Narayan, Padma; Hancock, Bruno C.

2003-01-01

Several common pharmaceutical excipient powders were compacted at a constant solid fraction (SF) in order to study the relationship between powder properties, compact surface roughness, and compact mechanical properties such as hardness, elasticity, and brittleness. The materials used in this study included microcrystalline cellulose (MCC), fumaric acid, mannitol, lactose monohydrate, spray dried lactose, sucrose, and dibasic calcium phosphate dihydrate. A slow consolidation process was used to make compacts at a SF of 0.85 (typical for most pharmaceutical tablets) from single excipient components. A model was proposed to describe the surface roughness of compacts based on the brittle or ductile deformation tendencies of the powder materials. The roughness profile would also be dependent upon the magnitude of the compression stress in relation to the yield stress (onset of irreversible deformation) values of the excipients. It was hypothesized that brittle materials would produce smooth compacts with high surface variability due to particle fracture, and the converse would apply for ductile materials. Compact surfaces should be smoother if the materials were compressed above their yield pressure values. Non-contact optical profilometry was used along with scanning electron microscopy to quantify and characterize the surface morphology of the excipient compacts. The roughness parameters R a (average roughness), R q (RMS roughness), R q /R a (ratio describing surface variability), and R sk (skewness) were found to correlate with the deformation properties of the excipients. Brittle materials such as lactose, sucrose, and calcium phosphate produced compacts with low values of R a and R q , high variability, and negative R sk . The opposite was found with plastic materials such as MCC, mannitol, and fumaric acid. The highly negative skewness values for brittle material compacts may indicate their propensity to be vulnerable to cracks or surface defects. These findings

The relationship between the particle properties, mechanical behavior, and surface roughness of some pharmaceutical excipient compacts

Energy Technology Data Exchange (ETDEWEB)

Narayan, Padma; Hancock, Bruno C

2003-08-25

Several common pharmaceutical excipient powders were compacted at a constant solid fraction (SF) in order to study the relationship between powder properties, compact surface roughness, and compact mechanical properties such as hardness, elasticity, and brittleness. The materials used in this study included microcrystalline cellulose (MCC), fumaric acid, mannitol, lactose monohydrate, spray dried lactose, sucrose, and dibasic calcium phosphate dihydrate. A slow consolidation process was used to make compacts at a SF of 0.85 (typical for most pharmaceutical tablets) from single excipient components. A model was proposed to describe the surface roughness of compacts based on the brittle or ductile deformation tendencies of the powder materials. The roughness profile would also be dependent upon the magnitude of the compression stress in relation to the yield stress (onset of irreversible deformation) values of the excipients. It was hypothesized that brittle materials would produce smooth compacts with high surface variability due to particle fracture, and the converse would apply for ductile materials. Compact surfaces should be smoother if the materials were compressed above their yield pressure values. Non-contact optical profilometry was used along with scanning electron microscopy to quantify and characterize the surface morphology of the excipient compacts. The roughness parameters R{sub a} (average roughness), R{sub q} (RMS roughness), R{sub q}/R{sub a} (ratio describing surface variability), and R{sub sk} (skewness) were found to correlate with the deformation properties of the excipients. Brittle materials such as lactose, sucrose, and calcium phosphate produced compacts with low values of R{sub a} and R{sub q}, high variability, and negative R{sub sk}. The opposite was found with plastic materials such as MCC, mannitol, and fumaric acid. The highly negative skewness values for brittle material compacts may indicate their propensity to be vulnerable to

Challenges and strategies to facilitate formulation development of pediatric drug products: Safety qualification of excipients.

Science.gov (United States)

Buckley, Lorrene A; Salunke, Smita; Thompson, Karen; Baer, Gerri; Fegley, Darren; Turner, Mark A

2018-02-05

A public workshop entitled "Challenges and strategies to facilitate formulation development of pediatric drug products" focused on current status and gaps as well as recommendations for risk-based strategies to support the development of pediatric age-appropriate drug products. Representatives from industry, academia, and regulatory agencies discussed the issues within plenary, panel, and case-study breakout sessions. By enabling practical and meaningful discussion between scientists representing the diversity of involved disciplines (formulators, nonclinical scientists, clinicians, and regulators) and geographies (eg, US, EU), the Excipients Safety workshop session was successful in providing specific and key recommendations for defining paths forward. Leveraging orthogonal sources of data (eg. food industry, agro science), collaborative data sharing, and increased awareness of the existing sources such as the Safety and Toxicity of Excipients for Paediatrics (STEP) database will be important to address the gap in excipients knowledge needed for risk assessment. The importance of defining risk-based approaches to safety assessments for excipients vital to pediatric formulations was emphasized, as was the need for meaningful stakeholder (eg, patient, caregiver) engagement. Copyright © 2017 Elsevier B.V. All rights reserved.

Structural changes of polymer-coated microgranules and excipients on tableting investigated by microtomography using synchrotron X-ray radiation.

Science.gov (United States)

Kajihara, Ryusuke; Noguchi, Shuji; Iwao, Yasunori; Suzuki, Yoshio; Terada, Yasuko; Uesugi, Kentaro; Itai, Shigeru

2015-03-15

Multiple-unit tablets consisting of polymer-coated microgranules and excipients have a number of advantageous pharmaceutical properties. Polymer-coated microgranules are known to often lose their functionality because of damage to the polymer coating caused by tableting, and the mechanism of polymer coating damage as well as the structural changes of excipients upon tableting had been investigated but without in-situ visualization and quantitative analysis. To elucidate the mechanism of coating damage, the internal structures of multiple-unit tablets were investigated by X-ray computed microtomography using synchrotron X-rays. Cross sectional images of the tablets with sub-micron spatial resolution clearly revealed that void spaces remained around the compressed excipient particles in the tablets containing an excipient composed of cellulose and lactose (Cellactose(®) 80), whereas much smaller void spaces remained in the tablets containing an excipient made of sorbitol (Parteck(®) SI 150). The relationships between the void spaces and the physical properties of the tablets such as hardness and disintegration were investigated. Damage to the polymer coating in tablets was found mainly where polymer-coated microgranules were in direct contact with each other in both types of tablets, which could be attributed to the difference in hardness of excipient particles and the core of the polymer-coated microgranules. Copyright © 2015 Elsevier B.V. All rights reserved.

Investigation of the effects of excipients on technological properties tablets of pyrola rotundifolia extract

OpenAIRE

Darzuli, Natalia; Hroshovyi, Taras; Sokolova, Kateryna; Podpletnyaya, Elena

2018-01-01

Aim of the work. To study the influence of excipients on the pharmacological and technological properties of round-leaved wintergreen extract tablets.Methods. The subject of the study were 27 series of round-leaved wintergreen extract tablets. The study of the influence of excipients on the pharmacological and technological properties of tablets, namely: abrasion, strength, disintegration, homogeneity were carried out in accordance with the requirements of SPhU 2 edition. The appearance of ta...

IDENTIFICATION OF PHARMACEUTICAL EXCIPIENT BEHAVIOR OF CHICKPEA (CICER ARIETINUM) STARCH IN GLICLAZIDE IMMEDIATE RELEASE TABLETS.

Science.gov (United States)

Meka, Venkata Srikanth; Yee, Phung; Sheshala, Ravi

2016-01-01

In the past few years, there are number of researchers carrying out their research on the excipients derived from polysaccharides and some of these researches show that natural excipients are comparable and can serve as an alternative to the synthetic excipients. Hence, the objectives of this research are to characterize the naturally sourced chickpea starch powder and to study the pharmaceutical excipient behavior of chickpea starch in gliclazide immediate release (IR) tablets. In this research, the binding properties of chickpea starch were compared to that of povidone, whereas the disintegrant properties of chickpea starch were compared to those of crospovidone, croscarmellose sodium and sodium starch glycolate. Flow property of chickpea starch was assessed with the measurement of bulk density, tapped density, compressibility index and angle of repose. Calibration curve for gliclazide in phosphate buffer pH 7.4 was developed. Gliclazide IR tablets were then produced with direct compression method. Physicochemical characteristics of the tablets, including thickness, tablet weight uniformity, hardness, disintegration time and friability were evaluated. Then, in vitro dissolution studies were performed by following United States Pharmacopeia (USP) dissolution method. The dissolution results were analyzed and compared with t30, t50, dissolution efficiency (DE). Lastly, drug-excipient compatibility studies, including Fourier transform infrared (FTIR) spectroscopic analysis and differential scanning calorimetric (DSC) analysis were carried out. Fair flow property was observed in the chickpea starch powder. Furthermore, the tablets produced passed all the tests in physicochemical characteristics evaluation except hardness and disintegration test. Additionally, in vitro dissolution studies show that chickpea starch acted as a disintegrant instead of a binder in gliclazide IR tablets and its disintegrant properties were comparable to those of crospovidone, croscarmellose

The potential of excipients to improve the efficiency of immuno-oncology therapy.

Directory of Open Access Journals (Sweden)

Shireesh Apte

2017-09-01

Full Text Available The cocktail of substances used in cell culture media to cryopreserve, transfect, grow, expand, fractionate, concentrate, wash and remove impurities from leukapheresis harvested T-cells are functional excipients. Even though most of them are not present in the final product, they nonetheless have the potential – during in vitro manufacture - to determine the subsequent in vivo proliferative capacity, persistance, safety and compositional phenotype of the injected re-engineered T-cells. Thus, while the chimeric antigen receptor and co-stimulatory signaling molecules are necessary for CAR-T cell functionality, they may not be sufficient to achieve this functionality unless manufactured using the right cocktail of functional excipients.

Effects of excipients on hydrate formation in wet masses containing theophylline

DEFF Research Database (Denmark)

Airaksinen, Sari; Luukkonen, Pirjo; Jørgensen, Anna

2003-01-01

its dissolution rate. The aim of this study was to investigate whether excipients, such as alpha-lactose monohydrate or the highly water absorbing silicified microcrystalline cellulose (SMCC) can influence the hydrate formation of theophylline. In particular, the aim was to study if SMCC offers...... protection against the formation of theophylline monohydrate relative to alpha-lactose monohydrate in wet masses after an overnight equilibration and the stability of final granules during controlled storage. In addition, the aim was to study the use of spectroscopic methods to identify hydrate formation...... in the formulations containing excipients. Off-line evaluation of materials was performed using X-ray powder diffractometry, near infrared and Raman spectroscopy. alpha-Lactose monohydrate with minimal water absorbing potential was not able to prevent but enhanced hydrate formation of theophylline. Even though SMCC...

Application of halloysite clay nanotubes as a pharmaceutical excipient.

Science.gov (United States)

Yendluri, Raghuvara; Otto, Daniel P; De Villiers, Melgardt M; Vinokurov, Vladimir; Lvov, Yuri M

2017-04-15

Halloysite nanotubes, a biocompatible nanomaterial of 50-60nm diameter and ca. 15nm lumen, can be used for loading, storage and sustained release of drugs either in its pristine form or with additional polymer complexation for extended release time. This study reports the development composite tablets based on 50wt.% of the drug loaded halloysite mixed with 45wt.% of microcrystalline cellulose. Powder flow and compressibility properties of halloysite (angle of repose, Carr's index, Hausner ratio, Brittle Fracture Index, tensile strength) indicate that halloysite is an excellent tablet excipient. Halloysite tubes can also be filled with nifedipine with ca. 6wt.% loading efficiency and sustained release from the nanotubes. Tablets prepared with drug loaded halloysite allowed for almost zero order nifedipine release for up to 20h. Nifedipine trapped in the nanotubes also protect the drug against light and significantly increased the photostability of the drug. All of these demonstrate that halloysite has the potential to be an excellent pharmaceutical excipient that is also an inexpensive, natural and abundantly available material. Copyright © 2017 Elsevier B.V. All rights reserved.

Evaluation of microwave oven heating for prediction of drug-excipient compatibilities and accelerated stability studies.

Science.gov (United States)

Schou-Pedersen, Anne Marie V; Østergaard, Jesper; Cornett, Claus; Hansen, Steen Honoré

2015-05-15

Microwave ovens have been used extensively in organic synthesis in order to accelerate reaction rates. Here, a set up comprising a microwave oven combined with silicon carbide (SiC) plates for the controlled microwave heating of model formulations has been applied in order to investigate, if a microwave oven is applicable for accelerated drug stability testing. Chemical interactions were investigated in three selected model formulations of drug and excipients regarding the formation of ester and amide reaction products. In the accelerated stability studies, a design of experiments (DoE) approach was applied in order to be able to rank excipients regarding reactivity: Study A: cetirizine with PEG 400, sorbitol, glycerol and propylene glycol. Study B: 6-aminocaproic acid with citrate, acetate, tartrate and gluconate. Study C: atenolol with citric, tartaric, malic, glutaric, and sorbic acid. The model formulations were representative for oral solutions (co-solvents), parenteral solutions (buffer species) and solid dosage forms (organic acids applicable for solubility enhancement). The DoE studies showed overall that the same impurities were generated by microwave oven heating leading to temperatures between 150°C and 180°C as compared to accelerated stability studies performed at 40°C and 80°C using a conventional oven. Ranking of the reactivity of the excipients could be made in the DoE studies performed at 150-180°C, which was representative for the ranking obtained after storage at 40°C and 80°C. It was possible to reduce the time needed for drug-excipient compatibility testing of the three model formulations from weeks to less than an hour in the three case studies. The microwave oven is therefore considered to be an interesting alternative to conventional thermal techniques for the investigation of drug-excipient interactions during preformulation. Copyright © 2015 Elsevier B.V. All rights reserved.

In Vitro and Ex Vivo Evaluation of Novel Curcumin-Loaded Excipient for Buccal Delivery.

Science.gov (United States)

Laffleur, Flavia; Schmelzle, Franziska; Ganner, Ariane; Vanicek, Stefan

2017-08-01

This study aimed to develop a mucoadhesive polymeric excipient comprising curcumin for buccal delivery. Curcumin encompasses broad range of benefits such as antioxidant, anti-inflammatory, and chemotherapeutic activity. Hyaluronic acid (HA) as polymeric excipient was modified by immobilization of thiol bearing ligands. L-Cysteine (SH) ethyl ester was covalently attached via amide bond formation between cysteine and the carboxylic moiety of hyaluronic acid. Succeeded synthesis was proved by H-NMR and IR spectra. The obtained thiolated polymer hyaluronic acid ethyl ester (HA-SH) was evaluated in terms of stability, safety, mucoadhesiveness, drug release, and permeation-enhancing properties. HA-SH showed 2.75-fold higher swelling capacity over time in comparison to unmodified polymer. Furthermore, mucoadhesion increased 3.4-fold in case of HA-SH and drug release was increased 1.6-fold versus HA control, respectively. Curcumin-loaded HA-SH exhibits a 4.4-fold higher permeation compared with respective HA. Taking these outcomes in consideration, novel curcumin-loaded excipient, namely thiolated hyaluronic acid ethyl ester appears as promising tool for pharyngeal diseases.

The Effect of Excipients on the Permeability of BCS Class III Compounds and Implications for Biowaivers

OpenAIRE

Parr, Alan; Hidalgo, Ismael J.; Bode, Chris; Brown, William; Yazdanian, Mehran; Gonzalez, Mario A.; Sagawa, Kazuko; Miller, Kevin; Jiang, Wenlei; Stippler, Erika S.

2015-01-01

Purpose Currently, the FDA allows biowaivers for Class I (high solubility and high permeability) and Class III (high solubility and low permeability) compounds of the Biopharmaceutics Classification System (BCS). Scientific evidence should be provided to support biowaivers for BCS Class I and Class III (high solubility and low permeability) compounds. Methods Data on the effects of excipients on drug permeability are needed to demonstrate that commonly used excipients do not affect the permea...

Nanocrystal cellulose as drug excipient in transdermal patch for wound healing: an overview

Science.gov (United States)

Zuki, S. A. Mohd; Rahman, N. Abd; Abu Bakar, N. F.

2018-03-01

Wound must be carefully treated to avoid serious infection that needs costly treatment. Method to enhance the recovery of the wound is crucial to have effective wound treatment. One of the technologies in wound treatment is transdermal patch that has the benefits of being non-invasive, easy to handle and permits constant drug dosage. In order to obtain a good controlled drug release, drug excipient needs to be investigated. Recently, natural Nanocrystal Cellulose (NCC) which can be synthesized from animal, algae, microorganism or plant has been actively used in drug delivery system as excipient. The application of NCC is advantageous due to its large surface area, biodegradable, non-toxic and abundance source.

EVALUATION OF MODIFIED RICE STARCH, A NEW EXCIPIENT FOR DIRECT COMPRESSION

NARCIS (Netherlands)

BOS, CE; BOLHUIS, GK; LERK, CF; DUINEVELD, CAA

1992-01-01

The compression characteristics of modified rice starch (Primotab(R)ET), a new excipient for the preparation of tablets by direct compression is evaluated. Modified rice starch is an agglomerated rice starch product. It has excellent flowing and disintegration properties. In contrast to other

Developmental toxicity assessment of common excipients using a stem cell-based in vitro morphogenesis model.

Science.gov (United States)

Yuan, Chloe J; Marikawa, Yusuke

2017-11-01

Various chemical compounds can inflict developmental toxicity when sufficiently high concentrations are exposed to embryos at the critical stages of development. Excipients, such as coloring agents and preservatives, are pharmacologically inactive ingredients that are included in various medications, foods, and cosmetics. However, concentrations that may adversely affect embryo development are largely unknown for most excipients. Here, the lowest observed adverse effect level (LOAEL) to inflict developmental toxicity was assessed for three coloring agents (allura red, brilliant blue, and tartrazine) and three preservatives (butylated hydroxyanisole, metabisulfite, and methylparaben). Adverse impact of a compound exposure was determined using the stem cell-based in vitro morphogenesis model, in which three-dimensional cell aggregates, or embryoid bodies (EBs), recapitulate embryonic processes of body axis elongation and patterning. LOAEL to impair EB morphogenesis was 200 μM for methylparaben, 400 μM for butylated hydroxyanisole, 600 μM for allura red and brilliant blue, and 1000 μM for metabisulfite. Gene expression analyses of excipient-treated EBs revealed that butylated hydroxyanisole and methylparaben significantly altered profiles of developmental regulators involved in axial elongation and patterning of the body. The present study may provide a novel in vitro approach to investigate potential developmental toxicity of common excipients with mechanistic insights. Copyright © 2017 Elsevier Ltd. All rights reserved.

Medicines, excipients and dietary intolerances.

Science.gov (United States)

2016-08-01

Medicinal products contain not only active drugs but also other ingredients included for a variety of purposes and collectively known as excipients.(1) People who wish to avoid a specific substance because of an allergy or intolerance may ask a healthcare professional about the constituents of a medicine and whether an alternative is available. In a previous article we discussed the issues facing people who wish to avoid certain substances for religious or cultural reasons.(2) Here, we provide an overview of several dietary conditions and the pharmaceutical issues that need to be considered by healthcare professionals advising on the suitability of a medicine. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Extraction and characterization of artocarpus integer gum as pharmaceutical excipient.

Science.gov (United States)

Farooq, Uzma; Malviya, Rishabha; Sharma, Pramod Kumar

2014-01-01

Natural polymers are widely used as excipients in pharmaceutical formulations. They are easily available, cheap and less toxic as compared to synthetic polymers. This study involves the extraction and characterization of kathal (Artocarpus integer) gum as a pharmaceutical excipient. Water was used as a solvent for extraction of the natural polymer. Yield was calculated with an aim to evaluate the efficacy of the process. The product was screened for the presence of Micrometric properties, and swelling index, flow behavior, surface tension, and viscosity of natural polymers were calculated. Using a water based extraction method, the yield of gum was found to be 2.85%. Various parameters such as flow behavior, organoleptic properties, surface tension, viscosity, loss on drying, ash value and swelling index together with microscopic studies of particles were done to characterize the extracted gum. The result showed that extracted kathal gum exhibited excellent flow properties. The gum was investigated for purity by carrying out chemical tests for different phytochemical constituents and only carbohydrates were found to be present. It had a good swelling index (13 ± 1). The pH and surface tension of the 1% gum solution were found to be 6 ± 0.5 and 0.0627 J/m2, respectively. The ash values such as total ash, acid insoluble ash, and water soluble ash were found to be 18.9%, 0.67% and 4% respectively. Loss on drying was 6.61%. The extracted gum was soluble in warm water and insoluble in organic solvents. The scanning electron micrograph (SEM) revealed rough and irregular particles of the isolated polymer. The results of the evaluated properties showed that kathal-derived gum has acceptable pH and organoleptic properties and can be used as a pharmaceutical excipient to formulate solid oral dosage forms.

The effects of three absorption-modifying critical excipients on the in vivo intestinal absorption of six model compounds in rats and dogs.

Science.gov (United States)

David, Dahlgren; Carl, Roos; Pernilla, Johansson; Christer, Tannergren; Anders, Lundqvist; Peter, Langguth; Markus, Sjöblom; Erik, Sjögren; Hans, Lennernäs

2018-05-11

Pharmaceutical excipients that may affect gastrointestinal (GI) drug absorption are called critical pharmaceutical excipients (CPEs), or absorption-modifying excipients (AMEs) if they act by altering the integrity of the intestinal epithelial cell membrane. Some of these excipients increase intestinal permeability, and subsequently the absorption and bioavailability of the drug. This could have implications for both the assessment of bioequivalence and the efficacy of the absorption-enhancing drug delivery system. The absorption-enhancing effects of AMEs/CPEs with different mechanisms (chitosan, sodium caprate, sodium dodecyl sulfate (SDS)) have previously been evaluated in the rat single-pass intestinal perfusion (SPIP) model. However, it remains unclear whether these SPIP data are predictive in a more in vivo like model. The same excipients were in this study evaluated in rat and dog intraintestinal bolus models. SDS and chitosan did exert an absorption-enhancing effect in both bolus models, but the effect was substantially lower than those observed in the rat SPIP model. This illustrates the complexity of the AME/CPE effects, and indicates that additional GI physiological factors need to be considered in their evaluation. We therefore recommend that AME/CPE evaluations obtained in transit-independent, preclinical permeability models (e.g. Ussing, SPIP) should be verified in animal models better able to predict in vivo relevant GI effects, at multiple excipient concentrations. Copyright © 2018. Published by Elsevier B.V.

Cationic Thiolated Poly(aspartamide) Polymer as a Potential Excipient for Artificial Tear Formulations.

Science.gov (United States)

Budai-Szűcs, Mária; Horvát, Gabriella; Szilágyi, Barnabás Áron; Gyarmati, Benjámin; Szilágyi, András; Berkó, Szilvia; Szabó-Révész, Piroska; Sandri, Giuseppina; Bonferoni, Maria Cristina; Caramella, Carla; Soós, Judit; Facskó, Andrea; Csányi, Erzsébet

2016-01-01

Dry eye disease is a relatively common ocular problem, which causes eye discomfort and visual disorders leading to a decrease in the quality of life. The aim of this study was to find a possible excipient for eye drop formulations, which is able to stabilize the tear film. A cationic thiolated polyaspartamide polymer, poly[(N-mercaptoethylaspartamide)-co-(N-(N',N'-dimethylaminoethyl)aspartamide)] (ThioPASP-DME), was used as a potential vehicle. Besides satisfying the basic requirements, the chemical structure of ThioPASP-DME is similar to those of ocular mucins as it is a protein-like polymer bearing a considerable number of thiol groups. The solution of the polymer is therefore able to mimic the physiological properties of the mucins and it can interact with the mucus layer via disulphide bond formation. The resultant mucoadhesion provides a prolonged residence time and ensures protective effect for the corneal/conjunctival epithelium. ThioPASP-DME also has an antioxidant effect due to the presence of the thiol groups. The applicability of ThioPASP-DME as a potential excipient in eye drops was determined by means of ocular compatibility tests and through examinations of the interactions with the mucosal surface. The results indicate that ThioPASP-DME can serve as a potential eye drop excipient for the therapy of dry eye disease.

Cationic Thiolated Poly(aspartamide Polymer as a Potential Excipient for Artificial Tear Formulations

Directory of Open Access Journals (Sweden)

Mária Budai-Szűcs

2016-01-01

Full Text Available Dry eye disease is a relatively common ocular problem, which causes eye discomfort and visual disorders leading to a decrease in the quality of life. The aim of this study was to find a possible excipient for eye drop formulations, which is able to stabilize the tear film. A cationic thiolated polyaspartamide polymer, poly[(N-mercaptoethylaspartamide-co-(N-(N′,N′-dimethylaminoethylaspartamide] (ThioPASP-DME, was used as a potential vehicle. Besides satisfying the basic requirements, the chemical structure of ThioPASP-DME is similar to those of ocular mucins as it is a protein-like polymer bearing a considerable number of thiol groups. The solution of the polymer is therefore able to mimic the physiological properties of the mucins and it can interact with the mucus layer via disulphide bond formation. The resultant mucoadhesion provides a prolonged residence time and ensures protective effect for the corneal/conjunctival epithelium. ThioPASP-DME also has an antioxidant effect due to the presence of the thiol groups. The applicability of ThioPASP-DME as a potential excipient in eye drops was determined by means of ocular compatibility tests and through examinations of the interactions with the mucosal surface. The results indicate that ThioPASP-DME can serve as a potential eye drop excipient for the therapy of dry eye disease.

Tamarind seed polysaccharide: A promising natural excipient for pharmaceuticals

OpenAIRE

Joshny Joseph; S N Kanchalochana; G Rajalakshmi; Vedha Hari; Ramya Devi Durai

2012-01-01

The natural polymers always have exceptional properties which make them distinct from the synthetic polymers and tamarind seed polysaccharide (TSP) is one such example which shows more valuable properties making it a useful excipient for a wide range of applications. TSP is a natural polysaccharide obtained from the seeds of Tamarindus indica, recently gaining a wide potential in the field of pharmaceutical and cosmetic industries. Its isolation and characterisation involve simple techniques ...

Risk assessment of supply chain for pharmaceutical excipients with AHP-fuzzy comprehensive evaluation.

Science.gov (United States)

Li, Maozhong; Du, Yunai; Wang, Qiyue; Sun, Chunmeng; Ling, Xiang; Yu, Boyang; Tu, Jiasheng; Xiong, Yerong

2016-04-01

As the essential components in formulations, pharmaceutical excipients directly affect the safety, efficacy, and stability of drugs. Recently, safety incidents of pharmaceutical excipients posing seriously threats to the patients highlight the necessity of controlling the potential risks. Hence, it is indispensable for the industry to establish an effective risk assessment system of supply chain. In this study, an AHP-fuzzy comprehensive evaluation model was developed based on the analytic hierarchy process and fuzzy mathematical theory, which quantitatively assessed the risks of supply chain. Taking polysorbate 80 as the example for model analysis, it was concluded that polysorbate 80 for injection use is a high-risk ingredient in the supply chain compared to that for oral use to achieve safety application in clinic, thus measures should be taken to control and minimize those risks.

Development and evaluation of Pleurotus tuber-regium-cornstarch composite as a direct compression multifunctional excipient.

Science.gov (United States)

Okoye, Ebere I; Onyekweli, Anthony O

2016-01-01

The aim was to develop a novel excipient from Pleurotus tuber-regium (PT)-cornstarch (CS) mixture and evaluate its multifunctional characteristics in tablet formulation. Composites were generated from dephytochemicalized PT and CS combined at 1:1 to 4:1 ratios and pregelatinized in a hot water bath at 65°C ± 2°C for 5 min. The paste was dried, pulverized, and screened through 150-μm sieve. PT-CS physical mixtures were prepared and their characteristics/functionalities in tableting chloroquine were compared to those of composites and microcrystalline cellulose (Avicel(®)). PT ash value was 0.40 ± 0.09% and heavy metal contents were below official limits. PT's differential scanning calorimetric (DSC) thermogram depicted broad melting peak at 329.5°C; this peak was attenuated by the presence of CS. Fourier transform infrared (FTIR) spectra predicted compatibility between PT and CS. Composites consolidated better and also flowed better than physical mixtures and Avicel(®). Increasing PT content enhanced the excipients' swellabilities, and composites possessed significantly (P plastic deformation with yield pressures significantly (P plastic deformation. The mechanical properties of chloroquine tablets were acceptable, with the 1:4 (PT:CS) imparting the best properties. Mean disintegration times for the commercial comparator and Avicel(®) -containing tablets were significantly higher (P < 0.05) than those of composites. Drug release from tablets formulated with composites were similar to the commercial comparator, but significantly higher (P < 0.05) than those of Avicel(®). The novel composites are excellent multifunctional excipients, the best (PT:CS 1:4) one showcasing potentially better mechanical functionality than Avicel(®), a popular multifunctional excipient.

Studies of beneficial interactions between active medicaments and excipients in pharmaceutical formulations.

Science.gov (United States)

Kalinkova, G N

1999-09-30

A review of "up to date" research findings leading to new concepts of the pharmaceutical formulations and their interactions has been presented. The rational approaches to the excipients choice as well as to their interactions with medicaments have been shown as a basis for modern modelling of pharmaceutical formulations. The importance of complexation, hydrogen bonding, ion-dipole, dipole-dipole and van der Waals attractions as the tools which can modify the physicochemical, pharmacological or pharmacokinetical behaviour of the medicaments has been emphasised. In vivo studies (carried out in healthy human subjects-volunteers, in beagle dogs, in rats etc.) and in vitro studies (on excised human skin, hairless mouse skin etc.) as well as studies of chemical stability and bioavailability serve also as a proof of these interactions. Therefore, excipients are important components of pharmaceutical formulations and they can take an active part in the improvement of the characteristics of formulations (but they may also reduce the effectiveness of some preparations). In this context, the so called active and inactive ingredients in pharmaceutical formulations are inexact, old and "out-of date". Their further use is only conventional. In conclusion, among the various modern techniques applied the combination of infrared spectroscopy and X-ray diffraction has been estimated as the most successful in proving the interactions between drugs and excipients. Finally, pharmaceutical formulations and their interactions have constituted a diverse and rapidly expanding field of Pharmacy (Pharmaceutical Technology, Pharmaceutical Industry and Pharmaceutical Sciences) which covers a wide range of numerical topics within an unified framework.

The effect of excipients on the release kinetics of diclofenac sodium and papaverine hydrochloride from composed tablets.

Science.gov (United States)

Kasperek, Regina; Trebacz, Hanna; Zimmer, Łukasz; Poleszak, Ewa

2014-01-01

For increased analgesic effect, new composed tablets containing diclofenac sodium (DIC) with an addition of papaverine hydrochloride (PAP) were prepared to investigate the mechanism of release of the active substances from tablets with different excipients in eight different formulations. To detect the possible interactions between active substances and excipients differential scanning calorimetry (DSC) was used. A shift of the melting point and enthalpy values of the physical mixtures of tablets components suggested a kind of interaction between components in certain formulations, however, the tabletting process was not disturbed in any of them. Kinetics of drug release from formulations was estimated by zero order, first order and Higuchi and Korsmeyer-Peppas models using results of dissolution of DIC and PAP from tablets. The study revealed that the mechanism of release of active substances was dependent on the excipients contained in tablets and the best fitted kinetics models were obtained for formulations with potentially prolonged release of DIC and PAP.

The impact of particle preparation methods and polymorphic stability of lipid excipients on protein distribution in microparticles

DEFF Research Database (Denmark)

Liu, Jingying; Christophersen, Philip C; Yang, Mingshi

2017-01-01

OBJECTIVE: The present study aimed at elucidating the influence of polymorphic stability of lipid excipients on the physicochemical characters of different solid lipid microparticles (SLM), with the focus on the alteration of protein distribution in SLM. METHODS: Labeled lysozyme was incorporated...... provides updated knowledge for rational development of lipid-based formulations for oral delivery of peptide or protein drugs.......OBJECTIVE: The present study aimed at elucidating the influence of polymorphic stability of lipid excipients on the physicochemical characters of different solid lipid microparticles (SLM), with the focus on the alteration of protein distribution in SLM. METHODS: Labeled lysozyme was incorporated...... into SLM prepared with different excipients, i.e. trimyristin (TG14), glyceryl distearate (GDS), and glyceryl monostearate (GMS), by water-oil-water (w/o/w) or solid-oil-water (s/o/w) method. The distribution of lysozyme in SLM and the release of the protein from SLM were evaluated by confocal laser...

DSC, FT-IR, NIR, NIR-PCA and NIR-ANOVA for determination of chemical stability of diuretic drugs: impact of excipients

Directory of Open Access Journals (Sweden)

Gumieniczek Anna

2018-03-01

Full Text Available It is well known that drugs can directly react with excipients. In addition, excipients can be a source of impurities that either directly react with drugs or catalyze their degradation. Thus, binary mixtures of three diuretics, torasemide, furosemide and amiloride with different excipients, i.e. citric acid anhydrous, povidone K25 (PVP, magnesium stearate (Mg stearate, lactose, D-mannitol, glycine, calcium hydrogen phosphate anhydrous (CaHPO4 and starch, were examined to detect interactions. High temperature and humidity or UV/VIS irradiation were applied as stressing conditions. Differential scanning calorimetry (DSC, FT-IR and NIR were used to adequately collect information. In addition, chemometric assessments of NIR signals with principal component analysis (PCA and ANOVA were applied.

Disproportionation of the calcium salt of atorvastatin in the presence of acidic excipients

DEFF Research Database (Denmark)

Christensen, Niels Peter Aae; Rantanen, Jukka; Cornett, Claus

2012-01-01

The aim of the present study was to combine vibrational spectroscopy and chemometrics for investigating excipient-induced disproportionation of the calcium salt of atorvastatin into the corresponding free acid form in environments relevant to manufacturing and storage of solid dosage formulations...

Enhancing Nutraceutical Bioavailability from Raw and Cooked Vegetables Using Excipient Emulsions: Influence of Lipid Type on Carotenoid Bioaccessibility from Carrots.

Science.gov (United States)

Zhang, Ruojie; Zhang, Zipei; Zou, Liqiang; Xiao, Hang; Zhang, Guodong; Decker, Eric Andrew; McClements, David Julian

2015-12-09

The influence of the nature of the lipid phase in excipient emulsions on the bioaccessibility and transformation of carotenoid from carrots was investigated using a gastrointestinal tract (GIT) model. Excipient emulsions were fabricated using whey protein as an emulsifier and medium-chain triglycerides (MCT), fish oil, or corn oil as the oil phase. Changes in particle size, charge, and microstructure were measured as the carrot-emulsion mixtures were passed through simulated mouth, stomach, and small intestine regions. Carotenoid bioaccessibility depended on the type of lipids used to form the excipient emulsions (corn oil > fish oil ≫ MCT), which was attributed to differences in the solubilization capacity of mixed micelles formed from different lipid digestion products. The transformation of carotenoids was greater for fish oil and corn oil than for MCT, which may have been due to greater oxidation or isomerization. The bioaccessibility of the carotenoids was higher from boiled than raw carrots, which was attributed to greater disruption of the plant tissue facilitating carotenoid release. In conclusion, excipient emulsions are highly effective at increasing carotenoid bioaccessibility from carrots, but lipid type must be optimized to ensure high efficacy.

Evaluation about wettability, water absorption or swelling of excipients through various methods and the correlation between these parameters and tablet disintegration.

Science.gov (United States)

Yang, Baixue; Wei, Chen; Yang, Yang; Wang, Qifang; Li, Sanming

2018-04-06

To evaluate parameters about wettability, water absorption or swelling of excipients in forms of powders or dosage through various methods systematically and explore its correlation with tablet disintegration. The water penetration and swelling of powders with different proportions of excipients including microcrystalline cellulose (MCC), mannitol, low-substituted hydroxypropyl cellulose (L-HPC), crospolyvinylpyrrolidone (PVPP), carboxymethyl starch sodium (CMS-Na), croscarmellose sodium (CCMC-Na) and magnesium stearate (MgSt) were determined by Washburn capillary rise. Both contact angle of water on the excipient compacts and surface swelling volume were measured by sessile drop technique. Moreover, the test about water absorption and swelling of compacts was fulfilled by a modified method. Eventually, the disintegration of tablets with or without loratadine was performed according to the method described in USP. These parameters were successfully identified by the methods above, which proved that excipient wettability or swelling properties varied with the structure of excipients. For example, MgSt could improve the water uptake, while impeded tablet swelling. Furthermore, in the present study it is verified that tablet disintegration was closely related to these parameters, especially wetting rate and initial water absorption rate. The higher wetting rate of water on tablet or initial water absorption rate, the faster swelling it be, resulting in the shorter tablet disintegration time. The methods utilized in the present study were feasible and effective. The disintegration of tablets did relate to these parameters, especially wetting rate and initial water absorption rate.

Safe excipient exposure in neonates and small children - protocol for the SEEN project

DEFF Research Database (Denmark)

Valeur, Kristine Svinning; Hertel, Steen Axel; Lundstrøm, Kaare Engell

2017-01-01

are treated with potentially harmful excipients. METHODS: This is a retrospective cohort study based on chart-audit on multi-medicated patients ≤ 5 years of age treated at the Rigshospitalet, Denmark. Preparations with ethanol, propylene glycol, benzyl alcohol, parabens, acesulfame p, aspartame, glycerol...

Condensational growth of combination drug-excipient submicrometer particles for targeted high efficiency pulmonary delivery: comparison of CFD predictions with experimental results.

Science.gov (United States)

Longest, P Worth; Hindle, Michael

2012-03-01

The objective of this study was to investigate the hygroscopic growth of combination drug and excipient submicrometer aerosols for respiratory drug delivery using in vitro experiments and a newly developed computational fluid dynamics (CFD) model. Submicrometer combination drug and excipient particles were generated experimentally using both the capillary aerosol generator and the Respimat inhaler. Aerosol hygroscopic growth was evaluated in vitro and with CFD in a coiled tube geometry designed to provide residence times and thermodynamic conditions consistent with the airways. The in vitro results and CFD predictions both indicated that the initially submicrometer particles increased in mean size to a range of 1.6-2.5 μm for the 50:50 combination of a non-hygroscopic drug (budesonide) and different hygroscopic excipients. CFD results matched the in vitro predictions to within 10% and highlighted gradual and steady size increase of the droplets, which will be effective for minimizing extrathoracic deposition and producing deposition deep within the respiratory tract. Enhanced excipient growth (EEG) appears to provide an effective technique to increase pharmaceutical aerosol size, and the developed CFD model will provide a powerful design tool for optimizing this technique to produce high efficiency pulmonary delivery.

Excipient-drug pharmacokinetic interactions: Effect of disintegrants on efflux across excised pig intestinal tissues

Directory of Open Access Journals (Sweden)

Werner Gerber

2018-04-01

Full Text Available Pharmaceutical excipients were designed originally to be pharmacologically inert. However, certain excipients were found to have altering effects on drug pharmacodynamics and/or pharmacokinetics. Pharmacokinetic interactions may be caused by modulation of efflux transporter proteins, intercellular tight junctions and/or metabolic enzyme amongst others. In this study, five disintegrants from different chemical classes were evaluated for P-glycoprotein (P-gp related inhibition and tight junction modulation effects. Bi-directional transport studies of the model compound, Rhodamine 123 (R123 were conducted in the absence (control group and presence (experimental groups of four concentrations of each selected disintegrant across excised pig jejunum tissue. The results showed that some of the selected disintegrants (e.g. Ac-di-sol® and Kollidon® CL-M increased R123 absorptive transport due to inhibition of P-gp related efflux, while another disintegrant (e.g. sodium alginate changed R123 transport due to inhibition of P-gp in conjunction with a transient opening of the tight junctions in a concentration dependent way. It may be concluded that the co-application of some disintegrants to the intestinal epithelium may lead to pharmacokinetic interactions with drugs that are susceptible to P-gp related efflux. However, the clinical significance of these in vitro permeation findings should be confirmed by means of in vivo studies. Keywords: Disintegrants, Excipient, Ex vivo, P-glycoprotein, Pharmacokinetic interactions, Rhodamine 123

Evaluation of microwave oven heating for prediction of drug-excipient compatibilities and accelerated stability studies

DEFF Research Database (Denmark)

Schou-Pedersen, Anne Marie V; Østergaard, Jesper; Cornett, Claus

2015-01-01

, if a microwave oven is applicable for accelerated drug stability testing. Chemical interactions were investigated in three selected model formulations of drug and excipients regarding the formation of ester and amide reaction products. The accelerated stability studies performed in the microwave oven using...... a design of experiments (DoE) approach in order to be able to rank excipients regarding reactivity: Study A: cetirizine with PEG 400, sorbitol, glycerol and propylene glycol. Study B: 6-aminocaproic acid with citrate, acetate, tartrate and gluconate. Study C: atenolol with citric, tartaric, malic, glutaric......, and sorbic acid. The model formulations were representative for oral solutions (co-solvents), parenteral solutions (buffer species) and solid dosage forms (organic acids applicable for solubility enhancement). The DoE studies showed overall that the same impurities were generated by microwave oven heating...

Quality by Design (QbD) Approach for Development of Co-Processed Excipient Pellets (MOMLETS) By Extrusion-Spheronization Technique.

Science.gov (United States)

Patel, Hetal; Patel, Kishan; Tiwari, Sanjay; Pandey, Sonia; Shah, Shailesh; Gohel, Mukesh

2016-01-01

Microcrystalline cellulose (MCC) is an excellent excipient for the production of pellets by extrusion spheronization. However, it causes slow release rate of poorly water soluble drugs from pellets. Co-processed excipient prepared by spray drying (US4744987; US5686107; WO2003051338) and coprecipitation technique (WO9517831) are patented. The objective of present study was to develop co-processed MCC pellets (MOMLETS) by extrusion-spheronization technique using the principle of Quality by Design (QbD). Co-processed excipient core pellets (MOMLETS) were developed by extrusion spheronization technique using Quality by Design (QbD) approach. BCS class II drug (telmisartan) was layered onto it in a fluidized bed processor. Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQA) for pellets were identified. Risk assessment was reported using Ishikawa diagram. Plackett Burman design was used to check the effect of seven independent variables; superdisintegrant, extruder speed, ethanol: water, spheronizer speed, extruder screen, pore former and MCC: lactose; on percentage drug release at 30 min. Pareto chart and normal probability plot was constructed to identify the significant factors. Box-Behnken design (BBD) using three most significant factors (Extruder screen size, type of superdisintegrant and type of pore former) was used as an optimization design. The control space was identified in which desired quality of the pellets can be obtained. Co-processed excipient core pellets (MOMLETS) were successfully developed by QbD approach. Versatility, Industrial scalability and simplicity are the main features of the proposed research. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Significance of excipients to enhance the bioavailability of poorly water-soluble drugs in oral solid dosage forms: A Review

Science.gov (United States)

Vadlamudi, Manoj Kumar; Dhanaraj, Sangeetha

2017-11-01

Nowadays most of the drug substances are coming into the innovation pipeline with poor water solubility. Here, the influence of excipients will play a significant role to improve the dissolution of poorly aqueous soluble compounds. The drug substance needs to be dissolved in gastric fluids to get the better absorption and bioavailability of an orally administered drug. Dissolution is the rate-controlling stage for drugs which controls the rate and degree of absorption. Usually, poorly soluble oral administrated drugs show a slower dissolution rate, inconsistent and incomplete absorption which can lead to lower bioavailability. The low aqueous solubility of BCS class II and IV drugs is a major challenge in the drug development and delivery process. Several technologies have been used in an attempt to progress the bioavailability of poorly water-soluble drug compounds which include solid dispersions, lipid-based formulations, micronization, solvent evaporation, co-precipitation, ordered mixing, liquid-solid compacts, solvent deposition inclusion complexation, and steam aided granulation. In fact, most of the technologies require excipient as a carrier which plays a significant role in improving the bioavailability using Hypromellose acetate succinate, Cyclodextrin, Povidone, Copovidone, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Crospovidone, Starch, Dimethylacetamide, Polyethylene glycol, Sodium lauryl sulfate, Polysorbate, Poloxamer. Mesoporous silica and so on. This review deliberates about the excipients significance on bioavailability enhancement of drug products in a single platform along with pragmatically proved applications so that user can able to select the right excipients as per the molecule.

Condensational Growth of Combination Drug-Excipient Submicrometer Particles for Targeted High Efficiency Pulmonary Delivery: Comparison of CFD Predictions with Experimental Results

Science.gov (United States)

Hindle, Michael

2011-01-01

Purpose The objective of this study was to investigate the hygroscopic growth of combination drug and excipient submicrometer aerosols for respiratory drug delivery using in vitro experiments and a newly developed computational fluid dynamics (CFD) model. Methods Submicrometer combination drug and excipient particles were generated experimentally using both the capillary aerosol generator and the Respimat inhaler. Aerosol hygroscopic growth was evaluated in vitro and with CFD in a coiled tube geometry designed to provide residence times and thermodynamic conditions consistent with the airways. Results The in vitro results and CFD predictions both indicated that the initially submicrometer particles increased in mean size to a range of 1.6–2.5 µm for the 50:50 combination of a non-hygroscopic drug (budesonide) and different hygroscopic excipients. CFD results matched the in vitro predictions to within 10% and highlighted gradual and steady size increase of the droplets, which will be effective for minimizing extrathoracic deposition and producing deposition deep within the respiratory tract. Conclusions Enhanced excipient growth (EEG) appears to provide an effective technique to increase pharmaceutical aerosol size, and the developed CFD model will provide a powerful design tool for optimizing this technique to produce high efficiency pulmonary delivery. PMID:21948458

Evidence-based nanoscopic and molecular framework for excipient functionality in compressed orally disintegrating tablets.

Directory of Open Access Journals (Sweden)

Ali Al-Khattawi

Full Text Available The work investigates the adhesive/cohesive molecular and physical interactions together with nanoscopic features of commonly used orally disintegrating tablet (ODT excipients microcrystalline cellulose (MCC and D-mannitol. This helps to elucidate the underlying physico-chemical and mechanical mechanisms responsible for powder densification and optimum product functionality. Atomic force microscopy (AFM contact mode analysis was performed to measure nano-adhesion forces and surface energies between excipient-drug particles (6-10 different particles per each pair. Moreover, surface topography images (100 nm2-10 µm2 and roughness data were acquired from AFM tapping mode. AFM data were related to ODT macro/microscopic properties obtained from SEM, FTIR, XRD, thermal analysis using DSC and TGA, disintegration testing, Heckel and tabletability profiles. The study results showed a good association between the adhesive molecular and physical forces of paired particles and the resultant densification mechanisms responsible for mechanical strength of tablets. MCC micro roughness was 3 times that of D-mannitol which explains the high hardness of MCC ODTs due to mechanical interlocking. Hydrogen bonding between MCC particles could not be established from both AFM and FTIR solid state investigation. On the contrary, D-mannitol produced fragile ODTs due to fragmentation of surface crystallites during compression attained from its weak crystal structure. Furthermore, AFM analysis has shown the presence of extensive micro fibril structures inhabiting nano pores which further supports the use of MCC as a disintegrant. Overall, excipients (and model drugs showed mechanistic behaviour on the nano/micro scale that could be related to the functionality of materials on the macro scale.

Evidence-Based Nanoscopic and Molecular Framework for Excipient Functionality in Compressed Orally Disintegrating Tablets

Science.gov (United States)

Al-khattawi, Ali; Alyami, Hamad; Townsend, Bill; Ma, Xianghong; Mohammed, Afzal R.

2014-01-01

The work investigates the adhesive/cohesive molecular and physical interactions together with nanoscopic features of commonly used orally disintegrating tablet (ODT) excipients microcrystalline cellulose (MCC) and D-mannitol. This helps to elucidate the underlying physico-chemical and mechanical mechanisms responsible for powder densification and optimum product functionality. Atomic force microscopy (AFM) contact mode analysis was performed to measure nano-adhesion forces and surface energies between excipient-drug particles (6-10 different particles per each pair). Moreover, surface topography images (100 nm2–10 µm2) and roughness data were acquired from AFM tapping mode. AFM data were related to ODT macro/microscopic properties obtained from SEM, FTIR, XRD, thermal analysis using DSC and TGA, disintegration testing, Heckel and tabletability profiles. The study results showed a good association between the adhesive molecular and physical forces of paired particles and the resultant densification mechanisms responsible for mechanical strength of tablets. MCC micro roughness was 3 times that of D-mannitol which explains the high hardness of MCC ODTs due to mechanical interlocking. Hydrogen bonding between MCC particles could not be established from both AFM and FTIR solid state investigation. On the contrary, D-mannitol produced fragile ODTs due to fragmentation of surface crystallites during compression attained from its weak crystal structure. Furthermore, AFM analysis has shown the presence of extensive micro fibril structures inhabiting nano pores which further supports the use of MCC as a disintegrant. Overall, excipients (and model drugs) showed mechanistic behaviour on the nano/micro scale that could be related to the functionality of materials on the macro scale. PMID:25025427

Analysis of Pharmaceutical Excipient MCC Avicel PH102 Using Compaction Equations

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Peciar Peter

2016-07-01

Full Text Available This paper focuses on the characterization of the tabletting process and analysis one of the most common pharmaceutical excipients MCC Avicel PH102 by Heckel, Kawakita, Cooper-Eaton and Adams compaction equations. Experimental material was determined by measuring its parameters as particle size distribution, angle of wall friction and flow properties and for more detailed characteristics of the material particles, microscopy images of the powder before and after compressing were created.

Performance of Deacetyled Glucomannan as Iron Encapsulation Excipient

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Wardhani Dyah H.

2018-01-01

Full Text Available Encapsulation protects iron from degradation or oxidation possibilities due to its encapsulation material. Glucomannan (GM is a neutral polysaccharide consist of D-mannose and D-glucose connected with β-1,4 linkage. Deactylation transforms solubility of glucomannan as well as its gel structure. These properties support for excipient application. The aim of this work was to determine performance of deacetylated glucomannan as iron matrix. Deacetylation was conducted heterogeneously. Deacetylation did not change the backbone of GM. Higher alkali concentration has better ability to encapsulate iron. Extended deacetylation time and alkali concentration affect insignificantly on the performance of encapsulation to protect iron from oxidation. The release of iron from the matrix influences by deacetylation degree.

Detection of compatibility between baclofen and excipients with aid of infrared spectroscopy and chemometry.

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Rojek, Barbara; Wesolowski, Marek; Suchacz, Bogdan

2013-12-01

In the paper infrared (IR) spectroscopy and multivariate exploration techniques: principal component analysis (PCA) and cluster analysis (CA) were applied as supportive methods for the detection of physicochemical incompatibilities between baclofen and excipients. In the course of research, the most useful rotational strategy in PCA proved to be varimax normalized, while in CA Ward's hierarchical agglomeration with Euclidean distance measure enabled to yield the most interpretable results. Chemometrical calculations confirmed the suitability of PCA and CA as the auxiliary methods for interpretation of infrared spectra in order to recognize whether compatibilities or incompatibilities between active substance and excipients occur. On the basis of IR spectra and the results of PCA and CA it was possible to demonstrate that the presence of lactose, β-cyclodextrin and meglumine in binary mixtures produce interactions with baclofen. The results were verified using differential scanning calorimetry, differential thermal analysis, thermogravimetry/differential thermogravimetry and X-ray powder diffraction analyses. Copyright © 2013 Elsevier B.V. All rights reserved.

Characterization of Protein-Excipient Microheterogeneity in Biopharmaceutical Solid-State Formulations by Confocal Fluorescence Microscopy.

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Koshari, Stijn H S; Ross, Jean L; Nayak, Purnendu K; Zarraga, Isidro E; Rajagopal, Karthikan; Wagner, Norman J; Lenhoff, Abraham M

2017-02-06

Protein-stabilizer microheterogeneity is believed to influence long-term protein stability in solid-state biopharmaceutical formulations and its characterization is therefore essential for the rational design of stable formulations. However, the spatial distribution of the protein and the stabilizer in a solid-state formulation is, in general, difficult to characterize because of the lack of a functional, simple, and reliable characterization technique. We demonstrate the use of confocal fluorescence microscopy with fluorescently labeled monoclonal antibodies (mAbs) and antibody fragments (Fabs) to directly visualize three-dimensional particle morphologies and protein distributions in dried biopharmaceutical formulations, without restrictions on processing conditions or the need for extensive data analysis. While industrially relevant lyophilization procedures of a model IgG1 mAb generally lead to uniform protein-excipient distribution, the method shows that specific spray-drying conditions lead to distinct protein-excipient segregation. Therefore, this method can enable more definitive optimization of formulation conditions than has previously been possible.

EXCI-CEST: Exploiting pharmaceutical excipients as MRI-CEST contrast agents for tumor imaging.

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Longo, Dario Livio; Moustaghfir, Fatima Zzahra; Zerbo, Alexandre; Consolino, Lorena; Anemone, Annasofia; Bracesco, Martina; Aime, Silvio

2017-06-15

Chemical Exchange Saturation Transfer (CEST) approach is a novel tool within magnetic resonance imaging (MRI) that allows visualization of molecules possessing exchangeable protons with water. Many molecules, employed as excipients for the formulation of finished drug products, are endowed with hydroxyl, amine or amide protons, thus can be exploitable as MRI-CEST contrast agents. Their high safety profiles allow them to be injected at very high doses. Here we investigated the MRI-CEST properties of several excipients (ascorbic acid, sucrose, N-acetyl-d-glucosamine, meglumine and 2-pyrrolidone) and tested them as tumor-detecting agents in two different murine tumor models (breast and melanoma cancers). All the investigated molecules showed remarkable CEST contrast upon i.v. administration in the range 1-3ppm according to the type of mobile proton groups. A marked increase of CEST contrast was observed in tumor regions up to 30min post injection. The combination of marked tumor contrast enhancement and lack of toxicity make these molecules potential candidates for the diagnosis of tumors within the MRI-CEST approach. Copyright © 2017 Elsevier B.V. All rights reserved.

Drug-Drug/Drug-Excipient Compatibility Studies on Curcumin using Non-Thermal Methods

OpenAIRE

Moorthi Chidambaram; Kathiresan Krishnasamy

2014-01-01

Purpose: Curcumin is a hydrophobic polyphenol isolated from dried rhizome of turmeric. Clinical usefulness of curcumin in the treatment of cancer is limited due to poor aqueous solubility, hydrolytic degradation, metabolism, and poor oral bioavailability. To overcome these limitations, we proposed to fabricate curcumin-piperine, curcumin-quercetin and curcumin-silibinin loaded polymeric nanoformulation. However, unfavourable combinations of drug-drug and drug-excipient may result in interacti...

Evaluation of Chitosan-Microcrystalline Cellulose Blends as Direct Compression Excipients

Directory of Open Access Journals (Sweden)

Emmanuel O. Olorunsola

2017-01-01

Full Text Available This study was aimed at evaluating chitosan-microcrystalline cellulose blends as direct compression excipients. Crab shell chitosan, α-lactose monohydrate, and microcrystalline cellulose powders were characterized. Blends of the microcrystalline cellulose and chitosan in ratios 9 : 1, 4 : 1, 2 : 1, and 1 : 1 as direct compression excipients were made to constitute 60% of metronidazole tablets. Similar tablets containing blends of the microcrystalline cellulose and α-lactose monohydrate as well as those containing pure microcrystalline cellulose were also produced. The compact density, tensile strength, porosity, disintegration time, and dissolution rate of tablets were determined. Chitosan had higher moisture content (7.66% and higher moisture sorption capacity (1.33% compared to microcrystalline cellulose and lactose. It also showed better flow properties (Carr’s index of 18.9% and Hausner’s ratio of 1.23. Compact density of tablets increased but tensile strength decreased with increase in the proportion of chitosan in the binary mixtures. In contrast to lactose, the disintegration time increased and the dissolution rate decreased with increase in the proportion of chitosan. This study has shown that chitosan promotes flowability of powder mix and rapid disintegration of tablet. However, incorporation of equal proportions of microcrystalline cellulose and chitosan leads to production of extended-release tablet. Therefore, chitosan promotes tablet disintegration at low concentration and enables extended-release at higher concentration.

Compatibility of chewing gum excipients with the amino acid L-cysteine and stability of the active substance in directly compressed chewing gum formulation.

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Kartal, Alma; Björkqvist, Mikko; Lehto, Vesa-Pekka; Juppo, Anne Mari; Marvola, Martti; Sivén, Mia

2008-09-01

Using L-cysteine chewing gum to eliminate carcinogenic acetaldehyde in the mouth during smoking has recently been introduced. Besides its efficacy, optimal properties of the gum include stability of the formulation. However, only a limited number of studies exist on the compatibility of chewing gum excipients and stability of gum formulations. In this study we used the solid-state stability method, Fourier transform infrared spectroscopy and isothermal microcalorimetry to investigate the interactions between L-cysteine (as a free base or as a salt) and excipients commonly used in gum. These excipients include xylitol, sorbitol, magnesium stearate, Pharmagum S, Every T Toco and Smily 2 Toco. The influence of temperature and relative humidity during a three-month storage period on gum formulation was also studied. Cysteine alone was stable at 25 degrees C/60% RH and 45 degrees C/75% RH whether stored in open or closed glass ambers. As a component of binary mixtures, cysteine base remained stable at lower temperature and humidity but the salt form was incompatible with all the studied excipients. The results obtained with the different methods corresponded with each other. At high temperature and humidity, excipient incompatibility with both forms of cysteine was obvious. Such sensitivity to heat and humidity during storage was also seen in studies on gum formulations. It was also found that cysteine is sensitive to high pressure and increase in temperature induced by compression. The results suggest that the final product should be well protected from temperature and humidity and, for example, cooling process before compression should be considered.

The influence of co-formers on the dissolution rates of co-amorphous sulfamerazine/excipient systems

DEFF Research Database (Denmark)

Gniado, Katarzyna; Löbmann, Korbinian; Rades, Thomas

2016-01-01

A comprehensive study on the dissolution properties of three co-amorphous sulfamerazine/excipient systems, namely sulfamerazine/deoxycholic acid, sulfamerazine/citric acid and sulfamerazine/sodium taurocholate (SMZ/DA, SMZ/CA and SMZ/NaTC; 1:1 molar ratio), is reported. While all three co...

Glycation of polyclonal IgGs: Effect of sugar excipients during stability studies.

Science.gov (United States)

Leblanc, Y; Bihoreau, N; Jube, M; Andre, M-H; Tellier, Z; Chevreux, G

2016-05-01

A number of intravenous immunoglobulin preparations are stabilized with sugar additives that may lead over time to undesirable glycation reactions especially in liquid formulation. This study aimed to evaluate the reactivity of sugar excipients on such preparations in condition of temperature, formulation and concentration commonly used for pharmaceutical products. Through an innovative LC-MS method reported to characterize post-translational modifications of IgGs Fc/2 fragments, a stability study of IVIg formulated with reducing and non-reducing sugars has been undertaken. The rate of polyclonal IgGs glycation was investigated during 6months at 5, 25, 30 and 40°C. High levels of glycation were observed with reducing sugars such as glucose and maltose in the first months of the stability study from 25°C. Non-reducing sugars presented a low reactivity even at the highest tested temperature (40°C). Furthermore, a site by site analysis was performed by MS/MS to determine the glycation sites which were mainly identified at Lys246, Lys248 and Lys324. This work points out the high probability of glycation reactions in some commercialized products and describes a useful method to characterize IVIg glycated products issued from reducing sugar excipients. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Extraction and Characterization of Boswellia Serrata Gum as Pharmaceutical Excipient.

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Panta, Sumedha; Malviya, Rishabha; Sharma, Pramod

2015-01-01

This manuscript deals with the purification and characterization of Boswellia serrata gum as a suspending agent. The Boswellia serrata gum was purchased as crude material, purified and further characterized in terms of organoleptic properties and further micromeritic studies were carried out to characterize the polymer as a pharmaceutical excipient. The suspending properties of the polymer were also evaluated. The results showed that the extracted gum possesses optimum organoleptic as well as micromeritic and suspending properties. To characterize Boswellia serrata gum as a natural excipient. Boswellia serrata gum, paracetamol, distilled water. The results showed that the extracted gum possesses optimum organoleptic as well as micromeritic and suspending properties. It is concluded from the research work that the gum extracted from Boswellia serrata shows the presence of carbohydrates after chemical tests. All the organoleptic properties evaluated were found to be acceptable. The pH was found to be slightly acidic. Swelling Index reveals that the gum swells well in water. Total ash value was within the limits. The values of angle of repose and Carr's Index of powdered gum powder showed that the flow property was good. IR spectra confirmed the presence of alcohol, amines, ketones, anhydrides and aromatic rings. The suspending properties of Boswellia serrata gum were found to be higher as compared to gum acacia while the flow rate of Boswellia serrata gum (1% suspension) was less than gum acacia (1% suspension). The viscosity measurement of both Boswellia serrata gum suspension and gum acacia suspension showed approximately similar results.

Formation, Physicochemical Characterization, and Thermodynamic Stability of the Amorphous State of Drugs and Excipients.

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Martino, Piera Di; Magnoni, Federico; Peregrina, Dolores Vargas; Gigliobianco, Maria Rosa; Censi, Roberta; Malaj, Ledjan

2016-01-01

Drugs and excipients used for pharmaceutical applications generally exist in the solid (crystalline or amorphous) state, more rarely as liquid materials. In some cases, according to the physicochemical nature of the molecule, or as a consequence of specific technological processes, a compound may exist exclusively in the amorphous state. In other cases, as a consequence of specific treatments (freezing and spray drying, melting and co-melting, grinding and compression), the crystalline form may convert into a completely or partially amorphous form. An amorphous material shows physical and thermodynamic properties different from the corresponding crystalline form, with profound repercussions on its technological performance and biopharmaceutical properties. Several physicochemical techniques such as X-ray powder diffraction, thermal methods of analysis, spectroscopic techniques, gravimetric techniques, and inverse gas chromatography can be applied to characterize the amorphous form of a compound (drug or excipient), and to evaluate its thermodynamic stability. This review offers a survey of the technologies used to convert a crystalline solid into an amorphous form, and describes the most important techniques for characterizing the amorphous state of compounds of pharmaceutical interest.

Effectiveness of supersaturation promoting excipients on albendazole concentrations in upper gastrointestinal lumen of fasted healthy adults.

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Kourentas, Alexandros; Vertzoni, Maria; Symillides, Mira; Goumas, Konstantinos; Gibbon, Robert; Butler, James; Reppas, Christos

2016-08-25

To evaluate the impact of dosage form relevant levels of a polymeric precipitation inhibitor and of lipid excipients on supersaturation of upper gastrointestinal contents with albendazole, a lipophilic weak base. Albendazole concentrations in stomach and in duodenum were evaluated after administration of 1) a suspension in water (Susp-Control), 2) a suspension in water in which hydroxyprolylmethylcellulose E5 (HPMC E5) had been pre-dissolved (Susp-HPMC), and 3) and 4) two contrasting designs of lipid based suspensions dispersed in water (Susp-IIIA and Susp-IV), on a cross-over basis to fasted healthy adults. Limited, but statistically significant supersaturation of duodenal contents was observed after Susp-HPMC, Susp-IIIA, and Susp-IV; supersaturation was more consistent after Susp-HPMC administration. Based on total albendazole amount per volume, gastric secretions did not significantly alter volumes of bulk gastric contents during the first 40min post administration of a glass of non-caloric water-based fluid. Αlbendazole gastric concentrations were higher than in the administered suspensions, but similar for all four formulations. Gastric emptying of albendazole after administration of Susp-Control or Susp-HPMC was slower than after administration of Susp-IIIA or Susp-IV. Small amounts of HPMC E5 were as effective as lipid excipients in achieving supersaturation of duodenal contents with albendazole, a fast precipitating weak base, in fasted adults. However, compared with the effect of HPMC E5 the effect of lipid excipients was delayed and variable. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of excipients and formulation types on compressional properties of diclofenac.

Science.gov (United States)

Ayorinde, John Oluwasogo; Itiola, Adelanwa Oludele; Odeniyi, Michael Ayodele

2013-01-01

Different models used to characterize powders have not been extended to granule behavior in tablet technology. Hence, Kawakaita equation and tapping experiments were used to compare the effect of different excipients on the properties of powders and granules in diclofenac formulations containing corn starch (DCS), lactose (DL) and dicalcium phosphate (DDCP). The binding properties of Albizia gum from Albizia zygia tree were also compared with those of gelatin in the granule formulations. Diclofenac (powder and granule) formulations were characterized for particle size and particle size distribution. Volume reduction was done by subjecting materials to N number of taps. Values of maximum volume reduction (a 'determined') and index of compressibility (b) were obtained from the plots of N/C against powder volume reduction with tapping (C). Another value for a (a' calculated) were obtained from Kawakita equations. The individual and interaction effects of type of diluent (X1) and formulation (X2) on the characteristics of powder and granule were determined, using a 22 factorial experimental design. The mean granule size increased with binder concentration, larger granules were obtained with Albizia gum than gelatin in the formulations. In DCS, a was lower in granules, granules had higher values of a than powders in DDCP (p Diclofenac had higher compressibility index (b) with the excipients. Generally, b was higher in granules than in powder formulations (p properties. Granules and powders can be characterized using the same parameters. Albizia gum was shown to confer good flow and compression properties in diclofenac formulations.

Dissolution and Solubility Enhancement of the Highly Lipophilic Drug Phenytoin via Interaction with Poly(N-isopropylacrylamide-co-vinylpyrrolidone) Excipients.

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Widanapathirana, Lakmini; Tale, Swapnil; Reineke, Theresa M

2015-07-06

Excipients of natural or synthetic origin play an important role in pharmaceutical performance to enhance the solubility, bioavailability, release, and stability of insoluble drugs. Herein, a series of seven excipient models was prepared by both homopolymerization and copolymerization of 1-vinyl-2-pyrrolidone (VP) and N-isopropylacrylamide (NIPAAm) by free radical polymerization yielding two homopolymers poly(VP) and poly(NIPAAm) and five copolymers of poly(NIPAAm-co-VP) at difference compositions. While the VP monomer provided aqueous solubility at a variety of conditions to the excipient, the incorporation of NIPAAm into the copolymer offered additional hydrogen bond donating sites to optimize the drug-polymer interactions in the system. Due to the presence of NIPAAm, the copolymers were sensitive to temperature as well. It was found that as the proportion of VP was increased (from 0 to 100%), the lower critical solution temperature (LCST) and the water solubility of the polymer models increased. To examine the role of specific drug-polymer interactions during dissolution on drug solubility and bioavailability, the polymers were formulated with the anticonvulsant drug phenytoin, which is a poorly water-soluble BCS class II drug where oral absorption is limited by the drug solubility. Amorphous solid dispersions (ASD) were prepared via spray drying of phenytoin with the polymer excipient models to contain 10% and 25% by weight drug loading. Physical characterization of the ASDs by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) revealed that the polymers held the drug in a high-energy amorphous phase in all the formulations prepared. All ASDs exhibited improved in vitro dissolution rates compared to drug only and physical mixtures of the polymers and the drug. Drug solubility was the highest with the ASDs containing poly(NIPAAm-co-VP) 60:40 and 50:50, which showed a solubility enhancement of near 14-fold increase compared to pure drug

Advanced qualification of pharmaceutical excipient suppliers by multiple analytics and multivariate analysis combined.

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Hertrampf, A; Müller, H; Menezes, J C; Herdling, T

2015-11-10

Pharmaceutical excipients have different functions within a drug formulation, consequently they can influence the manufacturability and/or performance of medicinal products. Therefore, critical to quality attributes should be kept constant. Sometimes it may be necessary to qualify a second supplier, but its product will not be completely equal to the first supplier product. To minimize risks of not detecting small non-similarities between suppliers and to detect lot-to-lot variability for each supplier, multivariate data analysis (MVA) can be used as a more powerful alternative to classical quality control that uses one-parameter-at-a-time monitoring. Such approach is capable of supporting the requirements of a new guideline by the European Parliament and Council (2015/C-95/02) demanding appropriate quality control strategies for excipients based on their criticality and supplier risks in ensuring quality, safety and function. This study compares calcium hydrogen phosphate from two suppliers. It can be assumed that both suppliers use different manufacturing processes. Therefore, possible chemical and physical differences were investigated by using Raman spectroscopy, laser diffraction and X-ray powder diffraction. Afterwards MVA was used to extract relevant information from each analytical technique. Both CaHPO4 could be discriminated by their supplier. The gained knowledge allowed to specify an enhanced strategy for second supplier qualification. Copyright © 2015 Elsevier B.V. All rights reserved.

A systematic evaluation of solubility enhancing excipients to enable the generation of permeability data for poorly soluble compounds in Caco-2 model.

Science.gov (United States)

Shah, Devang; Paruchury, Sundeep; Matta, Muralikrishna; Chowan, Gajendra; Subramanian, Murali; Saxena, Ajay; Soars, Matthew G; Herbst, John; Haskell, Roy; Marathe, Punit; Mandlekar, Sandhya

2014-01-01

The study presented here identified and utilized a panel of solubility enhancing excipients to enable the generation of flux data in the Human colon carcinoma (Caco-2) system for compounds with poor solubility. Solubility enhancing excipients Dimethyl acetamide (DMA) 1 % v/v, polyethylene glycol (PEG) 400 1% v/v, povidone 1% w/v, poloxamer 188 2.5% w/v and bovine serum albumin (BSA) 4% w/v did not compromise Caco-2 monolayer integrity as assessed by trans-epithelial resistance measurement (TEER) and Lucifer yellow (LY) permeation. Further, these excipients did not affect P-glycoprotein (P-gp) mediated bidirectional transport of digoxin, permeabilities of high (propranolol) or low permeability (atenolol) compounds, and were found to be inert to Breast cancer resistant protein (BCRP) mediated transport of cladribine. This approach was validated further using poorly soluble tool compounds, atazanavir (poloxamer 188 2.5% w/v) and cyclosporine A (BSA 4% w/v) and also applied to new chemical entity (NCE) BMS-A in BSA 4% w/v, for which Caco-2 data could not be generated using the traditional methodology due to poor solubility (solubility of atazanavir by >8 fold whereas BSA 4% w/v increased the solubility of cyclosporine A and BMS-A by >2-4 fold thereby enabling permeability as well as efflux liability estimation in the Caco-2 model with reasonable recovery values. To conclude, addition of excipients such as poloxamer 188 2.5% w/v and BSA 4% w/v to HBSS leads to a significant improvement in the solubility of the poorly soluble compounds resulting in enhanced recoveries without modulating transporter-mediated efflux, expanding the applicability of Caco-2 assays to poorly soluble compounds.

Overview on zein protein: a promising pharmaceutical excipient in drug delivery systems and tissue engineering.

Science.gov (United States)

Labib, Gihan

2018-01-01

Natural pharmaceutical excipients have been applied extensively in the past decades owing to their safety and biocompatibility. Zein, a natural protein of plant origin offers great benefit over other synthetic polymers used in controlled drug and biomedical delivery systems. It was used in a variety of medical fields including pharmaceutical and biomedical drug targeting, vaccine, tissue engineering, and gene delivery. Being biodegradable and biocompatible, the current review focuses on the history and the medical application of zein as an attractive still promising biopolymer. Areas covered: The current review gives a broadscope on zein as a still promising protein excipient in different fields. Zein- based drug and biomedical delivery systems are discussed with special focus on current and potential application in controlled drug delivery systems, and tissue engineering. Expert opinion: Zein as a protein of natural origin can still be considered a promising polymer in the field of drug delivery systems as well as in tissue engineering. Although different researchers spotted light on zein application in different industrial fields extensively, the feasibility of its use in the field of drug delivery replenished by investigators in recent years has not yet been fully approached.

EPR response characterization of drugs excipients for applying in accident dosimetry; Caracterizacao da resposta RPE dos excipientes dos medicamentos para aplicacao em dosimetria de acidente

Energy Technology Data Exchange (ETDEWEB)

Marczewski, Barbara S.; Rodrigues Junior, Orlando; Galante, Ocimar L.; Costa, Zelia M. da; Campos, Leticia L. [Instituto de Pesquisas Energeticas e Nucleares (IPEN), Sao Paulo, SP (Brazil)

2002-07-01

Some drugs are widely used by the population and can be employed to dose retrospective. The carbohydrates (saccharides), commonly used as excipients in the pharmaceutical industry, produce a quantity of free radicals after gamma irradiation, making them useful for dosimetry in emergency or accident situations that imply in dose evaluation from the materials found nearly or in contact with victims. In general, EPR signal from pulverized pills of some drugs are very complex due to the variety of components in the formulation. Because of this fact, some pharmaceutical excipients identified in the pill composition were also analysed by EPR spectrometry. On the counter drugs were studied: Cebion glucose, AAS, Aspirina, Conmel, Lacto-Purga and sugar substitutive ZeroCal. The excipients were: lactose, amide, anhydrous glucose and magnesium stearate. In some samples the number of radicals produced increased with the dose, showing a linear response for a dose range of interest and an adequate sensibility for dosimetry in accident cases.

Development of lyophilization cycle and effect of excipients on the stability of catalase during lyophilization

OpenAIRE

Lale, Shantanu V; Goyal, Monu; Bansal, Arvind K

2011-01-01

Introduction: The purpose of the present study was to screen excipients such as amino acids and non-aqueous solvents for their stabilizing effect on catalase, a model protein, for lyophilization. The present study also includes optimization of lyophilization cycle for catalase formulations, which is essential from the commercial point of view, since lyophilization is an extremely costly process. Materials and Methods: Activity of catalase was determined using catalase activity assay. Differen...

Drug-Excipient Interactions in the Solid State: The Role of Different Stress Factors.

Science.gov (United States)

Gressl, Corinna; Brunsteiner, Michael; Davis, Adrian; Landis, Margaret; Pencheva, Klimentina; Scrivens, Garry; Sluggett, Gregory W; Wood, Geoffrey P F; Gruber-Woelfler, Heidrun; Khinast, Johannes G; Paudel, Amrit

2017-12-04

Understanding properties and mechanisms that govern drug degradation in the solid state is of high importance to ensure drug stability and safety of solid dosage forms. In this study, we attempt to understand drug-excipient interactions in the solid state using both theoretical and experimental approaches. The model active pharmaceutical ingredients (APIs) under study are carvedilol (CAR) and codeine phosphate (COP), which are known to undergo esterification with citric acid (CA) in the solid state. Starting from the crystal structures of two different polymorphs of each compound, we calculated the exposure and accessibility of reactive hydroxyl groups for a number of relevant crystal surfaces, as well as descriptors that could be associated with surface stabilities using molecular simulations. Accelerated degradation experiments at elevated temperature and controlled humidity were conducted to assess the propensity of different solid forms of the model APIs to undergo chemical reactions with anhydrous CA or CA monohydrate. In addition, for CAR, we studied the solid state degradation at varying humidity levels and also under mechano-activation. Regarding the relative degradation propensities, we found that variations in the exposure and accessibility of molecules on the crystal surface play a minor role compared to the impact of molecular mobility due to different levels of moisture. We further studied drug-excipient interactions under mechano-activation (comilling of API and CA) and found that the reaction proceeded even faster than in physical powder mixtures kept at accelerated storage conditions.

Zein as a Pharmaceutical Excipient in Oral Solid Dosage Forms: State of the Art and Future Perspectives.

Science.gov (United States)

Berardi, Alberto; Bisharat, Lorina; AlKhatib, Hatim S; Cespi, Marco

2018-05-07

Zein is the main storage protein of corn and it has several industrial applications. Mainly in the last 10-15 years, zein has emerged as a potential pharmaceutical excipient with unique features. Zein is a natural, biocompatible and biodegradable material produced from renewable sources. It is insoluble, yet due to its amphiphilic nature, it has self-assembling properties, which have been exploited for the formation of micromicroparticle and nanoparticle and films. Moreover, zein can hydrate so it has been used in swellable matrices for controlled drug release. Other pharmaceutical applications of zein in oral drug delivery include its incorporation in solid dispersions of poorly soluble drugs and in colonic drug delivery systems. This review describes the features of zein significant for its use as a pharmaceutical excipient for oral drug delivery, and it summaries the literature relevant to macroscopic zein-based oral dosage forms, i.e. tablets, capsules, beads and powders. Particular attention is paid to the most novel formulations and applications of zein. Moreover, gaps of knowledge as well as possible venues for future investigations on zein are highlighted.

[A CASE OF ANAPHYLAXIS IN THE PEDIATRIC PATIENT WITH MILK ALLERGY DUE TO TRACES OF MILK PROTEIN IN THE LACTOSE USED AS AN EXCIPIENT OF INAVIR INHALATION].

Science.gov (United States)

Morikawa, Miki; Kanemitsu, Yoshitomi; Tsukamoto, Hiroki; Morikawa, Akimasa; Tomioka, Yoshihisa

2016-05-01

The patient was a 6-year-old female with milk allergy and persistent asthma. She experienced anaphylactic reactions just after the inhalation of Inavir (Laninamivir Octanoate Hydrate) to treat flu infection. A skin-prick test showed positive reactions for Inavir inhaler powder and lactose used as an excipient but negative for Laninamivir. Same results were obtained in a drug-stimulated basophil activation test. The lactose excipient in Inavir inhaler powder was supposed to contain milk proteins, which caused anaphylactic reactions. To test this possibility, we examined the contamination of allergic milk proteins in the lactose excipient and found the smear band by silver staining, which was identified as β-lactoglobulin (β-LG) by Western blotting using specific monoclonal antibody and patient's sera. The β-LG in Inavir was supposed to be glycosylated with lactose because the molecular weight was slightly higher than β-LG standard reference as seen in mobility. In fact, the incubation with lactose in vitro tended to increase molecular weight. Following these results, we herein report that the trace amounts of β-LG contaminated in the lactose excipient of Inavir could cause immediate allergic reactions. The risk that the lactose-containing dry powder inhalers cause allergic reactions for patients with cow's milk allergy need to be reminded. In particular, the use for flu patients should be paid careful attention because of increased airway hypersensitivity in those patients.

Pharmaceutical excipients influence the function of human uptake transporting proteins.

Science.gov (United States)

Engel, Anett; Oswald, Stefan; Siegmund, Werner; Keiser, Markus

2012-09-04

Although pharmaceutical excipients are supposed to be pharmacologically inactive, solubilizing agents like Cremophor EL have been shown to interact with cytochrome P450 (CYP)-dependent drug metabolism as well as efflux transporters such as P-glycoprotein (ABCB1) and multidrug resistance associated protein 2 (ABCC2). However, knowledge about their influence on the function of uptake transporters important in drug disposition is very limited. In this study we investigated the in vitro influence of polyethylene glycol 400 (PEG), hydroxypropyl-β-cyclodextrin (HPCD), Solutol HS 15 (SOL), and Cremophor EL (CrEL) on the organic anion transporting polypeptides (OATP) 1A2, OATP2B1, OATP1B1, and OATP1B3 and the Na(+)/taurocholate cotransporting polypeptide (NTCP). In stably transfected human embryonic kidney cells we analyzed the competition of the excipients with the uptake of bromosulfophthalein in OATP1B1, OATP1B3, OATP2B1, and NTCP, estrone-3-sulfate (E(3)S) in OATP1A2, OATP1B1, and OATP2B1, estradiol-17β-glucuronide in OATP1B3, and taurocholate (TA) in OATP1A2 and NTCP cells. SOL and CrEL were the most potent inhibitors of all transporters with the strongest effect on OATP1A2, OATP1B3, and OATP2B1 (IC(50) < 0.01%). HPCD also strongly inhibited all transport proteins but only for substrates containing a sterane-backbone. Finally, PEG seems to be a selective and potent modulator of OATP1A2 with IC(50) values of 0.05% (TA) and 0.14% (E(3)S). In conclusion, frequently used solubilizing agents were shown to interact substantially with intestinal and hepatic uptake transporters which should be considered in drug development. However, the clinical relevance of these findings needs to be evaluated in further in vivo studies.

The Cumulative Daily Tolerance Levels of Potentially Toxic Excipients Ethanol and Propylene Glycol Are Commonly Exceeded in Neonates and Infants

DEFF Research Database (Denmark)

Valeur, Kristine Svinning; Hertel, Steen Axel; Lundstrøm, Kaare Engell

2018-01-01

neonates and infants and compare these levels to the tolerance limits found in guidelines published by European Medicines Agency (EMA). As part of the SEEN study, all medicinal products administered to neonates and infants were recorded. All included neonates received ≥2 medicinal products/day and infants...... ≥3 medicinal products/day. Daily excipient levels were calculated based on quantities obtained from manufacturers or databases. Excipient levels were compared to tolerance limits proposed by the EMA. Altogether, 470 neonates and 160 infants were included, recording 4207 prescriptions and 316 products...... exceed tolerance limit of 6 mg/kg/day. Of the total number of prescriptions involving PG-containing medicinal products (n = 174), 70% would alone exceed a maximum tolerance limit of 50 mg/kg/day. Maximal daily exposure to ethanol (1563 mg/kg/day) or PG (954 mg/kg/day) exceeded the tolerance limits...

Amino acids as co-amorphous excipients for simvastatin and glibenclamide

DEFF Research Database (Denmark)

Laitinen, Riikka; Löbmann, Korbinian; Grohganz, Holger

2014-01-01

to a few drugs and amino acids. To facilitate the rational selection of amino acids, the practical importance of the amino acid coming from the biological target site of the drug (and associated intermolecular interactions) needs to be established. In the present study, the formation of co......-amorphous systems using cryomilling and combinations of two poorly water-soluble drugs (simvastatin and glibenclamide) with the amino acids aspartic acid, lysine, serine, and threonine was investigated. Solid-state characterization with X-ray powder diffraction, differential scanning calorimetry, and Fourier...... in the mixtures. Interestingly, a favorable effect by the excipients on the tautomerism of amorphous glibenclamide in the co-amorphous blends was seen, as the formation of the thermodynamically less stable imidic acid tautomer of glibenclamide was suppressed compared to that of the pure amorphous drug...

Structure elucidation and quantification of impurities formed between 6-aminocaproic acid and the excipients citric acid and sorbitol in an oral solution using high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy

DEFF Research Database (Denmark)

Schou-Pedersen, Anne Marie V; Cornett, Claus; Nyberg, Nils

2015-01-01

Concentrated solutions containing 6-aminocaproic acid and the excipients citric acid and sorbitol have been studied at temperatures of 50 °C, 60 °C, 70 °C and 80 °C as well as at 20 °C. It has previously been reported that the commonly employed citric acid is a reactive excipient, and it is there......Concentrated solutions containing 6-aminocaproic acid and the excipients citric acid and sorbitol have been studied at temperatures of 50 °C, 60 °C, 70 °C and 80 °C as well as at 20 °C. It has previously been reported that the commonly employed citric acid is a reactive excipient...... and cyclized 6-aminocaproic acid, i.e., caprolactam. No reaction products between d-sorbitol and 6-aminocaproic acid could be observed. 3-Hydroxy-3,4-dicarboxy-butanamide-N-hexanoic acid, dimer and caprolactam were also observed after storage at 20 °C for 3 months. The findings imply that an oral solution of 6...

Characterization of cellulose biomass for use as an excipient in pharmaceutical field

International Nuclear Information System (INIS)

Garcia, Keth R.; Turella, Tais C.; Santos, Venina dos; Brandalise, Rosmary N.; Angeli, Valeria W.

2015-01-01

Every day the industry of paper and cellulose discards large amounts of waste. An alternative to reuse this kind of biomass is to transform part of it in cellulose nanocrystals and nanofibrils to be used as excipients in pharmaceutical field. Thus, cellulose fibrils were obtained in nanoscale using mill and fibrils' characterization study were performed by scanning electron microscopy, transmission electron microscopy, thermal analysis, differential scanning calorimetry, infrared Fourier transform and X-rays diffraction. Hence, the methodology used to obtain and characterize nanocellulose was effective and the fibers/fibrils lengths are in nanometer dimension with high potential to apply in the pharmaceutical field. (author)

Effects of excipients on the tensile strength, surface properties and free volume of Klucel® free films of pharmaceutical importance

International Nuclear Information System (INIS)

Gottnek, Mihály; Süvegh, Károly; Pintye-Hódi, Klára; Regdon, Géza

2013-01-01

The physicochemical properties of polymers planned to be applied as mucoadhesive films were studied. Two types of Klucel ® hydroxypropylcellulose (LF and MF) were used as film-forming polymers. Hydroxypropylcellulose was incorporated in 2 w/w% with glycerol and xylitol as excipients and lidocaine base as an active ingredient at 5, 10 or 15 w/w% of the mass of the film-forming polymer. The free volume changes of the films were investigated by positron annihilation lifetime spectroscopy, the mechanical properties of the samples were measured with a tensile strength tester and contact angles were determined to assess the surface properties of the films. It was found that the Klucel ® MF films had better physicochemical properties than those of the LF films. Klucel ® MF as a film-forming polymer with lidocaine base and both excipients at 5 w/w% exhibited physicochemical properties and good workability. The excipients proved to exert strong effects on the physicochemical properties of the tested systems and it is very important to study them intensively in preformulation studies in the pharmaceutical technology in order to utilise their benefits and to avoid any disadvantageous effects. - Highlights: • Glycerol increases, whereas xylitol decreases the free volume of both LF and MF HPC. • Both xylitol and glycerol increase the tensile strength of MF films. • The tensile strength of the MF product makes it suitable for pharmaceutical use. • The surface properties reveal a macroscopically stable film structure. • All measurements indicate a macroscopically homogeneous film structure

Simultaneous Quantification of Three Polymorphic Forms of Carbamazepine in the Presence of Excipients Using Raman Spectroscopy

Directory of Open Access Journals (Sweden)

Marco Farias

2014-09-01

Full Text Available The occurrence of polymorphic transitions is a serious problem for pharmaceutical companies, because it can affect the bioavailability of the final product. With several known polymorphic forms carbamazepine is one of the most problematic drugs in this respect. Raman spectroscopy is a vibrational technique that is becoming very important in the pharmaceutical field, mainly due to its highly specific molecular fingerprint capabilities and easy use as a process analytical tool. However, multivariate methods are necessary both for identification and quantification. In this work an analytical methodology using Raman spectroscopy and interval Partial Least Squares Regression (iPLS, was developed in order to quantify mixtures of carbamazepine polymorphs in the presence of the most common excipients. The three polymorphs CBZ I, CBZ III and CBZ DH (which is a dihydrate were synthesized and characterized by PXRD and DSC. Subsequently, tablets were manufactured using excipients and 15 different mixtures of carbamazepine polymorphs. The iPLS model presented average prediction validation errors of 1.58%, 1.04% and 0.22% wt/wt, for CBZ I, CBZ III and CBZ DH, respectively, considering the whole mass of the tablet. The model presents a good prediction capacity and the proposed methodology could be used to perform quality control in final products.

Characterizing compaction-induced thermodynamic changes in a common pharmaceutical excipient.

Science.gov (United States)

Wurster, Dale Eric; Buckner, Ira S

2012-08-01

Work, heat, and internal energy change values were measured during compression of a common pharmaceutical tablet excipient, anhydrous lactose, using a compression calorimeter. Heat of solution measurements were used independently to measure the energy change caused by compaction. Both the compression calorimeter and the heat of solution measurements showed an increase in anhydrous lactose's energy state as a result of the net compression and decompression process. Excellent agreement between the energy change measured by compression calorimetry (0.94 J/g) and the energy change measured by solution calorimetry (0.91 J/g) strongly supports the data and results generated by the compression calorimeter. Furthermore, specific volume and specific surface area measurements were used to investigate the nature of the measured energy increase. The results indicate that the vast majority of the stored energy is most likely associated with residual strain within the compacted particles. Copyright © 2012 Wiley Periodicals, Inc.

Effects of excipients on the tensile strength, surface properties and free volume of Klucel{sup ®} free films of pharmaceutical importance

Energy Technology Data Exchange (ETDEWEB)

Gottnek, Mihály [Department of Pharmaceutical Technology, University of Szeged, Eötvös utca 6, H-6720 Szeged (Hungary); Süvegh, Károly [Laboratory of Nuclear Chemistry, Eötvös Loránd University, P.O. Box 32, H-1518 Budapest 112 (Hungary); Pintye-Hódi, Klára [Department of Pharmaceutical Technology, University of Szeged, Eötvös utca 6, H-6720 Szeged (Hungary); Regdon, Géza [Department of Pharmaceutical Technology, University of Szeged, Eötvös utca 6, H-6720 Szeged (Hungary)

2013-08-15

The physicochemical properties of polymers planned to be applied as mucoadhesive films were studied. Two types of Klucel{sup ®} hydroxypropylcellulose (LF and MF) were used as film-forming polymers. Hydroxypropylcellulose was incorporated in 2 w/w% with glycerol and xylitol as excipients and lidocaine base as an active ingredient at 5, 10 or 15 w/w% of the mass of the film-forming polymer. The free volume changes of the films were investigated by positron annihilation lifetime spectroscopy, the mechanical properties of the samples were measured with a tensile strength tester and contact angles were determined to assess the surface properties of the films. It was found that the Klucel{sup ®} MF films had better physicochemical properties than those of the LF films. Klucel{sup ®} MF as a film-forming polymer with lidocaine base and both excipients at 5 w/w% exhibited physicochemical properties and good workability. The excipients proved to exert strong effects on the physicochemical properties of the tested systems and it is very important to study them intensively in preformulation studies in the pharmaceutical technology in order to utilise their benefits and to avoid any disadvantageous effects. - Highlights: • Glycerol increases, whereas xylitol decreases the free volume of both LF and MF HPC. • Both xylitol and glycerol increase the tensile strength of MF films. • The tensile strength of the MF product makes it suitable for pharmaceutical use. • The surface properties reveal a macroscopically stable film structure. • All measurements indicate a macroscopically homogeneous film structure.

Spherical composite particles of rice starch and microcrystalline cellulose: A new coprocessed excipient for direct compression

OpenAIRE

Limwong, Vasinee; Sutanthavibul, Narueporn; Kulvanich, Poj

2004-01-01

Composite particles of rice starch (RS) and microcrystalline cellulose were fabricated by spray-drying technique to be used as a directly compressible excipient. Two size fractions of microcry stalline cellulose, sieved (MCS) and jet milled (MCJ), having volumetric mean diameter (D50) of 13.61 and 40.51 μm, respectively, were used to form composite particles with RS in various mixing ratios. The composite particles produced were evaluated for their powder and compression properties. Although ...

Using the Slug Mucosal Irritation Assay to Investigate the Tolerability of Tablet Excipients on Human Skin in the Context of the Use of a Nipple Shield Delivery System.

Science.gov (United States)

Kendall, Richard; Lenoir, Joke; Gerrard, Stephen; Scheuerle, Rebekah L; Slater, Nigel K H; Tuleu, Catherine

2017-04-01

Neonates are particularly challenging to treat. A novel patented drug delivery device containing a rapidly disintegrating tablet held within a modified nipple shield (NSDS) was designed to deliver medication to infants during breastfeeding. However concerns exist around dermatological nipple tolerability with no pharmaceutical safety assessment guidance to study local tissue tolerance of the nipple and the areola. This is the first Slug Mucosal Irritation (SMI) study to evaluate irritancy potential of GRAS excipients commonly used to manufacture rapidly disintegrating immediate release solid oral dosage form METHODS: Zinc sulphate selected as the antidiarrheal model drug that reduces infant mortality, was blended with functional excipients at traditional levels [microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, magnesium stearate]. Slugs were exposed to blends slurried in human breast milk to assess their stinging, itching or burning potential, using objective values such as mucus production to categorize irritation potency RESULTS: Presently an in vivo assay, previously validated for prediction of ocular and nasal irritation, was used as an alternative to vertebrate models to anticipate the potential maternal dermatological tolerability issues to NSDS tablet components. The excipients did not elicit irritancy. However, mild irritancy was observed when zinc sulphate was present in blends. These promising good tolerability results support the continued investigation of these excipients within NSDS rapidly disintegrating tablet formulations. Topical local tolerance effects being almost entirely limited to irritation, the slug assay potentially adds to the existing preformulation toolbox, and may sit in between the in vitro and existing in vivo assays.

Functional Salad Dressing as an Excipient Food

Directory of Open Access Journals (Sweden)

Sibel Karakaya

2015-10-01

Full Text Available The aim of this study is to develop salad dressing as an excipient food that can be used to enhance beneficial effects of salads when co-ingested together. The compounds that include bioactive constituents different from other salad dressings are germinated seed and sprouts of lentils and cowpeas, and caseinomacropeptide isolated from whey. The proximate composition, total phenols and total flavonoids of salad dressing were determined. Its beneficial effects on health (antioxidant activity, antidiabetic activity, bile acid binding capacity, and angiotensin converting enzyme inhibitory activity were determined using in vitro methods.
Energy value of salad dressing is 111 kcal/100 g and 11.41% of the energy value of the salad dressing is provided by protein. Total phenol content is 79 mg CE/100 g. Salad dressing displayed higher antioxidant activity against DPPH radical (130 mM Trolox/100 g than that of ORAC value (72 mM Trolox/100 g. Salad dressing inhibited ACE by approximately 37%. Expected glycemic index of salad dressing was 74.0 and belongs to high glycemic index foods. Contrary to, salad dressing inhibited α-glucosidase and α-amylase with the IC50 values 1.77 mg protein/mL and 2.40 mg protein/mL, respectively. Relative to cholestyramine, bile acid binding capacity of salad dressing is 39.85%.

Choice of excipients for gelly-like pulp prepared ex tempore "on a spoon"- "placebo" and with sartans.

Science.gov (United States)

Wolska, Eliza; Kluk, Anna; Zarazińska, Magda; Boniecka, Magdalena; Sznitowska, Małgorzata

2016-01-01

To ensure safe oral administration, pediatric patients require an appropriate dosage form to be swallowed without relevant difficulties. Ex tempore hydrated powders, forming viscous pulp "on a spoon", have recently gained much interest as pediatric formulations. The aim of this study was to evaluate the viscosity-increasing substances and disintegrants, alone or in mixtures, as excipients suitable for preparing such formulations, with candesartan and valsartan chosen as model active substances. The mixtures of excipients were prepared in the form of powders, granules or lyophilizates, which were evaluated in terms of their ability to form a homogenous mass after hydration with a small amount of water. The best compositions were tested with candesartan cilexetil and valsartan (2% and 10% w/w, respectively). Performed studies include macroscopic, organoleptic and microscopic observations, as well as a textural analysis, determination of gelation time and rheological measurements. Mixtures of guar gum, lactose and one of the disintegrants (F-Melt M, Prosolv 50, Prosolv Easy, Lycatab, Pharmaburst, Pearlitol) demonstrated the best properties. With regard to drug-incorporating formulations, granules were evaluated as the most satisfying form, while the functional properties of lyophilized formulations were poor. Granules with candesartan cilexetil (2%) were found to be the most promising for further development.

A PAT-based qualification of pharmaceutical excipients produced by batch or continuous processing.

Science.gov (United States)

Hertrampf, A; Müller, H; Menezes, J C; Herdling, T

2015-10-10

Pharmaceutical excipients have an influence on the main requirements for medicinal products (viz., quality, safety and efficacy) but also on their manufacturability. During product lifecycle it may become necessary to introduce minor changes (e.g., to continuously improve it) or major changes in the validated process (e.g., moving it to a new production site, replacing process version or even disruptively changing processing type). Those changes can influence the critical to quality attributes of the product. Therefore, it is important to enhance process understanding to avoid the risk of any significant quality changes. Process analytical technology can support better decision making and risk-management as required in quality by design - viz., by many pharmaceutical regulatory authorities. This study compares the quality of the pharmaceutical excipient sodium carbonate (anhydrous) produced either in a batch or a continuous process. For continuous processing two different production lines were available that differed on the dryer and crystallizer types used. Therefore their influence on critical to quality attributes of sodium carbonate was investigated for each of the three processing alternatives. The overall goal was to identify which of the continuous processes ensures a similar product quality to batch processing. Namely, changes on chemical and physical attributes of the product were investigated with Raman spectroscopy, laser diffraction and X-ray powder diffraction. Principal component analysis, a very common multivariate analysis technique, was applied to extract relevant information from small differences at multiple spectral regions from samples from each process type and from each analytical technique used. Changing processing from batch to continuous improved consistency of certain attributes (e.g., particle size distribution) but affected others. However, the increased process/product knowledge gained can lead to an enhanced control strategy and

Influence of different excipients on the properties of hard gelatin capsules with metamizole sodium

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Rogowska Magdalena

2016-09-01

Full Text Available Metamizole is an effective non-opioid analgesic drug used in the treatment of acute and chronic pain. Due to induced potentially life-threatening blood disorders, metamizole was withdrawn from market in many parts of the world, however, it is one of the most popular analgesics in Poland that is available as an over the counter drug. Patients tend to prefer capsules over tablets, as they are easier to swallow and taste better. The powder-filled capsules also have greater bioavailability and require less excipients, as compared to tablets. Polymic excipients are mainly used in capsule filling, and have influence upon the physico-chemical properties of the hard gelatin capsules and the powder formulation. The aim of the study was to determine whether various combinations of polymers impact the disintegration time and pharmaceutical availability of hard gelatin capsules with metamizole sodium. The results of our work demonstrated that the 80% of all active substance was released in all tested formulations within 15 minutes. Herein, the capsule containing lactose monohydrate had the longest release (4% after 2 min., while capsules containing mannitol had the fastest release (81.2% after 2 min.. Moreover, the addition of HPMC to capsules with lactose brought about a slight increase in the metamizole release rate, while the addition of PVP 30 to capsules with microcrystalline cellulose slightly accelerated release. This data suggests that the use of different polymers in capsules formulation brings about changes in the physical properties of powders and modifies the release profile of metamizole. In our study, the most preferred formulation was one containing microcrystalline cellulose (good powder properties and fairly fast release.

Screening of polysaccharides from tamarind, fenugreek and jackfruit seeds as pharmaceutical excipients.

Science.gov (United States)

Nayak, Amit Kumar; Pal, Dilipkumar; Santra, Kousik

2015-08-01

The paper describes the isolation and screening of plant polysaccharides namely tamarind seed polysaccharide (TSP), fenugreek seed mucilage (FSM) and jackfruit seed starch (JFSS) from tamarind (Tamarindus indica L.) seeds, fenugreek (Trigonella foenum-graecum L.) seeds and jackfruit (Artocarpus heterophyllus L.) seeds, respectively. The yields of isolated dried TSP, FSM and JFSS were 47.00%, 17.36% and 18.86%, respectively. Various physicochemical properties like colour, odour, taste, solubility in water, pH and viscosity of these isolated plant polysaccharides were assessed. Isolated polysaccharide samples were subjected to some phytochemical identification tests. FTIR and (1)H NMR analyses of isolated polysaccharides were performed, which suggest the presence of sugar residues. Isolated TSP, FSM and JFSS can be used as pharmaceutical excipients in various pharmaceutical formulations. Copyright © 2015 Elsevier B.V. All rights reserved.

A new generation of starch products as excipient in pharmaceutical tablets .1. Preparation and binding properties of high surface area potato starch products

NARCIS (Netherlands)

Wierik, GHPT; ArendsScholte, AW; Eissens, AC; Lerk, CF

1996-01-01

A new pharmaceutical excipient with a high binding capacity was prepared from potato starch by enzymatic degradation, followed by suitable dehydration of the precipitated and filtered retrograded starch to produce high specific surface area products. Thermal dehydration methods like drying at room

Evaluation of co-processed excipients used for direct compression of orally disintegrating tablets (ODT) using novel disintegration apparatus.

Science.gov (United States)

Brniak, Witold; Jachowicz, Renata; Krupa, Anna; Skorka, Tomasz; Niwinski, Krzysztof

2013-01-01

The compendial method of evaluation of orodispersible tablets (ODT) is the same disintegration test as for conventional tablets. Since it does not reflect the disintegration process in the oral cavity, alternative methods are proposed that are more related to in vivo conditions, e.g. modified dissolution paddle apparatus, texture analyzer, rotating shaft apparatus, CCD camera application, or wetting time and water absorption ratio measurement. In this study, three different co-processed excipients for direct compression of orally disintegrating tablets were compared (Ludiflash, Pharmaburst, F-Melt). The properties of the prepared tablets such as tensile strength, friability, wetting time and water absorption ratio were evaluated. Disintegration time was measured using the pharmacopoeial method and the novel apparatus constructed by the authors. The apparatus was based on the idea of Narazaki et al., however it has been modified. Magnetic resonance imaging (MRI) was applied for the analysis of the disintegration mechanism of prepared tablets. The research has shown the significant effect of excipients, compression force, temperature, volume and kind of medium on the disintegration process. The novel apparatus features better correlation of disintegration time with in vivo results (R(2) = 0.9999) than the compendial method (R(2) = 0.5788), and presents additional information on the disintegration process, e.g. swelling properties.

Physicochemical and Antimicrobial Properties of Cocoa Pod Husk Pectin Intended as a Versatile Pharmaceutical Excipient and Nutraceutical

Directory of Open Access Journals (Sweden)

Ofosua Adi-Dako

2016-01-01

Full Text Available The physicochemical and antimicrobial properties of cocoa pod husk (CPH pectin intended as a versatile pharmaceutical excipient and nutraceutical were studied. Properties investigated include pH, moisture content, ash values, swelling index, viscosity, degree of esterification (DE, flow properties, SEM, FTIR, NMR, and elemental content. Antimicrobial screening and determination of MICs against test microorganisms were undertaken using agar diffusion and broth dilution methods, respectively. CPH pectin had a DE of 26.8% and exhibited good physicochemical properties. Pectin had good microbiological quality and exhibited pseudoplastic, shear thinning behaviour, and high swelling capacity in aqueous media. The DE, FTIR, and NMR results were similar to those of previous studies and supported highly acetylated low methoxy pectin. CPH pectin was found to be a rich source of minerals and has potential as a nutraceutical. Pectin showed dose-dependent moderate activity against gram positive and gram negative microorganisms but weak activity against Listeria spp. and A. niger. The MICs of pectin ranged from 0.5 to 4.0 mg/mL, with the highest activity against E. coli and S. aureus (MIC: 0.5–1.0 mg/mL and the lowest activity against A. niger (MIC: 2.0–4.0 mg/mL. The study has demonstrated that CPH pectin possesses the requisite properties for use as a nutraceutical and functional pharmaceutical excipient.

Characterisation of a novel, multifunctional, co-processed excipient and its effect on release profile of paracetamol from tablets prepared by direct compression

Directory of Open Access Journals (Sweden)

Sylvester Okhuelegbe Eraga

2015-09-01

Conclusions: The drug-excipient ratios of 1:3 and 1:4 gave pharmaceutically acceptable tablets that met the British Pharmacopoeia specifications. The t50% value of the 1:4 batch of tablets may find its usefulness in formulating drugs for which a fast onset of action is desired.

In vitro profiling of the vaginal permeation potential of anti-HIV microbicides and the influence of formulation excipients.

Science.gov (United States)

Grammen, Carolien; Augustijns, Patrick; Brouwers, Joachim

2012-11-01

In the search for an effective anti-HIV microbicidal gel, limited drug penetration into the vaginal submucosa is a possible reason for failed protection against HIV transmission. To address this issue in early development, we here describe a simple in vitro strategy to predict the tissue permeation potential of vaginally applied drugs, based on solubility, permeability and flux assessment. We demonstrated this approach for four model microbicides (tenofovir, darunavir, saquinavir mesylate and dapivirine) and additionally examined the influence of formulation excipients on the permeation potential. When formulated in an aqueous-based HEC gel, high flux values across an HEC-1A cell layer were reached by tenofovir, as a result of its high aqueous solubility. In contrast, saquinavir and dapivirine fluxes remained low due to poor permeability and solubility, respectively. These low fluxes suggest limited in vivo tissue penetration, possibly leading to lack of efficacy. Dapivirine fluxes, however, could be enhanced up to 30-fold, by including formulation excipients such as polyethylene glycol 1000 (20%) or cyclodextrins (5%) in the HEC gels. Alternative formulations, i.e. emulsions or silicone elastomer gels, were less effective in flux enhancement compared to cyclodextrin-HEC gels. In conclusion, implementing the proposed solubility and permeability profiling in early microbicide development may contribute to the successful selection of promising microbicide candidates and appropriate formulations. Copyright © 2012 Elsevier B.V. All rights reserved.

Use of a screening method to determine excipients which optimize the extent and stability of supersaturated drug solutions and application of this system to solid formulation design.

Science.gov (United States)

Vandecruys, Roger; Peeters, Jef; Verreck, Geert; Brewster, Marcus E

2007-09-05

Assessing the effect of excipients on the ability to attain and maintain supersaturation of drug-based solution may provide useful information for the design of solid formulations. Judicious selection of materials that affect either the extent or stability of supersaturating drug delivery systems may be enabling for poorly soluble drug candidates or other difficult-to-formulate compounds. The technique suggested herein is aimed at providing a screening protocol to allow preliminary assessment of these factors based on small to moderate amounts of drug substance. A series of excipients were selected that may, by various mechanisms, affect supersaturation including pharmaceutical polymers such as HMPC and PVP, surfactants such as Polysorbate 20, Cremophor RH40 and TPGS and hydrophilic cyclodextrins such as HPbetaCD. Using a co-solvent based method and 25 drug candidates, the data suggested, on the whole, that the surfactants and the selected cyclodextrin seemed to best augment the extent of supersaturation but had variable benefits as stabilizers, while the pharmaceutical polymers had useful effect on supersaturation stability but were less helpful in increasing the extent of supersaturation. Using these data, a group of simple solid dosage forms were prepared and tested in the dog for one of the drug candidates. Excipients that gave the best extent and stability for the formed supersaturated solution in the screening assay also gave the highest oral bioavailability in the dog.

Entirely S-protected chitosan: A promising mucoadhesive excipient for metronidazole vaginal tablets.

Science.gov (United States)

Lupo, Noemi; Fodor, Benjamin; Muhammad, Ijaz; Yaqoob, Muhammad; Matuszczak, Barbara; Bernkop-Schnürch, Andreas

2017-12-01

Synthesis and evaluation of an entirely S-protected chitosan as mucoadhesive excipient for vaginal drug delivery. N-acetyl-cysteine was linked to 6-mercaptonicotinamide via disulphide exchange reaction. The obtained ligand, NAC-6-MNA, was subsequently attached to chitosan by carbodiimide mediated amide bond formation in two concentrations. The synthesized S-protected chitosan was chemically characterized and mucoadhesive properties and stability against oxidation were investigated. Moreover, metronidazole tablets comprising the S-protected chitosan were evaluated regarding water uptake capacity, disintegration behaviour, residence time on vaginal mucosa, release of the encapsulated drug and antimicrobial activity. S-protected chitosan displayed 160±19 (CS-MNA-160) and 320±38 (CS-MNA-320)µmol of ligand per gram of polymer. At pH 4.2, CS-MNA-160 and CS-MNA-320 showed 5.2-fold and 6.2-fold increase in mucus viscosity in comparison to unmodified chitosan (One-way ANOVA, pchitosan remained stable against oxidation in presence of 0.5%v/v hydrogen peroxide. Metronidazole tablets consisting in S-protected chitosan showed prolonged residence time on vaginal mucosa and improved water uptake capacity and disintegration time in comparison to tablets consisting of unmodified chitosan. Moreover, CS-MNA-320 metronidazole tablets displayed prolonged drug release and antimicrobial activity. On the basis of the achieved results, entirely S-protected chitosan represents a promising excipient for the development of metronidazole vaginal tablets. S-protected thiomers are polymers modified with thiol groups protected by aromatic ligands and characterized by strong mucoadhesive properties and high stability against oxidation. Up to date, the entirely S-protection of thiol groups was achieved via the synthesis of the ligand 2-((2-amino-2-carboxyethyl)disulfanyl)nicotinic acid) which can be directly bound to the backbone of polymers bearing carboxylic moieties as pectin. However, this

Thiolated polymers: evaluation of their potential as dermoadhesive excipients.

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Grießinger, Julia Anita; Bonengel, Sonja; Partenhauser, Alexandra; Ijaz, Muhammad; Bernkop-Schnürch, Andreas

2017-02-01

The objective of this study was to evaluate and compare four different thiolated polymers regarding their dermoadhesive potential. Therefore, three hydrophilic polymers (poly(acrylic acid), Carbopol 971 and carboxymethylcellulose) and a lipophilic polymer (silicone oil) were chosen to generate thiolated polymers followed by characterization. The total work of adhesion (TWA) and the maximum detachment force (MDF) of formulations containing modified and unmodified polymers were investigated on skin obtained from pig ears using a tensile sandwich technique. The synthesis of thiolated polymers provided 564 µmol, 1079 µmol, 482 µmol and 217 µmol thiol groups per gram poly(acrylic acid), Carbopol 971, carboxymethylcellulose and silicone oil, respectively. Hydrogels containing poly(acrylic acid)-cysteine, Carbopol 971-cysteine, and carboxymethylcellulose-cysteamine exhibited a 6-fold, 25-fold and 9-fold prolonged adhesion on porcine skin than the hydrogel formulations prepared from the corresponding unmodified polymers, respectively. Furthermore, thiolation of silicone oil with thioglycolic acid led to a 5-fold improvement in adhesion compared to the unmodified silicone oil. A comparison between the four thiolated polymer formulations showed a clear correlation between the amount of coupled thiol groups and the TWA. According to these results thiomers might also be useful excipients to provide a prolonged dermal resistance time of various formulations.

Contrasting the crospovidones functionality as excipients for direct compression

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Daniel García Ramírez

2015-03-01

Full Text Available Specific values of technological properties of excipients allow the establishment of numerical parameters to define and compare their functionality. This study investigates the functionality of Polyplasdones XL and XL10. Parameters studied included tablet disintegration profiles, compactibility profiles and powder flow. The results allowed the establishment of quantitative surrogate functionalities of technological performance, such as absolute number, and as a value relative to the known microcrystalline cellulose type 102. Moreover, the establishment of an explicit functionality to improve the technological performance of two diluents and a model drug was investigated, as was setting up of these functionalities, as quantitative values, to determine the input variables of each material and its probable functionality in a drug product. Disintegration times of pure Polyplasdone XL and its admixtures were around half that of Polyplasdone XL10. The improvement in tablet compactibility was 25-50% greater for Polyplasdone XL10 than Polyplasdone XL. Crospovidones proportions of up to 10% have little effect on the flow properties of other powders, although pure Polyplasdone XL10 and its admixtures display compressibility indexes about 20% greater than Polyplasdone XL. The observed results are in line with a smaller particle size of Polyplasdone XL10 compared to Polyplasdone XL.

Determination of As, Cd, Hg and Pb in continuous use drugs and excipients by plasma-based techniques in compliance with the United States Pharmacopeia requirements

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da Silva, Caroline Santos; Pinheiro, Fernanda Costa; do Amaral, Clarice Dias Britto; Nóbrega, Joaquim Araújo

2017-12-01

Some inorganic impurities are toxic to human health even when present at low concentrations and therefore must be carefully monitored in products as continuous use drugs. This work aimed the development of a simple microwave-assisted digestion procedure for different types of drugs and excipients and the analytical determination of elemental impurities according to the new regulations of the United States Pharmacopeia (USP) 232 and 233 using inductively coupled plasma optical emission spectrometry (ICP-OES) or inductively coupled plasma mass spectrometry (ICP-MS). Eight drugs samples and two excipients of different brands were microwave-assisted digested with inverse aqua regia. Addition and recovery experiments were performed according to J values, once permissible daily exposure value is specific for each element and estimated according to the maximum daily dose of drug indicated by the label. Samples were spiked with values of 1.5J in order to check accuracies for As, Cd, Hg, and Pb. Recoveries obtained by ICP-OES ranged from 75 to 148% and for ICP-MS ranged from 74 to 120%. The limits of detection for ICP-OES ranged from 0.4 to 17 mg kg- 1 and for ICP-MS from 7.4 to 41.6 μg kg- 1. Both analytical methods were adequate in terms of accuracies and sensitivities. Considering the maximum daily dose, all drugs samples and excipients contained As, Cd, Hg and Pb below the maximum limits stipulated by USP since all of them presented contents below respective limits of detection.

Comparison of the effect of two excipients (karite nut butter and vaseline on the efficacy of Cocos nucifera, Elaeis guineensis and Carapa procera oil-based repellents formulations against mosquitoes biting in Ivory Coast

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Konan Y.L.

2003-06-01

Full Text Available Repellents in the form of dermal pomades are recommended as a protection against awakening and bedtime mosquito bites. If synthesis repellents are available, they are nevertheless not common and the prices remain out of reach for the communities concerned. The people therefore have to resort more and more to traditional concoctions, some of which have been shown to be effective. After demonstrating that oil-based formulations (lotions, creams, pomades of Cocos nucifera (coconut, Elaeis guineensis (oil palm and Carapa procera (gobi were effective against mosquitoes, it became necessary to study the impact of the two excipients used in their manufacture, on the effectiveness of the repellents. Experiments were carried with Anopheles gambiae and Aedes aegypti under lobaratory conditions and any other mosquitoes collected under field conditions in Ivory Coast. The laboratory results indicate that the average protection times obtained with formulations with karite nut butter as excipient (54.8 ± 37.0 mn and 74.6 ± 26.4 mn respectively on An. gambiae and Ae. aegypti are higher than those recorded with vaseline as excipient (respectively 42.7 ± 30.0 mn and 60.8 ± 33.9 mn. On the other hand, under field conditions, the biting rate percentage reduction obtained with the products with karite nut butter and vaseline excipient were similar (respectively 29.8 % and 35.9 % for all mosquitoes collected and 45.7 % and 47.4 % against An. gambiae. Nevertheless, the use of karite nut butter on repellent products should be encouraged because its sale price is very lower (10 time less than the vaseline's.

Comparison of the effect of two excipients (karite nut butter and vaseline) on the efficacy of Cocos nucifera, Elaeis guineensis and Carapa procera oil-based repellents formulations against mosquitoes biting in Ivory Coast.

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Konan, Y L; Sylla, M S; Doannio, J M; Traoré, S

2003-06-01

Repellents in the form of dermal pomades are recommended as a protection against awakening and bedtime mosquito bites. If synthesis repellents are available, they are nevertheless not common and the prices remain out of reach for the communities concerned. The people therefore have to resort more and more to traditional concoctions, some of which have been shown to be effective. After demonstrating that oil-based formulations (lotions, creams, pomades) of Cocos nucifera (coconut), Elaeis guineensis (oil palm) and Carapa procera (gobi) were effective against mosquitoes, it became necessary to study the impact of the two excipients used in their manufacture, on the effectiveness of the repellents. Experiments were carried with Anopheles gambiae and Aedes aegypti under lobaratory conditions and any other mosquitoes collected under field conditions in Ivory Coast. The laboratory results indicate that the average protection times obtained with formulations with karite nut butter as excipient (54.8 +/- 37.0 mn and 74.6 +/- 26.4 mn respectively on An. gambiae and Ae. aegypti) are higher than those recorded with vaseline as excipient (respectively 42.7 +/- 30.0 mn and 60.8 +/- 33.9 mn). On the other hand, under field conditions, the biting rate percentage reduction obtained with the products with karite nut butter and vaseline excipient were similar (respectively 29.8% and 35.9% for all mosquitoes collected and 45.7% and 47.4% against An. gambiae). Nevertheless, the use of karite nut butter on repellent products should be encouraged because its sale price is very lower (10 time less) than the vaseline's.

Fractal aspects of the flow and shear behaviour of free-flowable particle size fractions of pharmaceutical directly compressible excipient sorbitol.

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Hurychová, Hana; Lebedová, Václava; Šklubalová, Zdenka; Dzámová, Pavlína; Svěrák, Tomáš; Stoniš, Jan

Flowability of powder excipients is directly influenced by their size and shape although the granulometric influence of the flow and shear behaviour of particulate matter is not studied frequently. In this work, the influence of particle size on the mass flow rate through the orifice of a conical hopper, and the cohesion and flow function was studied for four free-flowable size fractions of sorbitol for direct compression in the range of 0.080-0.400 mm. The particles were granulometricaly characterized using an optical microscopy; a boundary fractal dimension of 1.066 was estimated for regular sorbitol particles. In the particle size range studied, a non-linear relationship between the mean particle size and the mass flow rate Q10 (g/s) was detected having amaximum at the 0.245mm fraction. The best flow properties of this fraction were verified with aJenike shear tester due to the highest value of flow function and the lowest value of the cohesion. The results of this work show the importance of the right choice of the excipient particle size to achieve the best flow behaviour of particulate material.Key words: flowability size fraction sorbitol for direct compaction Jenike shear tester fractal dimension.

Spherical composite particles of rice starch and microcrystalline cellulose: a new coprocessed excipient for direct compression.

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Limwong, Vasinee; Sutanthavibul, Narueporn; Kulvanich, Poj

2004-03-12

Composite particles of rice starch (RS) and microcrystalline cellulose were fabricated by spray-drying technique to be used as a directly compressible excipient. Two size fractions of microcrystalline cellulose, sieved (MCS) and jet milled (MCJ), having volumetric mean diameter (D50) of 13.61 and 40.51 microm, respectively, were used to form composite particles with RS in various mixing ratios. The composite particles produced were evaluated for their powder and compression properties. Although an increase in the microcrystalline cellulose proportion imparted greater compressibility of the composite particles, the shape of the particles was typically less spherical with rougher surface resulting in a decrease in the degree of flowability. Compressibility of composite particles made from different size fractions of microcrystalline cellulose was not different; however, using MCJ, which had a particle size range close to the size of RS (D50 = 13.57 microm), provided more spherical particles than using MCS. Spherical composite particles between RS and MCJ in the ratio of 7:3 (RS-MCJ-73) were then evaluated for powder properties and compressibility in comparison with some marketed directly compressible diluents. Compressibility of RS-MCJ-73 was greater than commercial spray-dried RS (Eratab), coprocessed lactose and microcrystalline cellulose (Cellactose), and agglomerated lactose (Tablettose), but, as expected, lower than microcrystalline cellulose (Vivapur 101). Flowability index of RS-MCJ-73 appeared to be slightly lower than Eratab but higher than Vivapur 101, Cellactose, and Tablettose. Tablets of RS-MCJ-73 exhibited low friability and good self-disintegrating property. It was concluded that these developed composite particles could be introduced as a new coprocessed direct compression excipient.

Structural investigation of spherical hollow excipient Mannit Q by X-ray microtomography.

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Kajihara, Ryusuke; Noguchi, Shuji; Iwao, Yasunori; Yasuda, Yuki; Segawa, Megumi; Itai, Shigeru

2015-11-10

The structure of Mannit Q particles, an excipient made by spray-drying a d-mannitol solution, and Mannit Q tablets were investigated by synchrotron X-ray microtomography. The Mannit Q particles had a spherical shape with a hollow core. The shells of the particles consisted of fine needle-shaped crystals, and columnar crystals were present in the hollows. These structural features suggested the following formation mechanism for the hollow particles:during the spray-drying process, the solvent rapidly evaporated from the droplet surface, resulting in the formation of shells made of fine needle-shaped crystals.Solvent remaining inside the shells then evaporated slowly and larger columnar crystals grew as the hollows formed. Although most of the Mannit Q particles were crushed on tableting, some of the particles retained their hollow structures, probably because the columnar crystals inside the hollows functioned as props. This demonstrated that the tablets with porous void spaces may be readily manufactured using Mannit Q. Copyright © 2015 Elsevier B.V. All rights reserved.

Solid-state mAbs and ADCs subjected to heat-stress stability conditions can be covalently modified with buffer and excipient molecules.

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Valliere-Douglass, John F; Lewis, Patsy; Salas-Solano, Oscar; Jiang, Shan

2015-02-01

We report that a unique type of chemical modification occurs on lyophilized proteins. Freeze-dried mAbs and antibody-drug conjugates (ADCs) can be covalently modified with buffer and excipient molecules on the side chains of Glu, Asp, Thr, and Ser amino acids when subjected to temperature stress. The reaction occurs primarily via condensation of common buffers and excipients such as histidine, tris, trehalose and sucrose, with Glu and Asp carboxylates in the primary sequence of proteins. The reaction was also found to proceed through condensation of carboxylate containing buffers such as citrate, with Thr and Ser hydroxyls in the primary sequence of proteins. Based on the mass of the covalent adducts observed on mAbs and ADCs, it is apparent that the reaction produces water as a product and is thus favored in a low moisture environments such as a lyophilized protein cake. Herein, we present the evidence for the covalent modification of proteins drawn from case studies of in-depth characterization of heat-stressed mAbs and ADCs in the solid state. We also demonstrate how common charge variant assays such as imaged capillary isoelectric focusing and mass spectrometry can be used to monitor this specific class of protein modification. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Influence of Excipients and Spray Drying on the Physical and Chemical Properties of Nutraceutical Capsules Containing Phytochemicals from Black Bean Extract.

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Guajardo-Flores, Daniel; Rempel, Curtis; Gutiérrez-Uribe, Janet A; Serna-Saldívar, Sergio O

2015-12-03

Black beans (Phaseolus vulgaris L.) are a rich source of flavonoids and saponins with proven health benefits. Spray dried black bean extract powders were used in different formulations for the production of nutraceutical capsules with reduced batch-to-batch weight variability. Factorial designs were used to find an adequate maltodextrin-extract ratio for the spray-drying process to produce black bean extract powders. Several flowability properties were used to determine composite flow index of produced powders. Powder containing 6% maltodextrin had the highest yield (78.6%) and the best recovery of flavonoids and saponins (>56% and >73%, respectively). The new complexes formed by the interaction of black bean powder with maltodextrin, microcrystalline cellulose 50 and starch exhibited not only bigger particles, but also a rougher structure than using only maltodextrin and starch as excipients. A drying process prior to capsule production improved powder flowability, increasing capsule weight and reducing variability. The formulation containing 25.0% of maltodextrin, 24.1% of microcrystalline cellulose 50, 50% of starch and 0.9% of magnesium stearate produced capsules with less than 2.5% weight variability. The spray drying technique is a feasible technique to produce good flow extract powders containing valuable phytochemicals and low cost excipients to reduce the end-product variability.

Graft copolymers of ethyl methacrylate on waxy maize starch derivatives as novel excipients for matrix tablets: physicochemical and technological characterisation.

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Marinich, J A; Ferrero, C; Jiménez-Castellanos, M R

2009-05-01

Nowadays, graft copolymers are being used as an interesting option when developing a direct compression excipient for controlled release matrix tablets. New graft copolymers of ethyl methacrylate (EMA) on waxy maize starch (MS) and hydroxypropylstarch (MHS) were synthesised by free radical polymerization and alternatively dried in a vacuum oven (OD) or freeze-dried (FD). This paper evaluates the performance of these new macromolecules and discusses the effect of the carbohydrate nature and drying process on their physicochemical and technological properties. Grafting of EMA on the carbohydrate backbone was confirmed by IR and NMR spectroscopy, and the grafting yields revealed that graft copolymers present mainly a hydrophobic character. The graft copolymerization also leads to more amorphous materials with larger particle size and lower apparent density and water content than carbohydrates (MS, MHS). All the products show a lack of flow, except MHSEMA derivatives. MSEMA copolymers underwent much plastic flow and less elastic recovery than MHSEMA copolymers. Concerning the effect of drying method, FD derivatives were characterised by higher plastic deformation and less elasticity than OD derivatives. Tablets obtained from graft copolymers showed higher crushing strength and disintegration time than tablets obtained from raw starches. This behaviour suggests that these copolymers could be used as excipients in matrix tablets obtained by direct compression and with a potential use in controlled release.

Effect of Kollidon VA®64 particle size and morphology as directly compressible excipient on tablet compression properties.

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Chaudhary, R S; Patel, C; Sevak, V; Chan, M

2018-01-01

The study evaluates use of Kollidon VA ® 64 and a combination of Kollidon VA ® 64 with Kollidon VA ® 64 Fine as excipient in direct compression process of tablets. The combination of the two grades of material is evaluated for capping, lamination and excessive friability. Inter particulate void space is higher for such excipient due to the hollow structure of the Kollidon VA ® 64 particles. During tablet compression air remains trapped in the blend exhibiting poor compression with compromised physical properties of the tablets. Composition of Kollidon VA ® 64 and Kollidon VA ® 64 Fine is evaluated by design of experiment (DoE). A scanning electron microscopy (SEM) of two grades of Kollidon VA ® 64 exhibits morphological differences between coarse and fine grade. The tablet compression process is evaluated with a mix consisting of entirely Kollidon VA ® 64 and two mixes containing Kollidon VA ® 64 and Kollidon VA ® 64 Fine in ratio of 77:23 and 65:35. A statistical modeling on the results from the DoE trials resulted in the optimum composition for direct tablet compression as combination of Kollidon VA ® 64 and Kollidon VA ® 64 Fine in ratio of 77:23. This combination compressed with the predicted parameters based on the statistical modeling and applying main compression force between 5 and 15 kN, pre-compression force between 2 and 3 kN, feeder speed fixed at 25 rpm and compression range of 45-49 rpm produced tablets with hardness ranging between 19 and 21 kp, with no friability, capping, or lamination issue.

Survivability of freeze-dried probiotic Pediococcus pentosaceus strains GS4, GS17 and Lactobacillus gasseri (ATCC 19992 during storage with commonly used pharmaceutical excipients within a period of 120 days

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Mayur Bagad

2017-10-01

Conclusions: Commonly used excipients can be considered as a vehicle for delivering active principle in probiotic formulation and for sustaining the viability and stability of probiotic strains for a period of 120 d.

l-Cystine-Crosslinked Polypeptide Nanogel as a Reduction-Responsive Excipient for Prostate Cancer Chemotherapy

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Liang He

2016-01-01

Full Text Available Smart polymer nanogel-assisted drug delivery systems have attracted more and more attention in cancer chemotherapy because of their well-defined morphologies and pleiotropic functions in recent years. In this work, an l-cystine-crosslinked reduction-responsive polypeptide nanogel of methoxy poly(ethylene glycol-poly(l-phenylalanine-co-l-cystine (mPEG-P(LP-co-LC was employed as a smart excipient for RM-1 prostate cancer (PCa chemotherapy. Doxorubicin (DOX, as a regular chemotherapy drug, was embedded in the nanogel. The loading nanogel marked as NG/DOX was shown to exhibit glutathione (GSH-induced swelling and GSH-accelerated DOX release. Subsequently, NG/DOX showed efficient cellular uptake and proliferation inhibition. Furthermore, NG/DOX presented enhanced antitumor efficacy and security in an RM-1 PCa-grafted mouse model in vivo, indicating its great potential for clinical treatment.

Effects of frequently used pharmaceutical excipients on the organic cation transporters 1-3 and peptide transporters 1/2 stably expressed in MDCKII cells.

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Otter, Marcus; Oswald, Stefan; Siegmund, Werner; Keiser, Markus

2017-03-01

There is ample evidence that pharmaceutical excipients, which are supposed to be pharmacologically inactive, have an impact on drug metabolism and efflux transport. So far, little is known whether they also modulate uptake transporter proteins. We have recently shown that commonly used solubilizing agents exert significant effects on the function of organic anion uptake transporting polypeptides. Therefore, we investigated in this study the influence of frequently used pharmaceutical excipients on the transport activity of organic cation transporters OCT1, OCT2 and OCT3 and the peptide transporters PEPT1 and PEPT2. Inhibition of the OCTs and PEPTs by the excipients polyethylene glycol 400 (PEG), hydroxypropyl-β-cyclodextrin (HPCD), Solutol® HS15 (SOL), Cremophor® EL (CrEL), Tween® 20 (Tw20), Tween® 80 (Tw80), Kolliphor® P188 (P188) and Kolliphor® P407 (P407) was evaluated using stably transfected MDCKII cells with radio-labeled reference substrates and established inhibitors as controls. Intracellular accumulation of [3H]-1-methyl-4-phenylpyridinium (MPP + ) for the OCTs and [3H]-glycyl-sarcosine (Gly-Sar) for the PEPTs was measured by liquid scintillation counting after cell lysis. Our studies revealed that PEG, HPCD, SOL, CrEL, Tw20 and Tw80 were potent inhibitors of OCT1-3 (e.g., Tw20 IC 50 values<0.04%). Cellular uptake of Gly-Sar by PEPT1 and PEPT2 was strongly inhibited by both Tw20 and Tw80. SOL was also a strong inhibitor of PEPT1 and PEPT2 (e.g., SOL IC 50 values<0.02%), while CrEL showed significantly inhibition of only PEPT2. The substantial inhibitory effects of certain solubilizing agents on OCTs and PEPTs should be considered if they are to be used in dosage forms for new chemical entities and registered drugs to avoid misinterpretation of pharmacokinetic data and undesired drug interactions. Copyright © 2016 Elsevier B.V. All rights reserved.

Thiomers: potential excipients for non-invasive peptide delivery systems.

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Bernkop-Schnürch, Andreas; Krauland, Alexander H; Leitner, Verena M; Palmberger, Thomas

2004-09-01

In recent years thiolated polymers or so-called thiomers have appeared as a promising alternative in the arena of non-invasive peptide delivery. Thiomers are generated by the immobilisation of thiol-bearing ligands to mucoadhesive polymeric excipients. By formation of disulfide bonds with mucus glycoproteins, the mucoadhesive properties of these polymers are improved up to 130-fold. Due to formation of inter- and intramolecular disulfide bonds within the thiomer itself, dosage forms such as tablets or microparticles display strong cohesive properties resulting in comparatively higher stability, prolonged disintegration times and a more controlled release of the embedded peptide drug. The permeation of peptide drugs through mucosa can be improved by the use of thiolated polymers. Additionally some thiomers exhibit improved inhibitory properties towards peptidases. The efficacy of thiomers in non-invasive peptide delivery could be demonstrated by various in vivo studies. Tablets comprising a thiomer and pegylated insulin, for instance, resulted in a pharmacological efficacy of 7% after oral application to diabetic mice. Furthermore, a pharmacological efficacy of 1.3% was achieved in rats by oral administration of calcitonin tablets comprising a thiomer. Human growth hormone in a thiomer-gel was applied nasally to rats and led to a bioavailability of 2.75%. In all these studies, formulations comprising the corresponding unmodified polymer had only a marginal or no effect. According to these results drug carrier systems based on thiomers seem to be a promising tool for non-invasive peptide drug delivery.

Solid-State NMR Investigation of Drug-Excipient Interactions and Phase Behavior in Indomethacin-Eudragit E Amorphous Solid Dispersions.

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Lubach, Joseph W; Hau, Jonathan

2018-02-20

To investigate the nature of drug-excipient interactions between indomethacin (IMC) and methacrylate copolymer Eudragit® E (EE) in the amorphous state, and evaluate the effects on formulation and stability of these amorphous systems. Amorphous solid dispersions containing IMC and EE were spray dried with drug loadings from 20% to 90%. PXRD was used to confirm the amorphous nature of the dispersions, and DSC was used to measure glass transition temperatures (T g ). 13 C and 15 N solid-state NMR was utilized to investigate changes in local structure and protonation state, while 1 H T 1 and T 1ρ relaxation measurements were used to probe miscibility and phase behavior of the dispersions. T g values for IMC-EE solid dispersions showed significant positive deviations from predicted values in the drug loading range of 40-90%, indicating a relatively strong drug-excipient interaction. 15 N solid-state NMR exhibited a change in protonation state of the EE basic amine, with two distinct populations for the EE amine at -360.7 ppm (unprotonated) and -344.4 ppm (protonated). Additionally, 1 H relaxation measurements showed phase separation at high drug load, indicating an amorphous ionic complex and free IMC-rich phase. PXRD data showed all ASDs up to 90% drug load remained physically stable after 2 years. 15 N solid-state NMR experiments show a change in protonation state of EE, indicating that an ionic complex indeed forms between IMC and EE in amorphous solid dispersions. Phase behavior was determined to exhibit nanoscale phase separation at high drug load between the amorphous ionic complex and excess free IMC.

Effect of milling on DSC thermogram of excipient adipic acid.

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Ng, Wai Kiong; Kwek, Jin Wang; Yuen, Aaron; Tan, Chin Lee; Tan, Reginald

2010-03-01

The purpose of this research was to investigate why and how mechanical milling results in an unexpected shift in differential scanning calorimetry (DSC) measured fusion enthalpy (Delta(fus)H) and melting point (T(m)) of adipic acid, a pharmaceutical excipient. Hyper differential scanning calorimetry (hyper-DSC) was used to characterize adipic acid before and after ball-milling. An experimental study was conducted to evaluate previous postulations such as electrostatic charging using the Faraday cage method, crystallinity loss using powder X-ray diffraction (PXRD), thermal annealing using DSC, impurities removal using thermal gravimetric analysis (TGA) and Karl Fischer titration. DSC thermograms showed that after milling, the values of Delta(fus)H and T(m) were increased by approximately 9% and 5 K, respectively. Previous suggestions of increased electrostatic attraction, change in particle size distribution, and thermal annealing during measurements did not explain the differences. Instead, theoretical analysis and experimental findings suggested that the residual solvent (water) plays a key role. Water entrapped as inclusions inside adipic acid during solution crystallization was partially evaporated by localized heating at the cleaved surfaces during milling. The correlation between the removal of water and melting properties measured was shown via drying and crystallization experiments. These findings show that milling can reduce residual solvent content and causes a shift in DSC results.

Thiolated alkyl-modified carbomers: Novel excipients for mucoadhesive emulsions.

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Bonengel, Sonja; Hauptstein, Sabine; Leonaviciute, Gintare; Griessinger, Julia; Bernkop-Schnürch, Andreas

2015-07-30

The aim of this study was the design and evaluation of mucoadhesive emulsifying polymeric excipients. Three thiol bearing ligands with increasing pKa values of their sulfhydryl group, namely 4-aminothiophenol (pKa=6.86), l-cysteine (pKa=8.4) and d/l-homocysteine (pKa=10.0) were coupled to the polymeric backbone of alkyl-modified carbomer (PA1030). Resulting conjugates displayed 818.5μmol 4-aminothiophenol, 698.5μmol cysteine and 651.5μmol homocysteine per gram polymer and were evaluated regarding the reactivity of thiol groups, emulsifying and mucoadhesive properties. In general, the synthesized conjugates showed a pH dependent reactivity, whereby the fastest oxidation occurred in PA1030-cysteine, as almost no free thiol groups could be detected after 120min. Emulsification of medium chain triglycerides was feasible with all synthesized conjugates leading to oil-in-water-emulsions. Emulsions with PA1030-cysteine displayed the highest stability and the smallest droplet size among the tested formulations. Oxidation and consequently cross-linking of the thiomers prior to the emulsification process led to an overall decreased emulsion stability. Evaluating mucosal residence time of thiomer emulsions on porcine buccal mucosa, a 9.2-fold higher amount of formulation based on PA1030-cysteine remained on the mucosal tissue within 3h compared to the unmodified polymer. According to these results, the highest reactive ligand l-cysteine seems to be most promising in order to obtain thiolated polymers for the preparation of mucoadhesive o/w-emulsions. Copyright © 2015 Elsevier B.V. All rights reserved.

Evaluation of the light scattering and the turbidity microtiter plate-based methods for the detection of the excipient-mediated drug precipitation inhibition.

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Petruševska, Marija; Urleb, Uroš; Peternel, Luka

2013-11-01

The excipient-mediated precipitation inhibition is classically determined by the quantification of the dissolved compound in the solution. In this study, two alternative approaches were evaluated, one is the light scattering (nephelometer) and other is the turbidity (plate reader) microtiter plate-based methods which are based on the quantification of the compound precipitate. Following the optimization of the nephelometer settings (beam focus, laser gain) and the experimental conditions, the screening of 23 excipients on the precipitation inhibition of poorly soluble fenofibrate and dipyridamole was performed. The light scattering method resulted in excellent correlation (r>0.91) between the calculated precipitation inhibitor parameters (PIPs) and the precipitation inhibition index (PI(classical)) obtained by the classical approach for fenofibrate and dipyridamole. Among the evaluated PIPs AUC100 (nephelometer) resulted in only four false positives and lack of false negatives. In the case of the turbidity-based method a good correlation of the PI(classical) was obtained for the PIP maximal optical density (OD(max), r=0.91), however, only for fenofibrate. In the case of the OD(max) (plate reader) five false positives and two false negatives were identified. In conclusion, the light scattering-based method outperformed the turbidity-based one and could be reliably used for identification of novel precipitation inhibitors. Copyright © 2013 Elsevier B.V. All rights reserved.

Determination of drug, excipients and coating distribution in pharmaceutical tablets using NIR-CI

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Anna Palou

2012-04-01

Full Text Available The growing interest of the pharmaceutical industry in Near Infrared-Chemical Imaging (NIR-CI is a result of its high usefulness for quality control analyses of drugs throughout their production process (particularly of its non-destructive nature and expeditious data acquisition. In this work, the concentration and distribution of the major and minor components of pharmaceutical tablets are determined and the spatial distribution from the internal and external sides has been obtained. In addition, the same NIR-CI allowed the coating thickness and its surface distribution to be quantified. Images were processed to extract the target data and calibration models constructed using the Partial Least Squares (PLS algorithms. The concentrations of Active Pharmaceutical Ingredient (API and excipients obtained for uncoated cores were essentially identical to the nominal values of the pharmaceutical formulation. But the predictive ability of the calibration models applied to the coated tablets decreased as the coating thickness increased. Keywords: Near infrared Chemical Imaging (NIR-CI, Hyperspectral imaging, Component distribution, Tablet coating distribution, Partial Least Squares (PLS regression

Role of excipients in hydrate formation kinetics of theophylline in wet masses studied by near-infrared spectroscopy

DEFF Research Database (Denmark)

Jørgensen, Anna C; Airaksinen, Sari; Karjalainen, Milja

2004-01-01

. Anhydrous theophylline was chosen as the hydrate-forming model drug compound and two excipients, silicified microcrystalline cellulose (SMCC) and alpha-lactose monohydrate, with different water absorbing properties, were used in formulation. An early stage of wet massing was studied with anhydrous...... theophylline and its 1:1 (w/w) mixtures with alpha-lactose monohydrate and SMCC with 0.1g/g of purified water. The changes in the state of water were monitored using near-infrared spectroscopy, and the conversion of the crystal structure was verified using X-ray powder diffraction (XRPD). SMCC decreased...... the hydrate formation rate by absorbing water, but did not inhibit it. The results suggest that alpha-lactose monohydrate slightly increased the hydrate formation rate in comparison with a mass comprising only anhydrous theophylline....

Evaluation and Modification of Commercial Dry Powder Inhalers for the Aerosolization of a Submicrometer Excipient Enhanced Growth (EEG) Formulation

Science.gov (United States)

Son, Yoen-Ju; Longest, P. Worth; Tian, Geng; Hindle, Michael

2013-01-01

The aim of this study was to evaluate and modify commercial dry powder inhalers (DPIs) for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation. The optimized device and formulation combination was then tested in a realistic in vitro mouth-throat - tracheobronchial (MT-TB) model. An optimized EEG submicrometer powder formulation, consisting of albuterol sulfate (drug), mannitol (hygroscopic excipient), L-leucine (dispersion enhancer) and poloxamer 188 (surfactant) in a ratio of 30:48:20:2 was prepared using a Büchi Nano spray dryer. The aerosolization performance of the EEG formulation was evaluated with 5 conventional DPIs: Aerolizer, Novolizer, HandiHaler, Exubera and Spiros. To improve powder dispersion, the HandiHaler was modified with novel mouth piece (MP) designs. The aerosol performance of each device was assessed using a next generation impactor (NGI) at airflow rates generating a pressure drop of 4 kPa across the DPI. In silico and in vitro deposition and hygroscopic growth of formulations was studied using a MT-TB airway geometry model. Both Handihaler and Aerolizer produced high emitted doses (ED) together with a significant submicrometer aerosol fraction. A modified HandiHaler with a MP including a three-dimensional (3D) array of rods (HH-3D) produced a submicrometer particle fraction of 38.8% with a conventional fine particle fraction (% <5µm) of 97.3%. The mass median diameter (MMD) of the aerosol was reduced below 1 µm using this HH-3D DPI. The aerosol generated from the modified HandiHaler increased to micrometer size (2.8 µm) suitable for pulmonary deposition, when exposed to simulated respiratory conditions, with negligible mouth-throat (MT) deposition (2.6 %). PMID:23608613

Managing acute pain in patients who report lactose intolerance: the safety of an old excipient re-examined.

Science.gov (United States)

Mill, Deanna; Dawson, Jessica; Johnson, Jacinta Lee

2018-05-01

Lactose intolerance is exceedingly common, reportedly affecting up to 70% of the world's population, leading to both abdominal and systemic symptoms. Current treatment focuses predominantly on restricting dietary consumption of lactose. Given lactose is one of the most commonly used excipients in the pharmaceutical industry, consideration must be given to the lactose content and therefore safety of pharmaceutical preparations prescribed for patients with lactose intolerance. This article summarizes the current literature examining the likelihood of inducing adverse effects through the administration of lactose-containing pharmaceutical preparations in patients reporting lactose intolerance, describes how to assess this risk on an individual patient basis and reviews suitable analgesic options for this population. A case study is presented detailing a patient reporting lactose intolerance who insists on treatment with the lactose-free product codeine/ibuprofen (Nurofen Plus) rather than other codeine-free analgesics. It is important to assess the likelihood of lactose as an excipient inducing symptoms in this scenario, as reluctance to cease codeine could suggest codeine dependence, an issue that is becoming increasingly common in countries such as Australia and Canada. Given codeine dependence is associated with serious sequelae including hospitalization and death, the patient must either be reassured the lactose component in their prescribed analgesics will not induce symptoms or an alternative treatment strategy must be confirmed. General recommendations applying theory from the literature to the management of acute pain in lactose-intolerant patients are discussed and specific treatment options are outlined. Although large inter-individual variability is reported, most lactose-intolerant patients can tolerate the small quantities of lactose found in pharmaceutical preparations. Cumulative lactose exposure can be assessed in patients taking multiple medications

Safety and regulatory review of dyes commonly used as excipients in pharmaceutical and nutraceutical applications.

Science.gov (United States)

Pérez-Ibarbia, Leire; Majdanski, Tobias; Schubert, Stephanie; Windhab, Norbert; Schubert, Ulrich S

2016-10-10

Color selection is one of the key elements of building a strong brand development and product identity in the pharmaceutical industry, besides to prevent counterfeiting. Moreover, colored pharmaceutical dosage forms may increase patient compliance and therapy enhancement. Although most synthetic dyes are classified as safe, their regulations are stricter than other classes of excipients. Safety concerns have increased during the last years but the efforts to change to natural dyes seem to be not promising. Their instability problems and the development of "non-toxic" dyes is still a challenge. This review focuses specifically on the issues related to dye selection and summarizes the current regulatory status. A deep awareness of toxicological data based on the public domain, making sure the compliance of standards for regulation and safety for successful product development is provided. In addition, synthetic strategies are provided to covalently bind dyes on polymers to possibly overcome toxicity issues. Copyright © 2016 Elsevier B.V. All rights reserved.

Isolation, characterization and investigation of Cordia dichotoma fruit polysaccharide as a herbal excipient.

Science.gov (United States)

Pawar, Harshal Ashok; Jadhav, Pravin

2015-01-01

The objective of the present research work was to isolate, purify and characterize Cordia dichotoma gum and investigate its disintegration property in oral tablets. The isolated gum was tested for physicochemical characteristics such as solubility, pH (1% w/w in water), swelling index, loss on drying, ash value, bulk and tapped density, Carr's index, Hausner's ratio and angle of repose. The Orodispersible tablets of valsartan were prepared by direct compression method and evaluated for average weight (mg), drug content (%), thickness (mm), hardness (kg/cm(2)), friability (%), wetting time (sec), water absorption ratio (%) and disintegration time (sec). FTIR studies revealed that there was no interaction between drug, gum and other excipients used in the study. The F4 batch with disintegration time 26.34 ± 0.78 s and in vitro release 99.64 ± 0.43% was selected as optimized formulation. This formulation was compared with conventional marketed formulation and was found superior. Batch F4 was subjected to stability studies for three months and was tested for its disintegration time, drug contents and dissolution behaviour. Batch F4 was found stable for three months at accelerated temperature. Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical stability of insulin. 3. Influence of excipients, formulation, and pH.

Science.gov (United States)

Brange, J; Langkjaer, L

1992-01-01

The influence of auxiliary substances and pH on the chemical transformations of insulin in pharmaceutical formulation, including various hydrolytic and intermolecular cross-linking reactions, was studied. Bacteriostatic agents had a profound stabilizing effect--phenol > m-cresol > methylparaben--on deamidation as well as on insulin intermolecular cross-linking reactions. Of the isotonicity substances, NaCl generally had a stabilizing effect whereas glycerol and glucose led to increased chemical deterioration. Phenol and sodium chloride exerted their stabilizing effect through independent mechanisms. Zinc ions, in concentrations that promote association of insulin into hexamers, increase the stability, whereas higher zinc content had no further influence. Protamine gave rise to additional formation of covalent protamine-insulin products which increased with increasing protamine concentration. The impact of excipients on the chemical processes seems to be dictated mainly via an influence on the three-dimensional insulin structure. The effect of the physical state of the insulin on the chemical stability was also complex, suggesting an intricate dependence of intermolecular proximity of involved functional groups. At pH values below five and above eight, insulin degrades relatively fast. At acid pH, deamidation at residue A21 and covalent insulin dimerization dominates, whereas disulfide reactions leading to covalent polymerization and formation of A- and B-chains prevailed in alkaline medium. Structure-reactivity relationship is proposed to be a main determinant for the chemical transformation of insulin.

Physicochemical and in vitro deposition properties of salbutamol sulphate/ipratropium bromide and salbutamol sulphate/excipient spray dried mixtures for use in dry powder inhalers.

Science.gov (United States)

Corrigan, Deirdre O; Corrigan, Owen I; Healy, Anne Marie

2006-09-28

The physicochemical and aerodynamic properties of spray dried powders of the drug/drug mixture salbutamol sulphate/ipratropium bromide were investigated. The in vitro deposition properties of spray dried salbutamol sulphate and the spray dried drug/excipient mixtures salbutamol sulphate/lactose and salbutamol sulphate/PEG were also determined. Spray drying ipratropium bromide monohydrate resulted in a crystalline material from both aqueous and ethanolic solution. The product spray dried from aqueous solution consisted mainly of ipratropium bromide anhydrous. There was evidence of the presence of another polymorphic form of ipratropium bromide. When spray dried from ethanolic solution the physicochemical characterisation suggested the presence of an ipratropium bromide solvate with some anhydrous ipratropium bromide. Co-spray drying salbutamol sulphate with ipratropium bromide resulted in amorphous composites, regardless of solvent used. Particles were spherical and of a size suitable for inhalation. Twin impinger studies showed an increase in the fine particle fraction (FPF) of spray dried salbutamol sulphate compared to micronised salbutamol sulphate. Co-spray dried salbutamol sulphate:ipratropium bromide 10:1 and 5:1 systems also showed an increase in FPF compared to micronised salbutamol sulphate. Most co-spray dried salbutamol sulphate/excipient systems investigated demonstrated FPFs greater than that of micronised drug alone. The exceptions to this were systems containing PEG 4000 20% or PEG 20,000 40% both of which had FPFs not significantly different from micronised salbutamol sulphate. These two systems were crystalline unlike most of the other spray dried composites examined which were amorphous in nature.

Influence of polymeric excipient properties on crystal hydrate formation kinetics of caffeine in aqueous slurries.

Science.gov (United States)

Gift, Alan D; Southard, Leslie A; Riesberg, Amanda L

2012-05-01

The influence of polymeric excipients on the hydrate transformation of caffeine (CAF) was studied. Anhydrous CAF was added to aqueous solutions containing different additives and the transformation to the hydrate form was monitored using in-line Raman spectroscopy. Various properties of two known inhibitors of CAF hydrate formation, polyacrylic acid (PAA) and polyvinyl alcohol (PVA), were investigated. For inhibition by PAA, a pH dependence was observed: at low pH, the inhibition was greatest, whereas no inhibitory effects were observed at pH above 6.5. For PVA, grades with high percent hydrolysis were the most effective at inhibiting the transformation. In addition, PVA with higher molecular weight showed slightly more inhibition than the shorter chain PVA polymers. A variety of other hydroxyl containing compounds were examined but none inhibited the CAF anhydrate-to-hydrate transformation. The observed inhibitory effects of PAA and PVA are attributed to the large number of closely spaced hydrogen bond donating groups of the polymer molecule, which can interact with the CAF hydrate crystal. Copyright © 2012 Wiley Periodicals, Inc.

Carnauba wax as a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of highly soluble drugs.

Science.gov (United States)

Nart, Viviane; Beringhs, André O'Reilly; França, Maria Terezinha; de Espíndola, Brenda; Pezzini, Bianca Ramos; Stulzer, Hellen Karine

2017-01-01

Mini-tablets are a new tendency in solid dosage form design for overcoming therapeutic obstacles such as impaired swallowing and polypharmacy therapy. Among their advantages, these systems offer therapeutic benefits such as dose flexibility and combined drug release patterns. The use of lipids in the formulation has also drawn considerable interest as means to modify the drug release from the dosage form. Therefore, this paper aimed at developing sustained release mini-tablets containing the highly soluble drugs captopril and metformin hydrochloride. Carnauba wax was used as a lipid component in melt granulation, targeting the improvement of the drugs poor flowability and tabletability, as well as to sustain the drug release profiles in association with other excipients. To assist sustaining the drug release, Ethocel™ (EC) and Kollicoat® SR 30D associated with Opadry® II were employed as matrix-forming and reservoir-forming materials, respectively. The neat drugs, granules and the bulk formulations were evaluated for their angle of repose, compressibility index, Hausner ratio and tabletability. Mini-tablets were evaluated for their weight variation, hardness, friability, drug content and in-vitro drug release. The results indicated that melt granulation with carnauba wax improved the flow and the tabletability of the drugs, allowing the preparation of mini-tablets with adequate tensile strength under reduced compaction pressures. All mini-tablet formulations showed acceptable hardness (within the range of 1.16 to 3.93Kp) and friability (carnauba wax proved to be a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of soluble drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

Development and Validation of a Chromatography Method Using Tandem UV/Charged Aerosol Detector for Simultaneous Determination of Amlodipine Besylate and Olmesartan Medoxomil: Application to Drug-Excipient Compatibility Study

Directory of Open Access Journals (Sweden)

Ariadne M. Brondi

2017-01-01

Full Text Available A study was carried out to investigate compatibility of amlodipine besylate and olmesartan medoxomil with a variety of pharmaceutical excipients. Both drugs are antihypertensive agents that can be administered alone, in monotherapy, or in pharmaceutical association. The studies were performed using binary and ternary mixtures, and samples were stored for 3 and 6 months at 40°C under 75% relative humidity and dry conditions. For this study, a method based on high-performance liquid chromatography (HPLC was developed and validated for the simultaneous determination of amlodipine besylate and olmesartan medoxomil in samples from pharmaceutical preformulation studies using diode array detector (DAD and charged aerosol detector (CAD. The runtime per sample was 10 min with retention time of 7.926 min and 4.408 min for amlodipine and olmesartan, respectively. The validation was performed according to ICH guidelines. The calibration curve presents linear dynamic range from 12 to 250 μg mL−1 for amlodipine and from 25 to 500 μg mL−1 for olmesartan with coefficient of determination (R2 ≥ 0.9908 while repeatability and reproducibility (expressed as relative standard deviation were lower than 1.0%. The excipients such as corn starch, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, talc, polyvinylpyrrolidone, lactose monohydrate, and polyethylene glycol showed potential incompatibilities after accelerated stability testing.

S-protected thiolated hydroxyethyl cellulose (HEC): Novel mucoadhesive excipient with improved stability.

Science.gov (United States)

Leonaviciute, Gintare; Bonengel, Sonja; Mahmood, Arshad; Ahmad Idrees, Muneeb; Bernkop-Schnürch, Andreas

2016-06-25

The aim of this study was the design of novel S-protected thiolated hydroxyethyl cellulose (HEC) and the assessment of its mucoadhesive properties and biodegradability compared to the corresponding unmodified polymer. Thiolated HEC was S-protected via disulfide bond formation between 6-mercaptonicotinamide (6-MNA) and the thiol substructures of the polymer. In vitro screening of mucoadhesive properties was accomplished using two different methods: rotating cylinder studies and viscosity measurements. Moreover, biodegradability of these polymers by cellulase, xylanase and lysozyme was evaluated. MTT and LDH assays were performed on Caco-2 cells to determine the cytotoxicity of S-protected thiolated HEC. Thiolated HEC displayed 280.09±1.70μmol of free thiol groups per gram polymer. S-protected thiolated HEC exhibiting 270.8±21.11μmol immobilized 6-MNA ligands per gram of polymer was shown being 2.4-fold more mucoadhesive compared to thiolated HEC. No mucoadhesion was observed in case of unmodified HEC. Results were in a good agreement with rheological studies. The presence of free thiol moieties likely caused lower degree of hydrolysis by xylanase, whereas the degradation by both enzymes cellulase and xylanase was more hampered when 6-MNA was introduced as ligand for thiol group's protection. Findings in cell viability revealed that all three conjugates were non-toxic. S-protection of thiolated hydroxyethyl cellulose improved mucoadhesive properties and provided pronounced stability towards enzymatic attack, that makes this excipient superior for non-invasive drug administration over thiolated and unmodified forms. Copyright © 2016 Elsevier Ltd. All rights reserved.

Characterization of cellulose biomass for use as an excipient in pharmaceutical field; Caracterizacao de biomassa de celulose para utilizacao como excipiente na area farmaceutica

Energy Technology Data Exchange (ETDEWEB)

Garcia, Keth R.; Turella, Tais C.; Santos, Venina dos; Brandalise, Rosmary N. [Universidade de Caxias do Sul (UCS), Caxias do Sul, RS (Brazil). Centro de Ciencias Exatas e da Tecnologia; Angeli, Valeria W., E-mail: rnbranda@ucs.br [Universidade de Caxias do Sul (UCS), Caxias do Sul, RS (Brazil). Centro de Ciencias Biologicas e da Saude

2015-07-01

Every day the industry of paper and cellulose discards large amounts of waste. An alternative to reuse this kind of biomass is to transform part of it in cellulose nanocrystals and nanofibrils to be used as excipients in pharmaceutical field. Thus, cellulose fibrils were obtained in nanoscale using mill and fibrils' characterization study were performed by scanning electron microscopy, transmission electron microscopy, thermal analysis, differential scanning calorimetry, infrared Fourier transform and X-rays diffraction. Hence, the methodology used to obtain and characterize nanocellulose was effective and the fibers/fibrils lengths are in nanometer dimension with high potential to apply in the pharmaceutical field. (author)

Presença de excipientes com potencial para indução de reações adversas em medicamentos comercializados no Brasil The presence of pharmaceutical excipients as possible cause of adverse drug reactions (ADR - situation in Brazil

Directory of Open Access Journals (Sweden)

Antonio Vinicios Alves da Silva

2008-09-01

Full Text Available Os excipientes farmacêuticos podem ser os responsáveis por inúmeras Reações Adversas a Medicamentos (RAM. O objetivo do trabalho foi identificar a presença de possíveis excipientes indutores de RAM em medicamentos comercializados no Brasil. Foram listados os 12 produtos mais vendidos no mercado brasileiro para análise. A detecção dos excipientes ocorreu a partir da consulta à composição da fórmula farmacêutica dos produtos, realizada de Agosto a Setembro/04, no Dicionário de Especialidades Farmacêuticas, sites SAC do laboratório produtor, e ficha técnica disponível no site da ANVISA. A identificação dos excipientes, possíveis causadores de RAM, foi realizada a partir de consulta à literatura. Foram identificadas 35 apresentações farmacêuticas, 26 classificadas como medicamentos de venda livre (71,4% e 15 de uso pediátrico (42,8%. Entre os excipientes identificados (n=100, nove eram possíveis causadores de RAM: metilparabeno, propilparabeno, corante amarelo tartrazina, bissulfito de sódio, benzoato de sódio, lactose, cloreto de benzalcônio, sorbitol e álcool benzílico, sendo identificados em sete apresentações de uso pediátrico (18,9% e doze de venda livre (32,4%. Os resultados demonstram a necessidade de maior atenção por parte dos profissionais de saúde, dos usuários de medicamentos e da avaliação pelos sistemas de farmacovigilância, da presença de excipientes como possíveis indutores de RAM.Pharmaceutical excipients can be responsible for many ADR. The objectives of this study were to identify the presence of possible excipients as cause of ADR in drugs commercialized in Brazil. Twelve medicines with high indices of sales in Brazil, were selected to analysis. The bibliographic research about the Pharmaceutical Preparations (PP was carried from August to September/04. The sources of information used were Pharmaceutical Specialties Dictionary, web sites and customer services from the manufacturers

Viscoelastic characterization of compacted pharmaceutical excipient materials by analysis of frequency-dependent mechanical relaxation processes

Science.gov (United States)

Welch, K.; Mousavi, S.; Lundberg, B.; Strømme, M.

2005-09-01

A newly developed method for determining the frequency-dependent complex Young's modulus was employed to analyze the mechanical response of compacted microcrystalline cellulose, sorbitol, ethyl cellulose and starch for frequencies up to 20 kHz. A Debye-like relaxation was observed in all the studied pharmaceutical excipient materials and a comparison with corresponding dielectric spectroscopy data was made. The location in frequency of the relaxation peak was shown to correlate to the measured tensile strength of the tablets, and the relaxation was interpreted as the vibrational response of the interparticle hydrogen and van der Waals bindings in the tablets. Further, the measured relaxation strength, holding information about the energy loss involved in the relaxation processes, showed that the weakest material in terms of tensile strength, starch, is the material among the four tested ones that is able to absorb the most energy within its structure when exposed to external perturbations inducing vibrations in the studied frequency range. The results indicate that mechanical relaxation analysis performed over relatively broad frequency ranges should be useful for predicting material properties of importance for the functionality of a material in applications such as, e.g., drug delivery, drug storage and handling, and also for clarifying the origin of hitherto unexplained molecular processes.

A novel approach to support formulation design on twin screw wet granulation technology: Understanding the impact of overarching excipient properties on drug product quality attributes.

Science.gov (United States)

Willecke, N; Szepes, A; Wunderlich, M; Remon, J P; Vervaet, C; De Beer, T

2018-04-21

The overall objective of this work is to understand how excipient characteristics influence the drug product quality attributes and process performance of a continuous twin screw wet granulation process. The knowledge gained in this study is intended to be used for Quality by Design (QbD)-based formulation design and formulation optimization. Three principal components which represent the overarching properties of 8 selected pharmaceutical fillers were used as factors, whereas factors 4 and 5 represented binder type and binder concentration in a design of experiments (DoE). The majority of process parameters were kept constant to minimize their influence on the granule and drug product quality. 27 DoE batches consisting of binary filler/binder mixtures were processed via continuous twin screw wet granulation followed by tablet compression. Multiple linear regression models were built providing understanding of the impact of filler and binder properties on granule and tablet quality attributes (i.e. 16 DoE responses). The impact of fillers on the granule and tablet responses was more dominant compared to the impact of binder type and concentration. The filler properties had a relevant effect on granule characteristics, such as particle size, friability and specific surface area. Binder type and concentration revealed a relevant influence on granule flowability and friability as well as on the compactability (required compression force during tableting to obtain target hardness). In order to evaluate the DoE models' validity, a verification of the DoE models was performed with new formulations (i.e. a new combination of filler, binder type and binder concentration) which were initially not included in the dataset used to build the DoE models. The combined PCA (principle component analysis)/DoE approach allowed to link the excipient properties with the drug product quality attributes. Copyright © 2018 Elsevier B.V. All rights reserved.

Compatibility studies of nevirapine in physical mixtures with excipients for oral HAART

Energy Technology Data Exchange (ETDEWEB)

Oliveira, G.G.G. de; Ferraz, H.G. [Department of Pharmacy, Faculty of Pharmaceutical Health, University of Sao Paulo, Sao Paulo 05508-900 (Brazil); Severino, P. [Department of Biotechnological Processes, School of Chemical Engineering, University of Campinas, Campinas 13083-970 (Brazil); Department of Pharmaceutical Technology, Faculty of Health Sciences, Fernando Pessoa University, Porto 4200-150 (Portugal); Souto, E.B., E-mail: eliana@ufp.edu.pt [Department of Pharmaceutical Technology, Faculty of Health Sciences, Fernando Pessoa University, Porto 4200-150 (Portugal); Institute for Biotechnology and Bioengineering, Centre for Genomics and Biotechnology, University of Tras-os-Montes e Alto Douro (IBB-CGB/UTAD), 5001-801 Vila Real (Portugal)

2013-03-01

Nevirapine is a hydrophobic non-nucleoside reverse transcriptase inhibitor, used in first line regimens of highly active antiretroviral therapy (HAART). The drug has more than one crystalline form, which may have implications for its behaviour during production and also for its in vivo performance. This study was aimed at exploring the suitability of thermoanalytical methods for the solid-state characterization of commercial crystalline forms of nevirapine. The drug powder was characterized by ultraviolet spectrophotometry, stereoscopy, scanning electron microscopy, wide-angle X-ray diffraction, measurements of density, flowability, solubility and intrinsic dissolution rate (IDR), differential scanning calorimetry, thermogravimetric analysis, and photostability measurements. The results showed that nevirapine has high stability and is not susceptible to degradation under light exposure. The drug showed compatibility with the excipients tested (lactose, microcrystalline cellulose, polyvinylpyrrolidone and polyvinyl acetate copolymer (PVP/PVA), and hydroxypropylmethylcellulose (HPMC)). Nevirapine has low solubility, an acid medium being the most appropriate medium for assessing the release of the drug from dosage forms. However, the data obtained from IDR testing indicate that dissolution is the critical factor for the bioavailability of this drug. - Graphical abstract: Bulk nevirapine powder analysed by scanning electron microscopy and the drug solubility profile in various buffer solutions. The pH values of the media in which the tests were conducted are also presented. Highlights: Black-Right-Pointing-Pointer Nevirapine shows more than one crystalline form, that influence its in vivo and in vitro behaviour. Black-Right-Pointing-Pointer DSC and TGA were used for solid-state characterization of crystalline forms of nevirapine. Black-Right-Pointing-Pointer Nevirapine is compatible with lactose, microcrystalline cellulose, PVP/PVA copolymers and HPMC. Black

Compatibility studies of nevirapine in physical mixtures with excipients for oral HAART

International Nuclear Information System (INIS)

Oliveira, G.G.G. de; Ferraz, H.G.; Severino, P.; Souto, E.B.

2013-01-01

Nevirapine is a hydrophobic non-nucleoside reverse transcriptase inhibitor, used in first line regimens of highly active antiretroviral therapy (HAART). The drug has more than one crystalline form, which may have implications for its behaviour during production and also for its in vivo performance. This study was aimed at exploring the suitability of thermoanalytical methods for the solid-state characterization of commercial crystalline forms of nevirapine. The drug powder was characterized by ultraviolet spectrophotometry, stereoscopy, scanning electron microscopy, wide-angle X-ray diffraction, measurements of density, flowability, solubility and intrinsic dissolution rate (IDR), differential scanning calorimetry, thermogravimetric analysis, and photostability measurements. The results showed that nevirapine has high stability and is not susceptible to degradation under light exposure. The drug showed compatibility with the excipients tested (lactose, microcrystalline cellulose, polyvinylpyrrolidone and polyvinyl acetate copolymer (PVP/PVA), and hydroxypropylmethylcellulose (HPMC)). Nevirapine has low solubility, an acid medium being the most appropriate medium for assessing the release of the drug from dosage forms. However, the data obtained from IDR testing indicate that dissolution is the critical factor for the bioavailability of this drug. - Graphical abstract: Bulk nevirapine powder analysed by scanning electron microscopy and the drug solubility profile in various buffer solutions. The pH values of the media in which the tests were conducted are also presented. Highlights: ► Nevirapine shows more than one crystalline form, that influence its in vivo and in vitro behaviour. ► DSC and TGA were used for solid-state characterization of crystalline forms of nevirapine. ► Nevirapine is compatible with lactose, microcrystalline cellulose, PVP/PVA copolymers and HPMC. ► The acid form of nevirapine is the most appropriate for assessing release profile from

Application of a Biodegradable Polyesteramide Derived from L-Alanine as Novel Excipient for Controlled Release Matrix Tablets.

Science.gov (United States)

Bonillo Martínez, Ana Dora; Galán, Inés Carmen Rodríguez; Bellver, María Victoria Margarit

2017-11-01

This pre-formulation study assays the capacity of the polyesteramide PADAS, poly (L-alanine-dodecanediol-L-alanine-sebacic), as an insoluble tablet excipient matrix for prolonged drug release. The flow properties of PADAS were suitable for tableting, and the compressibility of tablets containing exclusively PADAS was evaluated by ESEM observation of the microstructure. The tablets were resistant to crushing and non-friable and they did not undergo disintegration (typical features of an inert matrix). Tablets containing 33.33% sodium diclofenac (DF), ketoprofen (K) or dexketoprofen trometamol (DK-T) as a model drug, in addition with 66.67% of polymer, were formulated, and the absence of interactions between the components was confirmed by differential scanning calorimetry. Dissolution tests showed that PADAS retained DF and K and prolonged drug release, following a Higuchi kinetic. The tablets containing DK-T did not retain the drug sufficiently for prolonged release to be established. Tablets containing DK-T and 66.67, 83.33 or 91.67% PADAS, compressed at 44.48 or 88.96 kN, were elaborated to determine the influence of the polymer amount and of the compression force on DK-T release. Both parameters significantly delayed drug release, except when the proportion of polymer was 91.67%.

Preliminary studies of the development of a direct compression cellulose excipient from bagasse.

Science.gov (United States)

Padmadisastra, Y; Gonda, I

1989-06-01

Bagasse is an unused by-product in cane sugar manufacture. Bagasse from sugar cane manually harvested in Indonesia was transformed to pulp by mechanical means and repeated autoclaving in 1.4% NaOH. It was then subjected to cycles of bleaching with hypochlorite and acid hydrolysis with 2.5 M HCl to produce 'microcrystalline' cellulose (MCC). Extraction of waxes by petroleum ether was necessary in order to improve the disintegration properties of tablets made from this material, DICEB III. When the bagasse-derived cellulose was reconstituted by recombining different proportions of selected sieve cuts to have a similar sieve size distribution as the commercially available MCC, Avicel PH102, it was found that the latter and DICEB III also had similar crystallinity as measured by X-ray powder diffraction (degree of crystallinity 2.8 +/- 0.2). The crystallinity and flow index were also relatively insensitive to most of the changes in the manufacturing procedure, indicating that the production process was quite robust. Directly compressed tablets were made containing 50 mg of caffeine and 500 mg of either Avicel PH102 or DICEB III to approximately the same hardness (11.6 +/- 1.1 and 13.7 +/- 0.5 kPa, respectively). They displayed similar satisfactory disintegration and dissolution behavior. However, DICEB III required greater compaction pressures than Avicel PH102, perhaps because the former was not spray dried to give spherical agglomerates of particles of uniform size as the commercial product. Rather, DICEB III consisted mainly of single irregular particles. Further work is required to improve the new excipient and to explore if the bagasse from mechanically harvested sugar cane (often contaminated by soil) could also be used for production of MCC.

Development of modified release 3D printed tablets (printlets) with pharmaceutical excipients using additive manufacturing.

Science.gov (United States)

Goyanes, Alvaro; Fina, Fabrizio; Martorana, Annalisa; Sedough, Daniel; Gaisford, Simon; Basit, Abdul W

2017-07-15

The aim of this study was to manufacture 3D printed tablets (printlets) from enteric polymers by single filament fused deposition modeling (FDM) 3D printing (3DP). Hot melt extrusion was used to generate paracetamol-loaded filaments from three different grades of the pharmaceutical excipient hypromellose acetate succinate (HPMCAS), grades LG, MG and HG. One-step 3DP was used to process these filaments into enteric printlets incorporating up to 50% drug loading with two different infill percentages (20 and 100%). X-ray Micro Computed Tomography (Micro-CT) analysis revealed that printlets with 20% infill had cavities in the core compared to 100% infill, and that the density of the 50% drug loading printlets was higher than the equivalent formulations loaded with 5% drug. In biorelevant bicarbonate dissolution media, drug release from the printlets was dependent on the polymer composition, drug loading and the internal structure of the formulations. All HPMCAS-based printlets showed delayed drug release properties, and in the intestinal conditions, drug release was faster from the printlets prepared with polymers with a lower pH-threshold: HPMCAS LG > HPMCAS MG > HPMCAS HG. These results confirm that FDM 3D printing makes it possible not only to manufacture delayed release printlets without the need for an outer enteric coating, but it is also feasible to adapt the release profile in response to the personal characteristics of the patient, realizing the full potential of additive manufacturing in the development of personalised dose medicines. Copyright © 2017 Elsevier B.V. All rights reserved.

Excipient-mediated alteration in drug bioavailability in the rat depends on the sex of the animal.

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Mai, Yang; Afonso-Pereira, Francisco; Murdan, Sudaxshina; Basit, Abdul W

2017-09-30

The pharmaceutical excipient, polyethylene glycol 400 (PEG 400), unexpectedly alters the bioavailability of the BCS class III drug ranitidine in a sex-dependent manner. As ranitidine is a substrate for the efflux transporter P-glycoprotein (P-gp), we hypothesized that the sex-related influence could be due to interactions between PEG 400 and P-gp. In this study, we tested this hypothesis by: i) measuring the influence of PEG 400 on the oral bioavailability of another P-gp substrate (ampicillin) and of a non-P-gp substrate (metformin); and ii) measuring the effect of PEG 400 on drug bioavailability in the presence of a P-gp inhibitor (cyclosporine A) in male and female rats. We found that PEG 400 significantly increased (pbioavailability of ampicillin (the P-gp substrate) in male rats, but not in female ones. In contrast, PEG 400 had no influence on the bioavailability of the non-P-gp substrate, metformin in male or female rats. Inhibition of P-gp by oral pre-treatment with cyclosporine A increased the bioavailability of the P-gp substrates (ampicillin and ranitidine) in males and females (pbioavailability of metformin in either male or female rats. These results prove the hypothesis that the sex-specific effect of PEG 400 on the bioavailability of certain drugs is due to the interaction of PEG 400 with the efflux transporter P-gp. Copyright © 2017 Elsevier B.V. All rights reserved.

Evaluation of Three Chitin Metal Silicate Co-Precipitates as a Potential Multifunctional Single Excipient in Tablet Formulations

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Rana Al-Shaikh Hamid

2010-05-01

Full Text Available The performance of the novel chitin metal silicate (CMS co-precipitates as a single multifunctional excipient in tablet formulation using direct compression and wet granulation methods is evaluated. The neutral, acidic, and basic drugs Spironolactone (SPL, ibuprofen (IBU and metronidazole (MET, respectively, were used as model drugs. Commercial Aldactone®, Fleximex® and Dumazole® tablets containing SPL, IBU and MET, respectively, and tablets made using Avicel® 200, were used in the study for comparison purposes. Tablets of acceptable crushing strength (>40 N were obtained using CMS. The friability values for all tablets were well below the maximum 1% USP tolerance limit. CMS produced superdisintegrating tablets (disintegration time < 1 min with the three model drugs. Regarding the dissolution rate, the sequence was as follow: CMS > Fleximex® > Avicel® 200, CMS > Avicel® 200 > Dumazole® and Aldactone® > Avicel® 200 > CMS for IBU, MET and SPL, respectively. Compressional properties of formulations were analyzed using density measurements and the compression Kawakita equation as assessment parameters. On the basis of DSC results, CMS co precipitates were found to be compatible with the tested drugs. Conclusively, the CMS co-precipitates have the potential to be used as filler, binder, and superdisintegrant, all-in-one, in the design of tablets by the direct compression as well as wet granulation methods.

Structure elucidation and quantification of impurities formed between 6-aminocaproic acid and the excipients citric acid and sorbitol in an oral solution using high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy.

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Schou-Pedersen, Anne Marie V; Cornett, Claus; Nyberg, Nils; Østergaard, Jesper; Hansen, Steen Honoré

2015-03-25

Concentrated solutions containing 6-aminocaproic acid and the excipients citric acid and sorbitol have been studied at temperatures of 50°C, 60°C, 70°C and 80°C as well as at 20°C. It has previously been reported that the commonly employed citric acid is a reactive excipient, and it is therefore important to thoroughly investigate a possible reaction between 6-aminocaproic acid and citric acid. The current study revealed the formation of 3-hydroxy-3,4-dicarboxy-butanamide-N-hexanoic acid between 6-aminocaproic acid and citric acid by high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance spectroscopy (NMR). Less than 0.03% of 6-aminocaproic acid was converted to 3-hydroxy-3,4-dicarboxy-butanamide-N-hexanoic acid after 30 days of storage at 80°C. Degradation products of 6-aminocaproic acid were also observed after storage at the applied temperatures, e.g., dimer, trimer and cyclized 6-aminocaproic acid, i.e., caprolactam. No reaction products between D-sorbitol and 6-aminocaproic acid could be observed. 3-Hydroxy-3,4-dicarboxy-butanamide-N-hexanoic acid, dimer and caprolactam were also observed after storage at 20°C for 3 months. The findings imply that an oral solution of 6-aminocaproic acid is relatively stable at 20°C at the pH values 4.00 and 5.00 as suggested in the USP for oral formulations. Compliance with the ICH guideline Q3B is expected. Copyright © 2015 Elsevier B.V. All rights reserved.

PREPARATION AND CHARACTERIZATION OF CO-PROCESSED EXCIPIENT-PREGELATINIZED CASSAVA STARCH PROPIONATE AS A MATRIX IN THE GASTRORETENTIVE DOSAGE FORM

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Junaedi

2011-11-01

Full Text Available The gastroretentive dosage form is designed to prolong the gastric residence time of the drug delivery system whichalso results in the development of an appropriate excipient. The purpose of this study is to develop and characterize coprocessedexcipient made from carrageenan (kappa-iota = 1:1 and pregelatinized cassava starch propionate (PCSP inratios of 1:1, 1:2, and 1:3. PCSP was prepared with propionic anhydride in an aqueous medium. The product was mixedwith carrageenan (kappa-iota = 1:1, as well as characterized physicochemical and functional properties. The coprocessedexcipient was then used as a mucoadhesive granule and floating tablet. The USP Basket was selected toperform the dissolution test of the granules in HCl buffer (pH 1.2 and distilled water for 8 hours each. Mucoadhesiveproperties were evaluated using bioadhesive through a vitro test and wash-off test. As for the floating tablet, the USPPaddle was selected to perform the dissolution test of the tablets in 0.1 N HCl for 10 hours. The floating lag time andfloating time were tested in 0.1 N HCl for 24 hours. The result of these studies indicated that co-processed excipientcarrageenan-PCSP can retard dosage form in gastric and drug controlled release, thus making it a suitable material forthe gastroretentive dosage form.

Development of novel diclofenac potassium controlled release tablets by wet granulation technique and the effect of co-excipients on in vitro drug release rates.

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Shah, Shefaatullah; Khan, Gul Majid; Jan, Syed Umer; Shah, Kifayatullah; Hussain, Abid; Khan, Haroon; Khan, Haroon; Khan, Haroon; Khan, Kamran Ahmad

2012-01-01

The aim of the present study was the formulation and evaluation of controlled release polymeric tablets of Diclofenac Potassium by wet granulation method for the release rate, release pattern and the mechanism involved in drug release. Formulations having three grades of polymer Ethocel (7P; 7FP, 10P, 10FP, 100P, 100FP) in several drugs to polymer ratios (10:3 and 10:1) were compressed into tablets using wet granulation method. Co-excipients were added to some selected formulations to investigate their enhancement effect on in vitro drug release patterns. In vitro drug release studies were performed using USP Method-1 (Rotating Basket method) and Phosphate buffer (pH 7.4) was used as a dissolution medium. The similarities and dissimilarities of release profiles of test formulations with reference standard were checked using f2 similarity factor and f1 dissimilarity factor. Mathematical/Kinetic models were employed to determine the release mechanism and drug release kinetics.

A novel pharmaceutical excipient: Coprecipitation of calcium and magnesium silicate using brine-seawater in date palm cellulose as an absorbing host

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Mohammad Hamaidi

2017-09-01

Full Text Available This research aims to produce a cost competitive and innovative pharmaceutical additive with multi-purpose use in the pharmaceutical industry from Saudi Arabia natural resources and bio-wastes. The waste substance, brine, and the naturally occurring compound, sodium silica, were reacted together to produce water insoluble calcium and magnesium silicate salts [WISS]. The purity index WISS was compared with synthetic Mg silicae.The produced particle size was 1.994 µm. Date palm cellulose [DPC] with a high purity index [0.99] was produced from the biomass waste of date palm tree. DPC was used as a host for coprecipitation of synthetic calcium magnesium silicate within its intimate structures. The interaction between the cellulose polymer and silicates is physical in nature. WISS-DPC was more flowable than DPC. In SEM, the particles of DPC were fibrous and irregular in shape, while WISS-DPC showed more regular shape than DPC. Tablets prepared from WISS-DPC were harder and had lower disintegration time at all compression forces compared to those made from DPC. The produced excipient had excellent compaction and disintegration properties and could be used as a superdisintegrant and tablet binder in pharmaceutical industries.

The effect of polymeric excipients on the physical properties and performance of amorphous dispersions: Part I, free volume and glass transition.

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Li, Jinjiang; Zhao, Junshu; Tao, Li; Wang, Jennifer; Waknis, Vrushali; Pan, Duohai; Hubert, Mario; Raghavan, Krishnaswamy; Patel, Jatin

2015-02-01

To investigate the structural effect of polymeric excipients on the behavior of free volume of drug-polymer dispersions in relation to glass transition. Two drugs (indomethacin and ketoconazole) were selected to prepare amorphous dispersions with PVP, PVPVA, HPC, and HPMCAS through spray drying. The physical attributes of the dispersions were characterized using SEM and PXRD. The free volume (hole-size) of the dispersions along with drugs and polymers was measured using positron annihilation lifetime spectroscopy (PALS). Their glass transition temperatures (Tgs) were determined using DSC and DMA. FTIR spectra were recorded to identify hydrogen bonding in the dispersions. The chain structural difference-flexible (PVP and PVPVA) vs. inflexible (HPC and HPMCAS)-significantly impacts the free volume and Tgs of the dispersions as well as their deviation from ideality. Relative to Tg, free volume seems to be a better measure of hydrogen bonding interaction for the dispersions of PVP, HPC, and HPMCAS. The free volume of polymers and their dispersions in general appears to be related to their conformations in solution. Both the backbone chain rigidity of polymers as well as drug-polymer interaction can impact the free volume and glass transition behaviors of the dispersions.

Dissolution stability studies of suspensions of prolonged-release diclofenac microcapsules prepared by the Wurster process: I. Eudragit-based formulation and possible drug-excipient interaction.

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Adeyeye, M C; Mwangi, E; Katondo, B; Jain, A; Ichikawa, H; Fukumori, Y

2005-06-01

The aim was to evaluate possible interaction in solid and liquid state of the drug with formulation excipients consequent to very fast drug release of diclofenac-Eudragit prolonged release microcapsules. The microcapsules were prepared by drug layering on calcium carbonate cores and coated with Eudragit RS 30D and L30D-55 as previously reported. Suspension of the microcapsules was prepared using microcrystalline cellulose/sodium carboxymethyl cellulose (Avicel CL-611) as medium. In vitro dissolution testing of the suspension was done, and, based on the dissolution results, possible interaction between diclofenac and Eudragit and Avicel in the medium was studied. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) analyses were performed using 1:1 binary, 1:1:1 ternary mixtures and a ratio equivalent to that in the formulation. The mixtures were prepared by mixing the dispersions--Eudragit RS 30D or L30D-55 with the drug or other components, followed by drying at 60 degrees C for 48 h. Dry mixing was done using the powder equivalents of the polymers, Eudragit RS PO and L100-55, Avicel and calcium carbonate. In vitro dissolution of the suspended microcapsules showed a very fast release after 48 h (T50 = microcapsules (T50 = 6 h). DSC curves of the formulation components or microcapsules did not show the characteristic endothermic peak of diclofenac at 287 degrees C. Powder X-ray diffraction of the binary or ternary mixtures of diclofenac and Eudragit polymers indicated reduction, shift or modification of the crystalline peaks of the drug or excipients at 2theta of 12 degrees and 18 degrees , suggestive of interaction. Some changes in drug peak characteristics at 18 degrees and 23 degrees were observed for Avicel/drug mixture, though not significant. The DSC curves of the binary mixture of diclofenac co-dried with liquid forms of Eudragit (i.e. RS 30D or L30D-55) revealed greater interaction compared to the curves of drug and powdered forms of

Excipientes de medicamentos e as informações da bula Pharmaceutical excipients and the information on drug labels

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Aracy Pereira Silveira Balbani

2006-06-01

preservatives, dyes, sweeteners and flavouring substances in 73 pharmaceutical preparations of 35 medicines for oral administration, according to drug labeling information about the excipients. METHODS: 35 medications were selected, both over-the-counter and prescription durgs, marketed in Brazil. The sample included: analgesic/antipyretic, antimicrobial, mucoregulatory, cough and cold, decongestant, antihistamine, bronchodilator, corticosteroid, antiinflammatory and vitamin medications. We collected data on 73 preparations of these drugs, according to drug labeling information regarding preservatives, dyes, sweeteners and flavourings. RESULTS: Methylparaben and propylparaben were the most common preservatives found (43% and 35.6% respectively. The most common sweeteners were: sucrose (sugar (53.4%, sodium saccharin (38.3% and sorbitol (36.9%. Twenty-one medicines (28,7% contained two sweeteners. Colourless medicines predominated (43.8%, followed by those with sunset yellow dye (FD&C yellow no. 6 (15%. Five products (6.8% contained more than one colour agent. Tartrazine (FD&C yellow no. 5 was present in seven preparations (9.5%. Fruit was the most common flavouring found (83%. Labelings of drugs which contained sugar frequently omitted its exact concentration (77%. Of the four labelings of medicines which contained aspartame, two did not warn patients regarding phenylketonuria. CONCLUSION: Omission and inacuracy of drug labeling information on pharmaceutical excipients may expose susceptible individuals to adverse reactions caused by preservatives and dyes. Complications of inadvertent intake of sugar-containing medicines by diabetics, or aspartame intake by patients with phenylketonuria may also occur.

Understanding and optimizing the dual excipient functionality of sodium lauryl sulfate in tablet formulation of poorly water soluble drug: wetting and lubrication.

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Aljaberi, Ahmad; Chatterji, Ashish; Dong, Zedong; Shah, Navnit H; Malick, Waseem; Singhal, Dharmendra; Sandhu, Harpreet K

2013-01-01

To evaluate and optimize sodium lauryl sulfate (SLS) and magnesium stearate (Mg.St) levels, with respect to dissolution and compaction, in a high dose, poorly soluble drug tablet formulation. A model poorly soluble drug was formulated using high shear aqueous granulation. A D-optimal design was used to evaluate and model the effect of granulation conditions, size of milling screen, SLS and Mg.St levels on tablet compaction and ejection. The compaction profiles were generated using a Presster(©) compaction simulator. Dissolution of the kernels was performed using a USP dissolution apparatus II and intrinsic dissolution was determined using a stationary disk system. Unlike kernels dissolution which failed to discriminate between tablets prepared with various SLS contents, the intrinsic dissolution rate showed that a SLS level of 0.57% was sufficient to achieve the required release profile while having minimal effect on compaction. The formulation factors that affect tablet compaction and ejection were identified and satisfactorily modeled. The design space of best factor setting to achieve optimal compaction and ejection properties was successfully constructed by RSM analysis. A systematic study design helped identify the critical factors and provided means to optimize the functionality of key excipient to design robust drug product.

Aerosol Drug Delivery During Noninvasive Positive Pressure Ventilation: Effects of Intersubject Variability and Excipient Enhanced Growth

Science.gov (United States)

Walenga, Ross L.; Kaviratna, Anubhav; Hindle, Michael

2017-01-01

Abstract Background: Nebulized aerosol drug delivery during the administration of noninvasive positive pressure ventilation (NPPV) is commonly implemented. While studies have shown improved patient outcomes for this therapeutic approach, aerosol delivery efficiency is reported to be low with high variability in lung-deposited dose. Excipient enhanced growth (EEG) aerosol delivery is a newly proposed technique that may improve drug delivery efficiency and reduce intersubject aerosol delivery variability when coupled with NPPV. Materials and Methods: A combined approach using in vitro experiments and computational fluid dynamics (CFD) was used to characterize aerosol delivery efficiency during NPPV in two new nasal cavity models that include face mask interfaces. Mesh nebulizer and in-line dry powder inhaler (DPI) sources of conventional and EEG aerosols were both considered. Results: Based on validated steady-state CFD predictions, EEG aerosol delivery improved lung penetration fraction (PF) values by factors ranging from 1.3 to 6.4 compared with conventional-sized aerosols. Furthermore, intersubject variability in lung PF was very high for conventional aerosol sizes (relative differences between subjects in the range of 54.5%–134.3%) and was reduced by an order of magnitude with the EEG approach (relative differences between subjects in the range of 5.5%–17.4%). Realistic in vitro experiments of cyclic NPPV demonstrated similar trends in lung delivery to those observed with the steady-state simulations, but with lower lung delivery efficiencies. Reaching the lung delivery efficiencies reported with the steady-state simulations of 80%–90% will require synchronization of aerosol administration during inspiration and reducing the size of the EEG aerosol delivery unit. Conclusions: The EEG approach enabled high-efficiency lung delivery of aerosols administered during NPPV and reduced intersubject aerosol delivery variability by an order of magnitude. Use of an in

Aerosol Drug Delivery During Noninvasive Positive Pressure Ventilation: Effects of Intersubject Variability and Excipient Enhanced Growth.

Science.gov (United States)

Walenga, Ross L; Longest, P Worth; Kaviratna, Anubhav; Hindle, Michael

2017-06-01

Nebulized aerosol drug delivery during the administration of noninvasive positive pressure ventilation (NPPV) is commonly implemented. While studies have shown improved patient outcomes for this therapeutic approach, aerosol delivery efficiency is reported to be low with high variability in lung-deposited dose. Excipient enhanced growth (EEG) aerosol delivery is a newly proposed technique that may improve drug delivery efficiency and reduce intersubject aerosol delivery variability when coupled with NPPV. A combined approach using in vitro experiments and computational fluid dynamics (CFD) was used to characterize aerosol delivery efficiency during NPPV in two new nasal cavity models that include face mask interfaces. Mesh nebulizer and in-line dry powder inhaler (DPI) sources of conventional and EEG aerosols were both considered. Based on validated steady-state CFD predictions, EEG aerosol delivery improved lung penetration fraction (PF) values by factors ranging from 1.3 to 6.4 compared with conventional-sized aerosols. Furthermore, intersubject variability in lung PF was very high for conventional aerosol sizes (relative differences between subjects in the range of 54.5%-134.3%) and was reduced by an order of magnitude with the EEG approach (relative differences between subjects in the range of 5.5%-17.4%). Realistic in vitro experiments of cyclic NPPV demonstrated similar trends in lung delivery to those observed with the steady-state simulations, but with lower lung delivery efficiencies. Reaching the lung delivery efficiencies reported with the steady-state simulations of 80%-90% will require synchronization of aerosol administration during inspiration and reducing the size of the EEG aerosol delivery unit. The EEG approach enabled high-efficiency lung delivery of aerosols administered during NPPV and reduced intersubject aerosol delivery variability by an order of magnitude. Use of an in-line DPI device that connects to the NPPV mask appears to be a

Comparison of the Local Tolerability to 5 Long-acting Drug Nanosuspensions with Different Stabilizing Excipients, Following a Single Intramuscular Administration in the Rat.

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Chamanza, Ronnie; Darville, Nicolas; van Heerden, Marjolein; De Jonghe, Sandra

2018-01-01

To investigate the effects of common nanosuspension-stabilizing excipients on the nature and temporal evolution of histopathological changes at intramuscular (i.m.) administration sites, 5 groups of 39 male rats per group received a single injection of 1 of the 5 analogous crystalline drug nanosuspensions containing 200 mg/ml of an antiviral compound with particle sizes of ±200 nm and identical vehicle compositions, except for the type of nanosuspension stabilizer. The investigated stabilizers were poloxamer 338, poloxamer 407, d-α-tocopherol polyethylene glycol 1,000-succinate (TPGS), polysorbate 80, and polysorbate 80 combined with egg phosphatidylglycerol. Histopathology and immunohistochemistry revealed progressive inflammatory changes at the i.m. administration sites and the draining lymph nodes that differed according to the time point of sacrifice and the type of stabilizer. Although the overall time course of inflammatory changes was similar across the groups, differences in the nature, severity, and timing of the inflammatory response were observed between animals injected with poloxamer- or TPGS-containing nanosuspensions and those injected with formulations containing polysorbate 80. A more severe and prolonged active inflammatory phase, the presence of multinucleate giant cells, prolonged macrophage infiltration of the formulation depot, and more persistent histiocytic infiltrates in the lymph nodes were observed in the polysorbate 80-containing nanosuspension groups. Such vehicle-mediated effects could influence the overall tolerability profile of long-acting nanosuspensions.

Radiolabelling of potential colonic delivery systems by neutron activation. An evaluation based on physiochemical properties of excipients and formulations

International Nuclear Information System (INIS)

Ahrabi, Sayeh

1999-01-01

The effects of neutron irradiation on the physicochemical properties of some potential release-controlling excipients for oral delivery to colon (based on microbially degradable polysaccharide or a combination of pH- and time-dependent mechanisms) were initially investigated. The aim was to choose the most irradiation-resistant ones for the development of a colonic delivery system to be radiolabelled by the neutron activation procedure. However, no correlation between the extent of irradiation-induced changes of the release-controlling polymers and the in vitro properties of the final formulation was observed. Incorporation of samarium oxide (Sm 2 O 3 ) resulted in retardation of the drug release through the diffusion layer. The influence of neutron activation factors on the properties of some suppository combinations was also studied. The effect of the admixture of Sm 2 O 3 on the dissolution and disintegration of the suppositories was more profound than the effect of neutron irradiation. In hydrophilic suppositories, the effect of Sm 2 O 3 was dependent on the type, amount and the physicochemical characteristics of the incorporated drug. In lipophilic suppositories, the release-controlling effect of Sm 2 O 3 was hypothesised to be due to its insoluble micronised particles blocking the drug diffusion layer. The neutron activation procedure could be utilised for radiolabelling potential oral and rectal colonic drug delivery systems. However, to avoid alteration in the crucial in vitro characteristics of the formulations, the amount, the particle size and the aggregated particle characteristics of the lanthanide salt (e.g. Sm 2 O 3 or samarium stearate) together with the neutron irradiation dose should be controlled precisely for each dosage system. For the systems investigated in this work the release-controlling mechanism of the dosage form seems to be a key parameter to predict the extent of the influence of neutron activation factors on the in vitro properties

The integration of physiologically-targeted skin care in the management of atopic dermatitis: focus on the use of a cleanser and moisturizer system incorporating a ceramide precursor, filaggrin degradation products, and specific "skin-barrier-friendly" excipients.

Science.gov (United States)

Del Rosso, James Q; Kircik, Leon H

2013-07-01

Atopic dermatitis (AD) may be considered the "poster disease" for exemplifying the significance of abnormalities of the epidermal barrier that occur predominantly within the stratum corneum (SC) and upper epidermis. Specifically, impairments of the SC permeability barrier, antimicrobial barrier, and immunologic barrier contribute markedly to the fundamental pathophysiology of AD. The multiple clinical sequelae associated with epidermal barrier impairments inherent to AD include dry skin, pruritus, increased skin sensitivity to irritants and allergens, eczematous skin changes, staphylococcal skin and anterior nares colonization, and increase in some cutaneous infections (ie, molluscum contagiosum). This article addresses the pathophysiology of AD with clinically relevant correlations, and discusses the scientific basis of a specially designed cleanser and moisturizer system that incorporates ceramide technology and filaggrin degradation products along with other "barrier-friendly" excipients.

On the role of API in determining porosity, pore structure and bulk modulus of the skeletal material in pharmaceutical tablets formed with MCC as sole excipient.

Science.gov (United States)

Ridgway, Cathy; Bawuah, Prince; Markl, Daniel; Zeitler, J Axel; Ketolainen, Jarkko; Peiponen, Kai-Erik; Gane, Patrick

2017-06-30

The physical properties and mechanical integrity of pharmaceutical tablets are of major importance when loading with active pharmaceutical ingredient(s) (API) in order to ensure ease of processing, control of dosage and stability during transportation and handling prior to patient consumption. The interaction between API and excipient, acting as functional extender and binder, however, is little understood in this context. The API indomethacin is combined in this study with microcrystalline cellulose (MCC) at increasing loading levels. Tablets from the defined API/MCC ratios are made under conditions of controlled porosity and tablet thickness, resulting from different compression conditions, and thus compaction levels. Mercury intrusion porosimetry is used to establish the accessible pore volume, pore size distribution and, adopting the observed region of elastic intrusion-extrusion at high pressure, an elastic bulk modulus of the skeletal material is recorded. Porosity values are compared to previously published values derived from terahertz (THz) refractive index data obtained from exactly the same tablet sample sets. It is shown that the elastic bulk modulus is dependent on API wt% loading under constant tablet preparation conditions delivering equal dimensions and porosity. The findings are considered of novel value in respect to establishing consistency of tablet production and optimisation of physical properties. Copyright © 2017 Elsevier B.V. All rights reserved.

Radiolabelling of potential colonic delivery systems by neutron activation. An evaluation based on physiochemical properties of excipients and formulations

Energy Technology Data Exchange (ETDEWEB)

Ahrabi, Sayeh

1999-07-01

The effects of neutron irradiation on the physicochemical properties of some potential release-controlling excipients for oral delivery to colon (based on microbially degradable polysaccharide or a combination of pH- and time-dependent mechanisms) were initially investigated. The aim was to choose the most irradiation-resistant ones for the development of a colonic delivery system to be radiolabelled by the neutron activation procedure. However, no correlation between the extent of irradiation-induced changes of the release-controlling polymers and the in vitro properties of the final formulation was observed. Incorporation of samarium oxide (Sm{sub 2}O{sub 3}) resulted in retardation of the drug release through the diffusion layer. The influence of neutron activation factors on the properties of some suppository combinations was also studied. The effect of the admixture of Sm{sub 2}O{sub 3} on the dissolution and disintegration of the suppositories was more profound than the effect of neutron irradiation. In hydrophilic suppositories, the effect of Sm{sub 2}O{sub 3} was dependent on the type, amount and the physicochemical characteristics of the incorporated drug. In lipophilic suppositories, the release-controlling effect of Sm{sub 2}O{sub 3} was hypothesised to be due to its insoluble micronised particles blocking the drug diffusion layer. The neutron activation procedure could be utilised for radiolabelling potential oral and rectal colonic drug delivery systems. However, to avoid alteration in the crucial in vitro characteristics of the formulations, the amount, the particle size and the aggregated particle characteristics of the lanthanide salt (e.g. Sm{sub 2}O{sub 3} or samarium stearate) together with the neutron irradiation dose should be controlled precisely for each dosage system. For the systems investigated in this work the release-controlling mechanism of the dosage form seems to be a key parameter to predict the extent of the influence of neutron

A quality-by-design study for an immediate-release tablet platform: examining the relative impact of active pharmaceutical ingredient properties, processing methods, and excipient variability on drug product quality attributes.

Science.gov (United States)

Kushner, Joseph; Langdon, Beth A; Hicks, Ian; Song, Daniel; Li, Fasheng; Kathiria, Lalji; Kane, Anil; Ranade, Gautam; Agarwal, Kam

2014-02-01

The impact of filler-lubricant particle size ratio variation (3.4-41.6) on the attributes of an immediate-release tablet was compared with the impacts of the manufacturing method used (direct compression or dry granulation) and drug loading (1%, 5%, and 25%), particle size (D[4,3]: 8-114 μm), and drug type (theophylline or ibuprofen). All batches were successfully manufactured, except for direct compression of 25% drug loading of 8 μm (D[4,3]) drug, which exhibited very poor flow properties. All manufactured tablets possessed adequate quality attributes: tablet weight uniformity 1 MPa, friability ≤ 0.2% weight loss, and disintegration time impact on blend and granulation particle size and granulation flow, whereas drug property variation dominated blend flow, ribbon solid fraction, and tablet quality attributes. Although statistically significant effects were observed, the results of this study suggest that the manufacturability and performance of this immediate-release tablet formulation is robust to a broad range of variation in drug properties, both within-grade and extra-grade excipient particle size variations, and the choice of manufacturing method. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Evaluation of the Impact of Excipients and an Albendazole Salt on Albendazole Concentrations in Upper Small Intestine Using an In Vitro Biorelevant Gastrointestinal Transfer (BioGIT) System.

Science.gov (United States)

Kourentas, Alexandros; Vertzoni, Maria; Khadra, Ibrahim; Symillides, Mira; Clark, Hugh; Halbert, Gavin; Butler, James; Reppas, Christos

2016-09-01

An in vitro biorelevant gastrointestinal transfer (BioGIT) system was assessed for its ability to mimic recently reported albendazole concentrations in human upper small intestine after administration of free base suspensions to fasted adults in absence and in presence of supersaturation promoting excipients (hydroxypropylmethylcellulose and lipid self-emulsifying vehicles). The in vitro method was also used to evaluate the likely impact of using the sulfate salt on albendazole concentrations in upper small intestine. In addition, BioGIT data were compared with equilibrium solubility data of the salt and the free base in human aspirates and biorelevant media. The BioGIT system adequately simulated the average albendazole gastrointestinal transfer process and concentrations in upper small intestine after administration of the free base suspensions to fasted adults. However, the degree of supersaturation observed in the duodenal compartment was greater than in vivo. Albendazole sulfate resulted in minimal increase of albendazole concentrations in the duodenal compartment of the BioGIT, despite improved equilibrium solubility observed in human aspirates and biorelevant media, indicating that the use of a salt is unlikely to lead to any significant oral absorption advantage for albendazole. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Microstructural effects in drug release by solid and cellular polymeric dosage forms: A comparative study.

Science.gov (United States)

Blaesi, Aron H; Saka, Nannaji

2017-11-01

In recent studies, we have introduced melt-processed polymeric cellular dosage forms to achieve both immediate drug release and predictable manufacture. Dosage forms ranging from minimally-porous solids to highly porous, open-cell and thin-walled structures were prepared, and the drug release characteristics investigated as the volume fraction of cells and the excipient molecular weight were varied. In the present study, both minimally-porous solid and cellular dosage forms consisting of various weight fractions of Acetaminophen drug and polyethylene glycol (PEG) excipient are prepared and analyzed. Microstructures of the solid forms and the cell walls range from single-phase solid solutions of the excipient and a small amount of drug molecules to two-phase composites of the excipient and tightly packed drug particles. Results of dissolution experiments show that the minimally-porous solid forms disintegrate and release drug by slow surface erosion. The erosion rate decreases as the drug weight fraction is increased. By contrast, the open-cell structures disintegrate rapidly by viscous exfoliation, and the disintegration time is independent of drug weight fraction. Drug release models suggest that the solid forms erode by convective mass transfer of the faster-eroding excipient if the drug volume fraction is small. At larger drug volume fractions, however, the slower-eroding drug particles hinder access of the free-flowing fluid to the excipient, thus slowing down erosion of the composite. Conversely, the disintegration rate of the cellular forms is limited by diffusion of the dissolution fluid into the excipient phase of the thin cell walls. Because the wall thickness is of the order of the drug particle size, and the particles are enveloped by the excipient during melt-processing, the drug particles cannot hinder diffusion through the excipient across the walls. Thus the disintegration time of the cellular forms is mostly unaffected by the volume fraction of drug

Preparation and evaluation of diclofenac sodium orally disintegrating tablets

Directory of Open Access Journals (Sweden)

Iancu Valeriu

2016-06-01

Full Text Available Orally disintegrating tablets (ODTs are dosage forms which disintegrate in mouth within seconds without need of water. This type of quality in dosage form can be attained by addition of different varieties of excipients. Pharmaburst™ 500 is a co-processed excipient system which allows rapid disintegration and low adhesion to punches. The aim of the present study was to develop and evaluate 25 mg diclofenac sodium ODTs (orodispersible tablets batches by direct compression method at different compression forces 10 kN (F1 and 20 kN (F2 and directly compressible excipients used in different ratio (Avicel PH 102, magnesium stearate and coprocessed excipient Pharmaburst™ 500, 70% and 80% w/w. The obtained batches were analyzed for appearance, tablet thickness, uniformity of weight, hardness, friability, disintegration time, and non-compendial methods (wetting time. Co-processed Pharmaburst™ 500 excipient 70% used for sodium diclofenac ODT obtaining determined good results for quality control tests evaluation.

Characterization of physicochemical properties of hydroxypropyl methylcellulose (HPMC) type 2208 and their influence on prolonged drug release from matrix tablets

OpenAIRE

Devjak Novak, Sabina; Šporar, Elena; Vrečer, Franc; Baumgartner, Saša

2015-01-01

The key physicochemical properties of functional excipients should be identified, and the influence of their variability on the properties of the final dosage form should be evaluated during the development phase. Excipients produced by different manufacturers and/or by differentb manufacturing processes should have comparable properties. Hydroxypropyl methylcellulose (HPMC) with a high molecular weight is a functional excipient often used in solid matrix systems with prolonged release of act...

An accurate and precise representation of drug ingredients.

Science.gov (United States)

Hanna, Josh; Bian, Jiang; Hogan, William R

2016-01-01

In previous work, we built the Drug Ontology (DrOn) to support comparative effectiveness research use cases. Here, we have updated our representation of ingredients to include both active ingredients (and their strengths) and excipients. Our update had three primary lines of work: 1) analysing and extracting excipients, 2) analysing and extracting strength information for active ingredients, and 3) representing the binding of active ingredients to cytochrome P450 isoenzymes as substrates and inhibitors of those enzymes. To properly differentiate between excipients and active ingredients, we conducted an ontological analysis of the roles that various ingredients, including excipients, have in drug products. We used the value specification model of the Ontology for Biomedical Investigations to represent strengths of active ingredients and then analyzed RxNorm to extract excipient and strength information and modeled them according to the results of our analysis. We also analyzed and defined dispositions of molecules used in aggregate as active ingredients to bind cytochrome P450 isoenzymes. Our analysis of excipients led to 17 new classes representing the various roles that excipients can bear. We then extracted excipients from RxNorm and added them to DrOn for branded drugs. We found excipients for 5,743 branded drugs, covering ~27% of the 21,191 branded drugs in DrOn. Our analysis of active ingredients resulted in another new class, active ingredient role. We also extracted strengths for all types of tablets, capsules, and caplets, resulting in strengths for 5,782 drug forms, covering ~41% of the 14,035 total drug forms and accounting for ~97 % of the 5,970 tablets, capsules, and caplets in DrOn. We represented binding-as-substrate and binding-as-inhibitor dispositions to two cytochrome P450 (CYP) isoenzymes (CYP2C19 and CYP2D6) and linked these dispositions to 65 compounds. It is now possible to query DrOn automatically for all drug products that contain active

Physical Stability of Freeze-Dried Isomalt Diastereomer Mixtures

DEFF Research Database (Denmark)

Koskinen, Anna-Kaisa; Fraser-Miller, Sara J.; Bøtker, Johan P.

2016-01-01

Purpose Isomalt is a sugar alcohol used as an excipient in commercially available solid oral dosage forms. The potential of isomalt as a novel freeze-drying excipient was studied in order to increase knowledge of the behavior of isomalt when it is freeze-dried. Methods Isomalt was freeze-dried in......Purpose Isomalt is a sugar alcohol used as an excipient in commercially available solid oral dosage forms. The potential of isomalt as a novel freeze-drying excipient was studied in order to increase knowledge of the behavior of isomalt when it is freeze-dried. Methods Isomalt was freeze......-dried in four different diastereomer compositions and its physical stability was investigated with differential scanning calorimetry, Fourier-transform infrared and Raman spectroscopy, X-ray powder diffraction, Karl-Fischer titration and thermogravimetric analysis in order to verify the solid state form...... of the diastereomer compositions showed signs of physical instability when stored in the highest relative humidity condition. The four different crystalline diastereomer mixtures showed specific identifiable solid state properties. Conclusions Isomalt was shown to be a suitable excipient for freeze-drying. Preferably...

P-glycoprotein inhibition of drug resistant cell lines by nanoparticles.

Science.gov (United States)

Singh, Manu Smriti; Lamprecht, Alf

2016-01-01

Several pharmaceutical excipients are known for their ability to interact with cell membrane lipids and reverse the phenomenon of multidrug resistance (MDR) in cancer. Interestingly, many excipients act as stabilizers and are key ingredients in a variety of nano-formulations. In this study, representatives of ionic and non-ionic excipients were used as surface active agents in nanoparticle (NP) formulations to utilize their MDR reversing potential. In-vitro assays were performed to elucidate particle-cell interaction and accumulation of P-glycoprotein (P-gp) substrates-rhodamine-123 and calcein AM, in highly drug resistant glioma cell lines. Chemosensitization achieved using NPs and their equivalent dose of free excipients was assessed with the co-administered anti-cancer drug doxorubicin. Among the excipients used, non-ionic surfactant, Cremophor® EL, and cationic surfactant, cetyltrimethylammonuium bromide (CTAB), demonstrated highest P-gp modulatory activity in both free solution form (up to 7-fold lower IC50) and as a formulation (up to 4.7-fold lower IC50) as compared to doxorubicin treatment alone. Solutol® HS15 and Tween® 80 exhibited considerable chemosensitization as free solution but not when incorporated into a formulation. Sodium dodecyl sulphate (SDS)-based nanocarriers resulted in slightly improved cytotoxicity. Overall, the results highlight and envisage the usage of excipient in nano-formulations in a bid to improve chemosensitization of drug resistant cancer cells towards anti-cancer drugs.

A novel co-processed directly compressible release-retarding polymer: In vitro, solid state and in vivo evaluation

Directory of Open Access Journals (Sweden)

Prashant Kumar Choudhari

2018-06-01

Full Text Available Directly compressible (DC co-processed excipient capable of providing nearly zero order release with improved functionality was developed without any chemical modification by employed various techniques such as physical mixing, high shear mixer granulation and spray drying. Co-processed excipient was developed by using release retarding polymer Eudragit RSPO, separately, in combination with different concentration of hydroxyl propyl methyl cellulose 100 cps (Methocel K100 LV, HPMC, ethyl cellulose (Ethocel N50, EC and hydroxyl propyl cellulose (Klucel EF, HPC. All co-processed excipients were evaluated for their flow properties in terms of angle of repose, bulk density, tapped density, compressibility index and Hausner's ratio. Out of eighteen combinations, the nine co-processed excipients exhibited promising flow properties were found suitable for direct compression and formulated as tablets. Metoprolol succinate, a BCS Class I drug, was selected as a model drug and the formulation was developed employing direct compression approach. The developed tablets were evaluated for physical parameters like uniformity of weight, thickness, hardness, friability and assay. In vitro dissolution study confirms that formulation prepared using co-processed excipient showed sustained drug release. The optimized tablet formulation was characterized by DSC, FTIR and PXRD which confirms the absence of any chemical change during co-processing. The optimized formulation was kept for stability study for six months as per ICH guidelines and found to be stable. In vivo pharmacokinetic study of optimized formulation in rats showed similar pharmacokinetic behaviour as was observed with the marketed brand. Study revealed that co-processed excipient has advantage over polymers with single property and can be utilised for sustained release formulation. Keywords: Co-processed excipient, Metoprolol succinate, Extended-release, Direct compression, Zero-order release

NIR analysis of cellulose and lactose--application to ecstasy tablet analysis.

Science.gov (United States)

Baer, Ines; Gurny, Robert; Margot, Pierre

2007-04-11

Cellulose and lactose are the most frequently used excipients in illicit ecstasy production. The aim of this project was to use near infrared reflectance spectroscopy (NIRS) for the determination of the different chemical forms of these two substances, as well as for the differentiation of their origin (producer). It was possible to distinguish between the different chemical forms of both compounds, as well as between their origins (producers), although within limits. Furthermore, the possibilities to apply NIR for the analysis of substances such as found in illicit tablets were studied. First, a few cellulose and lactose samples were chosen to make mixtures with amphetamine at three degrees of purity (5, 10 and 15%), in order to study the resulting changes in the spectra as well as to simultaneously quantify amphetamine and identify the excipient. A PLS2 model could be build to predict concentrations and excipient. Secondarily, the technique was to be applied to real ecstasy tablets. About 40 ecstasy seizures were analysed with the aim to determine the excipient and to check them against each other. Identification of the excipients was not always obvious, especially when more than one excipient were present. However, a comparison between tablets appeared to give groups of similar samples. NIR analysis results in spectra representing the tablet blend as a whole taking into account all absorbing compounds. Although NIRS seems to be an appropriate method for ecstasy profiling, little is known about intra- and intervariability of compression batches.

On-line coupling of size exclusion chromatography with mixed-mode liquid chromatography for comprehensive profiling of biopharmaceutical drug product.

Science.gov (United States)

He, Yan; Friese, Olga V; Schlittler, Michele R; Wang, Qian; Yang, Xun; Bass, Laura A; Jones, Michael T

2012-11-02

A methodology based on on-line coupling of size exclusion chromatography (SEC) with mixed-mode liquid chromatography (LC) has been developed. The method allows for simultaneous measurement of a wide range of components in biopharmaceutical drug products. These components include the active pharmaceutical ingredient (protein) and various kinds of excipients such as cations, anions, nonionic hydrophobic surfactant and hydrophilic sugars. Dual short SEC columns are used to separate small molecule excipients from large protein molecules. The separated protein is quantified using a UV detector at 280 nm. The isolated excipients are switched, online, to the Trinity P1 mixed-mode column for separation, and detected by an evaporative light scattering detector (ELSD). Using a stationary phase with 1.7 μm particles in SEC allows for the use of volatile buffers for both SEC and mix-mode separation. This facilitates the detection of different excipients by ELSD and provides potential for online characterization of the protein with mass spectrometry (MS). The method has been applied to quantitate protein and excipients in different biopharmaceutical drug products including monoclonal antibodies (mAb), antibody drug conjugates (ADC) and vaccines. Copyright © 2012 Elsevier B.V. All rights reserved.

Novel Polyurethane Matrix Systems Reveal a Particular Sustained Release Behavior Studied by Imaging and Computational Modeling.

Science.gov (United States)

Campiñez, María Dolores; Caraballo, Isidoro; Puchkov, Maxim; Kuentz, Martin

2017-07-01

The aim of the present work was to better understand the drug-release mechanism from sustained release matrices prepared with two new polyurethanes, using a novel in silico formulation tool based on 3-dimensional cellular automata. For this purpose, two polymers and theophylline as model drug were used to prepare binary matrix tablets. Each formulation was simulated in silico, and its release behavior was compared to the experimental drug release profiles. Furthermore, the polymer distributions in the tablets were imaged by scanning electron microscopy (SEM) and the changes produced by the tortuosity were quantified and verified using experimental data. The obtained results showed that the polymers exhibited a surprisingly high ability for controlling drug release at low excipient concentrations (only 10% w/w of excipient controlled the release of drug during almost 8 h). The mesoscopic in silico model helped to reveal how the novel biopolymers were controlling drug release. The mechanism was found to be a special geometrical arrangement of the excipient particles, creating an almost continuous barrier surrounding the drug in a very effective way, comparable to lipid or waxy excipients but with the advantages of a much higher compactability, stability, and absence of excipient polymorphism.

Elucidation of Compression-Induced Surface Crystallization in Amorphous Tablets Using Sum Frequency Generation (SFG) Microscopy.

Science.gov (United States)

Mah, Pei T; Novakovic, Dunja; Saarinen, Jukka; Van Landeghem, Stijn; Peltonen, Leena; Laaksonen, Timo; Isomäki, Antti; Strachan, Clare J

2017-05-01

To investigate the effect of compression on the crystallization behavior in amorphous tablets using sum frequency generation (SFG) microscopy imaging and more established analytical methods. Tablets containing neat amorphous griseofulvin with/without excipients (silica, hydroxypropyl methylcellulose acetate succinate (HPMCAS), microcrystalline cellulose (MCC) and polyethylene glycol (PEG)) were prepared. They were analyzed upon preparation and storage using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, scanning electron microscopy (SEM) and SFG microscopy. Compression-induced crystallization occurred predominantly on the surface of the neat amorphous griseofulvin tablets, with minimal crystallinity being detected in the core of the tablets. The presence of various types of excipients was not able to mitigate the compression-induced surface crystallization of the amorphous griseofulvin tablets. However, the excipients affected the crystallization rate of amorphous griseofulvin in the core of the tablet upon compression and storage. SFG microscopy can be used in combination with ATR-FTIR spectroscopy and SEM to understand the crystallization behaviour of amorphous tablets upon compression and storage. When selecting excipients for amorphous formulations, it is important to consider the effect of the excipients on the physical stability of the amorphous formulations.

Risperidone – Solid-state characterization and pharmaceutical compatibility using thermal and non-thermal techniques

Energy Technology Data Exchange (ETDEWEB)

Daniel, Josiane Souza Pereira; Veronez, Isabela Pianna; Rodrigues, Larissa Lopes [Laboratório de Análise e Caracterização de Fármacos – LACFar, Instituto de Química, Universidade Federal de Alfenas, Alfenas, Minas Gerais (Brazil); Trevisan, Marcello G. [Laboratório de Análise e Caracterização de Fármacos – LACFar, Instituto de Química, Universidade Federal de Alfenas, Alfenas, Minas Gerais (Brazil); National Institute of Bioanalytics Science and Technology – INCTBio, Institute of Chemistry – UNICAMP, 13084-653, Campinas, São Paulo (Brazil); Garcia, Jerusa Simone, E-mail: jerusa.garcia@unifal-mg.edu.br [Laboratório de Análise e Caracterização de Fármacos – LACFar, Instituto de Química, Universidade Federal de Alfenas, Alfenas, Minas Gerais (Brazil)

2013-09-20

Highlights: • DSC was used to characterize Risperidone and study its compatibility with excipients. • FT-IR associated with PCA was used to complement DSC data. • LC analyzes confirmed the DSC and FT-IR/PCA results. • Risperidone was incompatible with three among five excipients evaluated. - Abstract: A full solid-state characterization of risperidone was conducted using differential scanning calorimetry (DSC), thermogravimetry (TG), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM) to examine its physicochemical properties and polymorphism. The primary aim of this work was to study the compatibility of risperidone with pharmaceutical excipients using DSC to obtain and compare the curves of the active pharmaceutical ingredient (API) and the excipients with their 1:1 (w/w) binary mixtures. These same binary mixtures were turned to room temperature and analyzed by FT-IR combined with principal component analysis (PCA) to evaluate solid-state incompatibilities. The chemical incompatibilities of these samples were verified using a stability-indicating liquid chromatography (LC) method to assay for the API and evaluate the formation of degradation products. All of these methods showed incompatibilities between risperidone and the excipients magnesium stearate, lactose and cellulose microcrystalline.

Quality control of the paracetamol drug by chemometrics and imaging spectroscopy in the near infrared region

Science.gov (United States)

Baptistao, Mariana; Rocha, Werickson Fortunato de Carvalho; Poppi, Ronei Jesus

2011-09-01

In this work, it was used imaging spectroscopy and chemometric tools for the development and analysis of paracetamol and excipients in pharmaceutical formulations. It was also built concentration maps to study the distribution of the drug in the tablets surface. Multivariate models based on PLS regression were developed for paracetamol and excipients concentrations prediction. For the construction of the models it was used 31 samples in the tablet form containing the active principle in a concentration range of 30.0-90.0% (w/w) and errors below to 5% were obtained for validation samples. Finally, the study of the distribution in the drug was performed through the distribution maps of concentration of active principle and excipients. The analysis of maps showed the complementarity between the active principle and excipients in the tablets. The region with a high concentration of a constituent must have, necessarily, absence or low concentration of the other one. Thus, an alternative method for the paracetamol drug quality monitoring is presented.

Optimization of self nanoemulsifying drug delivery system for poorly water-soluble drug using response surface methodology

DEFF Research Database (Denmark)

Ren, Shan; Mu, Huiling; Alchaer, Fadi

2013-01-01

impact of excipients on the performance of formulations as well as the fate of drug. The aim of this study was to rationalize the SNEDDS development procedure and to get a better understanding on the role of excipients on the SNEDDS. The formulations consist of soybean oil or rapeseed oil, Cremophor...

Intravaginal ring delivery of the reverse transcriptase inhibitor TMC 120 as an HIV microbicide.

Science.gov (United States)

Woolfson, A David; Malcolm, R Karl; Morrow, Ryan J; Toner, Clare F; McCullagh, Stephen D

2006-11-15

TMC 120 (Dapivirine) is a potent non-nucleoside reverse transcriptase inhibitor that is presently being developed as a vaginal HIV microbicide. To date, most vaginal microbicides under clinical investigation have been formulated as single-dose semi-solid gels, designed for application to the vagina before each act of intercourse. However, a clear rationale exists for providing long-term, controlled release of vaginal microbicides in order to afford continuous protection against heterosexually transmitted HIV infection and to improve user compliance. In this study we report on the incorporation of various pharmaceutical excipients into TMC 120 silicone, reservoir-type intravaginal rings (IVRs) in order to modify the controlled release characteristics of the microbicide. The results demonstrate that TMC 120 is released in zero-order fashion from the rings over a 28-day period and that release parameters could be modified by the inclusion of release-modifying excipients in the IVR. The hydrophobic liquid excipient isopropyl myristate had little effect on steady-state daily release rates, but did increase the magnitude and duration of burst release in proportion to excipient loading in the IVR. By comparison, the hydrophobic liquid poly(dimethylsiloxane) had little effect on TMC 120 release parameters. A hydrophilic excipient, lactose, had the surprising effect of decreasing TMC 120 burst release while increasing the apparent steady-state daily release in a concentration-dependent manner. Based on previous cell culture data and vaginal physiology, TMC120 is released from the various ring formulations in amounts potentially capable of maintaining a protective vaginal concentration. It is further predicted that the observed release rates may be maintained for at least a period of 1 year from a single ring device. TMC 120 release profiles and the mechanical properties of rings could be modified by the physicochemical nature of hydrophobic and hydrophilic excipients

A critical review on tablet disintegration.

Science.gov (United States)

Quodbach, Julian; Kleinebudde, Peter

2016-09-01

Tablet disintegration is an important factor for drug release and can be modified with excipients called tablet disintegrants. Tablet disintegrants act via different mechanisms and the efficacy of these excipients is influenced by various factors. In this review, the existing literature on tablet disintegration is critically reviewed. Potential disintegration mechanisms, as well as impact factors on the disintegration process will be discussed based on experimental evidence. Search terms for Scopus and Web of Science included "tablet disintegration", "mechanism tablet disintegration", "superdisintegrants", "disintegrants", "swelling force", "disintegration force", "disintegration mechanisms", as well as brand names of commonly applied superdisintegrants. References of identified papers were screened as well. Experimental data supports swelling and shape recovery as main mechanisms of action of disintegrants. Other tablet excipients and different manufacturing techniques greatly influence the disintegration process. The use of different excipients, experimental setups and manufacturing techniques, as well as the demand for original research led to a distinct patchwork of knowledge. Broader, more systematic approaches are necessary not only to structure the past but also future findings.

The effect of sesame and sunflower oils on the plasma disposition of ivermectin in goats.

Science.gov (United States)

Gokbulut, C; Karademir, U; Boyacioglu, M; McKellar, Q A

2008-10-01

The effect of sesame oil (SSO) and sunflower oil (SFO) (the excipients) on the plasma disposition of ivermectin (IVM) following intravenous (i.v.) and subcutaneous (s.c.) administration at a dosage of 200 microg/kg was investigated in goats. Ten clinically healthy crossbred goats were used in the study. The animals were allocated by weight and sex into two groups of five animals each. Group 1 (n = 5) received the drug and excipient by the i.v. route only and group 2 received drug and excipient by the s.c. route only. The study was designed according to a two-phase crossover design protocol. In the first phase three animals in group 1 were i.v. administered IVM (0.2 mg/kg) + SSO (1 mL) and the other two animals received IVM (0.2 mg/kg) + SFO (1 mL). In the second phase animals were crossed over and received the alternate excipient with IVM at the same dosages. In group 2 during the first phase, three animals were s.c. administered IVM (0.2 mg/kg) + SSO (1 mL) and the other two animals were received IVM (0.2 mg/kg) + SFO (1 mL). In the second phase animals were crossed over and received the alternate excipient with IVM at the same dosages. A 4-week washout period was allowed between the two phases. In group 2 significantly increased dermal thickness was observed at the s.c. injection site of the all animals which received IVM during phase I regardless of the excipient. There was almost no change observed at the injection site of any animal during the second phase of the study following s.c. administration. In group 2 the plasma concentrations of IVM in the second phase for both excipient combinations were much higher than the plasma concentrations following first administration and appeared to be related with the dermal changes. The mean plasma disposition of IVM in combination with SSO or SFO was similar following i.v. administration. Longer terminal elimination half-lives and resultant longer mean resident time were observed after s.c. administration of the both

Effect of Moisture Content of Chitin-Calcium Silicate on Rate of Degradation of Cefotaxime Sodium.

Science.gov (United States)

Al-Nimry, Suhair S; Alkhamis, Khouloud A

2018-04-01

Assessment of incompatibilities between active pharmaceutical ingredient and pharmaceutical excipients is an important part of preformulation studies. The objective of the work was to assess the effect of moisture content of chitin calcium silicate of two size ranges (two specific surface areas) on the rate of degradation of cefotaxime sodium. The surface area of the excipient was determined using adsorption method. The effect of moisture content of a given size range on the stability of the drug was determined at 40°C in the solid state. The moisture content was determined at the beginning and the end of the kinetic study using TGA. The degradation in solution was studied for comparison. Increasing the moisture content of the excipient of size range 63-180 μm (surface area 7.2 m 2 /g) from 3.88 to 8.06% increased the rate of degradation of the drug more than two times (from 0.0317 to 0.0718 h -1 ). While an opposite trend was observed for the excipient of size range moisture content moisture content of 8.54%, and the degradation in solid state at both moisture contents was higher than that in solution (0.0871 h -1 ). In conclusion, the rate of degradation in solid should be studied taking into consideration the specific surface area and moisture content of the excipient at the storage condition and it may be higher than that in solution.

Targeting Chemerin Receptor CMKLR1 in Multiple Sclerosis

Science.gov (United States)

2012-09-01

polycaprylactone. Oral delivery systems include tablets and capsules. These can contain excipients such as binders (e.g...Transmucosal delivery systems include patches, tablets , suppositories, pessaries, gels and creams, and can contain excipients such as solubilizers and...with no further testing. Magnetic resonance imaging ( MRI ) of the brain and spine is often used during the diagnostic process. MRI shows areas of

Comparative study of excipients for propanolol hydrochloryde tablets prepared by means of diferent techniques Estudo comparativo de excipientes em diferentes técnicas de preparação de comprimidos de cloridrato de propranolol

Directory of Open Access Journals (Sweden)

Cinara Maistro Mamprim

2001-11-01

Full Text Available Systemic arterial hipertension (SAH is one of the major factors in cardiovascular risk, since it contributes to the existence of more than 500 thousand cases of cerebral vascular accidents (CVA, 150 thousand deaths by cerebral hemorrhage and approximately a million myocardium infarctions (IAM. In Brazil, it is estimated that about 15% of the adult population can be considered hypertensive. Hypertension can be prevented by changes in lifestyle, although in most cases, the treatment with drugs becomes necessary. Propranolol hydrochloride is the drug chosen for the hypertensive elderly population who has had myocardium infarctation previously. The drug is commercially available as injections, solutions, capsules and tablets. Tablets can be prepared using three different techniques. The most used technique is the granulation by moisture. With the advance of new excipients available in the market for the Pharmaceutical Industry, a more simple and economical technique became possible, improving the physical and chemical stability of the product, reaching the goal of getting more efficient and safer medicine. The purpose of this study was to develop formulations of propranolol hydrochloride tablets through the variation of excipients and manufacture techniques. The propranolol hydrochloryde tablets were stored at 37o C and 50o C with 90% UR for 90 days, and analysed in pre-established time intervals the formulations were evaluated as for the physical and physical-chemical aspects.   A hipertensão arterial sistêmica (HAS é um dos mais importantes fatores de risco cardiovascular uma vez que contribui, mundialmente, com mais de 500 mil casos de acidentes cerebrovasculares (AVC, 150 mil mortes por hemorragia cerebral e aproximadamente um milhão de infartos de miocárdio (IAM. No Brasil estima-se que cerca de15% dos indivíduos adultos possam ser rotulados como hipertensos. A hipertensão pode ser prevenida com a mudança no estilo de vida, embora na

Estudios organolépticos, fisicoquímicos, microbiológicos e interacción con excipientes farmacéuticos de un extracto purificado de cera de Apis mellifera Organoleptic, physicochemical and microbiological studies and its interaction with pharmaceutical excipients of a purified extract from Apis mellifera wax

Directory of Open Access Journals (Sweden)

Víctor Luis González Canavaciolo

2010-09-01

Full Text Available El D-002, ingrediente activo antioxidante extraído de la cera de abejas Apis mellifera, fue caracterizado desde el punto de vista físicoquímico, de igual forma se analizó su interacción con excipientes de interés farmacéutico. El D-002 es un polvo fluido inodoro de color blanco a crema, con pérdidas por secado £ 1 %; es insoluble en agua y etanol, y muy ligeramente soluble en otros disolventes orgánicos. Su composición, determinada por cromatografía de gases, fue: 1-tetracosanol (6-15 %, 1-hexacosanol (7-20 %, 1-octacosanol (12-20 %, 1-triacontanol (25-35 % 1-dotriacontanol (18-25 % y 1-tetratriacontanol (£ 7,5 %, para una pureza ³ 85 %. Fue estable durante 5 años en la zona climática IV y su análisis por calorimetría diferencial de barrido mostró 2 transiciones de fusión a 59,0 y 81,1 °C sin descomposición, una alta estabilidad térmica hasta 200 °C, así como la ausencia de interacciones con lactosa, almidón, croscarmelosa sódica, polivinil pirrolidona, celulosa microcristalina y estearato de magnesio, lo que posibilita el empleo de estos excipientes en la formulación de las tabletas.The D002, an antioxidant active ingredient extracted from the Apis mellifera bees wax was characterized from the physicochemical point of view analyzing its interaction with excipients of pharmaceutical interest. The D-002 is a creamy white odourless fluid powder with losses by £ 1 % dry; it is water and ethanol insoluble and very slightly soluble in other organic solvents. Its composition, determined by gas chromatography was: 1-tetracosanol (6-15 %, 1-hexacosanol (7-20 %, 1-octacosanol (12-20 %, 1-triacontanol (25-35 %, 1-dotriacontanol (18-25 % and 1-tetratriacontaol (£ 7,5 % for ³ 85 % of purity. It remained stable during 5 years in the IV climatic zone and its analysis by differential scanning calorimetry showed 2 fusion transitions at 59.0 and 81.1 °C. without decomposition, a high thermal stability up to 200 °C, as well as a

Topical gel formulation and stability assessment of platelet lysate based on turbidimetric method

Directory of Open Access Journals (Sweden)

Soliman Mohammadi Samani

2015-06-01

Full Text Available Platelet-rich growth factors have attracted attentions of scientists and clinical practitioners who are involved in wound healing and regenerative medicine extensively, according to their unprecedented potential of promoting and catalyzing healing process. Platelet-rich growth factors are cost-benefit, available and more stable than recombinant human growth factors. These appealing characteristics have converted PRGF to one of the popular candidates for treatment of variety of wounds. According to these valuable properties, we decided to formulate and assess the effect of different excipients on the stability of such valuable protein based formulations. Different excipients have been chosen according to their effective ness on the stability of proteins and their application in other similar formulations. The stabilizing effect of excipients was evaluated by measuring heat-induced aggregation of growth factors by turbidimetric assay. Glycerol, glycine and dextrose were chosen as stabilizing excipients for these formulations. The results show that dextrose has more stabilizing effect on prevention of heat induced aggregation of the platelet lysate growth factors than glycerol and glycine. All of the formulations also contained antioxidant, chelating agents, preservative and carbopol934 in order to form appropriate gel.

On the exfoliating polymeric cellular dosage forms for immediate drug release.

Science.gov (United States)

Blaesi, Aron H; Saka, Nannaji

2016-06-01

The most prevalent pharmaceutical dosage forms at present-the oral immediate-release tablets and capsules-are granular solids. Though effective in releasing drug rapidly, development and manufacture of such dosage forms are fraught with difficulties inherent to particulate processing. Predictable dosage form manufacture could be achieved by liquid-based processing, but cast solid dosage forms are not suitable for immediate drug release due to their resistance to fluid percolation. To overcome this limitation, we have recently introduced cellular dosage forms that can be readily prepared from polymeric melts. It has been shown that open-cell structures comprising polyethylene glycol 8000 (PEG 8k) excipient and a drug exfoliate upon immersion in a dissolution medium. The drug is then released rapidly due to the large specific surface area of the exfoliations. In this work, we vary the molecular weight of the PEG excipient and investigate its effect on the drug release kinetics of structures with predominantly open-cell topology. We demonstrate that the exfoliation rate decreases substantially if the excipient molecular weight is increased from 12 to 100kg/mol, which causes the drug dissolution time to increase by more than a factor of ten. A model is then developed to elucidate the exfoliation behavior of cellular structures. Diverse transport processes are considered: percolation due to capillarity, diffusion of dissolution medium through the cell walls, and viscous flow of the saturated excipient. It is found that the lower exfoliation rate and the longer dissolution time of the dosage forms with higher excipient molecular weight are primarily due to the greater viscosity of the cell walls after fluid penetration. Copyright © 2016 Elsevier B.V. All rights reserved.

The Effect of Alcohol on Bead Performance of Encapsulated Iron Using Deacetylated Glucomannan

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Wardhani Dyah H.

2018-01-01

Full Text Available The success of encapsulation to protect iron from inhibitor degradation or oxidation depends on many factors including the excipient characteritics. Glucomannan, a neutral heterosaccharide, has a potential for the excipient. To improve the excipient performances, glucomannan is deacetylated to remove the acetyl groups by reacted with Na2CO3. This deacylated glucomannan is subject to bead formation after iron loading. The alcohol solution is commonly used in bead forming as dehydration medium during the encapsulation process. The objective of this work was to study the effect of alcohol on the bead performance of encapsulated iron using deacetylated glucomannan. The bead forming was conducted by dropping the excipient into ethanol and isopropyl alcohol (IPA solution at various concentrations (50, 60, 70, 80 and 90% and two condition temperatures (27-30° and 7-10°C. The encapsulation samples were subject to yield (YE and efficiency of encapsulation (EE. The concentration of alcohol showed a positive impact on the yield and efficiency of encapsulation. Ethanol has a better performance compared with that of IPA regarding yield and efficiency of encapsulation. The optimum of yield bead formation (69.67% and highest EE (66.80% were obtained at 90% ethanol. Temperature of dehydration did not affect the YE and EE significantly.

Application of experimental design in examination of the dissolution rate of carbamazepine from formulations: Characterization of the optimal formulation by DSC, TGA, FT-IR and PXRD analysis

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Krstić Marko

2015-01-01

Full Text Available Poor solubility is one of the key reasons for the poor bioavailability of these drugs. This paper displays a formulation of a solid surfactant system with carbamazepine, in order to increase its dissolution rate. Solid state surfactant systems are formed by application of fractal experimental design. Poloxamer 237 and Poloxamer 338 were used as surfactants and Brij® 35 was used as the co-surfactant. The ratios of the excipients and carbamazepine were varied and their effects on the dissolution rate of carbamazepine were examined. Moreover, the effects of the addition of natural (diatomite and a synthetic adsorbent carrier (Neusiline UFL2 on the dissolution rate of carbamazepine were also tested. The prepared surfactant systems were characterized and the influence of the excipients on possible changes of the polymorphous form of carbamazepine examined by application of analytical techniques (DSC, TGA, FT-IR, PXRD. It was determined that an appropriate selection of the excipient type and ratio could provide a significant increase in the carbamazepine dissolution rate. By application of analytical techniques, it was found that that the employed excipients induce a transition of carbamazepine into the amorphous form and that the selected sample was stable for three months, when kept under ambient conditions. [Projekat Ministarstva nauke Republike Srbije, br. TR34007

Stability of Proteins in Carbohydrates and Other Additives during Freezing: The Human Growth Hormone as a Case Study.

Science.gov (United States)

Arsiccio, Andrea; Pisano, Roberto

2017-09-21

Molecular dynamics is here used to elucidate the mechanism of protein stabilization by carbohydrates and other additives during freezing. More specifically, we used molecular dynamics simulations to obtain a quantitative estimation of the capability of various cryoprotectants to preserve a model protein, the human growth hormone, against freezing stresses. Three mechanisms were investigated, preferential exclusion, water replacement, and vitrification. Model simulations were finally validated upon experimental data in terms of the ability of excipients to prevent protein aggregation. Overall, we found that the preferential exclusion and vitrification mechanisms are important during the whole freezing process, while water replacement becomes dominant only toward the end of the cryoconcentration phase. The disaccharides were found to be the most efficient excipients, in regard to both preferential exclusion and water replacement. Moreover, sugars were in general more efficient than other excipients, such as glycine or sorbitol.

Implantable microencapsulated dopamine (DA): prolonged functional release of DA in denervated striatal tissue.

Science.gov (United States)

McRae, A; Hjorth, S; Mason, D; Dillon, L; Tice, T

1990-01-01

Biodegradable controlled-release microcapsule systems made with the biocompatible biodegradable polyester excipient poly [DL-lactide-co-gly-colide] constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional observations indicating that implantation of dopamine (DA) microcapsules encapsulated within two different polymer excipients into denervated striatal tissue assures a prolonged release of the transmitter in vivo. This technology has a considerable potential for basic and possibly clinical research.

Pharmaceutical properties of two ethenzamide-gentisic acid cocrystal polymorphs: Drug release profiles, spectroscopic studies and theoretical calculations.

Science.gov (United States)

Sokal, Agnieszka; Pindelska, Edyta; Szeleszczuk, Lukasz; Kolodziejski, Waclaw

2017-04-30

The aim of this study was to evaluate the stability and solubility of the polymorphic forms of the ethenzamide (ET) - gentisic acid (GA) cocrystals during standard technological processes leading to tablet formation, such as compression and excipient addition. In this work two polymorphic forms of pharmaceutical cocrystals (ETGA) were characterized by 13 C and 15 N solid-state nuclear magnetic resonance and Fourier transformed infrared spectroscopy. Spectroscopic studies were supported by gauge including projector augmented wave (GIPAW) calculations of chemical shielding constants.Polymorphs of cocrystals were easily identified and characterized on the basis of solid-state spectroscopic studies. ETGA cocrystals behaviour during direct compressionand tabletting with excipient addition were tested. In order to choose the best tablet composition with suitable properties for the pharmaceutical industry dissolution profile studies of tablets containing polymorphic forms of cocrystals with selected excipients were carried out. Copyright © 2017. Published by Elsevier B.V.

INFLUENCE OF CARBOXYMETHYLCELLULOSE SODIUM AND LUTROL ON THE SWELLING INDEX AND DISINTEGRATION TIME OF BIOMUCOADHESIVE TABLETS WITH MICONAZOLE NITRATE.

Science.gov (United States)

Birsan, Magdalena; Scutariu, Monica Mihaela; Cojocaru, Ileana

2016-01-01

PURPOSE. To develop original pharmaceutical formulation with miconazole nitrate, biomucoadhesive tablets, used in antifungal medication. The oral biomucoadhesive tablets with miconazole nitrate were developed by direct compression of the excipient mixture: carboxymethylcellulose sodium and lutrol 6000, excipients used for bioadhesivity, mannitol as a sugar substitute and aerosil as a lubricant. The main goal of the study is to determine the disintegration time and the swelling index of biomucoadhesive tablets with miconazole nitrate in order to estimate the time of contact with mucosa, respectively the prolongation of drug substance release. The swelling index was calculated depending on time in all the 5 formulations that included the carboxymethylcellulose sodium and Lutrol 6000 as matrix-forming, and the studied were time and association ratio between polymers. Analysing the results, we noticed that out of the four excipients we used, carboxymethylcellulose sodium had the higher influence on the swelling index and disintegration time.

Preformulation Studies for Generic Omeprazole Magnesium Enteric Coated Tablets

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C. O. Migoha

2015-01-01

Full Text Available Preformulation is an important step in the rational formulation of an active pharmaceutical ingredient (API. Micromeritics properties: bulk density (BD and tapped density (TD, compressibility index (Carr’s index, Hauser’s ratio (H, and sieve analysis were performed in order to determine the best excipients to be used in the formulation development of omeprazole magnesium enteric coated tablets. Results show that omeprazole magnesium has fair flow and compressibility properties (BD 0.4 g/mL, TD 0.485 g/mL, Carr’s index 17.5%, Hauser’s ratio 1.2, and sieve analysis time 5 minutes. There were no significant drug excipient interactions except change in colour in all three conditions in the mixture of omeprazole and aerosil 200. Moisture content loss on drying in all three conditions was not constant and the changes were attributed to surrounding environment during the test time. Changes in the absorption spectra were noted in the mixture of omeprazole and water aerosil only in the visible region of 350–2500 nm. Omeprazole magnesium alone and with all excipients showed no significant changes in omeprazole concentration for a 30-day period. Omeprazole magnesium formulation complies with USP standards with regards to the fineness, flowability, and compressibility of which other excipients can be used in the formulation.

Reducing or Eliminating Polysorbate Induced Anaphylaxis and Unwanted Immunogenicity in Biotherapeutics

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Edward Maggio

2017-09-01

Full Text Available The increasing use of biotherapeutics across a growing spectrum of neoplastic, autoimmune, and inflammatory diseases has resulted in a corresponding increase in hypersensitivity reactions. The origins of anaphylaxis are often attributed to undefined intrinsic properties of the biotherapeutic protein itself, ignoring the broader potential negative contributions of functional excipients, in particular polyoxyethylene containing surfactants such as polysorbate 80 and polysorbate 20 (Tween 80 and Tween 20. These surfactants allow biotherapeutics to meet the stringent challenges of extended shelf-life, increased solubility, protein aggregation prevention, reduced administration volume, and satisfactory reconstitution properties in the case of lyophilized biotherapeutics. The potential negative impact of certain functional excipients on product performance characteristics such as anaphylaxis and immunogenicity is often overlooked. While regulatory authorities understandably focus heavily on comparable efficacy in evaluating biosimilars, similar efficacy does not necessarily imply a similar safety profile between the originator and biosimilar products. Both unwanted immunogenicity and anaphylaxis do comprise major components of safety assessment, however, few if any attempts are made to differentiate drug-related from excipient-related anaphylaxis. Replacement of anaphylactogenic and immunogenic functional excipients with equally effective but safer alternatives will allow biotherapeutic developers to differentiate their biotherapeutic, biosimilar, or biobetter from the large number of nearly identical competitor products, simultaneously providing a substantial commercial benefit as well as critical clinical benefits for all concerned – patients, physicians, and third party payers.

Dissolution rate enhancement of piroxicam by ordered mixing.

Science.gov (United States)

Saharan, Vikas Anand; Choudhury, Pratim Kumar

2012-07-01

Micronized piroxicam was mixed with lactose, mannitol, sorbitol, maltitol and sodium chloride to produce ordered mixture in a glass vial by manual hand shaking method. The effect of excipients, surfactant, superdisintegrant, drug concentration and carrier particle size on dissolution rate was investigated. Dissolution rate studies of the prepared ordered mixtures revealed that all water soluble excipients increased the dissolution rate of piroxicam when compared to the dissolution rate of piroxicam or its suspension. Ordered mixture formulation PLF4, consisting of lactose as water soluble excipient, SSG (8% w/s) and SLS (1% w/w), released piroxcam at a very fast rate so much so that about 90% of the composition had passed into solution within 2 min. The order of the dissolution rate enhancement for ordered mixtures of various water soluble excipients was: lactose > mannitol > maltitol > sorbitol > sodium chloride. Carrier granules of size 355-710 µm were most effective in increasing the dissolution rate of drug from ordered mixtures. Decreasing the carrier particle size reduced drug dissolution from ordered mixtures. The dissolution rate of ordered mixtures consisting of 1-5% w/w piroxicam was superior to dissolution rate of piroxicam suspension. The dissolution data fitting and the resulting regression parameters indicated Hixson Crowell, cube root law, as the best fit to drug release data of ordered mixtures.

Final product analysis in the e-beam and gamma radiolysis of aqueous solutions of metoprolol tartrate

Energy Technology Data Exchange (ETDEWEB)

Slegers, Catherine [Universite Catholique de Louvain, Unite d' Analyse Chimique et Physico-chimique des Medicaments, CHAM 72.30, Avenue E. Mounier, 72, B-1200 Brussels (Belgium)]. E-mail: catherine.slegers@cham.ucl.ac.be; Tilquin, Bernard [Universite Catholique de Louvain, Unite d' Analyse Chimique et Physico-chimique des Medicaments, CHAM 72.30, Avenue E. Mounier, 72, B-1200 Brussels (Belgium)

2006-09-15

The radiostability of metoprolol tartrate aqueous solutions and the influence of the absorbed dose (0-50 kGy), dose rate (e-beam (EB) vs. gamma ({gamma})) and radioprotectors (pharmaceutical excipients) are investigated by HPLC-UV analyses and through computer simulations. The use of radioprotecting excipients is more promising than an increase in the dose rate to lower the degradation of metoprolol tartrate aqueous solutions for applications such as radiosterilization. The decontamination of metoprolol tartrate from waste waters by EB processing appears highly feasible.

Optimization of glibenclamide tablet composition through the combined use of differential scanning calorimetry and D-optimal mixture experimental design.

Science.gov (United States)

Mura, P; Furlanetto, S; Cirri, M; Maestrelli, F; Marras, A M; Pinzauti, S

2005-02-07

A systematic analysis of the influence of different proportions of excipients on the stability of a solid dosage form was carried out. In particular, a d-optimal mixture experimental design was applied for the evaluation of glibenclamide compatibility in tablet formulations, consisting of four classic excipients (natrosol as binding agent, stearic acid as lubricant, sorbitol as diluent and cross-linked polyvinylpyrrolidone as disintegrant). The goal was to find the mixture component proportions which correspond to the optimal drug melting parameters, i.e. its maximum stability, using differential scanning calorimetry (DSC) to quickly obtain information about possible interactions among the formulation components. The absolute value of the difference between the melting peak temperature of pure drug endotherm and that in each analysed mixture and the absolute value of the difference between the enthalpy of the pure glibenclamide melting peak and that of its melting peak in the different analyzed mixtures, were chosen as indexes of the drug-excipient interaction degree.

Composition profiling of seized ecstasy tablets by Raman spectroscopy.

Science.gov (United States)

Bell, S E; Burns, D T; Dennis, A C; Matchett, L J; Speers, J S

2000-10-01

Raman spectroscopy with far-red excitation has been investigated as a simple and rapid technique for composition profiling of seized ecstasy (MDMA, N-methyl-3,4-methylenedioxyamphetamine) tablets. The spectra obtained are rich in vibrational bands and allow the active drug and excipient used to bulk the tablets to be identified. Relative band heights can be used to determine drug/excipient ratios and the degree of hydration of the drug while the fact that 50 tablets per hour can be analysed allows large numbers of spectra to be recorded. The ability of Raman spectroscopy to distinguish between ecstasy tablets on the basis of their chemical composition is illustrated here by a sample set of 400 tablets taken from a large seizure of > 50,000 tablets that were found in eight large bags. The tablets are all similar in appearance and carry the same logo. Conventional analysis by GC-MS showed they contained MDMA. Initial Raman studies of samples from each of the eight bags showed that despite some tablet-to-tablet variation within each bag the contents could be classified on the basis of the excipients used. The tablets in five of the bags were sorbitol-based, two were cellulose-based and one bag contained tablets with a glucose excipient. More extensive analysis of 50 tablets from each of a representative series of sample bags have distribution profiles that showed the contents of each bag were approximately normally distributed about a mean value, rather than being mixtures of several discrete types. Two of the sorbitol-containing sample sets were indistinguishable while a third was similar but not identical to these, in that it contained the same excipient and MDMA with the same degree of hydration but had a slightly different MDMA/sorbitol ratio. The cellulose-based samples were badly manufactured and showed considerable tablet-to-tablet variation in their drug/excipient ratio while the glucose-based tablets had a tight distribution in their drug/excipient ratios

Kinetics of the esterification of active pharmaceutical ingredients containing carboxylic Acid functionality in polyethylene glycol

DEFF Research Database (Denmark)

Schou-Pedersen, Anne Marie V; Hansen, Steen Honoré; Moesgaard, Birthe

2014-01-01

Polyethylene glycols (PEGs) are attractive as excipients in the manufacture of drug products because they are water soluble and poorly immunogenic. They are used in various pharmaceutical preparations. However, because of their terminal hydroxyl groups, PEGs can participate in esterification reac......, it is important to be aware of this drug-excipient interaction, as it can reduce the shelf-life of a low-average molecular weight PEG formulation considerably. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2424-2433, 2014....

[Analysis of generic drug supply in France].

Science.gov (United States)

Taboulet, F; Haramburu, F; Latry, Ph

2003-09-01

The list of generic medicines (LGM), published since 1997 by the Agence Française de Sécurité Sanitaire des Produits de Santé (AFFSSaPS), the French Medicine Agency, concerns a special part of the medicines reimbursed by the National Health Insurance (Social Security). The objectives of the present study were: i) to describe the components of this list, based on pharmaceutical, economical and therapeutic characteristics, ii) to study differences between generic and reference products (formulations, excipients, prices, etc.), iii) to analyze information on excipients provided to health care professionals. The 21st version of the LGM (April 2001) was used. Therapeutic value was retrieved from the 2001 AFSSaPS report on the therapeutic value of 4490 reimbursed medicines. Information on excipients in the LGM and the Vidal dictionary (reference prescription book in France) was compared. The products included in the LGM represent 20% of all reimbursed medicines. The mean price differences between generics and their reference products vary between 30 and 50% for more than two thirds of the generic groups. The therapeutic value of the products of the LGM was judged important in 71% of cases (vs 63% for the 4409 assessed medicines) and insufficient in 13% of cases (vs 19%). Information on excipients is often missing and sometimes erroneous. Although the LGM is regularly revised and thus the generic market in perpetual change, the 2001 cross description of this pharmaceutical market provides much informations and raises some concern.

Preparation and evaluation of self-microemulsions for improved bioavailability of ginsenoside-Rh1 and Rh2.

Science.gov (United States)

Yang, Feifei; Zhou, Jing; Hu, Xiao; Yu, Stephanie Kyoungchun; Liu, Chunyu; Pan, Ruile; Chang, Qi; Liu, Xinmin; Liao, Yonghong

2017-10-01

Due to intestinal cytochrome P450 (CYP450)-mediated metabolism and P-glycoprotein (P-gp) efflux, poor oral bioavailability hinders ginsenoside-Rh1 (Rh1) and ginsenoside-Rh2 (Rh2) from clinical application. In this study, Rh1 and Rh2 were incorporated into two self-microemulsions (SME-1 and SME-2) to improve oral bioavailability. SME-1 contained both CYP450 and P-gp inhibitory excipients while SME-2 only consisted of P-gp inhibitory excipients. Results for release, cellular uptake, transport, and lymph node distribution demonstrated no significant difference between either self-microemulsions in vivo, but were elevated significantly in comparison to the free drug. The pharmaceutical profiles in vivo showed that the bioavailability of Rh1 in SME-1 (33.25%) was significantly higher than that in either SME-2 (21.28%) or free drug (12.92%). There was no significant difference in bioavailability for Rh2 between SME-1 (48.69%) or SME-2 (41.73%), although they both had remarkable increase in comparison to free drug (15.02%). We confirmed that SME containing CYP450 and P-gp inhibitory excipient could distinctively improve the oral availabilities of Rh1 compared to free drug or SME containing P-gp inhibitory excipient. No notable increase was observed between either SME for Rh2, suggesting that Rh2 undergoes P-gp-mediated efflux, but may not undergo distinct CYP450-mediated metabolism.

Comparison of directly compressed vitamin B12 tablets prepared from micronized rotary-spun microfibers and cast films.

Science.gov (United States)

Sebe, István; Bodai, Zsolt; Eke, Zsuzsanna; Kállai-Szabó, Barnabás; Szabó, Péter; Zelkó, Romána

2015-01-01

Fiber-based dosage forms are potential alternatives of conventional dosage forms from the point of the improved extent and rate of drug dissolution. Rotary-spun polymer fibers and cast films were prepared and micronized in order to direct compress after homogenization with tabletting excipients. Particle size distribution of powder mixtures of micronized fibers and films homogenized with tabletting excipients were determined by laser scattering particle size distribution analyzer. Powder rheological behavior of the mixtures containing micronized fibers and cast films was also compared. Positron annihilation lifetime spectroscopy was applied for the microstructural characterization of micronized fibers and films. The water-soluble vitamin B12 release from the compressed tablets was determined. It was confirmed that the rotary spinning method resulted in homogeneous supramolecularly ordered powder mixture, which was successfully compressed after homogenization with conventional tabletting excipients. The obtained directly compressed tablets showed uniform drug release of low variations. The results highlight the novel application of micronized rotary-spun fibers as intermediate for further processing reserving the original favorable powder characteristics of fibrous systems.

EPR study on non- and gamma-irradiated herbal pills

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Aleksieva, K., E-mail: katerina_bas@abv.b [Institute of Catalysis, Bulgarian Academy of Sciences, 1113 Sofia (Bulgaria); Lagunov, O. [Institute of Catalysis, Bulgarian Academy of Sciences, 1113 Sofia (Bulgaria); Dimov, K. [Institute of Cryobiology and Food Technologies, 1162 Sofia (Bulgaria); Yordanov, N.D. [Institute of Catalysis, Bulgarian Academy of Sciences, 1113 Sofia (Bulgaria)

2011-06-15

The results of EPR studies on herbal pills of marigold, hawthorn, yarrow, common balm, tutsan, nettle and thyme before and after gamma-irradiation are reported. Before irradiation all samples exhibit one weak singlet EPR line with a g-factor of 2.0048{+-}0.0005. After irradiation herbal pills could be separated in two groups according to their EPR spectra. Radiation-induced free radicals in pills of marigold, yarrow, nettle, tutsan and thyme could be attributed mainly to saccharide excipients. Tablets of hawthorn and common balm show 'cellulose-like' EPR spectrum, superimposed on partly resolved carbohydrate spectrum, due to the active part (herb) and inulin, which is present in the pills as an excipient. Fading study of the radiation-induced EPR signals confirms that sugar radicals are more stable than cellulose species. The reported results show that the presence of characteristic EPR spectra of herbal pills due to excipients or active part can be used as unambiguous proof of radiation processing within 35 or more days after irradiation.

EPR study on non- and gamma-irradiated herbal pills

International Nuclear Information System (INIS)

Aleksieva, K.; Lagunov, O.; Dimov, K.; Yordanov, N.D.

2011-01-01

The results of EPR studies on herbal pills of marigold, hawthorn, yarrow, common balm, tutsan, nettle and thyme before and after gamma-irradiation are reported. Before irradiation all samples exhibit one weak singlet EPR line with a g-factor of 2.0048±0.0005. After irradiation herbal pills could be separated in two groups according to their EPR spectra. Radiation-induced free radicals in pills of marigold, yarrow, nettle, tutsan and thyme could be attributed mainly to saccharide excipients. Tablets of hawthorn and common balm show 'cellulose-like' EPR spectrum, superimposed on partly resolved carbohydrate spectrum, due to the active part (herb) and inulin, which is present in the pills as an excipient. Fading study of the radiation-induced EPR signals confirms that sugar radicals are more stable than cellulose species. The reported results show that the presence of characteristic EPR spectra of herbal pills due to excipients or active part can be used as unambiguous proof of radiation processing within 35 or more days after irradiation.

EPR study on non- and gamma-irradiated herbal pills

Science.gov (United States)

Aleksieva, K.; Lagunov, O.; Dimov, K.; Yordanov, N. D.

2011-06-01

The results of EPR studies on herbal pills of marigold, hawthorn, yarrow, common balm, tutsan, nettle and thyme before and after gamma-irradiation are reported. Before irradiation all samples exhibit one weak singlet EPR line with a g-factor of 2.0048±0.0005. After irradiation herbal pills could be separated in two groups according to their EPR spectra. Radiation-induced free radicals in pills of marigold, yarrow, nettle, tutsan and thyme could be attributed mainly to saccharide excipients. Tablets of hawthorn and common balm show "cellulose-like" EPR spectrum, superimposed on partly resolved carbohydrate spectrum, due to the active part (herb) and inulin, which is present in the pills as an excipient. Fading study of the radiation-induced EPR signals confirms that sugar radicals are more stable than cellulose species. The reported results show that the presence of characteristic EPR spectra of herbal pills due to excipients or active part can be used as unambiguous proof of radiation processing within 35 or more days after irradiation.

Características tecnológicas de mezclas de senósidos A+B con excipientes para la formulación de tabletas Technological characteristics of mixtures of sennosides A + B with excipients for tablet formulations

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Eva Arce Fernández

2008-12-01

Full Text Available Se realizó un estudio de las propiedades tecnológicas del polvo de senósidos A+B concentrados con el fin de valorar la factibilidad de su procesamiento en la forma farmacéutica de tabletas. Las características estudiadas incluyen la compactabilidad, la presión de expulsión, el tiempo de desagregación y la velocidad de flujo del polvo. Los resultados obtenidos muestran que una mezcla de celulosa microcristalina tipo 102 con sílica coloidal sería un excipiente adecuado para aumentar hasta el doble la velocidad del flujo del polvo, hasta 4 veces la resistencia a la ruptura de las tabletas y disminuir a la mitad el tiempo necesario para la desagregación de estas. Las modificaciones en la formulación antes mencionadas no afectan de manera importante las propiedades de deslizamiento de las tabletas, al ser expulsadas desde la matriz en que se fabricaron.The technological properties of concentrates of sennosides A+B were studied with the purpose to evaluate the feasibility of its processing to the pharmaceutical form of tablets. The studied properties include the compactibility, the ejection pressure, the disintegration time and the rate of the powder flow. The obtained results show that a mixture of microcrystalline cellulose with colloidal silica is a suitable excipient to increase to the double the powder flow rate and 4 times the tablet strength and to reduce in 40 % the time necessary to disintegrate the tablets. The above mentioned formulation modifications do not affect in an important manner the gliding properties of the tablets being ejected from the die where they were compressed.

Vaginal suppositories containing Lactobacillus acidophilus: development and characterization.

Science.gov (United States)

Rodrigues, Francisca; Maia, Maria João; das Neves, José; Sarmento, Bruno; Amaral, Maria Helena; Oliveira, Maria Beatriz P P

2015-01-01

The aim of this study was to develop and characterize suppositories for vaginal delivery of Lactobacillus acidophilus. Formulations were performed in order to select suitable excipients based on suppository formation feasibility and cytotoxicity. Solid body and hollow-type suppositories were prepared by melting and molding using poly(ethylene glycol) (PEG) 400 and 4000 or Witepsol (WIT) H12 as excipients. L. acidophilus was incorporated in the molten mass before molding solid body suppositories or added as suspension into the cavity of hollow-type suppositories and sealed molten excipients. Cytotoxicity of the selected excipients was evaluated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and lactate dehydrogenase assays against VK2/E6E7, HEC-1-A and HeLa cells. Suppositories were characterized regarding organoleptic characteristics, mass uniformity, disintegration, breaking strength and L. acidophilus in vitro release. PEG 400, PEG 4000 and WIT H12 showed the absence of toxicity when tested using three different vaginal cell lines. Obtained vaginal suppositories presented uniform and mild texture, a content of about 1 × 10(8) colony-forming units, completely disintegrated in simulated vaginal environment in less than 60 min and provided sustained in vitro release of L. acidophilus. Release studies further demonstrated that incorporation of freeze-dried bacteria did not result in significant loss of viable bacteria, thus supporting that vaginal suppositories may possess good properties to promote the replacement of the vaginal flora in situations of urinary tract infection. Hollow-type suppositories showed to be promising delivery vehicles for vaginal delivery of probiotics.

Optimized conditions for MDCK permeability and turbidimetric solubility studies using compounds representative of BCS classes I-IV.

Science.gov (United States)

Taub, Mitchell E; Kristensen, Lisbeth; Frokjaer, Sven

2002-05-01

The solubility enhancing effects of various excipients, including their compatibility with in vitro permeability (P(app)) systems, was investigated using drugs representative of Biopharmaceutics Classification System (BCS) classes I-IV. Turbidimetric solubility determination using nephelometry and transport experiments using MDCK Strain I cell monolayers were employed. The highest usable concentration of each excipient [dimethyl sulfoxide (DMSO), ethanol, hydroxypropyl-beta-cyclodextrin (HPCD), and sodium taurocholate] was determined by monitoring apical (AP) to basolateral (BL) [14C]mannitol apparent permeability (P(app)) and the transepithelial electrical resistance (TEER) in transport experiments done at pH 6.0 and 7.4. The excipients were used in conjunction with compounds demonstrating relatively low aqueous solubility (amphotericin B, danazol, mefenamic acid, and phenytoin) in order to obtain a drug concentration >50 microM in the donor compartment. The addition of at least one of the selected excipients enhanced the solubility of the inherently poorly soluble compounds to >50 microM as determined via turbidimetric evaluation at pH 6.0 and 7.4. Ethanol and DMSO were found to be generally disruptive to the MDCK monolayer and were not nearly as useful as HPCD and sodium taurocholate. Sodium taurocholate (5 mM) was compatible with MDCK monolayers under all conditions investigated. Additionally, a novel in vitro system aimed at more accurately simulating in vivo conditions, i.e., a pH gradient (6.0 AP/7.4 BL), sodium taurocholate (5 mM, AP), and bovine serum albumin (0.25%, BL), was shown to generate more reliable P(app) values for compounds that are poorly soluble and/or highly protein bound.

Characterization of physicochemical properties of hydroxypropyl methylcellulose (HPMC) type 2208 and their influence on prolonged drug release from matrix tablets.

Science.gov (United States)

Devjak Novak, S; Šporar, E; Baumgartner, S; Vrečer, F

2012-07-01

The key physicochemical properties of functional excipients should be identified, and the influence of their variability on the properties of the final dosage form should be evaluated during the development phase. Excipients produced by different manufacturers and/or by different manufacturing processes should have comparable properties. Hydroxypropyl methylcellulose (HPMC) with a high molecular weight is a functional excipient often used in solid matrix systems with prolonged release of active pharmaceutical ingredients (API). This study investigates whether HPMC manufactured by two manufacturers using different chemical procedures differs in particle-size distribution, particle shape, particle morphology, chemical composition, and dissolution of diclofenac sodium as a model drug. NIR spectroscopy was introduced and calibration models were developed to detect physical differences among HPMC batches from two different origins. The physical differences between HPMC samples were additionally confirmed with scanning electron microscopy (SEM), gas chromatography (GC) measurements, and dissolution testing of hydrophilic matrix tablets. Our results prove that, even if HPMC polymers manufactured from two different sources comply with the pharmacopeial specification, they significantly differ in physicochemical properties and thus influence the properties of the formulated dosage forms. Copyright © 2012 Elsevier B.V. All rights reserved.

Thiomers and thiomer-based nanoparticles in protein and DNA drug delivery.

Science.gov (United States)

Hauptstein, Sabine; Bernkop-Schnürch, Andreas

2012-09-01

Thanks to advances in biotechnology, more and more highly efficient protein- and DNA-based drugs have been developed. Unfortunately, these kinds of drugs underlie poor non-parental bioavailability. To overcome hindrances like low mucosal permeability and enzymatic degradation polymeric excipients are utilized as drug carrier whereat thiolated excipients showed several promising qualities in comparison to the analogical unmodified polymer. The article deals with the comparatively easy modification of well-established polymers like chitosan or poly(acrylates) to synthesize thiomers. Further, the recently developed "next generation" thiomers e.g. preactivated or S-protected thiomers are introduced. Designative properties like mucoadhesion, uptake and permeation enhancement, efflux pump inhibition and protection against enzymatic degradation will be discussed and differences between first and next generation thiomers will be pointed out. Additionally, nanoparticles prepared with thiomers will be dealt with regarding to protein and DNA drug delivery as thiomers seem to be a promising approach to avoid parenteral application. Properties of thiomers per se and results of in vivo studies carried out so far for peptide and DNA drugs demonstrate their potential as multifunctional excipients. However, further investigations and optimizations have to be done before establishing a carrier system ready for clinical approval.

Chitin's Functionality as a Novel Disintegrant: Benchmarking Against Commonly Used Disintegrants in Different Physicochemical Environments.

Science.gov (United States)

Chaheen, Mohammad; Soulairol, Ian; Bataille, Bernard; Yassine, Ahmad; Belamie, Emmanuel; Sharkawi, Tahmer

2017-07-01

Disintegrants are used as excipients to ensure rapid disintegration of pharmaceutical tablets and further ensure proper dissolution of the active pharmaceutical ingredient. This study investigates disintegration mechanisms of chitin and common disintegrants. Swelling assessment (swelling force and swelling ratio) in different media, and compaction behavior (pure or mixed with other excipients) tabletability, deformation (Heckel modeling), and compact disintegration times were investigated on the tested disintegrants (alginic acid calcium salt, crospovidone, sodium starch glycolate, croscarmellose sodium, and chitin). Results show that the physicochemical properties of the disintegration medium such as pH and ionic strength, as well as other formulation ingredients, affect the disintegrant functionalities. Heckel analysis using the mean yield pressure "Py" shows that alginic acid calcium salt is the most brittle among the studied disintegrants, while crospovidone has the most plastic deformation mechanism, followed by chitin. Chitin showed good tabletability and disintegration properties that were not influenced by the physicochemical formulation environment. Chitin is largely available and easily modifiable and thus a promising material that could be used as a multifunctional excipient in tablet formulation. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Compatibilidad química del piracetam determinada por calorimetría diferencial de barrido Chemical compatibility of piracetam determined by differential scanning calorimetry

Directory of Open Access Journals (Sweden)

Luis Octavio Martínez Álvarez

2013-03-01

Full Text Available Introducción: en la primera etapa de preformulación de un medicamento se seleccionan los excipientes y es importante la realización de los estudios de compatibilidad química entre el ingrediente activo farmacéutico (IFA y excipientes. Una de las técnicas más rápidas para realizar dichos estudios es la Calorimetría diferencial de barrido (DSC, y como técnica complementaria la Termogravimetría (TG. Objetivo: empleando DSC y TG, se realiza un estudio de compatibilidad química entre IFA y excipientes preseleccionados, para comprobar la existencia o no de interacción química. Métodos: el equipo empleado fue el TA3000Mettler, aco­plado a la celda DSC20 y al horno TG50. El IFA utilizado fue Piracetam, y los excipientes: Kollidon VA 64, Estearato de magnesio, Celulosa microcristalina, Polietilenglicol 20 000 y Aerosil. Dichos excipientes se caracterizaron por DSC al igual que el IFA, al cual se le detectó la transición física de fusión. Para el estudio de compatibilidad se prepararon mezclas físicas binarias en una relación de concentración 1:1 Resultados: la figura 1 muestra la detección del punto de fusión por DSC del IFA. Se obtuvieron dos transiciones endotérmicas, comprobándose por TG cuál era la de fusión. La figura 2 muestra los termogramas de las mezclas formadas entre IFA y excipientes. Conclusiones: no se detectó aparición de nuevos picos, por lo que se infiere que no hay incompatibilidad química entre las sustancias estudiadas y se recomienda el uso de los excipientes para el desarrollo de la formulación farmacéutica.Introduction: the first phase of the drug preformulation comprises the selection of excipients and the conduction of studies on chemical compatibility between pharmacologically active ingredient and the excipients. One of the quickest techniques is the differential scanning calorimetry and the supplementary technique called thermogravimetic analysis. Objective: to conduct a chemical compatibility

Reaction between drug substances and pharmaceutical excipients

DEFF Research Database (Denmark)

Larsen, Jesper; Cornett, Claus; Jaroszewski, Jerzy Witold

2009-01-01

The reactivity of citric acid towards drug substances in the solid state was examined using the beta-blocker carvedilol as a model compound. The reaction mixtures were analysed by LC-MS, the reaction products were isolated by preparative HPLC, and the structures were elucidated by microprobe NMR...... spectroscopy. Heating a mixture of solid carvedilol and solid citric acid monohydrate for 96h at 50 degrees C resulted in the formation of about 3% of a symmetrical ester as well as of a number of other reaction products in smaller amounts. Formation of the symmetrical ester was also observed at room...... temperature. At 70 degrees C, the amounts of three isomeric esters formed reached 6-8%. The minor reaction products were citric acid amides, O-acetylcarvedilol, and esters of itaconic acid....

Peroral insulin delivery : new concepts and excipients

NARCIS (Netherlands)

Sadeghi, Assal M.M.

2008-01-01

A number of chitosan derivatives were synthesized and compared to the previously synthesized derivatives for their permeation enhancing activity. Using these derivatives insulin nanoparticles were prepared and their effect was compared to the free polymer and insulin in Caco-2 cells. The results

Compatibility and stability of valsartan in a solid pharmaceutical formulation

Directory of Open Access Journals (Sweden)

Tamíris Amanda Júlio

2013-12-01

Full Text Available Valsartan (VAL is a highly selective blocker of the angiotensin II receptor that has been widely used in the treatment of hypertension. Active pharmaceutical ingredient compatibility with excipients (crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose and titanium dioxide is usually evaluated in solid pharmaceutical development. Compatibility and stability can be evaluated by liquid chromatography. Studies were performed using binary mixtures of 1:1 (w/w VAL/excipient; samples were stored under accelerated stability test conditions (40 ºC at 75% relative humidity. The results indicate that VAL is incompatible with crospovidone and hypromellose, which reduced the VAL content and gave rise to new peaks in the chromatogram due to degradation products.

Differential scanning calorimetry as a screening technique in compatibility studies of acyclovir extended release formulations

International Nuclear Information System (INIS)

Barboza, Fernanda M.; Vecchia, Debora D.; Tagliari, Monika P.; Ferreira, Andrea Granada; Silva, Marcos A.S.; Stulzer, Hellen K.

2009-01-01

Acyclovir (ACV) has been investigated during the past years, mainly due to its antiviral activity. Assessment of possible incompatibility between an active component and different excipients along with the evaluation of thermal stability are crucial parts of a normal study prior to the final formulation setting of a medicine. Thermal analysis studies were used as important and complementary tools during pre-formulation to determine the compatibility of drug excipients with the purpose of developing an acyclovir extended release formulation. Fourier transform infrared spectroscopy and X-ray powder diffraction analyses were also realized. The results showed that ACV only exhibited interaction which could influence the stability of the product in the binary mixtures of ACV/magnesium stearate. (author)

Pharmaceutical powder compaction technology

National Research Council Canada - National Science Library

Çelik, Metin

2011-01-01

... through the compaction formulation process and application. Compaction of powder constituents both active ingredient and excipients is examined to ensure consistent and reproducible disintegration and dispersion profiles...

Elucidating the weak protein-protein interaction mechanisms behind the liquid-liquid phase separation of a mAb solution by different types of additives.

Science.gov (United States)

Wu, Guoliang; Wang, Shujing; Tian, Zhou; Zhang, Ning; Sheng, Han; Dai, Weiguo; Qian, Feng

2017-11-01

Liquid-liquid phase separation (LLPS) has long been observed during the physical stability investigation of therapeutic protein formulations. The buffer conditions and the presence of various excipients are thought to play important roles in the formulation development of monoclonal antibodies (mAbs). In this study, the effects of several small-molecule excipients (histidine, alanine, glycine, sodium phosphate, sodium chloride, sorbitol and sucrose) with diverse physical-chemical properties on LLPS of a model IgG1 (JM2) solutions were investigated by multiple techniques, including UV-vis spectroscopy, circular dichroism, differential scanning calorimetry/fluorimetry, size exclusion chromatography and dynamic light scattering. The LLPS of JM2 was confirmed to be a thermodynamic equilibrium process with no structural changes or irreversible aggregation of proteins. Phase diagrams of various JM2 formulations were constructed, suggesting that the phase behavior of JM2 was dependent on the solution pH, ionic strength and the presence of other excipients such as glycine, alanine, sorbitol and sucrose. Furthermore, we demonstrated that for this mAb, the interaction parameter (k D ) determined at low protein concentration appeared to be a good predictor for the occurrence of LLPS at high concentration. Copyright © 2017 Elsevier B.V. All rights reserved.

Evaluation of taste-masking effects of pharmaceutical sweeteners with an electronic tongue system.

Science.gov (United States)

Choi, Du Hyung; Kim, Nam Ah; Nam, Tack Soo; Lee, Sangkil; Jeong, Seong Hoon

2014-03-01

Electronic tongue systems have been developed for taste measurement of bitter drug substances in accurate taste comparison to development palatable oral formulations. This study was to evaluate the taste masking effect of conventional pharmaceutical sweeteners such as neohesperidin dihydrochalcone, sucrose, sucralose and aspartame. The model drugs were acetaminophen, ibuprofen, tramadol hydrochloride, and sildenafil citrate (all at 20 mM). The degree of bitterness was measured by a multichannel taste sensor system (an electronic tongue). The data was collected by seven sensors and analyzed by a statistical method of principal components analysis (PCA). The effect of taste masking excipient was dependent on the type of model drug. Changing the concentration of taste masking excipients affected the sensitivity of taste masking effect according to the type of drug. As the excipient concentration increased, the effect of taste masking increased. Moreover, most of the sensors showed a concentration-dependent pattern of the taste-masking agents as higher concentration provided higher selectivity. This might indicate that the sensors can detect small concentration changes of a chemical in solution. These results suggest that the taste masking could be evaluated based on the data of the electronic tongue system and that the formulation development process could be performed in a more efficient way.

Carboxymethyl starch and lecithin complex as matrix for targeted drug delivery: I. Monolithic mesalamine forms for colon delivery.

Science.gov (United States)

Mihaela Friciu, Maria; Canh Le, Tien; Ispas-Szabo, Pompilia; Mateescu, Mircea Alexandru

2013-11-01

For drugs expected to act locally in the colon, and for successful treatment, a delivery device is necessary, in order to limit the systemic absorption which decreases effectiveness and causes important side effects. Various delayed release systems are currently commercialized; most of them based on pH-dependent release which is sensitive to gastrointestinal pH variation. This study proposes a novel excipient for colon delivery. This new preparation consists in the complexation between carboxymethyl starch (CMS) and Lecithin (L). As opposed to existing excipients, the new complex is pH-independent, inexpensive, and easy to manufacture and allows a high drug loading. FTIR, X-ray, and SEM structural analysis all support the hypothesis of the formation of a complex. By minor variation of the excipient content within the tablet, it is possible to modulate the release time and delivery at specific sites of the gastrointestinal tract. This study opens the door to a new pH-independent delivery system for mesalamine targeted administration. Our novel formulation fits well with the posology of mesalamine, used in the treatment of Inflammatory Bowel Disease (IBD), which requires repeated administrations (1g orally four times a day) to maintain a good quality of life. Copyright © 2013 Elsevier B.V. All rights reserved.

Insights into the swelling process and drug release mechanisms from cross-linked pectin/high amylose starch matrices

Directory of Open Access Journals (Sweden)

Fernanda M. Carbinatto

2014-02-01

Full Text Available Cross-linked pectin/high amylose mixtures were evaluated as a new excipient for matrix tablets formulations, since the mixing of polymers and cross-linking reaction represent rational tools to reach materials with modulated and specific properties that meet specific therapeutic needs. Objective: In this work the influence of polymer ratio and cross-linking process on the swelling and the mechanism driving the drug release from swellable matrix tablets prepared with this excipient was investigated. Methods: Cross-linked samples were characterized by their micromeritic properties (size and shape, density, angle of repose and flow rate and liquid uptake ability. Matrix tablets were evaluated according their physical properties and the drug release rates and mechanisms were also investigated. Results: Cross-linked samples demonstrated size homogeneity and irregular shape, with liquid uptake ability insensible to pH. Cross-linking process of samples allowed the control of drug release rates and the drug release mechanism was influenced by both polymer ratio and cross-linking process. The drug release of samples with minor proportion of pectin was driven by an anomalous transport and the increase of the pectin proportion contributed to the erosion of the matrix. Conclusion: The cross-linked mixtures of high amylose and pectin showed a suitable excipient for slowing the drug release rates.

Co-spray Drying with HPMC as a Platform to Improve Direct Compaction Properties of Various Tablet Fillers.

Science.gov (United States)

Li, JinZhi; Zhao, LiJie; Lin, Xiao; Shen, Lan; Feng, Yi

2017-11-01

Many commonly used tablet fillers are not suitable for direct compaction process due to insufficient properties, mainly of flowability and compactability. This work therefore aimed to use co-spray drying with HPMC as a platform to improve direct compaction properties of various tablet fillers. Starch, calcium hydrogen phosphate dihydrate (DCPD), and mannitol were chosen as a representative of three types of commonly used fillers (i.e. organic macromolecules, water-insoluble inorganic salts, and water-soluble small molecular carbohydrates), respectively. The five-level central composite design-response surface methodology was used (i) to investigate the effects of HPMC level and solid content of the feed on various powder, tableting, and tablet properties of composite excipients, and (ii) to optimize the composition. The results showed that the impacts of the two factors on various properties of composite excipients showed great similarity, despite of significantly different primary properties of the parent fillers, and the HPMC level was the main contributor to the majority of the impacts. An increase in HPMC level significantly improved tablet tensile strength and various tableting parameters. For all the three fillers, their optimized composite excipients provided by the established models showed excellent performances as predicted. The platform suggested is confirmed to be effective and promising.

Achievement report for fiscal 1990 on research and development of electrically conductive polymeric materials; 1990 nendo dodensei kobunshi zairyo no kenkyu kaihatsu seika hokokusho

Energy Technology Data Exchange (ETDEWEB)

NONE

1991-03-01

It is intended to realize new electrically conductive materials characterized by light weight, corrosion resistance and easy-to-process performance, and electrical and electronic materials having functions different from those of metallic conduction mechanism. Therefore, activities were performed to seek technologies for polymeric materials having conductivity greater than 10{sup 5} S/cm and being stable and easy to process. Activities were taken in the following six fields: (1) new hydrocarbon conjugate polymers, (2) excipient conjugate conductive materials, (3) technologies to form thin films of graphite synthesized at low temperatures, (4) conductive polymers of hetero aromatic system, (5) research and development of conductive materials of the hetero containing system and the {pi} conjugate system, and (6) comprehensive investigative research. In (1), thin films of polyacetylene and polyacene systems were formed, in (2), excipient hydrocarbon conjugate polymers and excipient graphite materials were developed, in (3), a high-accuracy process controlled graphite thin film forming technology was developed, in (4), the conductivity was enhanced by using high-order structural control and molecular design, and stability of the conductive polymers of complex annular conjugate system was enhanced, and in (5), conductive polymers of the hetero containing system and the {pi} conjugate system, and flexible graphite fibers were developed. (NEDO)

2591-IJBCS-Article-Rokhaya Sylla Gueye

African Journals Online (AJOL)

hp

attapulgite, compared with Actapulgite® (antidiarrheal drug), composed of attapulgite. A sample of ..... industry Part I. Excipients and medical applications. ... Colloids and Surfaces : Biointerfaces, .... for dispersion palygorskite aggregates.

Fuzzy Logic-based expert system for evaluating cake quality of freeze-dried formulations

DEFF Research Database (Denmark)

Trnka, Hjalte; Wu, Jian-Xiong; van de Weert, Marco

2013-01-01

Freeze-drying of peptide and protein-based pharmaceuticals is an increasingly important field of research. The diverse nature of these compounds, limited understanding of excipient functionality, and difficult-to-analyze quality attributes together with the increasing importance of the biosimilar......Freeze-drying of peptide and protein-based pharmaceuticals is an increasingly important field of research. The diverse nature of these compounds, limited understanding of excipient functionality, and difficult-to-analyze quality attributes together with the increasing importance...... critical visual features such as the degree of cake collapse, glassiness, and color uniformity. On the basis of the IA outputs, a fuzzy logic system for analysis of these freeze-dried cakes was constructed. After this development phase, the system was tested with a new screening well plate. The developed...

In vitro Evaluation of PEGylated-Mucin Matrix as Carrier for Oral ...

African Journals Online (AJOL)

Index Medicus, JournalSeek, Journal Citation Reports/Science Edition, Directory of Open Access Journals. (DOAJ), African ..... molecular bonding, resulting from the interplay of the functional .... Pharmaceutical Excipients, 5th edn, London:.

Effect of thermal and chemical modifications on the mechanical and release properties of paracetamol tablet formulations containing corn, cassava and sweet potato starches as filler-binders

Directory of Open Access Journals (Sweden)

Mariam Vbamiunomhene Lawal

2015-07-01

Conclusions: Modification of the experimental starches improved the mechanical and release properties of directly compressed paracetamol tablet formulations. Thus, they can be developed for use as pharmaceutical excipients in specific formulations.

Evaluation of the suspending properties of Abizia zygia gum on ...

African Journals Online (AJOL)

Purpose: Some excipients are currently available for the formulation of pharmaceutical suspensions. ... Method: The suspending properties of Albizia zygia gum (family ... Characterization tests were carried out on purified Albizia zygia gum.

Thermodynamics of water-solid interactions in crystalline and amorphous pharmaceutical materials.

Science.gov (United States)

Sacchetti, Mark

2014-09-01

Pharmaceutical materials, crystalline and amorphous, sorb water from the atmosphere, which affects critical factors in the development of drugs, such as the selection of drug substance crystal form, compatibility with excipients, dosage form selection, packaging, and product shelf-life. It is common practice to quantify the amount of water that a material sorbs at a given relative humidity (RH), but the results alone provide minimal to no physicochemical insight into water-solid interactions, without which pharmaceutical scientists cannot develop an understanding of their materials, so as to anticipate and circumvent potential problems. This research was conducted to advance the science of pharmaceutical materials by examining the thermodynamics of solids with sorbed water. The compounds studied include nonhygroscopic drugs, a channel hydrate drug, a stoichiometric hydrate excipient, and an amorphous excipient. The water sorption isotherms were measured over a range of temperature to extract the partial molar enthalpy and entropy of sorbed water as well as the same quantities for some of the solids. It was found that water-solid interactions spanned a range of energy and entropy as a function of RH, which was unique to the solid, and which could be valuable in identifying batch-to-batch differences and effects of processing in material performance. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Study of the Formulation and Preparation of Chewable Tablets With a Calcium Complex Association and Vitamin D3

Directory of Open Access Journals (Sweden)

Emma Creţu

2010-06-01

Full Text Available The experimental study objective was the development of
chewable tablets with the calcium complex association, the minerals and vitamin D3 for children, subject to the rules as stipulated by the Romanian Pharmacopoeia Xth edition. Generating sources of calcium, used as raw materials in the preparation of these tablets are natural products represented by complex mineral rich in calcium - Lactoval (R HiCal (ratio of calcium and phosphorus is 2,2:1, report the same as breast milk and 30% bovine colostrums [1, 3], making the absorption of calcium should be increased. Also, in order to
fix and better absorb calcium in the body was added to make the preparation of these chewable tablets and vitamin D3.
Was chosen as a method of preparing direct compression. Excipients for direct compression are diluents-binder-disaggregated. They are unitary excipients or co-processed products, multi-processed excipients together to meet those properties: microcrystalline cellulose (Vivapur 102 Ludipress, lactose (Tablettose 80, Kollidon CL Isomalt DC 100. Was also added to a lubricant (magnesium stearate and sweetener and flavoring to carry out the preparation of tablets and after 30 days as provided Romanian Pharmacopoeia Xth and its 2001 supplement, which comprises: organoleptic control, uniformity of weight, strength, disintegration and their friability. Working method chosen and make the appropriate choice leads to tablets in terms of quality standards officinal.

Use of solid dispersions to increase stability of dithranol in topical formulations

Directory of Open Access Journals (Sweden)

Marilene Estanqueiro

2014-09-01

Full Text Available The present study was planned to improve the stability of dithranol using solid dispersions (SD. Two different SD at a 1:9 ratio of dithranol/excipient were prepared: one of them using glyceryl behenate as excipient and the other using a mixture of argan oil with stearic acid (1:8 ratio as excipient. Pure dithranol and SD of dithranol were incorporated in an oil-in-water cream and in a hydrophobic ointment in a drug/dermatological base ratio of 1:10. The physical and mechanical properties of semisolid formulations incorporating the pure drug and the developed SD were evaluated through rheological and textural analysis. To evaluate the stability, L*a*b* color space parameters of SD and semisolid formulations, and pH of hydrophilic formulations were determined at defined times, during one month. Each sample was stored at different conditions namely, light exposure (room temperature, high temperature exposition (37 °C (protected from light and protected from light (room temperature. Despite higher values of firmness and adhesiveness, hydrophobic ointment exhibited the best rheological features compared to the oil-in-water cream, namely a shear-thinning behavior and high thixotropy. These formulations have also presented more stability, with minor changes in L*a*b* color space parameters. The results of this study indicate that is possible to conclude that the developed SD contributed to the increased stability of dithranol.

CONDITIONING MICROBIAL PRODUCTS CONTAINING LACTIC BACTERIA WITH ORGANIC AND INORGANIC SUPPORTS FOR USE IN ANIMAL FEEDING

Directory of Open Access Journals (Sweden)

T VINTILĂ

2007-05-01

Full Text Available The stability in real time of three strains of lactic bacteria (Lactobacillus acidophilus, Lactobacillus plantarum, Enterococcus faecium mixed with different excipients was evaluated during a 6-months period. The excipients studied were: zeolite, calcium carbonate, perlite ceramic, wheat bran and Carboxymethyl cellulose (CMC. A part of liquid cultures and excipients mixtures were dried (12- 14% humidity and other part were sealed in plastic bags with over 70% humidity and preserved at +4oC. The cells were activated periodically by suspending aliquots from wet and dry products in 0.9% saline solution. The viability of lactic bacteria was evaluated by cultivation of diluted suspensions in MRS plates. The number of viable lactic cells is decreasing very slowly, or remains constant in calcium carbonate, ceramics and CMC dry products for al strains. In the case of zeolite, the viability of Lb. acidophilus and Lb. plantarum decrease to 0 in the first month, and the viability of Ec. faecium decrease 20 times in 6 months. As for wet products, the number of viable cells is increasing in the first 30 days for calcium carbonate and in the first 60 days for wheat bran. The numbers of viable cells decrease in both wet products, reaching values close to the viability in fresh products after 6 months of storage at +4oC.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Amoxicillin Trihydrate.

Science.gov (United States)

Thambavita, Dhanusha; Galappatthy, Priyadarshani; Mannapperuma, Uthpali; Jayakody, Lal; Cristofoletti, Rodrigo; Abrahamsson, Bertil; Groot, Dirk W; Langguth, Peter; Mehta, Mehul; Parr, Alan; Polli, James E; Shah, Vinod P; Dressman, Jennifer

2017-10-01

Literature and experimental data relevant to waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release solid oral dosage forms containing amoxicillin trihydrate are reviewed. Solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), therapeutic uses, therapeutic index, excipient interactions, as well as dissolution and BE and bioavailability studies were taken into consideration. Solubility and permeability studies indicate that amoxicillin doses up to 875 mg belong to BCS class I, whereas 1000 mg belongs to BCS class II and doses of more than 1000 mg belong to BCS class IV. Considering all aspects, the biowaiver procedure can be recommended for solid oral products of amoxicillin trihydrate immediate-release preparations containing amoxicillin as the single active pharmaceutical ingredient at dose strengths of 875 mg or less, provided (a) only the excipients listed in this monograph are used, and only in their usual amounts, (b) the biowaiver study is performed according to the World Health Organization-, U.S. Food and Drug Administration-, or European Medicines Agency-recommended method using the innovator as the comparator, and (c) results comply with criteria for "very rapidly dissolving" or "similarly rapidly dissolving." Products containing other excipients and those containing more than 875 mg amoxicillin per unit should be subjected to an in vivo BE study. Copyright © 2017 American Pharmacists Association®. All rights reserved.

3D printing of tablets containing multiple drugs with defined release profiles.

Science.gov (United States)

Khaled, Shaban A; Burley, Jonathan C; Alexander, Morgan R; Yang, Jing; Roberts, Clive J

2015-10-30

We have employed three-dimensional (3D) extrusion-based printing as a medicine manufacturing technique for the production of multi-active tablets with well-defined and separate controlled release profiles for three different drugs. This 'polypill' made by a 3D additive manufacture technique demonstrates that complex medication regimes can be combined in a single tablet and that it is viable to formulate and 'dial up' this single tablet for the particular needs of an individual. The tablets used to illustrate this concept incorporate an osmotic pump with the drug captopril and sustained release compartments with the drugs nifedipine and glipizide. This combination of medicines could potentially be used to treat diabetics suffering from hypertension. The room temperature extrusion process used to print the formulations used excipients commonly employed in the pharmaceutical industry. Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) and X-ray powder diffraction (XRPD) were used to assess drug-excipient interaction. The printed formulations were evaluated for drug release using USP dissolution testing. We found that the captopril portion showed the intended zero order drug release of an osmotic pump and noted that the nifedipine and glipizide portions showed either first order release or Korsmeyer-Peppas release kinetics dependent upon the active/excipient ratio used. Copyright © 2015. Published by Elsevier B.V.

Formulation strategy and evaluation of nanocrystal piroxicam orally disintegrating tablets manufacturing by freeze-drying.

Science.gov (United States)

Lai, Francesco; Pini, Elena; Corrias, Francesco; Perricci, Jacopo; Manconi, Maria; Fadda, Anna Maria; Sinico, Chiara

2014-06-05

Piroxicam (PRX) is a non-steroidal anti-inflammatory drug characterized by a poor water solubility and consequently by a low oral bioavailability. In this work, different nanocrystal orally disintegrating tablets (ODT) were prepared to enhance piroxicam dissolution rate and saturation solubility. PRX nanocrystals were prepared by means of high pressure homogenization technique using poloxamer 188 as stabilizer. Three different ODTs were prepared with the same nanosuspension using different excipients in order to study their effect on the PRX dissolution properties. PRX nanocrystal size and zeta potential were determined by photon correlation spectroscopy. Additional characterization of PRX nanocrystal ODT was carried out by infrared spectroscopy, X-ray powder diffractometry, differential scanning calorimetry. Dissolution study was performed in distilled water (pH 5.5) and compared with PRX coarse suspension ODT, PRX/poloxamer 188 physical mixture, bulk PRX samples and a PRX commercial ODT. All PRX nanocrystal ODT formulations showed a higher drug dissolution rate than coarse PRX ODT. PRX nanocrystal ODT prepared using gelatin or croscarmellose as excipient showed a higher PRX dissolution rate compared with the commercial formulation and ODT prepared using xanthan gum. Overall results confirmed that improved PRX dissolution rate is due to the increased surface-to-volume ratio due to the nanosized drug particle but also revealed the important role of different excipients used. Copyright © 2014 Elsevier B.V. All rights reserved.

The impact of hot melt extrusion and spray drying on mechanical properties and tableting indices of materials used in pharmaceutical development.

Science.gov (United States)

Iyer, Raman; Hegde, Shridhar; Zhang, Yu-E; Dinunzio, James; Singhal, Dharmendra; Malick, A; Amidon, Gregory

2013-10-01

The impact of melt extrusion (HME) and spray drying (SD) on mechanical properties of hypromellose acetate succinate (HPMCAS), copovidone, and their formulated blends was studied and compared with that of reference excipients. Tensile strength (TS), compression pressure (CP), elastic modulus (E), and dynamic hardness (Hd ) were determined along with Hiestand indices using compacts prepared at a solid fraction of ∼0.85. HPMCAS and copovidone exhibited lower Hd , lower CP, and lower E than the reference excipients and moderate TS. HPMCAS was found to be highly brittle based on brittle fracture index values. The CP was 24% and 61% higher for HPMCAS after SD and HME, respectively, than for unprocessed material along with a higher Hd . Furthermore, the TS of HPMCAS and copovidone decreased upon HME. Upon blending melt-extruded HPMCAS with plastic materials such as microcrystalline cellulose, the TS increased. These results suggest that SD and HME could impact reworkability by reducing deformation of materials and in case of HME, likely by increasing density due to heating and shear stress in a screw extruder. A somewhat similar effect was observed for the dynamic binding index (BId ) of the excipients and formulated blends. Such data can be used to quantitate the impact of processing on mechanical properties of materials during tablet formulation development. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Investigation of excipients’ nature influence on the quality indices of effervescent tablets of acetylsalicylic acid, paracetamol and ascorbic acid

Directory of Open Access Journals (Sweden)

О. V. Tryhubchak

2018-03-01

Full Text Available The priority objective of pharmaceutical science remains the creation and rational use of medicines. In recent years among these medicines particular attention is paid to the form of sparkling (fast-dissolving, gaseous or effervescent solid dosage forms – tablets, granules, powders, microspheres, capsules, suppositories and others. In the development of effervescent tablets, which are absent in the domestic market, a combination of acetylsalicylic acid, paracetamol and ascorbic acid was selected for experimental studies. The purpose of the work is to study the influence of excipients on the pharmaco-technological properties of effervescent tablets of acetylsalicylic acid, paracetamol and ascorbic acid. Materials and methods. In the course of the experiment, nine excipients from groups of fillers, leavens and binders were investigated. By studying qualitative factors, one of the plans of dispersion analysis was used, namely a three-factorial experiment based on the Hyper-Greek-Latin square. In experiments we used modern equipment for determining the bulk density of powders (ERWEKA GT, Germany, bulk density (ERWEKA SVM 202, Germany, tablet press (Korsh XL-100, Germany, uniformity of the weight of tablets (Mettler Toledo AB54-S, Switzerland, crushing resistance (ERWEKA TBH-525 WTO, Germany, abradability (ERWEKA TAR 200, Germany, disintegration time (ERWEKA ZT 33, Germany. Results. As a result of the statistical processing of experimental results, the influence of excipients on the pharmaco-technological parameters of mass for tableting (bulk density, density after compression, Carr's index, flow ability, slope angle, tableting process, tablet appearance, mass uniformity, abradability, resistance to crushing, disintegration and transparency of the solution were investigated. Conclusions. The influence of nine excipients on the pharmaco-technological characteristics of effervescent tablets of acetylsalicylic acid, paracetamol and ascorbic acid was

Functionality of innovative and generic celluloses in metronidazole formulations

Directory of Open Access Journals (Sweden)

Carmen Cristina Díaz Ramírez

2011-03-01

Full Text Available The wide variety of excipients available calls for evaluation of their functionality, in this case of the pharmaceutical performance of microcrystalline celluloses and sodium cross-linked carboxymethylcelluloses from different sources. This evaluation includes parameters such as powder flow, compactibility, ejection pressure and dissolution from fast-release tablets as well as from floating granules and controlled-release tablets. In a previous study, the excipient Carmacel® presented better disintegration properties compared to Croscarmellose®. However, the evaluation showed better compactibility performance for Croscarmellose®. These characteristics were observed using pure excipients. Nevertheless, these advantages have not been confirmed in tests employing immediate-release or modified-release formulations containing metronidazole. Regarding microcrystalline celluloses, the present comparative evaluation between pure Alfacel ® types 101 and 102 and pure Avicel® types 101 and 102 showed better compactibility performance for the latter. However, for metronidazole formulations, this advantage was not evident in the innovative excipient. Notwithstanding, this study revealed better compactibility performance of microcrystalline cellulose type 101. In terms of powder flow properties, Avicel® and Alfacel® showed similar performance. However, the results revealed better powder flow employing microcrystalline cellulose type 102 for both excipients. Based on the results obtained, it can be concluded that the employment of innovative and generic excipients have both advantages and disadvantages. The observed differences however, tend to disappear as the excipients are diluted in a formulation, thereby equalizing their influence on product performance.A variedade de excipientes disponível no mercado requer adequada seleção desses no que se refere à sua funcionalidade, como no caso de celuloses microcristalinas (Avicel® 101 e 102 e Alfacel

Primary Investigation of the Preparation of Nanoparticles by Precipitation

Czech Academy of Sciences Publication Activity Database

Vaculíková, E.; Grünwaldová, Veronika; Král, V.; Dohnal, J.; Jampílek, J.

2012-01-01

Roč. 17, č. 9 (2012), s. 11067-11078 ISSN 1420-3049 Institutional support: RVO:61388980 Keywords : steroids * nanoparticles * precipitation * excipients * dynamic light scattering Subject RIV: CA - Inorganic Chemistry Impact factor: 2.428, year: 2012

78 FR 2416 - Notice of Issuance of Final Determination Concerning Rybix® (Tramadol Hydrochloride) Tablets

Science.gov (United States)

2013-01-11

... sieve. An excipient is defined on www.thefreedictionary.com as ``an inactive substance that serves as...? LAW AND ANALYSIS: Pursuant to Subpart B of Part 177, 19 CFR 177.21 et seq., which implements Title III...

Thiolated chitosans: useful excipients for oral drug delivery.

Science.gov (United States)

Werle, Martin; Bernkop-Schnürch, Andreas

2008-03-01

To improve the bioavailability of orally administered drugs, formulations based on polymers are of great interest for pharmaceutical technologists. Thiolated chitosans are multifunctional polymers that exhibit improved mucoadhesive, cohesive and permeation-enhancing as well as efflux-pump-inhibitory properties. They can be synthesized by derivatization of the primary amino groups of chitosan with coupling reagents bearing thiol functions. Various data gained in-vitro as well as in-vivo studies clearly demonstrate the potential of thiolated chitosans for oral drug delivery. Within the current review, the synthesis and characterization of thiolated chitosans so far developed is summarized. Features of thiolated chitosans important for oral drug delivery are discussed as well. Moreover, different formulation approaches, such as matrix tablets and micro-/nanoparticles, as well as the applicability of thiolated chitosans for the oral delivery of various substance classes including peptides and efflux pump substrates, are highlighted.

Characterization of Grewia Gum, a Potential Pharmaceutical Excipient

Directory of Open Access Journals (Sweden)

Elijah.I.Nep

2010-03-01

Full Text Available Grewia gum was extracted from the inner stem bark of Grewia mollis and characterized by several techniques such as gas chromatography (GC, gel permeation chromatography (GPC, scanning electron microscopy (SEM, differential scanning calorimetry (DSC and thermogravimetric analysis of the extracted sample. Spectroscopic techniques such as x-ray photoelectron spectroscopy (XPS, fourier-transformed infrared (FT-IR, solid-state nuclear magnetic resonance (NMR, and 1H and 13C NMR techniques were also used to characterize the gum. The results showed that grewia gum is a typically amorphous polysaccharide gum containing glucose, rhamnose, galactose, arabinose and xylose as neutral sugars. It has an average molecular weight of 5925 kDa expressed as the pullulan equivalent. The gum slowly hydrated in water, dispersing and swelling to form a highly viscous dispersion exhibiting pseudoplastic flow behaviour. The polysaccharide gum is thermally stable and may have application as stabilizer or suspending agent in foods, cosmetics and in pharmaceuticals. It may have application as a binder or sustained-release polymer matrix in tablets or granulations.

Browse Title Index

African Journals Online (AJOL)

Items 51 - 100 of 246 ... ... for combating current and future diseases of global health importance, Abstract ... and evaluation of a tripartite novel excipient for direct compression of ... Vol 1, No 1 (2004), Diffuse Transcranial Electrical Stimulation ...

Original Research

African Journals Online (AJOL)

the active drug and to formulate the MD tablets by sublimation method. Metoclopramide HCl ... In order to achieve an acceptable palatability, the addition of flavors or sweeteners is ... pouring presieved drug excipient blend into a graduated ...

In-vitro evaluation of dexpanthenol-loaded nanofiber mats for wound ...

African Journals Online (AJOL)

admin

Methods: A novel bioactive wound dressing formulation with dexpanthenol was developed ... known as a natural body response when the skin .... The FT-IR analysis of pure excipients and drug .... a scaffold are very important in regulating the.

Development and characterization of controlled release polar lipid microparticles of candesartan cilexetil by solid dispersion

Science.gov (United States)

Kamalakkannan, V; Puratchikody, A; Ramanathan, L

2013-01-01

Candesartan cilexetil (CC) is a newer class of angiotensin II receptor antagonist used for the treatment of hypertension. The solubility of the CC is very poor and its oral bioavailability is only 15%. The controlledrelease polar lipid microparticles of CC (formulations F1, F2, F3 and F4) were prepared using variable erodible lipophilic excipients like hydrogenated castor oil, stearic acid, cetostearyl alcohol and carnauba wax by fusion method. The particle sizes of polar lipid microparticles were less than 50 microns and they were irregular in shape. Drug content ranged between 98.96 ± 2.1 and 101.9 ± 1.6% were present in all the formulations. The formulation F3 showed better drug release throughout the study period in a controlled release manner. Moreover, the in vitro release showed that all the formulations were best fitted to Higuchi model. Accelerated stability studies indicated that there was no significant changes in the chemical and physical characteristics of the formulated drug product during initial and at the end of the study period. The FTIR and DSC studies showed that there was no interaction between the drug and lipophilic excipients and no polymorphic transitions in all formulations. The X-ray diffraction peak of solid dispersion indicated that the crystalline nature of CC disappeared and no new peaks could be observed, suggesting the absence of interaction between drug and excipients. PMID:24019822

Incompatibilidad química y estabilidad térmica del baclofeno por análisis térmico

Directory of Open Access Journals (Sweden)

Luis Martínez Álvarez

1998-04-01

Full Text Available Se realizó un estudio de las posibles interacciones químicas entre el baclofeno, principio activo, y los distintos excipientes preseleccionados en la preformulación del baclofeno tableta, y al mismo tiempo un estudio de estabilidad térmica con el empleo de la calorimetría diferencial de barrido como técnica fundamental, la cual fue complementada con la cromatografía de capa fina y la espectroscopia infrarroja. Se obtuvo como resultado la no interacción química entre el principio activo y los excipientes; además se estableció un orden de estabilidad térmica con el propósito de realizar posibles sustituciones de algunos excipientes en la preformulación, con vistas a garantizar una mayor estabilidad del producto final.A study of the possible chemical interactions between baclofen, active principle, and the different excipients preselected in the preformulation of baclofen tablet was conducted. A study of thermic stability by using the differential scanning calorimetry, which was complemented with thin layer chromatography and infrared spectroscopy, was carried out at the same time. As a result, the non-chemical interaction between the active principle and the excipients was obtained, and an order of thermic stability was established aimed at making possible substitutions of some excipients in the preformulation in order to guarantees a greater stability of the final product.

Biodegraded polymers as materials for sowing of grain crops seeds

Directory of Open Access Journals (Sweden)

L. S. Shibryaeva

2015-01-01

Full Text Available Increase of efficiency of grain production, solution of problems of food security demand search and development of innovative technologies at all stages. One of ways of environmentally friendly production is sowing of seeds on an excipient located in the soil, for example, nonwoven fabric made of eco- decomposable decomposed biodegraded polymer. Biodegraded polymeric materials influence on sowing properties of grain crops seeds and provide realization of their potential productivity. The authors used an electroforming method with chloroform and a dichloroethane application to receive nonwoven fabric from poly-3-hydroxybutyrate (PHB and its compositions together with synthetic nitrile rubber (PHB-SNR. Polymeric material influences on energy of germination and viability of wheat seeds. Germination index is calculated, heat physical parameters are determined for the polymeric excipient. The major factor influencing seeds germination is a structure of nonwoven fabric. Water diffusion, its supply to seeds and their viability depend on morphological features of polymeric material. Polymer excipient structure influence on speed of development of root system on which, in turn, intensity of destruction of polymer depends. The best indicators of energy of germination and viability of seeds correspond to the greatest value of decrease of melting heat of PHB in mix PHB-SNR. In addition, among the studied samples of PHB-SNR the material received from blend of solvents is most effective. The cause is in feature of its structure favorable for a seed germination.

The effect of formulation additives on in vitro dissolution-absorption profile and in vivo bioavailability of telmisartan from brand and generic formulations.

Science.gov (United States)

Borbás, Enikő; Nagy, Zsombor K; Nagy, Brigitta; Balogh, Attila; Farkas, Balázs; Tsinman, Oksana; Tsinman, Konstantin; Sinkó, Bálint

2018-03-01

In this study, brand and four generic formulations of telmisartan, an antihypertensive drug, were used in in vitro simultaneous dissolution-absorption, investigating the effect of different formulation additives on dissolution and on absorption through an artificial membrane. The in vitro test was found to be sensitive enough to show even small differences between brand and generic formulations caused by the use of different excipients. By only changing the type of filler from sorbitol to mannitol in the formulation, the flux through the membrane was reduced by approximately 10%. Changing the salt forming agent as well resulted in approximately 20% of flux reduction compared to the brand formulation. This significant difference was clearly shown in the published in vivo results as well. The use of additional lactose monohydrate in the formulation also leads to approximately 10% reduction in flux. The results show that by changing excipients, the dissolution of telmisartan was not altered significantly, but the flux through the membrane was found to be significantly changed. These results pointed out the limitations of traditional USP dissolution tests and emphasized the importance of simultaneously measuring dissolution and absorption, which allows the complex effect of formulation excipients on both processes to be measured. Moreover, the in vivo predictive power of the simultaneous dissolution-absorption test was demonstrated by comparing the in vitro fluxes to in vivo bioequivalence study results. Copyright © 2018 Elsevier B.V. All rights reserved.

Comprehensive analysis of pharmaceutical products using simultaneous mixed-mode (ion-exchange/reversed-phase) and hydrophilic interaction liquid chromatography.

Science.gov (United States)

Kazarian, Artaches A; Nesterenko, Pavel N; Soisungnoen, Phimpha; Burakham, Rodjana; Srijaranai, Supalax; Paull, Brett

2014-08-01

Liquid chromatographic assays were developed using a mixed-mode column coupled in sequence with a hydrophilic interaction liquid chromatography column to allow the simultaneous comprehensive analysis of inorganic/organic anions and cations, active pharmaceutical ingredients, and excipients (carbohydrates). The approach utilized dual sample injection and valve-mediated column switching and was based upon a single high-performance liquid chromatography gradient pump. The separation consisted of three distinct sequential separation mechanisms, namely, (i) ion-exchange, (ii) mixed-mode interactions under an applied dual gradient (reversed-phase/ion-exchange), and (iii) hydrophilic interaction chromatography. Upon first injection, the Scherzo SS C18 column (Imtakt) provided resolution of inorganic anions and cations under isocratic conditions, followed by a dual organic/salt gradient to elute active pharmaceutical ingredients and their respective organic counterions and potential degradants. At the top of the mixed-mode gradient (high acetonitrile content), the mobile phase flow was switched to a preconditioned hydrophilic interaction liquid chromatography column, and the standard/sample was reinjected for the separation of hydrophilic carbohydrates, some of which are commonly known excipients in drug formulations. The approach afforded reproducible separation and resolution of up to 23 chemically diverse solutes in a single run. The method was applied to investigate the composition of commercial cough syrups (Robitussin®), allowing resolution and determination of inorganic ions, active pharmaceutical ingredients, excipients, and numerous well-resolved unknown peaks. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A pharmaceutical study on chlorzoxazone orodispersible tablets: formulation, in-vitro and in-vivo evaluation.

Science.gov (United States)

Moqbel, Helal Abdo; ElMeshad, Aliaa Nabil; El-Nabarawi, Mohamed Ahmed

2016-10-01

Muscle spasm needs prompt relief of symptoms. Chlorzoxazone is a centrally muscle relaxant. The aim of this study was to prepare chlorzoxazone orodispersible tablets (ODTs) allowing the drug to directly enter the systemic circulation and bypassing the first-pass metabolism for both enhancing its bioavailability and exerting a rapid relief of muscular spasm. ODTs were prepared by direct compression method using Pharmaburst®500, Starlac®, Pearlitol flash®, Prosolv® odt and F-melt® as co-processed excipients. Three ratios of the drug to the other excipients were used (0.5:1, 1:1 and 2:1). All ODTs were within the pharmacopeial limits for weight and content. ODTs containing Pharmaburst®500 showed the shortest wetting time (∼45.33 s), disintegration time (DT) (∼43.33 s) and dissolution (Q 15min 100.63%). By increasing the ratio of CLZ: Pharmaburst®500 from 0.5:1 to 1:1 and 2:1, the DT increased from 26.43 to 28.0 and 43.33 s, respectively. By using Prosolv® odt, ODTs failed to disintegrate in an acceptable time >180 s. DT of ODTs using different co-processed excipients can be arranged as follows: Pharmaburst® 500 tablets are a promising carrier for CLZ designed for management of muscle spasm due to the enhanced dissolution and rapid absorption of the drug through the oral mucosa.

Preparation of Candesartan and Atorvastatin Nanoparticles by Solvent Evaporation

Czech Academy of Sciences Publication Activity Database

Vaculíková, E.; Grünwaldová, Veronika; Král, V.; Dohnal, J.; Jampílek, J.

2012-01-01

Roč. 17, č. 11 (2012), s. 13221-13234 ISSN 1420-3049 Institutional support: RVO:61388980 Keywords : candesartan cilexetil * atorvastatin * nanoparticles * solvent evaporation * excipients * dynamic light scattering Subject RIV: CA - Inorganic Chemistry Impact factor: 2.428, year: 2012

Self-Assembly of Amphiphilic Block Copolypeptoids with C 2 -C 5 Side Chains in Aqueous Solution

KAUST Repository

Fetsch, Corinna; Flecks, Silvana; Gieseler, Dan; Marschelke, Claudia; Ulbricht, Juliane; van Pé e, Karl-Heinz; Luxenhofer, Robert

2014-01-01

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Nowadays, amphiphilic molecules play an important role in our life. In medical applications, amphiphilic block copolymers have attracted much attention as excipients in drug delivery systems. Here

Journal of Pharmaceutical and Allied Sciences - Vol 14, No 1 (2017)

African Journals Online (AJOL)

Physico-chemical properties of a modified biomaterial from Tympanotonus fuscata (periwinkle) shell powder considered as pharmaceutical excipient · EMAIL FULL TEXT EMAIL FULL TEXT DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. K.C Ugoeze, A Chukwu, 2417-2429 ...

Effect of cyclodextrin concentration on the oral bioavailability of danazol and cinnarizine in rats

DEFF Research Database (Denmark)

Holm, Rene; Olesen, Niels Erik; Andersen Hartvig, Rune

2016-01-01

Cyclodextrins (CDs) are frequently used as an excipient to enhance the intestinal drug absorption of compounds with a low aqueous solubility. However, there exists an intricate interplay between opposing effects that determine the optimal dosing criterion. These opposing effects are the benefits...... of circumventing the dissolution time required to dissolve the non-absorbable drug particles in the intestine versus the disadvantage of decreasing the concentration of the drug available to permeate the intestinal membrane if excessive CD concentrations are used. This study investigated whether...... that surplus CD concentrations can have a major effect on the pharmacokinetic profile of one compound and a minor effect on the pharmacokinetic profile of another. This suggests that there are some compounds where the CD excipient should be used with care and others where it can be used without major concerns....

Preparation of Risedronate Nanoparticles by Solvent Evaporation Technique

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Eliska Vaculikova

2014-11-01

Full Text Available One approach for the enhancement of oral drug bioavailability is the technique of nanoparticle preparation. Risedronate sodium (Biopharmaceutical Classification System Class III was chosen as a model compound with high water solubility and low intestinal permeability. Eighteen samples of risedronate sodium were prepared by the solvent evaporation technique with sodium dodecyl sulfate, polysorbate, macrogol, sodium carboxymethyl cellulose and sodium carboxymethyl dextran as nanoparticle stabilizers applied in three concentrations. The prepared samples were characterized by dynamic light scattering and scanning electron microscopy. Fourier transform mid-infrared spectroscopy was used for verification of the composition of the samples. The particle size of sixteen samples was less than 200 nm. Polysorbate, sodium carboxymethyl dextran and macrogol were determined as the most favourable excipients; the particle size of the samples of risedronate with these excipients ranged from 2.8 to 10.5 nm.

Plasticisation of amylodextrin by moisture. Consequences for compaction behaviour and tablet properties

NARCIS (Netherlands)

Steendam, R; Frijlink, H W; Lerk, C F

2001-01-01

Purpose: Amylodextrin, a starch-based controlled release excipient, spontaneously absorbs moisture during storage. The aim of this study was to investigate plasticisation of amylodextrin by moisture and its effect on compaction and tablet characteristics. Methods: The glass transition temperature

Formulation of Sustained-Release Matrix Tablets Using Cross ...

African Journals Online (AJOL)

Erah

phenomenon. At the molecular level, it involves .... mark with simulated gastric fluid (SGF, pH. 1.2). ... erosion of the polymeric chain while anomalous .... appeared at 186.7oC disappeared while a ... substances and excipients on gel dynamics.

Preparation and Evaluation of Alcohol-Alkaline-Treated Rice Starch ...

African Journals Online (AJOL)

lower in the presence of large particles (3.55 ± 0.56 min); high content of MRS ... Conclusion: MRS exhibits improved water solubility and swelling capacity compared with RS, and is ..... excipient: Modification of the permeability of starch by.

Optimization of composition and technology for tablets containing aspen bark extract

Directory of Open Access Journals (Sweden)

O. I. Onуshkiv

2015-04-01

Full Text Available Summary. Influence of quantitativefactorsof basic quality parameters has been investigated for tabletscontainingextractofaspenbark, receivedbydirect pressingmethodand mathematicalplanningof experiment.To set the optimal composition of tablets containingaspen bark extract the proportion ofProsolv 90, Ludiflash and Polyplasdone XL 10 has been studied. The relationship between the studied factors and parameters of tablets’ regression models has been described. As a result tablets containing aspen bark extractwith mentioned above formula match necessary pharmaco-technological parameters of State Pharmacopoeia of Ukraine. Introduction.Peptic and duodenal ulcer are serious problems in modern medicine. According to statistics this disease is found in 12,83 % of the adult population in Ukraine [1]. Among the remedies for treatment and prevention of peptic ulcers we can find herbal medicines that may be used in the treatment of pre-peptic conditions and during an acute period as a means of adjuvant therapy in combination with strong remedies [2]. An antacid, cytoprotective, anti-inflammatory and reparative actions of aspen bark extract were proved by the researches of domestic and foreign scientists [3, 4]. Previously, we researched the mutual influence of excipients on the main indicators of quality of aspen bark extract tablets obtained by direct compression method. Due to these researches the best excipientshave been selected. It is necessary to establish the optimal quantitative proportion of excipients in order to obtain the tablets with suitable parameters that satisfy the requirements of the State Pharmacopoeia of Ukraine (SPU [5, 6]. Rational selection of excipients requires wide range of studies to obtain the optimal composition of the tablets containing aspen bark extract. Using mathematical planning of the experiment gives the possibility to reduce the number of experiments and to obtain the most detailed results of researches about effects

The malaria scourge: the place of complementary traditional medicine

African Journals Online (AJOL)

The study of naturally occurring compounds has evinced impressive advances in pharmacology, physiology and clinical medicine. Tropical plants will continue to provide mankind with a dynamic natural laboratory as sources of important medicines, food, cosmetics, and natural pharmaceutical excipients. The WHO ...

Inhalable siRNA-loaded nano-embedded microparticles engineered using microfluidics and spray drying

DEFF Research Database (Denmark)

Agnoletti, Monica; Bohr, Adam; Thanki, Kaushik

2017-01-01

processing, and nanocomplexes could be reconstituted from the dry powders. The amorphous saccharide excipients trehalose and inulin provided better stabilization than crystalline mannitol, and they enabled full reconstitution of the nanocomplexes. In particular, a binary mixture of trehalose and inulin...

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

The optimal design of oral amorphous formulations benefits from the use of excipients to maintain drug supersaturation and thus ensures adequate absorption during intestinal transit. The use of surfactants for the maintenance of supersaturation in amorphous formulations has not been investigated ...

Formulation and In vitro Evaluation of Carvedilol Transdermal ...

African Journals Online (AJOL)

... effect was observed in F1 to F8 formulations, highlighting the interplay of ... Index Medicus, JournalSeek, Journal Citation Reports/Science Edition, ..... Raymond, C.R.; Paul, J.S.; Sian, C.O. Hand book of. Pharmaceutical Excipients. 5th ed.

76 FR 67746 - Revised Guidance for Industry on Impurities: Residual Solvents in New Veterinary Medicinal...

Science.gov (United States)

2011-11-02

...] Revised Guidance for Industry on Impurities: Residual Solvents in New Veterinary Medicinal Products... Veterinary Medicinal Products, Active Substances and Excipients (Revision)'' VICH GL18(R). This revised guidance has been developed for veterinary use by the International Cooperation on Harmonisation of...

Studies on tableting properties of lactose. Part 2. Consolidation and compaction of different types of crystalline lactose

NARCIS (Netherlands)

Vromans, H.; de Boer, A.H.; Bolhuis, G.K.; Lerk, C.F.; Kussendrager, K.D.; Bosch, H.

1985-01-01

Lactose is available in several crystalline forms, which differ in binding properties. A new method of estimating the fragmentation propensity was applied to investigate the consolidation and compaction behaviour of this excipient for direct compression. Mercury porosimetry was used to demonstrate

Polyols as filler-binders for disintegrating tablets prepared by direct compaction

NARCIS (Netherlands)

Bolhuis, Gerad K.; Rexwinkel, Erik G.; Zuurman, Klaas

Background: Although polyols are frequently used as tablet excipients in lozenges, chewing tablets, and orodisperse tablets, special directly compressible (DC) forms are recommended as filler-binder in common disintegrating tablets. Aim: In this article, DC types of isomalt, lactitol, mannitol,

[The use of natural and synthetic hydrophilic polymers in the formulation of metformin hydrochloride tablets with different profile release].

Science.gov (United States)

Kołodziejczyk, Michał Krzysztof; Kołodziejska, Justyna; Zgoda, Marian Mikołaj

2012-01-01

Metformin hydrochloride after buformin and phenformin belongs to the group of biguanid derivatives used as oral anti-diabetic drugs. The object of the study is the technological analysis and the potential effect of biodegradable macromolecular polymers on the technological and therapeutic parameters of oral anti-diabetic medicinal products with metformin hydrochloride: Siofor, Formetic, Glucophage, Metformax in doses of 500mg and 1000mg and Glucophage XR in a dose of 500 mg of modified release. Market therapeutic products containing 500 and 1000 mg of metformin hydrochloride in a normal formulation and 500 mg of metformin hydrochloride in a formulation of modified release were analyzed. Following research methods were used: technological analysis of tablets, study of disintegration time of tablets, evaluation of pharmaceutical availability of metformin hydrochloride from tested therapeutic products, mathematical and kinetic analysis of release profiles of metformin hydrochloride, statistical analysis of mean differences of release coefficients. The percentage of excipients in the XR formulation is higher and constitutes 50.5% of a tablet mass. However, in standard formulations the percentage is lower, between 5.5% and 12.76%. On the basis of the results of disintegration time studies, the analysed therapeutic products can be divided into two groups, regardless the dose. The first one are preparations with faster (not fast!) disintegration: Glucophage i Metformax. The second group are preparations with slower disintegration, more balanced in the aspect of a high dose of the biologically active substance: Formetic and Siofor. Products with a lower content of excipients (Metformax, Glucophage) disintegrate in a faster way. The disintegration rate of the products with a higher content of excipients (Formetic, Siofor) is slower. The appearance of metformin hydrochloride concentration in the gastrointestinal contents, balanced in time, caused by a slower disintegration

Development and Evaluation of Orally Disintegrating Tablets of ...

African Journals Online (AJOL)

... crospovidone and magnesium stearate as key excipients, and with cherry flavor and aspartame as flavor and sweetener, respectively. These formulations were then evaluated using pharmacopoeial and non-pharmacopoeial physical and chemical tests. Dissolution and assay tests were performed using USP apparatus II ...

The origin of life and the potential role of soaps

DEFF Research Database (Denmark)

Hanczyc, Martin M.; Monnard, Pierre-Alain

2016-01-01

Single chain amphiphiles, such as fatty acids and alkyl sulfates, have found industrial uses as emulsifying agents, lubricants, detergents and soaps. Fatty acids are also used as excipients and, because of their biochemical activity, even as active ingredients in drug formulations. The applications...

An Integrated Approach to Thermal Analysis of Pharmaceutical Solids

Science.gov (United States)

Riley, Shelley R. Rabel

2015-01-01

A three-tiered experiment for undergraduate Instrumental Analysis students is presented in which students characterize the solid-state thermal behavior of an active pharmaceutical ingredient (acetaminophen) and excipient (a-lactose hydrate) using differential scanning calorimetry, thermogravimetric analysis, and thermal microscopy. Students are…

Spray Drying of Suspensions for Pharma and Bio Products: Drying Kinetics and Morphology

DEFF Research Database (Denmark)

Sloth, Jakob; Jørgensen, Kåre; Bach, Poul

2009-01-01

An experimental investigation of the spray drying behavior of droplets containing excipients and carrier materials used in the pharmaceutical and biotechnological industries has been conducted. Specifically, rice starch suspensions with different amounts of TiO2, maltodextrin, dextrin, NaCl and N...

Formulation and Evaluation of Ascorbic acid Tablets by Direct ...

African Journals Online (AJOL)

Formulation and Evaluation of Ascorbic acid Tablets by Direct Compression using Microcrystalline Starch as a Direct Compression Excipient. ... Abstract. PURPOSE: To evaluate the tableting properties of microcrystalline starch (MCS) used as a direct ... RESULTS: Mechanical properties of tablets formulated with MCS were

75 FR 50771 - Draft Revised Guidance for Industry on Residual Solvents in New Veterinary Medicinal Products...

Science.gov (United States)

2010-08-17

...] (formerly Docket No. 1999D-4071) Draft Revised Guidance for Industry on Residual Solvents in New Veterinary...) entitled ``Residual Solvents in New Veterinary Medicinal Products, Active Substances and Excipients... 2001 final guidance), has been developed for veterinary use by the International Cooperation on...

Direct compression properties of microcrystalline cellulose and its ...

African Journals Online (AJOL)

The influence of silicified microcrystalline cellulose (SMCC) on the flow, compaction and tableting properties of metronidazole powder was investigated. The study compared medium grades of both SMCC and standard microcrystalline cellulose (MCC) as direct compressible excipients. The bulk densities, Hausner quotient ...

A Review of Disintegration Mechanisms and Measurement Techniques.

Science.gov (United States)

Markl, Daniel; Zeitler, J Axel

2017-05-01

Pharmaceutical solid dosage forms (tablets or capsules) are the predominant form to administer active pharmaceutical ingredients (APIs) to the patient. Tablets are typically powder compacts consisting of several different excipients in addition to the API. Excipients are added to a formulation in order to achieve the desired fill weight of a dosage form, to improve the processability or to affect the drug release behaviour in the body. These complex porous systems undergo different mechanisms when they come in contact with physiological fluids. The performance of a drug is primarily influenced by the disintegration and dissolution behaviour of the powder compact. The disintegration process is specifically critical for immediate-release dosage forms. Its mechanisms and the factors impacting disintegration are discussed and methods used to study the disintegration in-situ are presented. This review further summarises mathematical models used to simulate disintegration phenomena and to predict drug release kinetics.

Application of SeDeM expert systems in preformulation studies of pediatric ibuprofen ODT tablets.

Science.gov (United States)

Sipos, Emese; Oltean, Andrea Ramona; Szabó, Zoltán-István; Rédai, Emőke-Margit; Nagy, Gabriella Dónáth

2017-06-27

Pediatric, ibuprofen containing orodispersible tablets (ODTs) were prepared using the SeDeM expert system methodology. In order to facilitate formulation, directly compressible ibuprofen was employed (Ibuprofen DC 8TM) and characterized using its SeDeM profile. The mannitol based superdisintegrant Ludiflash® was characterized by the SeDeM-ODT expert system, which also allowed calculation of the optimal excipient concentration in order to obtain suitable tablet hardness and disintegration time. After adding a sweetener and a standard combination of lubricants, the optimized formulation was directly compressed into tablets and evaluated in terms of tablet hardness, friability, disintegration time and dissolution profile. The SeDeM method was applied to determine the amount of corrective excipient (Ludiflash®) required for the compression of Ibuprofen DC 85TM in order to achieve suitable ODTs. Adequate tablet hardness, disintegration time, friability and dissolution profiles were found during tablet evaluation.

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.

Preparation and evaluation of valsartan by a novel semi-solid self-microemulsifying delivery system using Gelucire 44/14.

Science.gov (United States)

Zhao, Kun; Yuan, Yue; Wang, Hui; Li, Panpan; Bao, Zhihong; Li, Yue

2016-10-01

The aim of the present study was to develop a novel semi-solid self-microemulsifying drug delivery system (SMEDDS) using Gelucire(®) 44/14 as oil with strong solid character to improve the oral bioavailability of poorly soluble drug valsartan. The solubility of valsartan in various excipients was determined, the pseudo-ternary phase diagram was constructed in order to screen the optimal excipients, and DSC analysis was performed to evaluate the melting point of SMEDDS. The optimal drug-loaded SMEDDS formulation was consisted of 30% Gelucire(®) 44/14 (oil), 40% Solutol(®) HS 15 (surfactant), and 30% Transcutol(®) P (cosurfactant) (w/w) with 80 mg valsartan/g excipients. The average droplet sizes of the optimized blank and drug-loaded SMEDDS formulations were 26.20 ± 1.43 and 33.34 ± 2.15 nm, and the melting points of them were 35.6 and 36.8 °C, respectively. The in vitro dissolution rate of optimal semi-solid SMEDDS was increased compared with commercial capsules, resulting in the 2.72-fold and 2.97-fold enhancement of Cmax and AUC0-t after oral administration in rats, respectively. These results indicated that the novel semi-solid SMEDDS formulation could potentially improve the oral bioavailability of valsartan, and the semi-solid SMEDDS was a desirable system than the traditional liquid SMEDDS because it was convenient for preparation, storage and transportation due to semi-solid state at room temperature and melted state at body temperature.

Biowaiver monograph for immediate-release solid oral dosage forms: fluconazole.

Science.gov (United States)

Charoo, Naseem; Cristofoletti, Rodrigo; Graham, Alexandra; Lartey, Paul; Abrahamsson, Bertil; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James; Shah, Vinod P; Dressman, Jennifer

2014-12-01

Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate release (IR) solid oral dosage forms containing fluconazole as the only active pharmaceutical ingredient (API) are reviewed. The decision is based on solubility, dissolution, permeability, therapeutic index, pharmacokinetic parameters, pharmacodynamic properties, and other relevant data. BE/bioavailability (BA) problems and drug-excipients interaction data were also reviewed and taken into consideration. According to the biopharmaceutics classification system (BCS), fluconazole in polymorphic forms II and III is a BCS class I drug and has a wide therapeutic index. BE of test formulations from many different manufacturers containing different excipients confirmed that the risk of bioinequivalence because of formulation and manufacturing factors is low. It was inferred that risk can be further reduced if in vitro studies are performed according to biowaiver guidelines. Thus, it is concluded that a biowaiver can be recommended for fluconazole IR dosage forms if (a) fluconazole is present as polymorphic form II or III or any other form/mixture showing high solubility, (b) the selection of excipients be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) countries for the same dosage form and used in their usual amounts, and (c) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving throughout the shelf life with similar dissolution profiles at pH 1.2, 4.5, and 6.8. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Simultaneous Determination of Famotidine and Flurbiprofen by High ...

African Journals Online (AJOL)

Purpose: To develop a selective, sensitive and accurate simultaneous High Performance Liquid Chromatography (HPLC) method for the analysis of flurbiprofen and famotidine tablet dosage form and excipients. Methods: A simultaneous method for the determination of the two drugs was employed. The assay consisted of ...

Effect of molecular weight and glass transition on relaxation and release behaviour of poly(DL-lactic acid) tablets

NARCIS (Netherlands)

Steendam, R.; Van Steenbergen, M.J.; Hennink, W.E.; Frijlink, H.W.; Lerk, C.F.

2001-01-01

Different molecular weight grades of poly(DL-lactic acid) were applied as release controlling excipients in tablets for oral drug administration. The role of molecular weight and glass transition in the mechanism of water-induced volume expansion and drug release of PDLA tablets was investigated.

Spectrophotometric and theoretical studies on the determination of ...

African Journals Online (AJOL)

... which a basic analytical laboratory can afford. No interference was observed from common pharmaceutical excipients and additives. ETMO ion pair has a larger interaction energy (higher stability) than ET-BCG ion pair as inferred from their interaction energies. Keywords: Density functional theory, Etilefrine hydrochloride, ...

Compaction properties of isomalt

NARCIS (Netherlands)

Bolhuis, Gerad K.; Engelhart, Jeffrey J. P.; Eissens, Anko C.

Although other polyols have been described extensively as filler-binders in direct compaction of tablets, the polyol isomalt is rather unknown as pharmaceutical excipient, in spite of its description in all the main pharmacopoeias. In this paper the compaction properties of different types of

Contact allergy to ingredients of topical medications : results of the European Surveillance System on Contact Allergies (ESSCA), 2009-2012

NARCIS (Netherlands)

Uter, Wolfgang; Spiewak, Radoslaw; Cooper, Susan M.; Wilkinson, Mark; Sanchez Perez, Javier; Schnuch, Axel; Schuttelaar, Marie-Louise

2016-01-01

PurposeThe aim of this study was to give an overview of the prevalence of contact allergy to active ingredients and excipients of topical medications across Europe. MethodsRetrospective analysis of data collected by the European Surveillance System on Contact Allergies () with substances applied to

Amino acids as co-amorphous stabilizers for poorly water soluble drugs--Part 1

DEFF Research Database (Denmark)

Löbmann, Korbinian; Grohganz, Holger; Laitinen, Riikka

2013-01-01

molecular weight excipients that form specific molecular interactions with the drug resulting in co-amorphous forms. The two poorly water soluble drugs carbamazepine and indomethacin were combined with amino acids from the binding sites of the biological receptors of these drugs. Mixtures of drug...

Improvement of the Crystal Stability and Dissolution Profile of ...

African Journals Online (AJOL)

This study was undertaken to improve the solubility of metronidazole by modifying its crystal characteristics using pharmaceutical excipients. Metronidazole granules were formulated with cashew gum (2 – 8% w/w) and microcrystalline cellulose (10% w/w) via kneading, solid dispersion, or physical mixing. Resulting ...

Studies on the physicochemical and functional properties of ...

African Journals Online (AJOL)

This study was aimed at developing pharmaceutical grade microcrystalline cellulose from Khaya grandifolia wood flakes as a tablet excipient. The microcrystalline cellulose coded KG-MCC, was obtained from Khaya grandifolia wood flakes by a two-stage sodium hydroxide delignification process followed by sodium ...

Relative bioavailability of three newly developed albendazole formulations : a randomized crossover study with healthy volunteers

NARCIS (Netherlands)

Rigter, I M; Schipper, H G; Koopmans, R P; van Kan, H J M; Frijlink, H W; Kager, P A; Guchelaar, H-J

2004-01-01

This study of healthy volunteers shows that the relative bioavailability of albendazole formulations that use arachis oil-polysorbate 80 or hydroxypropyl-beta-cyclodextrin as an excipient was enhanced 4.3- and 9.7-fold compared to the results seen with commercial tablets. Administration of macrogol

Relative bioavailability of three newly developed albendazole formulations: a randomized crossover study with healthy volunteers

NARCIS (Netherlands)

Rigter, I. M.; Schipper, H. G.; Koopmans, R. P.; van Kan, H. J. M.; Frijlink, H. W.; Kager, P. A.; Guchelaar, H.-J.

2004-01-01

This study of healthy volunteers shows that the relative bioavailability of albendazole formulations that use arachis oil-polysorbate 80 or hydroxypropyl-beta-cyclodextrin as an excipient was enhanced 4.3- and 9.7-fold compared to the results seen with commercial tablets. Administration of macrogol

Optimisation of the composition and production of mannitol/microcrystalline cellulose tablets

NARCIS (Netherlands)

Westerhuis, J.A; de Haan, P; Zwinkels, J; Jansen, W.T; Coenegracht, P.M J; Lerk, C.F

1996-01-01

Mixtures of mannitol and microcrystalline cellulose (MCC) were investigated on a small-production scale by granulation in a high-shear mixer and compression into tablets. For both excipients only a few cases of incompatibilities with active ingredients are known. Tablets with only MCC as the filler

Compounded laxative formulations for substituting phenolphthalein ...

African Journals Online (AJOL)

Results: Sennosides A & B were compatible with a wide variety of powdered excipients. However, these were incompatible with propyl paraben, sodium carbonate, stearic acid, citric acid, PEG, and sugar derivatives such as lactose, glucose and sorbitol when granulated with water. Not withstanding these interactions, it was ...

CONTROLLED-RELEASE OF PARACETAMOL FROM AMYLODEXTRIN TABLETS - IN-VITRO AND IN-VIVO RESULTS

NARCIS (Netherlands)

VANDERVEEN, J; EISSENS, AC; LERK, CF

Amylodextrin is a suitable excipient for the design of solid controlled-release systems. The release of paracetamol from tablets containing 30% drug and 70% amylodextrin was studied in vitro and in vivo. In vitro dissolution profiles showed almost-constant drug release rates during 8 hr, when

Formulation and Evaluation of Ascorbic acid Tablets by Direct ...

African Journals Online (AJOL)

PURPOSE: To evaluate the tableting properties of microcrystalline starch (MCS) used as a direct compression excipient in the formulation of ascorbic acid tablets and to compare with the properties of tablets produced using microcrystalline cellulose (MCC). METHODS: MCS was obtained by partial hydrolysis of cassava ( ...

Diclofenac sodium sustained release hot melt extruded lipid matrices.

Science.gov (United States)

Vithani, K; Cuppok, Y; Mostafa, S; Slipper, I J; Snowden, M J; Douroumis, D

2014-08-01

Sustained release diclofenac sodium (Df-Na) solid lipid matrices with Compritol® 888 ATO were developed in this study. The drug/lipid powders were processed via cold and hot melt extrusion at various drug loadings. The influence of the processing temperatures, drug loading and the addition of excipients on the obtained dissolution rates was investigated. The physicochemical characterization of the extruded batches showed the existence of crystalline drug in the extrudates with a small amount being solubilized in the lipid matrix. The drug content and uniformity on the tablet surface were also investigated by using energy dispersive X-ray microanalysis. The dissolution rates were found to depend on the actual Df-Na loading and the nature of the added excipients, while the effect of the processing temperatures was negligible. The dissolution mechanism of all extruded formulations followed Peppas-Korsemeyer law, based on the estimated determination coefficients and the dissolution constant rates, indicating drug diffusion from the lipid matrices.

Application of SeDeM expert systems in preformulation studies of pediatric ibuprofen ODT tablets

Directory of Open Access Journals (Sweden)

Sipos Emese

2017-06-01

Full Text Available Pediatric, ibuprofen containing orodispersible tablets (ODTs were prepared using the SeDeM expert system methodology. In order to facilitate formulation, directly compressible ibuprofen was employed (Ibuprofen DC 8TM and characterized using its SeDeM profile. The mannitol based superdisintegrant Ludiflash® was characterized by the SeDeM-ODT expert system, which also allowed calculation of the optimal excipient concentration in order to obtain suitable tablet hardness and disintegration time. After adding a sweetener and a standard combination of lubricants, the optimized formulation was directly compressed into tablets and evaluated in terms of tablet hardness, friability, disintegration time and dissolution profile. The SeDeM method was applied to determine the amount of corrective excipient (Ludiflash® required for the compression of Ibuprofen DC 85TM in order to achieve suitable ODTs. Adequate tablet hardness, disintegration time, friability and dissolution profiles were found during tablet evaluation.

Application of hanging drop technique to optimize human IgG formulations.

Science.gov (United States)

Li, Guohua; Kasha, Purna C; Late, Sameer; Banga, Ajay K

2010-01-01

The purpose of this work is to assess the hanging drop technique in screening excipients to develop optimal formulations for human immunoglobulin G (IgG). A microdrop of human IgG and test solution hanging from a cover slide and undergoing vapour diffusion was monitored by a stereomicroscope. Aqueous solutions of IgG in the presence of different pH, salt concentrations and excipients were prepared and characterized. Low concentration of either sodium/potassium phosphate or McIlvaine buffer favoured the solubility of IgG. Addition of sucrose favoured the stability of this antibody while addition of NaCl caused more aggregation. Antimicrobial preservatives were also screened and a complex effect at different buffer conditions was observed. Dynamic light scattering, differential scanning calorimetry and size exclusion chromatography studies were performed to further validate the results. In conclusion, hanging drop is a very easy and effective approach to screen protein formulations in the early stage of formulation development.

Primary investigation of the preparation of nanoparticles by precipitation.

Science.gov (United States)

Vaculikova, Eliska; Grunwaldova, Veronika; Kral, Vladimir; Dohnal, Jiri; Jampilek, Josef

2012-09-13

The absorption, distribution, biotransformation and excretion of a drug involve its transport across cell membranes. This process is essential and influenced by the characteristics of the drug, especially its molecular size and shape, solubility at the site of its absorption, relative lipid solubility, etc. One of the progressive ways for increasing bioavaibility is a nanoparticle preparation technique. Cholesterol, cholestenolone and pregnenolone acetate as model active pharmaceutical ingredients and some of the commonly used excipients as nanoparticle stabilizers were used in the investigated precipitation method that was modified and simplified and can be used as an effective and an affordable technique for the preparation of nanoparticles. All 120 prepared samples were analyzed by means of dynamic light scattering (Nanophox). The range of the particle size of the determined 100 nanoparticle samples was from 1 nm to 773 nm, whereas 82 samples contained nanoparticles of less than 200 nm. Relationships between solvents and used excipients and their amount are discussed.

Primary Investigation of the Preparation of Nanoparticles by Precipitation

Directory of Open Access Journals (Sweden)

Josef Jampilek

2012-09-01

Full Text Available The absorption, distribution, biotransformation and excretion of a drug involve its transport across cell membranes. This process is essential and influenced by the characteristics of the drug, especially its molecular size and shape, solubility at the site of its absorption, relative lipid solubility, etc. One of the progressive ways for increasing bioavaibility is a nanoparticle preparation technique. Cholesterol, cholestenolone and pregnenolone acetate as model active pharmaceutical ingredients and some of the commonly used excipients as nanoparticle stabilizers were used in the investigated precipitation method that was modified and simplified and can be used as an effective and an affordable technique for the preparation of nanoparticles. All 120 prepared samples were analyzed by means of dynamic light scattering (Nanophox. The range of the particle size of the determined 100 nanoparticle samples was from 1 nm to 773 nm, whereas 82 samples contained nanoparticles of less than 200 nm. Relationships between solvents and used excipients and their amount are discussed.

Synchrotron radiation-based Fourier-transform infrared spectromicroscopy for characterization of the protein/peptide distribution in single microspheres

Directory of Open Access Journals (Sweden)

Manli Wang

2015-05-01

Full Text Available The present study establishes a visualization method for the measurement of the distribution and localization of protein/peptide constituents within a single poly-lactide-co-glycolide (PLGA microsphere using synchrotron radiation–based Fourier-transform infrared spectromicroscopy (SR-FTIR. The representative infrared wavenumbers specific for protein/peptide (Exenatide and excipient (PLGA were identified and chemical maps at the single microsphere level were generated by measuring and plotting the intensity of these specific bands. For quantitative analysis of the distribution within microspheres, Matlab software was used to transform the map file into a 3D matrix and the matrix values specific for the drug and excipient were extracted. Comparison of the normalized SR-FTIR maps of PLGA and Exenatide indicated that PLGA was uniformly distributed, while Exenatide was relatively non-uniformly distributed in the microspheres. In conclusion, SR-FTIR is a rapid, nondestructive and sensitive detection technology to provide the distribution of chemical constituents and functional groups in microparticles and microspheres.

Active and passive immunity, vaccine types, excipients and licensing.

Science.gov (United States)

Baxter, David

2007-12-01

Abstract Immunity is the state of protection against infectious disease conferred either through an immune response generated by immunization or previous infection or by other non-immunological factors. This article reviews active and passive immunity and the differences between them: it also describes the four different commercially available vaccine types (live attenuated, killed/inactivated, subunit and toxoid): it also looks at how these different vaccines generate an adaptive immune response.

Cellulose Nanocrystal Membranes as Excipients for Drug Delivery Systems

Directory of Open Access Journals (Sweden)

Ananda M. Barbosa

2016-12-01

Full Text Available In this work, cellulose nanocrystals (CNCs were obtained from flax fibers by an acid hydrolysis assisted by sonochemistry in order to reduce reaction times. The cavitation inducted during hydrolysis resulted in CNC with uniform shapes, and thus further pretreatments into the cellulose are not required. The obtained CNC exhibited a homogeneous morphology and high crystallinity, as well as typical values for surface charge. Additionally, CNC membranes were developed from CNC solution to evaluation as a drug delivery system by the incorporation of a model drug. The drug delivery studies were carried out using chlorhexidine (CHX as a drug and the antimicrobial efficiency of the CNC membrane loaded with CHX was examined against Gram-positive bacteria Staphylococcus aureus (S. Aureus. The release of CHX from the CNC membranes is determined by UV-Vis. The obtaining methodology of the membranes proved to be simple, and these early studies showed a potential use in antibiotic drug delivery systems due to the release kinetics and the satisfactory antimicrobial activity.

Formulation and evaluation of antipsoriatic gel using natural excipients

Directory of Open Access Journals (Sweden)

Raghupatruni Jhansi Laxmi

2013-01-01

Conclusions: In vitro anti-psoriatic activity of F3 showed the significant orthokeratosis in the mouse tail test when compared to control thus indicating that the formulation is effective in treating psoriasis.

Gum from the bark of Anogeissius leiocarpus as a potential ...

African Journals Online (AJOL)

Gum from the bark of Anogeissius leiocarpusas a potential pharmaceutical raw material – granule properties. Philip F Builders, Olubayo O Kunle, Yetunde C Isimi. Abstract. With the continuous effort to discover and produce cheap but high quality excipients for drug production Anogeissius leiocarpus gum (ALG), a brownish ...

Development of an Optimised Losartan Potassium Press-Coated ...

African Journals Online (AJOL)

The optimised formulation was further characterized with Fourier-transform infrared spectroscopy (FTIR) and powder X-ray diffractometry (PXRD) to investigate any drug/excipient modifications/interactions. Results: The tensile strength values of all the PCT were between 1.12 and 1.23MNm-2 and friability was < 0.36 %.

Developments in the formulation and delivery of spray dried vaccines

NARCIS (Netherlands)

Kanojia, Gaurav; Have, Rimko Ten; Soema, Peter C; Frijlink, Henderik; Amorij, Jean-Pierre; Kersten, Gideon

2017-01-01

Spray drying is a promising method for the stabilization of vaccines, which are usually formulated as liquids. Usually, vaccine stability is improved by spray drying in the presence of a range of excipients. Unlike freeze drying, there is no freezing step involved, thus the damage related to this

Lactose contaminant as steroid degradation enhancer

NARCIS (Netherlands)

Nieuwmeyer, Florentine; Maarschalk, Kees van der Voort; Vromans, Herman

2008-01-01

Purpose. By pharmaceutical processes and in the presence of solid excipients physical-chemical changes are known to occur, leading to increased rate of chemical degradation. The purpose of this work was to determine the critical aspects in the stability of a steroid in the presence of a commonly

Controlled Release from Zein Matrices : Interplay of Drug Hydrophobicity and pH

NARCIS (Netherlands)

Bouman, Jacob; Belton, Peter; Venema, Paul; van der Linden, Erik; de Vries, Renko; Qi, Sheng

In earlier studies, the corn protein zein is found to be suitable as a sustained release agent, yet the range of drugs for which zein has been studied remains small. Here, zein is used as a sole excipient for drugs differing in hydrophobicity and isoelectric point: indomethacin, paracetamol and

Controlled Release from Zein Matrices

NARCIS (Netherlands)

Bouman, Jacob; Belton, Peter; Venema, Paul; Linden, Van Der Erik; Vries, De Renko; Qi, Sheng

2016-01-01

Purpose: In earlier studies, the corn protein zein is found to be suitable as a sustained release agent, yet the range of drugs for which zein has been studied remains small. Here, zein is used as a sole excipient for drugs differing in hydrophobicity and isoelectric point: indomethacin,

A Comparative Evaluation of the Flow and Compaction ...

African Journals Online (AJOL)

Patrick Erah

study was to evaluate the suitability of α-cellulose obtained from waste paper as a direct compression excipient. Method: The flow and compaction ... The continuous search for affordable locally available pharmaceutical raw .... and irregular primary particle. These features of the latter could result to formation of bridges and.

Lactose contaminant as steroid degradation enhancer

NARCIS (Netherlands)

Nieuwmeyer, Florentine; Maarschalk, Kees van der Voort; Vromans, Herman

Purpose. By pharmaceutical processes and in the presence of solid excipients physical-chemical changes are known to occur, leading to increased rate of chemical degradation. The purpose of this work was to determine the critical aspects in the stability of a steroid in the presence of a commonly

Processing, screening and microbiological characterization of ...

African Journals Online (AJOL)

Microcrystalline cellulose (MCC) obtained from the fresh stem of Laccosperma opacum (Rattan) found in coastal region of Niger Delta forest zones of West Africa was investigated to ascertain its microbiological standard for use as a potential pharmaceutical excipient. The product, coded LO-MCC, was prepared by treating ...

Maillard reaction of lactose and fluoxetine hydrochloride, a secondary amine.

Science.gov (United States)

Wirth, D D; Baertschi, S W; Johnson, R A; Maple, S R; Miller, M S; Hallenbeck, D K; Gregg, S M

1998-01-01

Analysis of commercially available generic formulations of fluoxetine HCl revealed the presence of lactose as the most common excipient. We show that such formulations are inherently less stable than formulations with starch as the diluent due to the Maillard reaction between the drug, a secondary amine hydrochloride, and lactose. The Amadori rearrangement product was isolated and characterized; the characterization was aided by reduction with sodium borohydride and subsequent characterization of this reduced adduct. The lactose-fluoxetine HCl reaction was examined in aqueous ethanol and in the solid state, in which factors such as water content, lubricant concentration, and temperature were found to influence the degradation. N-Formylfluoxetine was identified as a major product of this Maillard reaction and it is proposed that N-formyl compounds be used as markers for this drug-excipient interaction since they are easy to prepare synthetically. Many characteristic volatile products of the Maillard reaction have been identified by GC/MS, including furaldehyde, maltol, and 2,3-dihydro-3,5-dihydroxy-6-methyl-4 H-pyran-4-one. Close similarity between the degradation products of simple mixtures and formulated generic products was found; however, at least one product decomposed at a rate nearly 10 times that predicted from the simple models. Maillard products have also been identified in unstressed capsules. The main conclusion is that drugs which are secondary amines (not just primary amines as sometimes reported) undergo the Maillard reaction with lactose under pharmaceutically relevant conditions. This finding should be considered during the selection of excipients and stability protocols for drugs which are secondary amines or their salts, just as it currently is for primary amines.

Challenging Near InfraRed Spectroscopy discriminating ability for counterfeit pharmaceuticals detection

Energy Technology Data Exchange (ETDEWEB)

Storme-Paris, I. [Groupe de Chimie Analytique de Paris-Sud, EA 4041, IFR 141, School of Pharmacy, Univ Paris-Sud, 5 rue Jean Baptiste Clement, 92296 Chatenay-Malabry (France); Rebiere, H. [Laboratories and Control Department, French Health Products Safety Agency (AFSSAPS), 635 rue de la Garenne, 34740 Vendargues (France); Matoga, M. [Groupe de Chimie Analytique de Paris-Sud, EA 4041, IFR 141, School of Pharmacy, Univ Paris-Sud, 5 rue Jean Baptiste Clement, 92296 Chatenay-Malabry (France); Civade, C.; Bonnet, P.-A.; Tissier, M.H. [Laboratories and Control Department, French Health Products Safety Agency (AFSSAPS), 635 rue de la Garenne, 34740 Vendargues (France); Chaminade, P., E-mail: pierre.chaminade@u-psud.fr [Groupe de Chimie Analytique de Paris-Sud, EA 4041, IFR 141, School of Pharmacy, Univ Paris-Sud, 5 rue Jean Baptiste Clement, 92296 Chatenay-Malabry (France)

2010-01-25

This study was initiated by the laboratories and control department of the French Health Products Safety Agency (AFSSAPS) as part of the fight against the public health problem of rising counterfeit and imitation medicines. To test the discriminating ability of Near InfraRed Spectroscopy (NIRS), worse cases scenarios were first considered for the discrimination of various pharmaceutical final products containing the same Active Pharmaceutical Ingredient (API) with different excipients, such as generics of proprietary medicinal products (PMP). Two generic databases were explored: low active strength hard capsules of Fluoxetine and high strength tablets of Ciprofloxacin. Then 4 other cases involving suspicious samples, counterfeits and imitations products were treated. In all these cases, spectral differences between samples were studied, giving access to API or excipient contents information, and eventually allowing manufacturing site identification. A chemometric background is developed to explain the optimisation methodology, consisting in the choices of appropriate pretreatments, algorithms for data exploratory analyses (unsupervised Principal Component Analysis), and data classification (supervised cluster analysis, and Soft Independent Modelling of Class Analogy). Results demonstrate the high performance of NIRS, highlighting slight differences in formulations, such as 2.5% (w/w) in API strength, 1.0% (w/w) in excipient and even coating variations (<1%, w/w) with identical contents, approaching the theoretical limits of NIRS sensitivity. All the different generic formulations were correctly discriminated and foreign PMP, constituted of formulations slightly different from the calibration ones, were also all discriminated. This publication addresses the ability of NIRS to detect counterfeits and imitations and presents the NIRS as an ideal tool to master the global threat of counterfeit drugs.

Challenging Near InfraRed Spectroscopy discriminating ability for counterfeit pharmaceuticals detection

International Nuclear Information System (INIS)

Storme-Paris, I.; Rebiere, H.; Matoga, M.; Civade, C.; Bonnet, P.-A.; Tissier, M.H.; Chaminade, P.

2010-01-01

This study was initiated by the laboratories and control department of the French Health Products Safety Agency (AFSSAPS) as part of the fight against the public health problem of rising counterfeit and imitation medicines. To test the discriminating ability of Near InfraRed Spectroscopy (NIRS), worse cases scenarios were first considered for the discrimination of various pharmaceutical final products containing the same Active Pharmaceutical Ingredient (API) with different excipients, such as generics of proprietary medicinal products (PMP). Two generic databases were explored: low active strength hard capsules of Fluoxetine and high strength tablets of Ciprofloxacin. Then 4 other cases involving suspicious samples, counterfeits and imitations products were treated. In all these cases, spectral differences between samples were studied, giving access to API or excipient contents information, and eventually allowing manufacturing site identification. A chemometric background is developed to explain the optimisation methodology, consisting in the choices of appropriate pretreatments, algorithms for data exploratory analyses (unsupervised Principal Component Analysis), and data classification (supervised cluster analysis, and Soft Independent Modelling of Class Analogy). Results demonstrate the high performance of NIRS, highlighting slight differences in formulations, such as 2.5% (w/w) in API strength, 1.0% (w/w) in excipient and even coating variations (<1%, w/w) with identical contents, approaching the theoretical limits of NIRS sensitivity. All the different generic formulations were correctly discriminated and foreign PMP, constituted of formulations slightly different from the calibration ones, were also all discriminated. This publication addresses the ability of NIRS to detect counterfeits and imitations and presents the NIRS as an ideal tool to master the global threat of counterfeit drugs.

The intramammary efficacy of first generation cephalosporins against Staphylococcus aureus mastitis in mice.

Science.gov (United States)

Demon, Dieter; Ludwig, Carolin; Breyne, Koen; Guédé, David; Dörner, Julia-Charlotte; Froyman, Robrecht; Meyer, Evelyne

2012-11-09

Staphylococcus aureus-induced mastitis in cattle causes important financial losses in the dairy industry due to lower yield and bad milk quality. Although S. aureus is susceptible to many antimicrobials in vitro, treatment often fails to cure the infected udder. Hence, comprehensive evaluation of antimicrobials against S. aureus mastitis is desirable to direct treatment strategies. The mouse mastitis model is an elegant tool to evaluate antimicrobials in vivo while circumventing the high costs associated with bovine experiments. An evaluation of the antimicrobial efficacy of the intramammary (imam) applied first generation cephalosporins cefalexin, cefalonium, cefapirin and cefazolin, was performed using the S. aureus mouse mastitis model. In vivo determination of the effective dose 2log(10) (ED(2log10)), ED(4log10), protective dose 50 (PD(50)) and PD(100) in mouse mastitis studies, support that in vitro MIC data of the cephalosporins did not fully concur with the in vivo clinical outcome. Cefazolin was shown to be the most efficacious first generation cephalosporin to treat S. aureus mastitis whereas the MIC data indicate that cefalonium and cefapirin were more active in vitro. Changing the excipient for imam application from mineral oil to miglyol 812 further improved the antimicrobial efficacy of cefazolin, confirming that the excipient can influence the in vivo efficacy. Additionally, statistical analysis of the variation of S. aureus-infected, excipient-treated mice from fourteen studies emphasizes the strength of the mouse mastitis model as a fast, cost-effective and highly reproducible screening tool to assess the efficacy of antimicrobial compounds against intramammary S. aureus infection. Copyright © 2012 Elsevier B.V. All rights reserved.

The Effect of Formulation on Spray Dried Sabin Inactivated Polio Vaccine.

Science.gov (United States)

Kanojia, Gaurav; Ten Have, Rimko; Brugmans, Debbie; Soema, Peter C; Frijlink, Henderik W; Amorij, Jean-Pierre; Kersten, Gideon

2018-05-19

The objective of this study was to develop a stable spray dried formulation, containing the three serotypes of Sabin inactivated polio vaccine (sIPV), aiming for minimal loss of native conformation (D-antigen) during drying and subsequent storage. The influence of atomization and drying stress during spray drying on trivalent sIPV was investigated. This was followed by excipient screening, in which monovalent sIPV was formulated and spray dried. Excipient combinations and concentrations were tailored to maximize both the antigen recovery of respective sIPV serotypes after spray drying and storage (T= 40°C and t= 7 days). Furthermore, a fractional factorial design was developed around the most promising formulations to elucidate the contribution of each excipient in stabilizing D-antigen during drying. Serotype 1 and 2 could be dried with 98 % and 97 % recovery, respectively. When subsequently stored at 40°C for 7 days, the D-antigenicity of serotype 1 was fully retained. For serotype 2 the D-antigenicity dropped to 71 %. Serotype 3 was more challenging to stabilize and a recovery of 56 % was attained after drying, followed by a further loss of 37 % after storage at 40°C for 7 days. Further studies using a design of experiments approach demonstrated that trehalose/monosodium glutamate and maltodextrin/arginine combinations were crucial for stabilizing serotype 1 and 2, respectively. For sIPV serotype 3, the best formulation contained Medium199, glutathione and maltodextrin. For the trivalent vaccine it is therefore probably necessary to spray dry the different serotypes separately and mix the dry powders afterwards to obtain the trivalent vaccine. Copyright © 2018. Published by Elsevier B.V.

Development of a screening method for co-amorphous formulations of drugs and amino acids

DEFF Research Database (Denmark)

Kasten, Georgia; Grohganz, Holger; Rades, Thomas

2016-01-01

Using amino acids (AA) as low molecular weight excipients in the preparation of co-amorphous blends with the aim to stabilize the drug in the amorphous form have been discussed in a range of studies. However, there is currently no theoretical consensus behind which AA would be a suitable co...

Mechanism of Process-Induced Salt-to-Free Base Transformation of Pharmaceutical Products

DEFF Research Database (Denmark)

Bruun Hansen, Thomas; Qu, Haiyan

2014-01-01

pH-solubility profiles of a model drug in salt form was established and the mechanism of salt-to-free base form transformation was investigated by increasing pH of the system. Wet massing experiments along with suspension experiments were used to investigate the effects of excipients on the stabi...

A Comparative Evaluation of the Flow and Compaction ...

African Journals Online (AJOL)

Purpose: Alpha-cellulose obtained as pulp from fibrous plant materials has found use in the pharmaceutical industry as a disintegrant and direct compression diluent. The aim of this study was to evaluate the suitability of α-cellulose obtained from waste paper as a direct compression excipient. Method: The flow and ...

The tabletting properties of Stearolac-S | Onyechi | Journal of ...

African Journals Online (AJOL)

press was used to determine the unit ejection force of tablets made from the direct compression formulations. The effects of the excipients on tablet hardness, friability, disintegration and dissolution rate were also evaluated. Tablets containing 3 - 4 % w/w STEAROLAC-S gave unit ejection force values comparable to those ...

International Journal of Health Research

African Journals Online (AJOL)

HP

Dean's Office, College of Medicine. Madonna University, Elele ... determined to a greater degree by the excipients chosen because they .... varying compression loads. The tablets were stored over silica gel for 24 hr to allow for elastic recovery and hardening, and prevent false low yield values. The target tablet weight was ...

76 FR 5782 - Citric Acid and Certain Citrate Salts From Canada: Preliminary Results of Antidumping Duty...

Science.gov (United States)

2011-02-02

... United States Pharmacopeia and has been mixed with a functional excipient, such as dextrose or starch... instructed JBL Canada to report its prices and expenses in the currencies in which they were incurred, in... reported its home market price and expense data in Canadian dollars (CAD) and its U.S. market price and...

Formulation and optimization of chronomodulated press-coated tablet of carvedilol by Box–Behnken statistical design

Directory of Open Access Journals (Sweden)

Satwara RS

2012-08-01

Full Text Available Rohan S Satwara, Parul K PatelDepartment of Pharmaceutics, Babaria Institute of Pharmacy, Vadodara, Gujarat, IndiaObjective: The primary objective of the present investigation was to formulate and optimize chronomodulated press-coated tablets to deliver the antihypertensive carvedilol at an effective quantity predawn, when a blood pressure spike is typically observed in most hypertensive patients.Experimental work: Preformulation studies and drug excipient compatibility studies were carried out for carvedilol and excipients. Core tablets (6 mm containing carvedilol and 10-mm press-coated tablets were prepared by direct compression. The Box–Behnken experimental design was applied to these press-coated tablets (F1–F15 formula with differing concentrations of rate-controlling polymers. Hydroxypropyl methyl cellulose K4M, ethyl cellulose, and K-carrageenan were used as rate-controlling polymers in the outer layer. These tablets were subjected to various precompression and postcompression tests. The optimized batch was derived both by statistically (using desirability function and graphically (using Design Expert® 8; Stat-Ease Inc. Tablets formulated using the optimized formulas were then evaluated for lag time and in vitro dissolution.Results and discussion: Results of preformulation studies were satisfactory. No interaction was observed between carvedilol and excipients by ultraviolet, Fourier transform infrared spectroscopy, and dynamic light scattering analysis. The results of precompression studies and postcompression studies were within limits. The varying lag time and percent cumulative carvedilol release after 8 h was optimized to obtain a formulation that offered a release profile with 6 h lag time, followed by complete carvedilol release after 8 h. The results showed no significant bias between predicted response and actual response for the optimized formula.Conclusion: Bedtime dosing of chronomodulated press-coated tablets may offer a

Fast and non-destructive pore structure analysis using terahertz time-domain spectroscopy.

Science.gov (United States)

Markl, Daniel; Bawuah, Prince; Ridgway, Cathy; van den Ban, Sander; Goodwin, Daniel J; Ketolainen, Jarkko; Gane, Patrick; Peiponen, Kai-Erik; Zeitler, J Axel

2018-02-15

Pharmaceutical tablets are typically manufactured by the uni-axial compaction of powder that is confined radially by a rigid die. The directional nature of the compaction process yields not only anisotropic mechanical properties (e.g. tensile strength) but also directional properties of the pore structure in the porous compact. This study derives a new quantitative parameter, S a , to describe the anisotropy in pore structure of pharmaceutical tablets based on terahertz time-domain spectroscopy measurements. The S a parameter analysis was applied to three different data sets including tablets with only one excipient (functionalised calcium carbonate), samples with one excipient (microcrystalline cellulose) and one drug (indomethacin), and a complex formulation (granulated product comprising several excipients and one drug). The overall porosity, tablet thickness, initial particle size distribution as well as the granule density were all found to affect the significant structural anisotropies that were observed in all investigated tablets. The S a parameter provides new insights into the microstructure of a tablet and its potential was particularly demonstrated for the analysis of formulations comprising several components. The results clearly indicate that material attributes, such as particle size and granule density, cause a change of the pore structure, which, therefore, directly impacts the liquid imbibition that is part of the disintegration process. We show, for the first time, how the granule density impacts the pore structure, which will also affect the performance of the tablet. It is thus of great importance to gain a better understanding of the relationship of the physical properties of material attributes (e.g. intragranular porosity, particle shape), the compaction process and the microstructure of the finished product. Copyright © 2017 Elsevier B.V. All rights reserved.

Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors.

Science.gov (United States)

Hettiarachchi, Gaya; Samanta, Soumen K; Falcinelli, Shane; Zhang, Ben; Moncelet, Damien; Isaacs, Lyle; Briken, Volker

2016-03-07

Approximately, 40-70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility, and consequently, there is a high demand for excipients that can be used to formulate clinically relevant doses of these drug candidates. Here, proof-of-concept studies demonstrate the potential of our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as a solubilizing agent for insoluble drugs. M1 did not induce significant rates of mutations in various Salmonella typhimurium test strains during the Ames test, suggesting low genotoxicity. M1 also has low risk of causing cardiac toxicity in humans since it did not inhibit the human Ether-à-go-go-Related Gene channel as tested on transfected CHO cell lines via patch clamp analysis. Albendazole (ABZ) is a widely used antihelminthic agent but that has also shown promising efficacy against cancerous cells in vitro. However, due to its low aqueous solubility (2.7 μM) and poor pharmacokinetics, ABZ is clinically limited as an anticancer agent. Here we investigated the potential of M1 as a solubilizing excipient for ABZ formulation. A pharmacokinetic study indicated that ABZ escapes the peritoneal cavity resulting in 78% absolute bioavailability, while its active intermediate metabolite, albendazole sulfoxide, achieved 43% absolute bioavailability. The daily dosing of 681 mg/kg M1 complexed with 3.2 mg/kg of ABZ for 14 days did not result in significant weight loss or pathology in Swiss Webster mice. In vivo efficacy studies using this M1·ABZ inclusion complex showed significant decreases in tumor growth rates and increases in survival of mice bearing SK-OV-3 xenograft tumors. In conclusion, we provide substantial new evidence demonstrating that M1 is a safe and efficient excipient that enables in vivo parenteral delivery of poorly water-soluble APIs.

[Pharmaceutical drugs containing lactose can as a rule be used by persons with lactose intolerance].

Science.gov (United States)

Vinther, Siri; Rumessen, Jöri Johannes; Christensen, Mikkel

2015-03-09

Lactose is often used as an excipient in pharmaceutical drugs. Current evidence indicates that the amount of lactose in most drugs is not sufficient to cause symptoms in persons with lactose intolerance, although interindividual differences in sensitivity probably exist. Patient preferences and/or suboptimal treatment adherence could be reasons for considering lactose-free drug alternatives.

Laktoseholdige lægemidler kan som hovedregel indtages af personer med laktoseintolerans

DEFF Research Database (Denmark)

Vinther, Siri; Rumessen, Jüri Johannes; Christensen, Mikkel

2015-01-01

Lactose is often used as an excipient in pharmaceutical drugs. Current evidence indicates that the amount of lactose in most drugs is not sufficient to cause symptoms in persons with lactose intolerance, although interindividual differences in sensitivity probably exist. Patient preferences and....../or suboptimal treatment adherence could be reasons for considering lactose-free drug alternatives....

Surface modified zeolite-based granulates for the sustained release of diclofenac sodium.

Science.gov (United States)

Serri, Carla; de Gennaro, Bruno; Quagliariello, Vincenzo; Iaffaioli, Rosario Vincenzo; De Rosa, Giuseppe; Catalanotti, Lilia; Biondi, Marco; Mayol, Laura

2017-03-01

In this study, a granulate for the oral controlled delivery of diclofenac sodium (DS), an anionic sparingly soluble nonsteroidal anti-inflammatory drug, has been realized by wet granulation, using a surface modified natural zeolite (SMNZ) as an excipient. The surface modification of the zeolite has been achieved by means of a cationic surfactant, so as to allow the loading of DS through ionic interaction and bestow a control over the drug release mechanism. The granules possessed a satisfactory dosage uniformity, a flowability suitable for an oral dosage form manufacturing, along with a sustained drug release up to 9h, driven by both ion exchange and transport kinetics. Furthermore, the obtained granulate did not elicit a significant cytotoxicity and could also induce a prolonged anti-inflammatory effect on RAW264.7 cells. Taking also into account that natural zeolites are generally abundant and economic, SMNZ can be considered as an attracting alternative excipient for the production of granules with sustained release features. Copyright © 2016 Elsevier B.V. All rights reserved.

OPTIMIZATION OF FUROSEMIDE LIQUISOLID TABLETS PREPARATION PROCESS LEADING TO THEIR MASS AND SIZE REDUCTION.

Science.gov (United States)

Kurek, Mateusz; Woyna-Orlewicz, Krzysztof; Khalid, Mohammad Hassan; Jachowicz, Renata

2016-09-01

The great number of drug substances currently used in solid oral dosage forms is characterized by poor water solubility. Therefore, various methods of dissolution rate enhancement are an important topic of research interest in modem drug technology. The purpose of this study was to enhance the furosemide dissolution rate from liquisolid tablets while maintaining an acceptable size and mass. Two types of dibasic calcium phosphate (Fujicalin®/Emcompress®) and microcrystalline cellulose (Vivapur® 102/Vivapur® 12) were used as carriers and magnesium aluminometasilicate (Neusilin® US2) was used as a coating material. The flowable liquid retention potential for those excipients was tested by measuring the angle of slide. To evaluate the impact of used excipients on tablet properties fourteen tablet formulations were prepared. It was found that LS2 tablets containing spherically granulated dibasic calcium phosphate and magnesium aluminometasilicate exhibit the best dissolution profile and mechanical properties while tablets composed only with Neusilin® US2 was characterized by the smallest size and mass with preserved good mechanical properties and furosemide dissolution.

Well-plate freeze-drying

DEFF Research Database (Denmark)

Trnka, Hjalte; Rantanen, Jukka; Grohganz, Holger

2015-01-01

Abstract Context: Freeze-drying in presence of excipients is a common practice to stabilize biomacromolecular formulations. The composition of this formulation is known to affect the quality of the final product. Objective: The aim of this study was to evaluate freeze-drying in well-plates as a h......Abstract Context: Freeze-drying in presence of excipients is a common practice to stabilize biomacromolecular formulations. The composition of this formulation is known to affect the quality of the final product. Objective: The aim of this study was to evaluate freeze-drying in well......-plates as a high throughput platform for formulation screening of freeze-dried products. Methods: Model formulations consisting of mannitol, sucrose and bovine serum albumin were freeze-dried in brass well plates, plastic well plates and vials. Physical properties investigated were solid form, residual moisture......, cake collapse and reconstitution time. Results: Samples freeze-dried in well-plates had an acceptable visual cake appearance. Solid form analysis by high throughput X-ray powder diffraction indicated comparable polymorphic outcome independent of the container. The expected increase in moisture level...

[What medication should be prescribed to a patient with coeliac disease?

Science.gov (United States)

Pérez-Diez, C; Guillén-Lorente, S; Palomo-Palomo, P

2018-03-01

Coeliac disease is a permanent intolerance to gluten proteins from wheat, rye, barley and triticale. Although strict adherence is complicated, the only effective treatment is a gluten-free diet throughout life. Some drugs contain starch as an excipient, and there is a risk related to the gluten content, which must be avoided in these patients. Current legislation requires the analysis of the protein content of wheat starch, or the absence of starches from another source where rice, maize, or potato starches are used as excipients. But, it does not specify that reference should be made to traces of gluten that are residues of the process of production of the active ingredient. As regards the case described, there needs to be awareness of the importance of adequately informing patients and reviewing/updating current legislation to ensure the safe use of drugs. Copyright © 2017 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

Risk identification for quality on stage of pharmaceutical development of combined eye drops for glaucoma treatment

Directory of Open Access Journals (Sweden)

Олександр Миколайович Якубчук

2015-12-01

Full Text Available Aim: To identify the possible risks associated with critical quality attribute of combined eye drops for the treatment of glaucoma using of common risk evaluation methodologies for plannig a drug quality on the stage of pharmaceutical development. Methods: The paper used method of causal analysis. The maximal number of factors has been define to identify potential factors that provide most significant impact on the drug quality and Ishikawa diagram - graphical representation of causes and effects has been built.Results: Analysis allowed to organize the possible factors affecting the drug quality in the generalized categories: quality control methods, medicines and excipients, primary packaging, proper manufacturing conditions and the stage of the process. The most important factors that are carriers of the risk factors and may lead to negative effects have been identified for the generalized categories.Conclusions: Determined at the stage of pharmaceutical development potential critical quality attribute of AFI, excipients and primary packaging, critical parameters of the process, provide a better understanding, reduction and adoption of risk in subsequent stages of the life cycle of the drug

Developments in the formulation and delivery of spray dried vaccines.

Science.gov (United States)

Kanojia, Gaurav; Have, Rimko Ten; Soema, Peter C; Frijlink, Henderik; Amorij, Jean-Pierre; Kersten, Gideon

2017-10-03

Spray drying is a promising method for the stabilization of vaccines, which are usually formulated as liquids. Usually, vaccine stability is improved by spray drying in the presence of a range of excipients. Unlike freeze drying, there is no freezing step involved, thus the damage related to this step is avoided. The edge of spray drying resides in its ability for particles to be engineered to desired requirements, which can be used in various vaccine delivery methods and routes. Although several spray dried vaccines have shown encouraging preclinical results, the number of vaccines that have been tested in clinical trials is limited, indicating a relatively new area of vaccine stabilization and delivery. This article reviews the current status of spray dried vaccine formulations and delivery methods. In particular it discusses the impact of process stresses on vaccine integrity, the application of excipients in spray drying of vaccines, process and formulation optimization strategies based on Design of Experiment approaches as well as opportunities for future application of spray dried vaccine powders for vaccine delivery.

Tools to Ensure Safe Medicines: New Monograph Tests in USP-NF

Directory of Open Access Journals (Sweden)

Catherine Sheehan

2010-06-01

Full Text Available This paper describes USP-NF compendial updates to six ‘high-priority” excipient monographs: Glycerin, Propylene Glycol, Sorbitol Solution, Sorbitol Sorbitan Solution, Noncrystallizing Sorbitol Solution and Maltitol Solution. The USP-NF revisions arose from the Food and Drug Administration’s (FDA’s requests to include, as part of each monograph’s Identification test, a limit test to detect the presence of Diethylene Glycol (DEG, a toxic adulterant. These revisions align with the 2007 FDA Guidance for Industry: Testing of Glycerin for Diethylene Glycol (1, that drug product manufacturers perform a specific identity test for DEG on all containers of all lots of glycerin before glycerin is used in the manufacture and preparation of drug products. This paper describes several risk factors due to a complex global excipient supply chain, nonspecific specifications, inadequate supply chain qualification, and poor understanding of regulations. Strengthening and conformance to compendial specifications is one of the tools necessary to mitigate risk and help prevent the next DEG adulteration that is part of USP’s efforts to ensure safe medicines.

Developments in the formulation and delivery of spray dried vaccines

Science.gov (United States)

Kanojia, Gaurav; Have, Rimko ten; Soema, Peter C.; Frijlink, Henderik; Amorij, Jean-Pierre; Kersten, Gideon

2017-01-01

ABSTRACT Spray drying is a promising method for the stabilization of vaccines, which are usually formulated as liquids. Usually, vaccine stability is improved by spray drying in the presence of a range of excipients. Unlike freeze drying, there is no freezing step involved, thus the damage related to this step is avoided. The edge of spray drying resides in its ability for particles to be engineered to desired requirements, which can be used in various vaccine delivery methods and routes. Although several spray dried vaccines have shown encouraging preclinical results, the number of vaccines that have been tested in clinical trials is limited, indicating a relatively new area of vaccine stabilization and delivery. This article reviews the current status of spray dried vaccine formulations and delivery methods. In particular it discusses the impact of process stresses on vaccine integrity, the application of excipients in spray drying of vaccines, process and formulation optimization strategies based on Design of Experiment approaches as well as opportunities for future application of spray dried vaccine powders for vaccine delivery. PMID:28925794

Rapid classification of pharmaceutical ingredients with Raman spectroscopy using compressive detection strategy with PLS-DA multivariate filters.

Science.gov (United States)

Cebeci Maltaş, Derya; Kwok, Kaho; Wang, Ping; Taylor, Lynne S; Ben-Amotz, Dor

2013-06-01

Identifying pharmaceutical ingredients is a routine procedure required during industrial manufacturing. Here we show that a recently developed Raman compressive detection strategy can be employed to classify various widely used pharmaceutical materials using a hybrid supervised/unsupervised strategy in which only two ingredients are used for training and yet six other ingredients can also be distinguished. More specifically, our liquid crystal spatial light modulator (LC-SLM) based compressive detection instrument is trained using only the active ingredient, tadalafil, and the excipient, lactose, but is tested using these and various other excipients; microcrystalline cellulose, magnesium stearate, titanium (IV) oxide, talc, sodium lauryl sulfate and hydroxypropyl cellulose. Partial least squares discriminant analysis (PLS-DA) is used to generate the compressive detection filters necessary for fast chemical classification. Although the filters used in this study are trained on only lactose and tadalafil, we show that all the pharmaceutical ingredients mentioned above can be differentiated and classified using PLS-DA compressive detection filters with an accumulation time of 10ms per filter. Copyright © 2013 Elsevier B.V. All rights reserved.

A facile doxorubicin-dichloroacetate conjugate nanomedicine with high drug loading for safe drug delivery.

Science.gov (United States)

Yang, Conglian; Wu, Tingting; Qin, Yuting; Qi, Yan; Sun, Yu; Kong, Miao; Jiang, Xue; Qin, Xianya; Shen, Yaqi; Zhang, Zhiping

2018-01-01

Doxorubicin (DOX) is an effective chemotherapeutic agent but severe side effects limit its clinical application. Nanoformulations can reduce the toxicity while still have various limitations, such as complexity, low drug loading capability and excipient related concerns. An amphiphilic conjugate, doxorubicin-dichloroacetate, was synthesized and the corresponding nanoparticles were prepared. The in vitro cytotoxicity and intracellular uptake, in vivo imaging, antitumor effects and systemic toxicities of nanoparticles were carried out to evaluate the therapeutic efficiency of tumor. Doxorubicin-dichloroacetate conjugate can self-assemble into nanoparticles with small amount of DSPE-PEG 2000 , leading to high drug loading (71.8%, w/w) and diminished excipient associated concerns. The nanoparticles exhibited invisible systemic toxicity and high maximum tolerated dose of 75 mg DOX equiv./kg, which was 15-fold higher than that of free DOX. It also showed good tumor targeting capability and enhanced antitumor efficacy in murine melanoma model. This work provides a promising strategy to simplify the drug preparation process, increase drug loading content, reduce systemic toxicity as well as enhance antitumor efficiency.

Development of an Optimised Losartan Potassium Press-Coated ...

African Journals Online (AJOL)

Erah

2011-04-12

Apr 12, 2011 ... There was no modification or chemical interaction between the drug and the excipient. Conclusion: .... size and dried for 2 hrs at 450C in a hot air ... maintained at 37±2 °C as the disintegration fluid. Six tablets were placed in the disintegration apparatus (Electrolab, Model,. ED-2L. Mumbai,. India)) for each.

Isolation and structure elucidation of an interaction product of aminotadalafil found in an illegal health food product.

Science.gov (United States)

Häberli, Adrian; Girard, Philippe; Low, Min-Yong; Ge, Xiaowei

2010-09-21

An interaction product of aminotadalafil was isolated from an illegal health food product. The structure of the interaction product was elucidated by means of IR, NMR, and mass spectroscopy. The hitherto unknown compound was characterized as condensation product of aminotadalafil and hydroxymethylfuraldehyde and is probably the result of a drug-excipient incompatibility. Copyright 2010. Published by Elsevier B.V.

Incorporation of Certain Hydrophobic Excipients in the Core of Melt ...

African Journals Online (AJOL)

Patrick Erah

incorporation of hydrophobic materials (talc or magnesium stearate) in the core of such granules may further retard .... (500mg) was filled into a capsule shell and ... of the drug particles. The effect of melt granulation on the release profiles of paracetamol is shown in Fig 1. The melt granulations displayed a retarded release.

Physical stability of amorphous acetanilide derivatives improved by polymer excipients.

Science.gov (United States)

Miyazaki, Tamaki; Yoshioka, Sumie; Aso, Yukio

2006-08-01

Crystallization rates of drug-polymer solid dispersions prepared with acetaminophen (ACA) and p-aminoacetanilide (AAA) as model drugs, and polyvinylpyrrolidone and polyacrylic acid (PAA) as model polymers were measured in order to further examine the significance of drug-polymer interactions. The crystallization of AAA and ACA was inhibited by mixing those polymers. The most effective inhibition was observed with solid dispersions of AAA and PAA. The combination of AAA and PAA showed a markedly longer enthalpy relaxation time relative to drug alone as well as a higher T(g) than predicted by the Gordon-Taylor equation, indicating the existence of a strong interaction between the two components. These observations suggest that crystallization is effectively inhibited by combinations of drug and polymer that show a strong intermolecular interaction due to proton transfer between acidic and basic functional groups.

Compatibilidad química por calorimetría diferencial de barrido y termogravimetría del auranofin tabletas 3 mg Chemical compatibility of 3 mg Auranofin tablets demonstrated by differential scanning calorimetry and thermogravimetry

Directory of Open Access Journals (Sweden)

Luis Octavio Martínez Álvarez

2011-03-01

Full Text Available Como parte de la pre-estabilidad de la preformulación de auranofin tabletas, se realizó un estudio de compatibilidad química, para lo cual se emplearon técnicas de análisis térmico como la calorimetría diferencial de barrido y la termogravimetría. Previo a dichos estudios se caracterizó térmicamente por calorimetría diferencial de barrido el principio activo y cada uno de los excipientes. Posteriormente se procedió a la realización del estudio de compatibilidad química, mediante la preparación de mezclas físicas binarias entre el principio activo y cada uno de los excipientes. Se detectó por ambos métodos que el principio activo tuvo una transición física de fusión, no reportada en la literatura, lo que permitió poder calcular su pureza por calorimetría diferencial de barrido. Mediante la técnica calorimétrica fue posible inferir la ausencia de incompatibilidad química entre el principio activo y los excipientes estudiados. Además, mediante el cálculo de la energía de activación se estableció el siguiente orden de estabilidad térmica: auranofin:PVP> auranofin:lactosa> auranofin:explotab> auranofin:estearato> auranofin:aerosil> auranofin:celulosa, por lo que se recomienda el uso de estos excipientes en la elaboración de la formulación farmacéutica.As part of the pre-stability study of the Auranofin tablet pre-formulation, a chemical compatibility study was conducted using thermal analysis techniques such as the differential scanning calorimetry and the thermogravimetry. Prior to these studies, the active principle and each of the excipients were thermally characterized with the aid of the differential scanning calorimetry. Then, there proceeded to carry out the chemical compatibility study by preparing binary physical mixtures between the active principle and each of the excipients. Both methods showed that the active principle had a melting physical transition, not reported in the literature, which allowed

Multi-analytical approach for profiling some essential medical drugs

International Nuclear Information System (INIS)

Abubakar, M.

2015-07-01

Counterfeit and substandard pharmaceutical drugs are chiefly rampant in developing countries due to inadequate analytical facilities and lack of regulatory oversight. The production of counterfeit or substandard drugs is broadly problematic. Underestimating it therefore leads to morbidity, mortality, drug resistance, introduction of toxic substances into the body and loss of confidence in health care systems. Medical drugs that are often counterfeited range from antimalarial drugs to antiretroviral drugs with antibiotics being counterfeited the most. This research work, therefore, aims at contributing towards the establishment of measures/processes for distinguishing between fake and genuine amoxicillin drugs. This was achieved by the identification and quantification of the Active Pharmaceutical Ingredient (API) and the excipients in the drug formulation. The major analytical techniques employed for this research work were Instrumental Neutron Activation Analysis (INAA), X-ray Powder Diffraction (XRD), High Performance Liquid Chromatography (HPLC) and in vitro Dissolution Test. The amoxicillin samples analyzed were the foreign generic amoxicillin purchased from Ernest Chemists pharmacy at East Legon, Accra, the National Health Insurance Scheme (NHIS) amoxicillin purchased at Fair Mile pharmacy at West Legon, Accra and the Suspected Fake amoxicillin purchased at Okaishi market. For the establishment of fingerprint for identification of substandard amoxicillin, INAA was used to qualitatively determine the short lived radionuclides (excipients) which then facilitated the correct identification of the API and the excipient phases in each of the amoxicillin groups. The phases identified were Amoxicillin Trihydrate as the excipient, Magnesium Stearate (hydrated) and Magnesium Stearate (anhydrous) as the excipients. For Quality control purposes, High Performance Liquid Chromatography approach and also, the in vitro Dissolution test were conducted on each of the groups of

[Galenic forms for oral medication].

Science.gov (United States)

El Semman, Ousseid; Certain, Agnès; Bouziane, Faouzia; Arnaud, Philippe

2012-10-01

Galenic science is interested in the art and the way of formulating an active principle with an excipient in order for it to be administered to the patient. The pharmaceutical forms envisage different administration routes, including by mouth. Nurses need to handle and sometimes modify the pharmaceutical form of a drug to make it easier for the patient to take. This requires vigilance.

Smart Prosthetic Hand Technology - Phase 2

Science.gov (United States)

2011-05-01

functional magnetic resonance imaging (f- MRI ) was used to analyze the reciprocal adaptation between the human brain and the prosthetic hand by the...Schmidt PC. Influence of compacted hydrophobic and hydrophilic colloidal silicon dioxide on tableting properties of pharmaceutical excipients. Drug Dev...nanoparticles, and manganese nanoparticles) in magnetic resonance imaging ( MRI ) in the detection and staging of cancer [2]. 2.1 Iron Oxide

Use of the liquisolid compact technique for improvement of the dissolution rate of valsartan

Directory of Open Access Journals (Sweden)

Naveen Chella

2012-10-01

Full Text Available The aim of this study was to improve the dissolution rate of the poorly soluble drug valsartan by delivering the drug as a liquisolid compact. Liquisolid compacts were prepared using propylene glycol as solvent, Avicel PH102 as carrier, and Aerosil 200 as the coating material. The crystallinity of the newly formulated drug and the interaction between excipients was examined by X-ray powder diffraction and Fourier-transform infrared spectroscopy, respectively. The dissolution studies for the liquisolid formulation and the marketed product were carried out at different pH values. The results showed no change in the crystallinity of the drug and no interaction between excipients. The dissolution efficiency of valsartan at 15 min was increased from 4.02% for plain drug and 13.58% for marketed product to 29.47% for the liquisolid formulation. The increase in the dissolution rate was also found to be significant compared to the marketed product at lower pH values, simulating the gastric environment where valsartan is largely absorbed. The liquisolid technique appears to be a promising approach for improving the dissolution of poorly soluble drugs like valsartan.

NanoCrySP technology for generation of drug nanocrystals: translational aspects and business potential.

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Shete, Ganesh; Bansal, Arvind Kumar

2016-08-01

Drug nanocrystals have rapidly evolved into a mature drug delivery strategy in the last decade, with almost 16 products currently on the market. Several "top-down" technologies are available in the market for generation of nanocrystals. Despite several advantages, very few bottom-up technologies have been explored for commercial purpose. This short communication highlights a novel, bottom-up, spray drying based technology-NanoCrySP-to generate drug nanocrystals. Nanocrystals are generated in the presence of non-polymeric excipients that act as crystallization inducer for the drug. Excipients encourage crystallization of drug by plasticization, primary heterogeneous nucleation, and imparting physical barrier to crystal growth. Nanocrystals have shown significant improvement in dissolution and thereby oral bioavailability. NanoCrySP technology is protected through patents in India, the USA, and the European Union. NanoCrySP can be utilized for (i) pharmaceutical development of new chemical entities, (ii) differentiated products of existing molecules, and (iii) generic drug products. The aggregation of drug nanocrystals generated using NanoCrySP poses significant challenges in the nanocrystal-based product development. Addition of stabilizers either during spray drying or during dissolution has shown beneficial effects.

Preparation of Candesartan and Atorvastatin Nanoparticles by Solvent Evaporation

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Josef Jampilek

2012-11-01

Full Text Available The solubility, absorption and distribution of a drug are involved in the basic aspects of oral bioavailability Solubility is an essential characteristic and influences the efficiency of the drug. Over the last ten years, the number of poorly soluble drugs has steadily increased. One of the progressive ways for increasing oral bioavaibility is the technique of nanoparticle preparation, which allows many drugs to thus reach the intended site of action. Candesartan cilexetil and atorvastatin, belonging to class II of the biopharmaceutical classification system, were chosen as model active pharmaceutical ingredients in this study. Forty samples were prepared either by antisolvent precipitation/solvent evaporation method or by the emulsion/solvent evaporation technique with various commonly used surface-active excipients as nanoparticle stabilizers. All samples were analyzed by means of dynamic light scattering. The particle size of the determined 36 nanoparticle samples was to 574 nm, whereas 32 samples contained nanoparticles of less than 200 nm. Relationships between solvents and excipients used and their amount are discussed. Based on the results the investigated solvent evaporation methods can be used as an effective and an affordable technique for the preparation of nanoparticles.

Oromucosal film preparations: points to consider for patient centricity and manufacturing processes.

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Krampe, Raphael; Visser, J Carolina; Frijlink, Henderik W; Breitkreutz, Jörg; Woerdenbag, Herman J; Preis, Maren

2016-01-01

According to the European Pharmacopoeia, oromucosal films comprise mucoadhesive buccal films and orodispersible films. Both oral dosage forms receive considerable interest in the recent years as commercially available pharmaceutical products and as small scale personalized extemporaneous preparations. In this review, technological issues such as viscosity of the casting liquid, mechanical properties of the film, upscaling and the stability of the casting solution and produced films will be discussed. Furthermore, patient-related problems like appearance, mucosal irritation, taste, drug load, safety and biopharmaceutics are described. Current knowledge and directions for solutions are summarized. The viscosity of the casting solution is a key factor for producing suitable films. This parameter is amongst others dependent on the polymer and active pharmaceutical ingredient, and the further excipients that are used. For optimal patient compliance, an acceptable taste and palatability are desirable. Safe and inert excipients should be used and appropriate packaging should be provided to produced films. Absorption through the oral mucosa will vary for each active compound, formulation and patient, which gives rise to pharmacokinetic questions. Finally, the European Pharmacopoeia needs to specify methods, requirement and definitions for oromucosal film preparations based on bio-relevant data.

A structural investigation into the compaction behavior of pharmaceutical composites using powder X-ray diffraction and total scattering analysis.

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Moore, Michael D; Steinbach, Alison M; Buckner, Ira S; Wildfong, Peter L D

2009-11-01

To use advanced powder X-ray diffraction (PXRD) to characterize the structure of anhydrous theophylline following compaction, alone, and as part of a binary mixture with either alpha-lactose monohydrate or microcrystalline cellulose. Compacts formed from (1) pure theophylline and (2) each type of binary mixture were analyzed intact using PXRD. A novel mathematical technique was used to accurately separate multi-component diffraction patterns. The pair distribution function (PDF) of isolated theophylline diffraction data was employed to assess structural differences induced by consolidation and evaluated by principal components analysis (PCA). Changes induced in PXRD patterns by increasing compaction pressure were amplified by the PDF. Simulated data suggest PDF dampening is attributable to molecular deviations from average crystalline position. Samples compacted at different pressures were identified and differentiated using PCA. Samples compacted at common pressures exhibited similar inter-atomic correlations, where excipient concentration factored in the analyses involving lactose. Practical real-space structural analysis of PXRD data by PDF was accomplished for intact, compacted crystalline drug with and without excipient. PCA was used to compare multiple PDFs and successfully differentiated pattern changes consistent with compaction-induced disordering of theophylline as a single component and in the presence of another material.

Biowaiver monograph for immediate-release solid oral dosage forms: acetylsalicylic acid.

Science.gov (United States)

Dressman, Jennifer B; Nair, Anita; Abrahamsson, Bertil; Barends, Dirk M; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Zimmer, Markus

2012-08-01

A biowaiver monograph for acetylsalicylic acid (ASA) is presented. Literature and experimental data indicate that ASA is a highly soluble and highly permeable drug, leading to assignment of this active pharmaceutical ingredient (API) to Class I of the Biopharmaceutics Classification System (BCS). Limited bioequivalence (BE) studies reported in the literature indicate that products that have been tested are bioequivalent. Most of the excipients used in products with a marketing authorization in Europe are not considered to have an impact on gastrointestinal motility or permeability. Furthermore, ASA has a wide therapeutic index. Thus, the risks to the patient that might occur if a nonbioequivalent product were to be incorrectly deemed bioequivalent according to the biowaiver procedure appear to be minimal. As a result, the BCS-based biowaiver procedure can be recommended for approval of new formulations of solid oral dosage forms containing ASA as the only API, including both multisource and reformulated products, under the following conditions: (1) excipients are chosen from those used in ASA products already registered in International Conference on Harmonization and associated countries and (2) the dissolution profiles of the test and the comparator products comply with the BE guidance. Copyright © 2012 Wiley Periodicals, Inc.

High-amylose sodium carboxymethyl starch matrices: development and characterization of tramadol hydrochloride sustained-release tablets for oral administration.

Science.gov (United States)

Nabais, Teresa; Leclair, Grégoire

2014-01-01

Substituted amylose (SA) polymers were produced from high-amylose corn starch by etherification of its hydroxyl groups with chloroacetate. Amorphous high-amylose sodium carboxymethyl starch (HASCA), the resulting SA polymer, was spray-dried to obtain an excipient (SD HASCA) with optimal binding and sustained-release (SR) properties. Tablets containing different percentages of SD HASCA and tramadol hydrochloride were produced by direct compression and evaluated for dissolution. Once-daily and twice-daily SD HASCA tablets containing two common dosages of tramadol hydrochloride (100 mg and 200 mg), a freely water-soluble drug, were successfully developed. These SR formulations presented high crushing forces, which facilitate further tablet processing and handling. When exposed to both a pH gradient simulating the pH variations through the gastrointestinal tract and a 40% ethanol medium, a very rigid gel formed progressively at the surface of the tablets providing controlled drug-release properties. These properties indicated that SD HASCA was a promising and robust excipient for oral, sustained drug-release, which may possibly minimize the likelihood of dose dumping and consequent adverse effects, even in the case of coadministration with alcohol.

Formulation and Evaluation of Liquisolid Compacts for Olmesartan Medoxomil

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Shailesh T. Prajapati

2013-01-01

Full Text Available Olmesartan medoxomil is an angiotensin type II receptor blocker, antihypertensive agent, administered orally. It is highly lipophilic (log P 5.5 and a poorly water-soluble drug with absolute bioavailability of 26%. The poor dissolution rate of water-insoluble drugs is still a major problem confronting the pharmaceutical industry. The objective of the present investigation was to develop liquisolid compacts for olmesartan medoxomil to improve the dissolution rate. Liquisolid compacts were prepared using Acrysol El 135 as a solvent, Avicel PH 102, Fujicalin and Neusilin as carrier materials, and Aerosil as coating material in different ratios. The interaction between drug and excipients was characterized by DSC and FT-IR studies, which showed that there is no interaction between drug and excipients. The powder characteristics were evaluated by different flow parameters to comply with pharmacopoeial limits. The dissolution studies for liquisolid compacts and conventional formulations were carried out, and it was found that liquisolid compacts with 80% w/w of Acrysol EL 135 to the drug showed significant higher drug release rates than conventional tablets. Amongst carriers used Fujicalin and Neusilin were found to be more effective carrier materials for liquid adsorption.

Characterization of a New High-Dose Dry Powder Inhaler (DPI) Based on a Fluidized Bed Design.

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Farkas, Dale R; Hindle, Michael; Longest, P Worth

2015-11-01

The objective of this study was to develop a new high-efficiency dry powder inhaler (DPI) that can effectively aerosolize large masses (25-100 mg) of spray dried powder formulations. The DPI was designed to implement a concept similar to a fluidized bed for aerosolization using small mixing balls made of polytetrafluoroethylene along with a larger, hollow dosing sphere filled with the powder. The performance of the fluidized bed DPI was compared, based on emitted dose (ED) and aerosolization efficiency, to other recently developed capsule-based DPIs that were designed to accommodate smaller powder masses (~2-20 mg). The inhalers were tested with spray dried excipient enhanced growth (EEG) formulations that contained an antibiotic (ciprofloxacin) and hygroscopic excipient (mannitol). The new fluidized bed design produced an ED of 71% along with a mass median aerodynamic diameter of 1.53 μm and fine particle fractions <5 and 1 μm of 93 and 36%, respectively, when used to deliver a 100 mg loaded mass of EEG powder with the advantage of not requiring multiple capsules. Surprisingly, performance of the device was further improved by removing the mixing balls from the inhaler and only retaining the dose containment sphere.

Studying the Impact of Modified Saccharides on the Molecular Dynamics and Crystallization Tendencies of Model API Nifedipine.

Science.gov (United States)

Kaminska, E; Tarnacka, M; Wlodarczyk, P; Jurkiewicz, K; Kolodziejczyk, K; Dulski, M; Haznar-Garbacz, D; Hawelek, L; Kaminski, K; Wlodarczyk, A; Paluch, M

2015-08-03

Molecular dynamics of pure nifedipine and its solid dispersions with modified carbohydrates as well as the crystallization kinetics of active pharmaceutical ingredient (API) above and below the glass transition temperature were studied in detail by means of broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), and X-ray diffraction method. It was found that the activation barrier of crystallization increases in molecular dispersions composed of acetylated disaccharides, whereas it slightly decreases in those consisting of modified monocarbohydrates for the experiments carried out above the glass transition temperature. As shown by molecular dynamics simulations it can be related to the strength, character, and structure of intermolecular interactions between API and saccharides, which vary dependently on the excipient. Long-term physical stability studies showed that, in solid dispersions consisting of acetylated maltose and acetylated sucrose, the crystallization of nifedipine is dramatically slowed down, although it is still observable for a low concentration of excipients. With increasing content of modified carbohydrates, the crystallization of API becomes completely suppressed. This is most likely due to additional barriers relating to the intermolecular interactions and diffusion of nifedipine that must be overcome to trigger the crystallization process.

Promising applications in drug delivery systems of a novel β-cyclodextrin derivative obtained by green synthesis.

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García, Agustina; Leonardi, Darío; Lamas, María C

2016-01-15

An efficient and green method has been developed for the synthesis of succinyl-β-cyclodextrin in aqueous media obtaining very good yield. Acidic groups have been introduced in the synthesized carrier molecule to improve the guest-host affinity. To evaluate the suitability of the novel excipient focused to develop oral dosage forms, albendazole, a BSC class II compound, was chosen as a model drug. The β-cyclodextrin derivative and the inclusion complex were thoroughly characterized in solution and solid state by phase solubility studies, FT-IR spectroscopy, SEM, XRD, ESI-MS, DSC, 1D (1)H NMR, 1D (13)C NMR, selective 1D TOCSY, 2D COSY, 2D HSQC, 2D HMBC and ROESY NMR spectroscopy. Phase solubility studies indicated that both of them β-cyclodextrin and succinyl-β-cyclodextrin formed 1:1 inclusion complexes with albendazole, and the stability constants were 68M(-1) (β-cyclodextrin), 437M(-1) (succinyl-β-cyclodextrin), respectively. Water solubility and dissolution rate of albendazole were significantly improved in complex forms. Thus, the succinyl-β-cyclodextrin derivative could be a promising excipient to design oral dosage forms. Copyright © 2015 Elsevier Ltd. All rights reserved.

Crystal Morphology Engineering of Pharmaceutical Solids: Tabletting Performance Enhancement

OpenAIRE

Mirza, Sabiruddin; Miroshnyk, Inna; Heinämäki, Jyrki; Antikainen, Osmo; Rantanen, Jukka; Vuorela, Pia; Vuorela, Heikki; Yliruusi, Jouko

2009-01-01

Crystal morphology engineering of a macrolide antibiotic, erythromycin A dihydrate, was investigated as a tool for tailoring tabletting performance of pharmaceutical solids. Crystal habit modification was induced by using a common pharmaceutical excipient, hydroxypropyl cellulose, as an additive during crystallization from solution. Observed morphology of the crystals was compared with the predicted Bravais–Friedel–Donnay–Harker morphology. An analysis of the molecular arrangements along the ...

Multispectral UV imaging for surface analysis of MUPS tablets with special focus on the pellet distribution

DEFF Research Database (Denmark)

Novikova, Anna; Carstensen, Jens Michael; Rades, Thomas

2016-01-01

In the present study the applicability of multispectral UV imaging in combination with multivariate image analysis for surface evaluation of MUPS tablets was investigated with respect to the differentiation of the API pellets from the excipients matrix, estimation of the drug content as well as p...... image analysis is a promising approach for the automatic quality control of MUPS tablets during the manufacturing process....

AFM Colloidal Probe Measurements Implicate Capillary Condensation in Punch-Particle Surface Interactions during Tableting.

Science.gov (United States)

Badal Tejedor, Maria; Nordgren, Niklas; Schuleit, Michael; Millqvist-Fureby, Anna; Rutland, Mark W

2017-11-21

Adhesion of the powders to the punches is a common issue during tableting. This phenomenon is known as sticking and affects the quality of the manufactured tablets. Defective tablets increase the cost of the manufacturing process. Thus, the ability to predict the tableting performance of the formulation blend before the process is scaled-up is important. The adhesive propensity of the powder to the tableting tools is mostly governed by the surface-surface adhesive interactions. Atomic force microscopy (AFM) colloidal probe is a surface characterization technique that allows the measurement of the adhesive interactions between two materials of interest. In this study, AFM steel colloidal probe measurements were performed on ibuprofen, MCC (microcrystalline cellulose), α-lactose monohydrate, and spray-dried lactose particles as an approach to modeling the punch-particle surface interactions during tableting. The excipients (lactose and MCC) showed constant, small, attractive, and adhesive forces toward the steel surface after a repeated number of contacts. In comparison, ibuprofen displayed a much larger attractive and adhesive interaction increasing over time both in magnitude and in jump-in/jump-out separation distance. The type of interaction acting on the excipient-steel interface can be related to a van der Waals force, which is relatively weak and short-ranged. By contrast, the ibuprofen-steel interaction is described by a capillary force profile. Even though ibuprofen is not highly hydrophilic, the relatively smooth surfaces of the crystals allow "contact flooding" upon contact with the steel probe. Capillary forces increase because of the "harvesting" of moisture-due to the fast condensation kinetics-leaving a residual condensate that contributes to increase the interaction force after each consecutive contact. Local asperity contacts on the more hydrophilic surface of the excipients prevent the flooding of the contact zone, and there is no such adhesive

Effects of miglyol 812 on rats after 4 weeks of gavage as compared with methylcellulose/tween 80.

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Sellers, Rani S; Antman, M; Phillips, J; Khan, K N; Furst, S M

2005-01-01

Miglyol 812 is a medium-chain triglyceride used in toxicology studies as an excipient to improve test compound solubility/absorption. As part of a larger toxicology study, 15 Wistar Han IGS rats/sex/group were dosed by oral gavage for 4 weeks with 10 mL kg(-1) day(-1) of 100% Miglyol 812 or 0.5% methylcellulose/0.1% Tween 80 in water (MC-T) followed by 4 weeks without treatment to evaluate the potential effects of this excipient in long-term toxicology studies relative to a traditional excipient such as MC-T. Clinical signs evident during the dosing phase included soft and/or mucoid stool in 12/15 males and 11/15 females treated with Miglyol 812 but in no animals treated with MC-T. Animals treated with Miglyol 812 had a 6-7% statistically significant reduction in body weight gain as compared to MC-T-treated animals. Statistically significant changes in clinical chemistry parameters as compared to MC-T included decreased blood urea nitrogen (50% and 29% in males and females, respectively), increased cholesterol (1.6-fold and 1.5-fold in males and females, respectively), decreased total protein (6% and 8% in males and females, respectively), decreased globulins (15% and 11% in males and females, respectively), and increased triglycerides (2.8-fold and 1.7-fold in males and females, respectively). Absolute and relative thymic weights decreased 28% and 24%, respectively, in males, and 18% and 17%, respectively, in females without histological alterations. Histopathology revealed increased alveolar histiocytosis with focal interstitial inflammation in lungs in 5/10 males and 7/10 females treated with Miglyol 812 compared to only 1/10 males and 1/10 females treated with MC-T. All effects were reversible during the recovery period. Results of this study indicate that 100% miglyol 812 produces reversible gastrointestinal effects and decreases in body weight gains along with changes in several serum chemistry parameters. Therefore, it should not be considered innocuous when

Biowaiver monographs for immediate release solid oral dosage forms: piroxicam.

Science.gov (United States)

Shohin, Igor E; Kulinich, Julia I; Ramenskaya, Galina V; Abrahamsson, Bertil; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Groot, D W; Barends, Dirk M; Dressman, Jennifer B

2014-02-01

Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing piroxicam in the free acid form are reviewed. Piroxicam solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA), and corresponding dissolution data are taken into consideration. The available data suggest that according to the current biopharmaceutics classification system (BCS) and all current guidances, piroxicam would be assigned to BCS Class II. The extent of piroxicam absorption seems not to depend on manufacturing conditions or excipients, so the risk of bioinequivalence in terms of area under the curve (AUC) is very low, but the rate of absorption (i.e., BE in terms of Cmax ) can be affected by the formulation. Current in vitro dissolution methods may not always reflect differences in terms of Cmax for BCS Class II weak acids; however, minor differences in absorption rate of piroxicam would not subject the patient to unacceptable risks: as piroxicam products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR piroxicam solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients, which are also present in IR solid oral drug products containing piroxicam, which have been approved in ICH or associated countries, for instance, those presented in Table 3 of this paper; (b) both the test and comparator drug products dissolve 85% in 30 min or less at pH 1.2, 4.5, and 6.8; and (c) the test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When not all of these conditions can be fulfilled, BE of the products should be established in vivo. © 2013 Wiley Periodicals, Inc. and the

Orodispersible tablets containing taste-masked solid lipid pellets with metformin hydrochloride: Influence of process parameters on tablet properties.

Science.gov (United States)

Petrovick, Gustavo Freire; Kleinebudde, Peter; Breitkreutz, Jörg

2018-01-01

Compaction of multiparticulates into tablets, particularly into orodispersible tablets (ODTs), is challenging. The compression of pellets, made by solid lipid extrusion/spheronization processes, presents peculiar difficulties since solid lipids usually soften or melt at relatively low temperature ranges and due to applied mechanical forces. Until now, there are no reports in literature about the development of ODTs based on solid lipid pellets. To investigate the feasibility of producing such tablets, a design of experiment (DoE) approach was performed to elucidate the influence of compression force and amount of two co-processed excipients (Ludiflash ® and Parteck ® ODT) on properties of the tablets (friability, tensile strength, and disintegration time). ODTs (15 mm, flat-faced) with solid lipid pellets (250-1000 µm in diameter) containing 500 mg of metformin HCl, presenting immediate drug release profile and taste-masked properties, were targeted. During compression, a strong lamination of the tablets containing Parteck ® ODT was observed. This phenomenon was prominently observed when high compression forces (≥5 kN) and high excipient amounts (≥40%; w/w) were used. On the other hand, the DoE focused on tablets with Ludiflash ® showed better results regarding the production of ODTs. A positive influence of the compression force on the tensile strength and disintegration time of the tablets, regarding specifications of the Ph. Eur., was observed. The increase in the amount of this excipient resulted in fast disintegrating tablets, however, a negative influence on the tensile strength was noticed. After optimization of the parameters and formulation, based on the DoE results and considering the Ph. Eur. specifications for tablets, ODTs based on lipid pellets containing metformin HCl presenting immediate release profile (85% drug release in less than 30 min) and taste-masked properties (determined by an electronic tongue) were successfully

Thermogravimetric study of vinpocetine suppository

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N. А. Nаgоrnaya

2014-02-01

Full Text Available Introduction. Development of technology is the one of the main stage in creation of new medications. Technological process of suppository manufacturing includes sufficiently long thermoprocessing during suppository base making, addition of the active substances and homogenisation. This makes risk of chemical and physical transformations of active substances and excipients in suppository which can be destroyed and changed pharmacologicaly. Use of thermogravimetric analyses in pharmaceutical technology allows to study possibility of chemical interactions of components in the wide range of temperature. The aim of this work was to study thermoprocessing effects on suppository base with vinpocetine in temperature range of technological process of suppository manufacturing. Object. Vinpocetine rectal suppository (with 0,5% of surface-active substances, active substance (vinpocetine and excipients (twin 80, cacao oil were used as the objects of thermogravimetric investigation. Thermogravimetric analyses was carried out on the derivatograph «Shimadzu DTG-60» (Japan with the platinum-rhodium thermocouple by heating from 25°C to 200°C in the aluminium crucible. α-Al2O3 was used as standard. Heating speed was 10ºС in minute. Model mass was 14,23 – 34,4 mg. Conclusions. It was established that cacao oil is thermolabile substance with melting temperature 41,32 ºС. Surface-active substance twin 80 displays thermostability from 30 tо 100ºС. Vinpocetine derivatogramme confirmed its thermostability in temperature range from 30 tо 154 ºС. Derivatogramme of vinpocetine rectal suppository 0,01 and suppository base displayed the absence of critical temperature lower 100ºС. Insignificant mass loss (0,21% shows that fact. Investigation of composition over 100ºС wasn’t carried out because these temperatures aren’t used in technological process of suppository manufacturing. Presence of thermal effects on derivatogramme of vinpocetine rectal

Raman spectroscopy as a PAT for pharmaceutical blending: Advantages and disadvantages.

Science.gov (United States)

Riolo, Daniela; Piazza, Alessandro; Cottini, Ciro; Serafini, Margherita; Lutero, Emilio; Cuoghi, Erika; Gasparini, Lorena; Botturi, Debora; Marino, Iari Gabriel; Aliatis, Irene; Bersani, Danilo; Lottici, Pier Paolo

2018-02-05

Raman spectroscopy has been positively evaluated as a tool for the in-line and real-time monitoring of powder blending processes and it has been proved to be effective in the determination of the endpoint of the mixing, showing its potential role as process analytical technology (PAT). The aim of this study is to show advantages and disadvantages of Raman spectroscopy with respect to the most traditional HPLC analysis. The spectroscopic results, obtained directly on raw powders, sampled from a two-axis blender in real case conditions, were compared with the chromatographic data obtained on the same samples. The formulation blend used for the experiment consists of active pharmaceutical ingredient (API, concentrations 6.0% and 0.5%), lactose and magnesium stearate (as excipients). The first step of the monitoring process was selecting the appropriate wavenumber region where the Raman signal of API is maximal and interference from the spectral features of excipients is minimal. Blend profiles were created by plotting the area ratios of the Raman peak of API (A API ) at 1598cm -1 and the Raman bands of excipients (A EXC ), in the spectral range between 1560 and 1630cm -1 , as a function of mixing time: the API content can be considered homogeneous when the time-dependent dispersion of the area ratio is minimized. In order to achieve a representative sampling with Raman spectroscopy, each sample was mapped in a motorized XY stage by a defocused laser beam of a micro-Raman apparatus. Good correlation between the two techniques has been found only for the composition at 6.0% (w/w). However, standard deviation analysis, applied to both HPLC and Raman data, showed that Raman results are more substantial than HPLC ones, since Raman spectroscopy enables generating data rich blend profiles. In addition, the relative standard deviation calculated from a single map (30 points) turned out to be representative of the degree of homogeneity for that blend time. Copyright © 2017

A methodological evaluation and predictive in silico investigation into the multi-functionality of arginine in directly compressed tablets.

Science.gov (United States)

ElShaer, Amr; Kaialy, Waseem; Akhtar, Noreen; Iyire, Affiong; Hussain, Tariq; Alany, Raid; Mohammed, Afzal R

2015-10-01

The acceleration of solid dosage form product development can be facilitated by the inclusion of excipients that exhibit poly-/multi-functionality with reduction of the time invested in multiple excipient optimisations. Because active pharmaceutical ingredients (APIs) and tablet excipients present diverse densification behaviours upon compaction, the involvement of these different powders during compaction makes the compaction process very complicated. The aim of this study was to assess the macrometric characteristics and distribution of surface charges of two powders: indomethacin (IND) and arginine (ARG); and evaluate their impact on the densification properties of the two powders. Response surface modelling (RSM) was employed to predict the effect of two independent variables; Compression pressure (F) and ARG percentage (R) in binary mixtures on the properties of resultant tablets. The study looked at three responses namely; porosity (P), tensile strength (S) and disintegration time (T). Micrometric studies showed that IND had a higher charge density (net charge to mass ratio) when compared to ARG; nonetheless, ARG demonstrated good compaction properties with high plasticity (Y=28.01MPa). Therefore, ARG as filler to IND tablets was associated with better mechanical properties of the tablets (tablet tensile strength (σ) increased from 0.2±0.05N/mm(2) to 2.85±0.36N/mm(2) upon adding ARG at molar ratio of 8:1 to IND). Moreover, tablets' disintegration time was shortened to reach few seconds in some of the formulations. RSM revealed tablet porosity to be affected by both compression pressure and ARG ratio for IND/ARG physical mixtures (PMs). Conversely, the tensile strength (σ) and disintegration time (T) for the PMs were influenced by the compression pressure, ARG ratio and their interactive term (FR); and a strong correlation was observed between the experimental results and the predicted data for tablet porosity. This work provides clear evidence of the

How to stabilize cilazapril-containing solid dosage forms? The optimization of a final drug formulation

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Katarzyna Regulska

2017-03-01

Full Text Available Cilazapril, a moisture-sensitive compound, is known to undergo rapid degradation which could be additionally facilitated by the presence of excipients that contain or absorb moisture. Hence we investigated the stability of cilazapril in two commercially-available dosage forms and in binary mixtures with the selected excipients used in the studied commercial formulations i.e.: hypromellose, lactose monohydrate, maize starch and talc in order to detect any possible, stability-affecting incompatibilities. Also the impact of the blister made of oriented polyamide/aluminum/polyvinyl chloride//aluminum on cilazapril-containing tablets was researched. A validated HPLC and HPLC-MS methods were used for analysis and the isothermal stress testing conditions were applied (temperature range 318–343 K, relative humidity 76.4% for tablets and temperature 333 K, relative humidity range 50.9–76.4% for binary mixtures. It was shown that the degradation of cilazapril in both, model mixtures and tablets follows the autocatalytic model kinetics and it is more rapid than that observed for pure substance, evidenced by higher degradation rate constants. The immediate packaging protects cilazapril in tablets from degradation only in case of the original drug while in its blistered generic counterpart a slight but statistically insignificant increase of cilazapril decay occurs when compared to bare tablets (p < 0.05. The degradation product of cilazapril in tablets and binary mixtures was identified as cilazaprilat. It was also observed that the increase of relative humidity or the presence of hypromellose, lactose and talc significantly impairs the stability of cilazapril in the aforementioned order. Only maize starch exhibited a positive effect on cilazapril stability (10.8% loss of cilazapril in binary mixture after 360 days of stressing compared to 35% loss of pure cilazapril in analogous test conditions probably thanks to its moisture-scavenging properties

Preactivated thiolated pullulan as a versatile excipient for mucosal drug targeting.

Science.gov (United States)

Leonaviciute, Gintare; Suchaoin, Wongsakorn; Matuszczak, Barbara; Lam, Hung Thanh; Mahmood, Arshad; Bernkop-Schnürch, Andreas

2016-10-20

The purpose of the present study was to generate a novel mucoadhesive thiolated pullulan with protected thiol moieties and to evaluate its suitability as mucosal drug delivery system. Two different synthetic pathways: bromination-nucleophilic substitution and reductive amination including periodate cleavage were utilized to synthesize such thiolated pullulans. The thiomer (pullulan-cysteamine) with the highest amount of free thiol groups was further enrolled in a reaction with 6-mercaptonicotinamide and its presence in pullulan structure was confirmed via NMR analysis. Furthermore, unmodified, thiolated and preactivated thiolated pullulan were investigated in terms of mucoadhesion via rotating cylinder studies and rheological synergism method as well as their toxicity potential over Caco-2 cells. Comparing both methods the reductive amination seems to be the method of choice resulting in comparatively higher coupling rates. Using this procedure pullulan-cysteamine conjugate displayed 1522±158μmol immobilized thiol groups and 280±70μmol free thiol groups per gram polymer. Furthermore, 82% of free thiol groups on this conjugate were linked with 6-mercaptonicotinamide (6-MNA). The adhesion time on the rotating cylinder was up to 46-fold prolonged in case of the thiolated polymer and up to 75-fold in case of the preactivated polymer. Rheological measurements of modified pullulan samples showed 98-fold and 160-fold increase in dynamic viscosity upon the addition of mucus within 60min, whereas unmodified pullulan did not show an increase in viscosity at all. Both conjugates had a minor effect on Caco-2 cell viability. Because of these features preactivated thiolated pullulan seems to represent a promising type of mucoadhesive polymers for the development of various mucosal drug delivery systems. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of Colloidal Silica on Rheological Properties of Common Pharmaceutical Excipients.

Czech Academy of Sciences Publication Activity Database

Majerová, D.; Kulaviak, Lukáš; Růžička, Marek; Štěpánek, F.; Zámostný, P.

2016-01-01

Roč. 106, SI (2016), s. 2-8 ISSN 0939-6411. [International Granulation Workshop /7./. Sheffield, 29.06.2015-03.07.2015] R&D Projects: GA ČR(CZ) GA15-05534S Institutional support: RVO:67985858 Keywords : powder flow * cohesion * glidants Subject RIV: CI - Industrial Chemistry, Chemical Engineering Impact factor: 4.159, year: 2016

Cellulose nanofibers as excipient for the delivery of poorly soluble drugs

DEFF Research Database (Denmark)

Löbmann, Korbinian; Svagan, Anna J

2017-01-01

Poor aqueous solubility of drugs is becoming an increasingly pronounced challenge in the formulation and development of drug delivery systems. To overcome the limitations associated with these problematic drugs, formulation scientists are required to use enabling strategies which often demands...

Rapid voltammetric monitoring of melatonin in the presence of tablet excipients

International Nuclear Information System (INIS)

Ball, Andrew T.; Patel, Bhavik Anil

2012-01-01

Melatonin is an important neurohormonal chemical that is responsible for regulating sleep. Melatonin dietary supplements are available and utilised to counteract the effects of jet-lag or to aid sleep. Voltammetric detection with a boron-doped diamond electrode was utilised for the rapid monitoring of individual melatonin tablets. Melatonin was oxidised at a potential of +0.8 V vs. Ag|AgCl. Voltammetric measurements were carried out without the need of excessive sample preparation steps such as filtration. However dicalcium phosphate and carboxymethyl cellulose were shown to alter the electrochemical response. Calibration responses were linear over a concentration of 2–4 mg/25 ml of melatonin and a limit of detection of 0.06 mg/25 ml was observed. Volammetric recordings were only stable for one measurement, but the electrode surface could be replenished following a single wipe of an ethanol soaked lens cloth. This new assay was capable of analysing individual melatonin tablets within a total analysis time of 2.5 min. Overall this approach provides the basis for rapid electrochemical monitoring of pharmaceutical and dietary tablets without the need for extensive sample preparation.

[Lactose-containing tablets for patients with lactose intolerance?].

Science.gov (United States)

Picksak, Gesine; Stichtenoth, Dirk O

2009-01-01

Lactose is often used as an excipient in tablets because of its ideal characteristics. Most patients with lactose intolerance tolerate small amounts of lactose. However, the nocebo effect must be considered. Thus, patients should be informed about the very small amounts of lactose in the medication. If the patient is still suffering from gastrointestinal symptoms and there is no lactose-free alternative, the enzyme lactase can be substituted individually.

Application of ion chromatography in pharmaceutical and drug analysis.

Science.gov (United States)

Jenke, Dennis

2011-08-01

Ion chromatography (IC) has developed and matured into an important analytical methodology in a number of diverse applications and industries, including pharmaceuticals. This manuscript provides a review of IC applications for the determinations of active and inactive ingredients, excipients, degradation products, and impurities relevant to pharmaceutical analyses and thus serves as a resource for investigators looking for insights into the use of the IC methodology in this field of application.

Pharmaceutical aerosols. Study of their gamma radiation sterilization

International Nuclear Information System (INIS)

Sebert, P.

1984-10-01

The gamma radiation sterilization of pharmaceutical aerosols was studied. The following topics were investigated: radiosterilization of nitrogen protoxide used as a propellant; radiosterilization of packaging materials (aluminium containers, plastics valves); radio-sterilization of excipients and active ingredients. Most of the investigated materials proved to be stable to irradiation (2,5 Mrads) from pharmacopoeial aspect. Stability tests of the preparations packaged showed no change in the parameters investigated [fr

Influence of radiation treatment on pharmaceuticals. A study of the relevant literature

International Nuclear Information System (INIS)

Dahlhelm, H.; Boess, C.

2002-01-01

The present communication provides a quick overview of the behaviour of individual substances when treated with ionizing radiation while making reference to the respective original literature. The choosen form of an encyclopaedia enables the user to find information at a glance. It is based on parts I - XII of our review of literature on the influence of radiation treatment on pharmaceutical products and adjuvants/excipients we started in 1978. (orig.)

Insulin Inclusion into a Tragacanth Hydrogel: An Oral Delivery System for Insulin

OpenAIRE

Mokhamad Nur; Todor Vasiljevic

2018-01-01

Nanoparticles or microparticles created by physical complexation between two polyelectrolytes may have a prospective use as an excipient for oral insulin administration. Natural polymers such as tragacanth, alginate, dextran, pullulan, hyaluronic acid, gelatin and chitosan can be potential candidates for this purpose. In this research, insulin particles were prepared by the inclusion of insulin into a tragacanth hydrogel. The effect of the pH and concentration relationship involving polyelect...

Weak interactions in clobazam–lactose mixtures examined by differential scanning calorimetry: Comparison with the captopril–lactose system

International Nuclear Information System (INIS)

Toscani, S.; Cornevin, L.; Burgot, G.

2012-01-01

Highlights: ► Thermodynamic and kinetic parameters of weak interactions in binary systems by DSC. ► Energy-barrier decrease for lactose dehydration induced by clobazam. ► Recrystallisation of metastable liquid clobazam induced by anhydrous alpha lactose. ► Decrease of lactose dehydration temperature in binary mixtures with captopril. ► Increase of lactose dehydration enthalpy in binary mixtures with captopril. - Abstract: The thermal behaviour of binary mixtures of two drugs (clobazam and captopril, respectively) and a pharmaceutical excipient (lactose monohydrate) was measured with differential scanning calorimetry to determine thermodynamic and kinetic parameters (dehydration and melting enthalpies and dehydration and glass-transition activation energies) which might be affected by intermolecular interactions. A kinetic study showed that lactose dehydration is not a single-step conversion and that clobazam contributed to reduce the energy barrier for the bulk dehydration of the excipient. On the other hand, the physical interactions between metastable liquid clobazam and crystalline anhydrous α-lactose obtained from monohydrate dehydration gave rise to the recrystallisation of clobazam. In the captopril–lactose system, the liquid captopril influenced the lactose dehydration: a sharp increase of the dehydration enthalpy and a concurrent reduction of the dehydration temperature were observed. Finally, it turned out that solid-phase transitions were enhanced by the contact with a liquid phase.

Characterization of sildenafil citrate tablets of different sources by near infrared chemical imaging and chemometric tools.

Science.gov (United States)

Sabin, Guilherme P; Lozano, Valeria A; Rocha, Werickson F C; Romão, Wanderson; Ortiz, Rafael S; Poppi, Ronei J

2013-11-01

The chemical imaging technique by near infrared spectroscopy was applied for characterization of formulations in tablets of sildenafil citrate of six different sources. Five formulations were provided by Brazilian Federal Police and correspond to several trademarks of prohibited marketing and one was an authentic sample of Viagra. In a first step of the study, multivariate curve resolution was properly chosen for the estimation of the distribution map of concentration of the active ingredient in tablets of different sources, where the chemical composition of all excipients constituents was not truly known. In such cases, it is very difficult to establish an appropriate calibration technique, so that only the information of sildenafil is considered independently of the excipients. This determination was possible only by reaching the second-order advantage, where the analyte quantification can be performed in the presence of unknown interferences. In a second step, the normalized histograms of images from active ingredient were grouped according to their similarities by hierarchical cluster analysis. Finally it was possible to recognize the patterns of distribution maps of concentration of sildenafil citrate, distinguishing the true formulation of Viagra. This concept can be used to improve the knowledge of industrial products and processes, as well as, for characterization of counterfeit drugs. Copyright © 2013. Published by Elsevier B.V.

Application of Liquisolid Technology for Enhancing Solubility and Dissolution of Rosuvastatin

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Pavan Ram Kamble

2014-03-01

Full Text Available Purpose: Rosuvastatin is a poorly water soluble drug and the rate of its oral absorption is often controlled by the dissolution rate in the gastrointestinal tract. Hence it is necessary to increase the solubility of the Rosuvastatin. Methods: Several liquisolid tablets formulations containing various drug concentrations in liquid medication (ranging from 15% to 25% w/w were prepared. The ratio of Avicel PH 102 (carrier to Aerosil 200 (coating powder material was kept 10, 20, 30. The prepared liquisolid systems were evaluated for their flow properties and possible drug-excipient interactions by Infrared spectra (IR analysis, differential scanning calorimetry (DSC and X- ray powder diffraction (XRPD. Results: The liquisolid system showed acceptable flow properties. The IR and DSC studies demonstrated that there is no significant interaction between the drug and excipients. The XRPD analysis confirmed formation of a solid solution inside the compact matrix. The tabletting properties of the liquisolid compacts were within the acceptable limits. Liquisolid compacts demonstrated significantly higher drug release rates than those of conventional and marketed tablet due to increasing wetting properties and surface area of the drug. Conclusion: This study shows that liquisolid technique is a promising alternative for improvement of the dissolution rate of water insoluble drug.

Preparation and Characterization of Liquisolid Compacts for Improved Dissolution of Telmisartan

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Naveen Chella

2014-01-01

Full Text Available The objective of the present work was to obtain pH independent and improved dissolution profile for a poorly soluble drug, telmisartan using liquisolid compacts. Liquisolid compacts were prepared using Transcutol HP as vehicle, Avicel PH102 as carrier, and Aerosil 200 as a coating material. The formulations were evaluated for drug excipient interactions, change in crystallinity of drug, flow properties, and general quality control tests of tablets using Fourier transform infrared (FTIR spectroscopy, differential scanning calorimetry (DSC, X-ray diffraction (XRD, angle of repose, and various pharmacopoeial tests. In vitro dissolution studies were performed at three pH conditions (1.2, 4.5 and 7.4. Stability studies were performed at 40°C and 75% RH for three months. The formulation was found to comply with Indian pharmacopoeial limits for tablets. FTIR studies confirmed no interaction between drug and excipients. XRD and DSC studies indicate change/reduction in crystallinity of drug. Dissolution media were selected based on the solubility studies. The optimized formulation showed pH independent release profile with significant improvement P<0.005 in dissolution compared to plain drug and conventional marketed formulation. No significant difference was seen in the tablet properties, and drug release profile after storage for 3 months.

Preparation and Evaluation of Valsartan Liquid Filling Formulations for Soft Gels

Directory of Open Access Journals (Sweden)

Jyothi Sanaboina

2013-01-01

Full Text Available The present investigation includes the preparation of liquid filling formulations for soft gels using an antihypertensive drug, valsartan (VAL, in order to improve its dissolution properties and thereby its bioavailability. Formulations were prepared using excipients like polyethylene glycol 400 (PEG 400, propylene glycol (PG, polyvinylpyrrolidone (PVP K-30, antioxidants, ethanol, and purified water. Prepared formulations were evaluated for appearance, pH, drug content percentage, viscosity, stability, and in vitro dissolution studies. The compatibility between the drug and excipients in formulations was confirmed by FTIR spectra. The drug contents were in the range of 99.62-99.63 and the viscosity was in the range of 60.9–591.7 cps with all the formulations developed. Formulations containing 10 mg PVP K 30 gave better dissolution properties when compared to formulations without PVP K 30, and a complete drug dissolution was observed within 10 min and followed the first-order release kinetics. Stability studies were conducted for selected formulations (F4–F9 for a period of 6 months at room temperature (~30°C/65% RH. From the studies, it can be concluded that VAL liquid filling formulations for soft gels were successfully prepared with in vitro dissolution properties superior when compared to VAL itself.

Noncovalent PEGylation: different effects of dansyl-, L-tryptophan-, phenylbutylamino-, benzyl- and cholesteryl-PEGs on the aggregation of salmon calcitonin and lysozyme.

Science.gov (United States)

Mueller, Claudia; Capelle, Martinus A H; Seyrek, Emek; Martel, Sophie; Carrupt, Pierre-Alain; Arvinte, Tudor; Borchard, Gerrit

2012-06-01

Protein aggregation is a major instability that can occur during all stages of protein drug production and development. Protein aggregates may compromise the safety and efficacy of the final protein formulation. In this paper, various new excipients [phenylbutylamino-, benzyl-, and cholesteryl-polyethylene glycols (PEGs)] and their use for the reduction of aggregation of salmon calcitonin (sCT) and hen egg-white lysozyme (HEWL) by noncovalent PEGylation are presented. The ability to suppress aggregation of sCT in various buffer systems at a 1:1 molar ratio was assessed by following changes in protein conformation and aggregation state over time. The results are compared with that of dansyl- and L-tryptophan (Trp)-PEGs described in earlier publications. Furthermore, the influence of the different PEG-based excipients on the aggregation of HEWL was measured. HEWL aggregation was completely suppressed in the presence of cholesteryl-PEGs (2 and 5 kDa), whereas deterioration was observed using benzyl-methoxy polyethylene glycols (mPEGs; 2 and 5 kDa). Phenylbutylamino- and Trp-mPEG (2 kDa), as well as dansyl-PEGs of different molecular weight prolonged the lag phase of aggregation and reduced the aggregation velocity of HEWL. Copyright © 2012 Wiley Periodicals, Inc.

Study of drug release and tablet characteristics of silicone adhesive matrix tablets.

Science.gov (United States)

Tolia, Gaurav; Li, S Kevin

2012-11-01

Matrix tablets of a model drug acetaminophen (APAP) were prepared using a highly compressible low glass transition temperature (T(g)) polymer silicone pressure sensitive adhesive (PSA) at various binary mixtures of silicone PSA/APAP ratios. Matrix tablets of a rigid high T(g) matrix forming polymer ethyl cellulose (EC) were the reference for comparison. Drug release study was carried out using USP Apparatus 1 (basket), and the relationship between the release kinetic parameters of APAP and polymer/APAP ratio was determined to estimate the excipient percolation threshold. The critical points attributed to both silicone PSA and EC tablet percolation thresholds were found to be between 2.5% and 5% w/w. For silicone PSA tablets, satisfactory mechanical properties were obtained above the polymer percolation threshold; no cracking or chipping of the tablet was observed above this threshold. Rigid EC APAP tablets showed low tensile strength and high friability. These results suggest that silicone PSA could eliminate issues related to drug compressibility in the formulation of directly compressed oral controlled release tablets of poorly compressible drug powder such as APAP. No routinely used excipients such as binders, granulating agents, glidants, or lubricants were required for making an acceptable tablet matrix of APAP using silicone PSA. Copyright © 2012 Elsevier B.V. All rights reserved.

Hydrogels containing redispersible spray-dried melatonin-loaded nanocapsules: a formulation for transdermal-controlled delivery

Science.gov (United States)

Hoffmeister, Cristiane RD; Durli, Taís L.; Schaffazick, Scheila R.; Raffin, Renata P.; Bender, Eduardo A.; Beck, Ruy CR; Pohlmann, Adriana R.; Guterres, Sílvia S.

2012-05-01

The aim of the present study was to develop a transdermal system for controlled delivery of melatonin combining three strategies: nanoencapsulation of melatonin, drying of melatonin-loaded nanocapsules, and incorporation of nanocapsules in a hydrophilic gel. Nanocapsules were prepared by interfacial deposition of the polymer and were spray-dried using water-soluble excipients. In vitro drug release profiles were evaluated by the dialysis bag method, and skin permeation studies were carried out using Franz cells with porcine skin as the membrane. The use of 10% ( w/ v) water-soluble excipients (lactose or maltodextrin) as spray-drying adjuvants furnished redispersible powders (redispersibility index approximately 1.0) suitable for incorporation into hydrogels. All formulations showed a better controlled in vitro release of melatonin compared with the melatonin solution. The best controlled release results were achieved with hydrogels prepared with dried nanocapsules (hydrogels > redispersed dried nanocapsules > nanocapsule suspension > melatonin solution). The skin permeation studies demonstrated a significant modulation of the transdermal melatonin permeation for hydrogels prepared with redispersible nanocapsules. In this way, the additive effect of the different approaches used in this study (nanoencapsulation, spray-drying, and preparation of semisolid dosage forms) allows not only the control of melatonin release, but also transdermal permeation.

Transforming lipid-based oral drug delivery systems into solid dosage forms: an overview of solid carriers, physicochemical properties, and biopharmaceutical performance.

Science.gov (United States)

Tan, Angel; Rao, Shasha; Prestidge, Clive A

2013-12-01

The diversity of lipid excipients available commercially has enabled versatile formulation design of lipid-based drug delivery systems for enhancing the oral absorption of poorly water-soluble drugs, such as emulsions, microemulsions, micelles, liposomes, niosomes and various self-emulsifying systems. The transformation of liquid lipid-based systems into solid dosage forms has been investigated for several decades, and has recently become a core subject of pharmaceutical research as solidification is regarded as viable means for stabilising lipid colloidal systems while eliminating stringent processing requirements associated with liquid systems. This review describes the types of pharmaceutical grade excipients (silica nanoparticle/microparticle, polysaccharide, polymer and protein-based materials) used as solid carriers and the current state of knowledge on the liquid-to-solid conversion approaches. Details are primarily focused on the solid-state physicochemical properties and redispersion capacity of various dry lipid-based formulations, and how these relate to the in vitro drug release and solubilisation, lipid carrier digestion and cell permeation performances. Numerous in vivo proof-of-concept studies are presented to highlight the viability of these dry lipid-based formulations. This review is significant in directing future research work in fostering translation of dry lipid-based formulations into clinical applications.

Screening of anionic-modified polymers in terms of stability, disintegration, and swelling behavior.

Science.gov (United States)

Laffleur, Flavia; Ijaz, Muhammad; Menzel, Claudia

2017-11-01

This study aimed to screen the stability, disintegration, and swelling behavior of chemically modified anionic polymers. Investigated polymers were well-known and widely used staples of the pharmaceutical and medical field, namely, alginate (AL), carboxymethyl cellulose (CMC), polycarbophil (PC), and hyaluronic acid (HA). On the basis of amide bond formation between the carboxylic acid moieties of anionic polymers and the primary amino group of the modification ligand cysteine (CYS), the modified polymers were obtained. Unmodified polymers served as controls throughout all studies. With the Ellman's assay, modification degrees were determined of synthesized polymeric excipients. Stability assay in terms of erosion study at physiological conditions were performed. Moreover, water uptake of compressed polymeric discs were evaluated and further disintegration studies according to the USP were carried out to define the potential ranking. Results ranking figured out PCCYS > CMCCYS > HACYS > ALCYS in terms of water uptake capacity compared to respective controls. Cell viability assays on Caco-2 cell line as well as on RPMI 2650 (ATTC CCL30) proved modification not being harmful to those. Due to the results of this study, an intense screening of prominent anionic polymer derivate was performed in order to help the pharmaceutical research for the best choice of polymeric excipients for developments of controlled drug release systems.

Pharmaceutical Raw Material Identification Using Miniature Near-Infrared (MicroNIR) Spectroscopy and Supervised Pattern Recognition Using Support Vector Machine.

Science.gov (United States)

Sun, Lan; Hsiung, Chang; Pederson, Christopher G; Zou, Peng; Smith, Valton; von Gunten, Marc; O'Brien, Nada A

2016-05-01

Near-infrared spectroscopy as a rapid and non-destructive analytical technique offers great advantages for pharmaceutical raw material identification (RMID) to fulfill the quality and safety requirements in pharmaceutical industry. In this study, we demonstrated the use of portable miniature near-infrared (MicroNIR) spectrometers for NIR-based pharmaceutical RMID and solved two challenges in this area, model transferability and large-scale classification, with the aid of support vector machine (SVM) modeling. We used a set of 19 pharmaceutical compounds including various active pharmaceutical ingredients (APIs) and excipients and six MicroNIR spectrometers to test model transferability. For the test of large-scale classification, we used another set of 253 pharmaceutical compounds comprised of both chemically and physically different APIs and excipients. We compared SVM with conventional chemometric modeling techniques, including soft independent modeling of class analogy, partial least squares discriminant analysis, linear discriminant analysis, and quadratic discriminant analysis. Support vector machine modeling using a linear kernel, especially when combined with a hierarchical scheme, exhibited excellent performance in both model transferability and large-scale classification. Hence, ultra-compact, portable and robust MicroNIR spectrometers coupled with SVM modeling can make on-site and in situ pharmaceutical RMID for large-volume applications highly achievable. © The Author(s) 2016.

Effect of process parameters on crystal size and morphology of lactose in ultrasound-assisted crystallization

Energy Technology Data Exchange (ETDEWEB)

Patel, S.R.; Murthy, Z.V.P. [Chemical Engineering Department, S.V. National Institute of Technology, Surat - 395 007, Gujarat (India)

2011-03-15

{alpha}-lactose monohydrate is widely used as a pharmaceutical excipient. Drug delivery system requires the excipient to be of narrow particle size distribution with regular particle shape. Application of ultrasound is known to increase or decrease the growth rate of certain crystal faces and controls the crystal size distribution. In the present paper, effect of process parameters such as sonication time, anti-solvent concentration, initial lactose concentration and initial pH of sample on lactose crystal size, shape and thermal transition temperature was studied. The parameters were set according to the L{sub 9}-orthogonal array method at three levels and recovered lactose from whey by sonocrystallization. The recovered lactose was analyzed by particle size analyzer, scanning electron microscopy and differential scanning calorimeter. It was found that the morphology of lactose crystal was rod/needle like shape. Crystal size distribution of lactose was observed to be influenced by different process parameters. From the results of analysis of variance, the sonication time interval was found to be the most significant parameter affecting the volume median diameter of lactose with the highest percentage contribution (74.28%) among other parameters. (copyright 2011 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

Evaluation of γ-cyclodextrin effect on permeation of lipophilic drugs: application of cellophane/fused octanol membrane.

Science.gov (United States)

Muankaew, Chutimon; Jansook, Phatsawee; Loftsson, Thorsteinn

2017-06-01

According to the Biopharmaceutics Classification System, oral bioavailability of drugs is determined by their aqueous solubility and the ability of the dissolved drug molecules to permeate lipophilic biological membranes. Similarly topical bioavailability of ophthalmic drugs is determined by their solubility in the aqueous tear fluid and their ability to permeate the lipophilic cornea. Enabling pharmaceutical excipients such as cyclodextrins can have profound effect on the drug bioavailability. However, to fully appreciate such enabling excipients, the relationship between their effects and the physicochemical properties of the permeating drug needs to be known. In this study, the permeation enhancing effect of γ-cyclodextrin (γCD) on saturated drug solutions containing hydrocortisone (HC), irbesartan (IBS), or telmisartan (TEL) was evaluated using cellophane and fused cellulose-octanol membranes in a conventional Franz diffusion cell system. The flux (J), the flux ratio (J R ) and the apparent permeability coefficients (P app ) demonstrate that γCD increases drug permeability. However, its efficacy depends on the drug properties. Addition of γCD increased P app of HC (unionized) and IBS (partially ionized) through the dual membrane but decreased the P app of TEL (fully ionized) that displays low complexation efficacy. The dual cellophane-octanol membrane system was simple to use and gave reproducible results.

The STEP database through the end-users eyes--USABILITY STUDY.

Science.gov (United States)

Salunke, Smita; Tuleu, Catherine

2015-08-15

The user-designed database of Safety and Toxicity of Excipients for Paediatrics ("STEP") is created to address the shared need of drug development community to access the relevant information of excipients effortlessly. Usability testing was performed to validate if the database satisfies the need of the end-users. Evaluation framework was developed to assess the usability. The participants performed scenario based tasks and provided feedback and post-session usability ratings. Failure Mode Effect Analysis (FMEA) was performed to prioritize the problems and improvements to the STEP database design and functionalities. The study revealed several design vulnerabilities. Tasks such as limiting the results, running complex queries, location of data and registering to access the database were challenging. The three critical attributes identified to have impact on the usability of the STEP database included (1) content and presentation (2) the navigation and search features (3) potential end-users. Evaluation framework proved to be an effective method for evaluating database effectiveness and user satisfaction. This study provides strong initial support for the usability of the STEP database. Recommendations would be incorporated into the refinement of the database to improve its usability and increase user participation towards the advancement of the database. Copyright © 2015 Elsevier B.V. All rights reserved.

Quality Enhancement by Inclusion Complex Formation of Simvastatin Tablets

Directory of Open Access Journals (Sweden)

Emőke Rédai

2013-08-01

Full Text Available Introduction: Simvastatin is an inhibitor of hydroxy-methyl-glutaryl-coenzyme A reductase, used in the treatment of hypercholesterolemia. To enhance its bioavailability by inclusion complexation, as host molecule randommethyl-β-cyclodextrin had been used. After evaluating the complexes we chose the kneading product in 1:2 molar ratio for incorporation of 10 mg simvastatin tablets. Materials and methods: We prepared homogenous mixtures of the inclusion complex and some excipients. The tablets were prepared by direct compression. The tablets were evaluated in regard to: weight uniformity, thickness, diameter, hardness, friability, disintegration and dissolution profile. Results: Weights are in the range of 196-208 mg, diameter 6.83-6.86 mm, height 3.86-4.01 mm, hardness 78.3-113.1 N, friability 0.75- 1.19 %, disintegration above 15 minutes. The dissolved amounts of simvastatin from the tablets are higher compared to the dissolution of pure simvastatin, but lower than the dissolution of the complex itself. Excipients, like disintegrants and lubricants greatly influence the dissolution properties of the tablets. Conclusions: According to our results, tablets containing inclusion complex of simvastatin exhibit better solubility, according to the dissolved amount of simvastatin, than pure drug alone. Proper physical parameters of the tablets are obtained by application of 5 % Primellose

Design of an expert system for the development and formulation of push-pull osmotic pump tablets containing poorly water-soluble drugs.

Science.gov (United States)

Zhang, Zhi-hong; Dong, Hong-ye; Peng, Bo; Liu, Hong-fei; Li, Chun-lei; Liang, Min; Pan, Wei-san

2011-05-30

The purpose of this article was to build an expert system for the development and formulation of push-pull osmotic pump tablets (PPOP). Hundreds of PPOP formulations were studied according to different poorly water-soluble drugs and pharmaceutical acceptable excipients. The knowledge base including database and rule base was built based on the reported results of hundreds of PPOP formulations containing different poorly water-soluble drugs and pharmaceutical excipients and the experiences available from other researchers. The prediction model of release behavior was built using back propagation (BP) neural network, which is good at nonlinear mapping and learning function. Formulation design model was established based on the prediction model of release behavior, which was the nucleus of the inference engine. Finally, the expert system program was constructed by VB.NET associating with SQL Server. Expert system is one of the most popular aspects in artificial intelligence. To date there is no expert system available for the formulation of controlled release dosage forms yet. Moreover, osmotic pump technology (OPT) is gradually getting consummate all over the world. It is meaningful to apply expert system on OPT. Famotidine, a water insoluble drug was chosen as the model drug to validate the applicability of the developed expert system. Copyright © 2011 Elsevier B.V. All rights reserved.

Development of biodegradable methylprednisolone microparticles for treatment of articular pathology using a spray-drying technique

Science.gov (United States)

Tobar-Grande, Blanca; Godoy, Ricardo; Bustos, Paulina; von Plessing, Carlos; Fattal, Elias; Tsapis, Nicolas; Olave, Claudia; Gómez-Gaete, Carolina

2013-01-01

In this work, microparticles were prepared by spray-drying using albumin, chondroitin sulfate, and hyaluronic acid as excipients to create a controlled-release methylprednisolone system for use in inflammatory disorders such as arthritis. Scanning electron microscopy demonstrated that these microparticles were almost spherical, with development of surface wrinkling as the methylprednisolone load in the formulation was increased. The methylprednisolone load also had a direct influence on the mean diameter and zeta potential of the microparticles. Interactions between formulation excipients and the active drug were evaluated by x-ray diffraction, differential scanning calorimetry, and thermal gravimetric analysis, showing limited amounts of methylprednisolone in a crystalline state in the loaded microparticles. The encapsulation efficiency of methylprednisolone was approximately 89% in all formulations. The rate of methylprednisolone release from the microparticles depended on the initial drug load in the formulation. In vitro cytotoxic evaluation using THP-1 cells showed that none of the formulations prepared triggered an inflammatory response on release of interleukin-1β, nor did they affect cellular viability, except for the 9.1% methylprednisolone formulation, which was the maximum test concentration used. The microparticles developed in this study have characteristics amenable to a therapeutic role in inflammatory pathology, such as arthritis. PMID:23737670

New insights on poly(vinyl acetate)-based coated floating tablets: characterisation of hydration and CO2 generation by benchtop MRI and its relation to drug release and floating strength.

Science.gov (United States)

Strübing, Sandra; Abboud, Tâmara; Contri, Renata Vidor; Metz, Hendrik; Mäder, Karsten

2008-06-01

The purpose of this study was to investigate the mechanism of floating and drug release behaviour of poly(vinyl acetate)-based floating tablets with membrane controlled drug delivery. Propranolol HCl containing tablets with Kollidon SR as an excipient for direct compression and different Kollicoat SR 30 D/Kollicoat IR coats varying from 10 to 20mg polymer/cm2 were investigated regarding drug release in 0.1N HCl. Furthermore, the onset of floating, the floating duration and the floating strength of the device were determined. In addition, benchtop MRI studies of selected samples were performed. Coated tablets with 10mg polymer/cm2 SR/IR, 8.5:1.5 coat exhibited the shortest lag times prior to drug release and floating onset, the fastest increase in and highest maximum values of floating strength. The drug release was delayed efficiently within a time interval of 24 h by showing linear drug release characteristics. Poly(vinyl acetate) proved to be an appropriate excipient to ensure safe and reliable drug release. Floating strength measurements offered the possibility to quantify the floating ability of the developed systems and thus to compare different formulations more efficiently. Benchtop MRI studies allowed a deeper insight into drug release and floating mechanisms noninvasively and continuously.

Meticulous Overview on the Controlled Release Fertilizers

Directory of Open Access Journals (Sweden)

Siafu Ibahati Sempeho

2014-01-01

Full Text Available Owing to the high demand for fertilizer formulations that will exhaust the possibilities of nutrient use efficiency (NUE, regulate fertilizer consumption, and lessen agrophysicochemical properties and environmental adverse effects instigated by conventional nutrient supply to crops, this review recapitulates controlled release fertilizers (CRFs as a cutting-edge and safe way to supply crops’ nutrients over the conventional ways. Essentially, CRFs entail fertilizer particles intercalated within excipients aiming at reducing the frequency of fertilizer application thereby abating potential adverse effects linked with conventional fertilizer use. Application of nanotechnology and materials engineering in agriculture particularly in the design of CRFs, the distinctions and classification of CRFs, and the economical, agronomical, and environmental aspects of CRFs has been revised putting into account the development and synthesis of CRFs, laboratory CRFs syntheses and testing, and both linear and sigmoid release features of CRF formulations. Methodical account on the mechanism of nutrient release centring on the empirical and mechanistic approaches of predicting nutrient release is given in view of selected mathematical models. Compositions and laboratory preparations of CRFs basing on in situ and graft polymerization are provided alongside the physical methods used in CRFs encapsulation, with an emphasis on the natural polymers, modified clays, and superabsorbent nanocomposite excipients.

Formulation design of oral pediatric Acetazolamide suspension: dose uniformity and physico-chemical stability study.

Science.gov (United States)

Santoveña, Ana; Suárez-González, Javier; Martín-Rodríguez, Cristina; Fariña, José B

2017-03-01

The formulation of an active pharmaceutical ingredient (API) as oral solution or suspension in pediatrics is a habitual practice, due to the non-existence of many commercialized medicines in pediatric doses. It is also the simplest way to prepare and administer them to this vulnerable population. The design of a formulation that assures the dose and the system stability depends on the physico-chemical properties of the API. In this study, we formulate a class IV API, Acetazolamide (AZM) as suspension for oral administration to pediatric population. The suspension must comply attributes of quality, safety and efficacy for this route of administration. We use simple compounding procedures, as well as fewer pure excipients, as recommended for children. Mass and uniformity content assays and physical and chemical stability studies were performed. To quantify the API an UPLC method was used. We verified the physico-chemical stability of the suspensions and that they passed the mass test of the European Pharmacopeia (EP), but not the dose uniformity test. This reveals that AZM must be formulated as liquid forms with a more complex system of excipients (not usually indicated in pediatrics), or otherwise solid forms capable of assuring uniformity of mass and dose for every dosage unit.

Application of experimental design in examination of the dissolution rate of carbamazepine from formulations: Characterization of the optimal formulation by DSC, TGA, FT-IR and PXRD analysis

OpenAIRE

Krstić Marko; Ražić Slavica; Vasiljević Dragana; Spasojević Đurđija; Ibrić Svetlana

2015-01-01

Poor solubility is one of the key reasons for the poor bioavailability of these drugs. This paper displays a formulation of a solid surfactant system with carbamazepine, in order to increase its dissolution rate. Solid state surfactant systems are formed by application of fractal experimental design. Poloxamer 237 and Poloxamer 338 were used as surfactants and Brij® 35 was used as the co-surfactant. The ratios of the excipients and carbamazepine were varied...

Absorption and pharmacokinetics of grapefruit flavanones in beagles

OpenAIRE

Mata Bilbao, María de Lourdes; Andrés Lacueva, Ma. Cristina; Roura Carvajal, Elena; Jáuregui Pallarés, Olga; Escribano Ferrer, Elvira; Torre, Celina; Lamuela Raventós, Rosa Ma.

2007-01-01

The present study evaluated the pharmacokinetics of three different grapefruit flavanone forms in dog plasma and demonstrated their absorption after an oral intake of a grapefruit extract; pharmacokinetic parameters of these forms were also determined. Ten healthy beagles were administered 70 mg citrus flavonoids as a grapefruit extract contained in capsules, while two additional dogs were used as controls and given an excipient. The grapefruit flavanone naringin, along with its metabolites n...

IMPROVEMENT OF SOLUBILITY OF BADLY WATER SOLUBLE DRUG (IBUPROFEN) BY USING SURFACTANTS AND CARRIERS

OpenAIRE

Md. Zakaria Faruki*, Rishikesh, Elizabeth Razzaque, Mohiuddin Ahmed Bhuiyan

2013-01-01

ABSTRACT: Although there was a great interest in solid dispersion systems during the past four decades to increase dissolution rate and bioavailability of badly water-soluble drugs, their profitable use has been very limited, primarily because of manufacturing difficulties and stability problems. In this study solid solutions of drugs were generally produced by fusion method. The drug along with the excipients (surfactants and carriers) was heated first and then hardened by cooling to room te...

A rapid method for the determination of some antihypertensive and antipyretic drugs by thermometric titrimetry.

Science.gov (United States)

Abbasi, U M; Chand, F; Bhanger, M I; Memon, S A

1986-02-01

A simple and rapid method is described for the direct thermometric determination of milligram amounts of methyl dopa, propranolol hydrochloride, 1-phenyl-3-methylpyrazolone (MPP) and 2,3-dimethyl-1-phenylpyrazol-5-one (phenazone) in the presence of excipients. The compounds are reacted with N'-bromosuccinimide and the heat of reaction is used to determine the end-point of the titration. The time required is approximately 2 min, and the accuracy is analytically acceptable.

ROLE OF NATURAL POLYMERS IN SUSTAINED RELEASE DRUG DELIVERY SYSTEM: APPLICATIONS AND RECENT APPROACHES

OpenAIRE

Prakash Pawan; Porwal Mayur; Saxena Ashwin

2011-01-01

In recent years there have been important developments in different dosage forms for existing and newly designed drugs and natural products, and semi-synthetic as well as synthetic excipients often need to be used for a variety of purposes. Gums and mucilages are widely used natural materials for conventional and novel dosage forms. These natural materials have advantages over synthetic ones since they are chemically inert, nontoxic, less expensive, biodegradable and widely available. They c...

Development and evaluation of Ketoprofen sustained release matrix tablet using Hibiscus rosa-sinensis leaves mucilage

OpenAIRE

Kaleemullah, M.; Jiyauddin, K.; Thiban, E.; Rasha, S.; Al-Dhalli, S.; Budiasih, S.; Gamal, O.E.; Fadli, A.; Eddy, Y.

2016-01-01

Currently, the use of natural gums and mucilage is of increasing importance in pharmaceutical formulations as valuable drug excipient. Natural plant-based materials are economic, free of side effects, biocompatible and biodegradable. Therefore, Ketoprofen matrix tablets were formulated by employing Hibiscus rosa-sinensis leaves mucilage as natural polymer and HPMC (K100M) as a synthetic polymer to sustain the drug release from matrix system. Direct compression method was used to develop susta...

Effect of ?-cyclodextrin on Rheological Properties of some Viscosity Modifiers

OpenAIRE

Rao, G. Chandra Sekhara; Ramadevi, K.; Sirisha, K.

2014-01-01

Cyclodextrins are a group of novel excipients, extensively used in the present pharmaceutical industry. Sometimes they show significant interactions with other conventional additives used in the formulation of dosage forms. The effect of β-cyclodextrin on the rheological properties of aqueous solutions of some selected viscosity modifiers was studied in the present work. β-cyclodextrin showed two different types of effects on the rheology of the selected polymers. In case of natural polymers ...

Sustained Release Oral Nanoformulated Green Tea for Prostate Cancer Prevention

Science.gov (United States)

2013-05-01

epigallocatechin-3-gallate. Cancer Res. 2009;69:1712-6. 2. Adhami VM, Siddiqui IA, Syed DN, Lall RK, Mukhtar H. Oral infusion of pomegranate fruit ...and fungi , and is also known for its non-toxic, non-immunogenic properties (23). It has already been used as a pharmaceutical excipient, a weight loss...component EGCG and perceived toxicity associated with its long-term use affect its clinical outcome (36,37). This study suggests a different

The 3D model: explaining densification and deformation mechanisms by using 3D parameter plots.

Science.gov (United States)

Picker, Katharina M

2004-04-01

The aim of the study was to analyze very differently deforming materials using 3D parameter plots and consequently to gain deeper insights into the densification and deformation process described with the 3D model in order to define an ideal tableting excipient. The excipients used were dicalcium phosphate dihydrate (DCPD), sodium chloride (NaCl), microcrystalline cellulose (MCC), xylitol, mannitol, alpha-lactose monohydrate, maltose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC), cellulose acetate (CAC), maize starch, potato starch, pregelatinized starch, and maltodextrine. All of the materials were tableted to graded maximum relative densities (rhorel, max) using an eccentric tableting machine. The data which resulted, namely force, displacement, and time, were analyzed by the application of 3D modeling. Different particle size fractions of DCPD, CAC, and MCC were analyzed in addition. Brittle deforming materials such as DCPD exhibited a completely different 3D parameter plot, with low time plasticity, d, and low pressure plasticity, e, and a strong decrease in omega values when densification increased, in contrast to the plastically deforming MCC, which had much higher d, e, and omega values. e and omega values changed only slightly when densification increased for MCC. NaCl showed less of a decrease in omega values than DCPD did, and the d and e values were between those of MCC and DCPD. The sugar alcohols, xylitol and mannitol, behaved in a similar fashion to sodium chloride. This is also valid for the crystalline sugars, alpha-lactose monohydrate, and maltose. However, the sugars are more brittle than the sugar alcohols. The cellulose derivatives, HPMC, NaCMC, and CAC, are as plastic as MCC, however, their elasticity depends on substitution indicated by lower (more elastic) or higher (less elastic) omega values. The native starches, maize starch and potato starch, are very elastic, and pregelatinized starch and maltodextrine are

Impact of triblock copolymers on the biophysical function of naturally-derived lung surfactant

DEFF Research Database (Denmark)

Beck-Broichsitter, Moritz; Ruge, Christian A.; Bohr, Adam

2017-01-01

The current study aimed at investigating the general applicability of triblock copolymers consisting of poly(ethylene glycol) and poly(propylene glycol) (Pluronic®) as excipients for lung delivery. After thorough physicochemical characterization of the diverse polymers, their cytotoxicity...... was evaluated using alveolar epithelial cells. Next, a naturally-derived lung surfactant was challenged with the distinct triblock copolymers with respect to changes in microstructure, adsorption to the air/liquid interface and dynamic surface tension behavior under bubble pulsation. Biocompatibility assessment...

Physical mechanical and tablet formation properties of hydroxypropylcellulose: In pure form and in mixtures

OpenAIRE

Picker-Freyer, Katharina M.; Dürig, Thomas

2007-01-01

The aim of the study was to analyze hydroxypropylcellulose (HPC) in pure form and in excipient mixtures and to relate its physical and chemical properties to tablet binder functionality. The materials used were Klucel hydroxypropylcellulose grades ranging from low to high molecular weight (80–1000 kDa) of regular particle size (250 µm mean size) and fine particle size (80 µm mean size). These were compared with microcrystalline cellulose, spray-dried lactose, and dicalcium phosphate dihydrate...

Safety and efficacy of generic drugs with respect to brand formulation

OpenAIRE

Gallelli, Luca; Palleria, Caterina; De Vuono, Antonio; Mumoli, Laura; Vasapollo, Piero; Piro, Brunella; Russo, Emilio

2013-01-01

Generic drugs are equivalent to the brand formulation if they have the same active substance, the same pharmaceutical form and the same therapeutic indications and a similar bioequivalence respect to the reference medicinal product. The use of generic drugs is indicated from many countries in order to reduce medication price. However some points, such as bioequivalence and the role of excipients, may be clarified regarding the clinical efficacy and safety during the switch from brand to gener...

Survival of Probiotics in Hypromellose Capsules with Rice or Potato Maltodextrin Excipient.

Science.gov (United States)

Chen, Jinru; Bechman, Allison; Klu, Yaa Asantewaa Kafui; Phillips, Robert D

2016-09-28

There is currently no authorized or established therapeutic level/dose of probiotics for proposed health benefits; however, a daily probiotic consumption of 10 8 to 10 10 CFU has been recommended. This study determined the survival of 5 individual probiotic strains, Lactobacillus rhamnosus, Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus acidophilus, and Bifidobacterium lactis, along with a mixture of the 5 strains in hypromellose capsules with rice or potato maltodextrin at 4, 25, and 37 °C for 12 mo. Samples were collected monthly and plated on deMan-Rogosa Sharpe agar with 0.05% l-cysteine hydrochloride. Results showed that samples stored at 4 °C had an average count of 10 8 to 10 11 CFU/g of probiotic cells during the 12 mo period, whereas at 25 °C, L. rhamnosus and L. paracasei had an average counts below 10 8 CFU/g during the storage period. L. rhamnosus was the most vulnerable strain used in this study, having the least viable counts at all 3 storage temperatures. Probiotics stored in rice maltodextrin, on average, had higher probiotic counts compared to those stored in potato maltodextrin. Study suggests that to provide consumers with 10 8 to 10 10 CFU/d of probiotic cells, robust bacterial strains, suitable carriers, and a storage temperature of 4 °C are required. © 2016 Institute of Food Technologists®

Risperidone oral disintegrating mini-tablets: A robust-product for pediatrics

Directory of Open Access Journals (Sweden)

El-Say Khalid M.

2015-12-01

Full Text Available This study was aimed at developing risperidone oral disintegrating mini-tablets (OD-mini-tablets as age-appropriate formulations and to assess their suitability for infants and pediatric use. An experimental Box-Behnken design was applied to assure high quality of the OD-mini-tablets and reduce product variability. The design was employed to understand the influence of the critical excipient combinations on the production of OD-mini-tablets and thus guarantee the feasibility of obtaining products with dosage form uniformity. The variables selected were mannitol percent in Avicel (X1, swelling pressure of the superdisintegrant (X2, and the surface area of Aerosil as a glidant (X3. Risperidone-excipient compatibilities were investigated using FTIR and the spectra did not display any interaction. Fifteen formulations were prepared and evaluated for preand post-compression characteristics. The prepared ODmini- tablet batches were also assessed for disintegration in simulated salivary fluid (SSF, pH 6.2 and in reconstituted skimmed milk. The optimized formula fulfilled the requirements for crushing strength of 5 kN with minimal friability, disintegration times of 8.4 and 53.7 s in SSF and skimmed milk, respectively. This study therefore proposes the risperidone OD-mini-tablet formula having robust mechanical properties, uniform and precise dosing of medication with short disintegration time suitable for pediatric use.

Thermal behavior and compatibility analysis of the new chemical entity LPSF/FZ4

International Nuclear Information System (INIS)

Costa, Salvana Priscylla Manso; Ramos da Silva, Keyla Emanuelle; Rocha de Medeiros, Giovanna Christinne; Rolim, Larissa Araujo; Ferreira de Oliveira, Jamerson; Carmo Alves de Lima, Maria do; Galdino, Suely Lins; Pitta, Ivan da Rocha; Neto, Pedro Jose Rolim

2013-01-01

Highlights: • We determined the thermal behavior of isolated LPSF/FZ4. • We used the isothermal and non-isothermal methods. • We reported the time of the stability of LPSF/FZ4 was measured in 4 months. • We also performed a compatibility study associated with excipients. • We reported the possible interactions of the prototype with lactose. - Abstract: In this study, differential scanning calorimetry and thermogravimetry were employed to determine the thermal behavior of LPSF/FZ4 isolated and associated with excipients (amide, β-cyclodextrin, cellulose, lactose, stearate of magnesium, aerosil, sodium lauryl sulfate, polysorbate and polyvinylpyrrolidone). Thus, the purity of the prototype calculated was 98%. Isothermal and non-isothermal methods were used to determine the kinetic parameters of decomposition, finding a first-reaction order and activation energy (A e ) of 98.22 kJ mol −1 . Also, the time of the stability of LPSF/FZ4 was measured in 4 months. The compatibility study showed possible interactions of the prototype with lactose due to a change in its heat of fusion, a reduction of more than 40 °C in its stability and a reduction of approximately 30% in A e of its decomposition reaction. The study demonstrated the importance of using thermal analytical methods to characterize new drugs to enable the development and quality control of pharmaceutical products

Thermal behavior and compatibility analysis of the new chemical entity LPSF/FZ4

Energy Technology Data Exchange (ETDEWEB)

Costa, Salvana Priscylla Manso [Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco (Brazil); Ramos da Silva, Keyla Emanuelle, E-mail: ramos.keyla@gmail.com [Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco (Brazil); Instituto de Ciências Exatas e Tecnologia, Universidade Federal do Amazonas (Brazil); Rocha de Medeiros, Giovanna Christinne; Rolim, Larissa Araujo; Ferreira de Oliveira, Jamerson [Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco (Brazil); Carmo Alves de Lima, Maria do; Galdino, Suely Lins; Pitta, Ivan da Rocha [Departamento de Antibióticos, Universidade Federal de Pernambuco (Brazil); Neto, Pedro Jose Rolim [Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco (Brazil)

2013-06-20

Highlights: • We determined the thermal behavior of isolated LPSF/FZ4. • We used the isothermal and non-isothermal methods. • We reported the time of the stability of LPSF/FZ4 was measured in 4 months. • We also performed a compatibility study associated with excipients. • We reported the possible interactions of the prototype with lactose. - Abstract: In this study, differential scanning calorimetry and thermogravimetry were employed to determine the thermal behavior of LPSF/FZ4 isolated and associated with excipients (amide, β-cyclodextrin, cellulose, lactose, stearate of magnesium, aerosil, sodium lauryl sulfate, polysorbate and polyvinylpyrrolidone). Thus, the purity of the prototype calculated was 98%. Isothermal and non-isothermal methods were used to determine the kinetic parameters of decomposition, finding a first-reaction order and activation energy (A{sub e}) of 98.22 kJ mol{sup −1}. Also, the time of the stability of LPSF/FZ4 was measured in 4 months. The compatibility study showed possible interactions of the prototype with lactose due to a change in its heat of fusion, a reduction of more than 40 °C in its stability and a reduction of approximately 30% in A{sub e} of its decomposition reaction. The study demonstrated the importance of using thermal analytical methods to characterize new drugs to enable the development and quality control of pharmaceutical products.

Disintegration of nano-embedded microparticles after deposition on mucus: A mechanistic study.

Science.gov (United States)

Ruge, Christian A; Bohr, Adam; Beck-Broichsitter, Moritz; Nicolas, Valérie; Tsapis, Nicolas; Fattal, Elias

2016-03-01

The conversion of colloidal drug carriers/polymeric nanoparticles into dry microparticulate powders (e.g., by spray-drying) is a prominent approach to overcome the aerodynamic limitations of these formulations for delivery via inhalation. However, to what extent such nano-embedded microparticles disintegrate into individual/intact nanoparticles after contacting relevant physiological media has so far not been addressed. Polymeric nanoparticles were spray-dried into nano-embedded microparticles (NEMs) using different amounts of trehalose as embedding matrix excipient. Formulations were characterized and then evaluated for their disintegration behavior after aerosolization onto model mucus. Although a rapid and complete aqueous redispersion was observed for specific excipient/nanoparticle weight ratios (i.e., greater than 1/1), the same formulations revealed no disintegration after deposition onto a static mucus layer. Double-labeled NEMs powders (i.e., dual color staining of polymeric nanoparticles and trehalose) demonstrated rapid matrix dissolution, while the nanoparticle aggregates persisted. When deposited onto agitated mucus, however, sufficient disintegration of NEMs into individual polymeric nanoparticles was observed. These findings indicate that mechanical forces are necessary to overcome the attraction between individual nanoparticles found within the NEMs. Thus, it remains questionable whether the lung mechanics (e.g., breathing, mucociliary clearance) acting on these formulations will contribute to the overall disintegration process. Copyright © 2015 Elsevier B.V. All rights reserved.

Rapid analysis of ecstasy and related phenethylamines in seized tablets by Raman spectroscopy.

Science.gov (United States)

Bell, S E; Burns, D T; Dennis, A C; Speers, J S

2000-03-01

Raman spectroscopy with far-red excitation has been used to study seized, tableted samples of MDMA (N-methyl-3,4-methylenedioxyamphetamine) and related compounds (MDA, MDEA, MBDB, 2C-B and amphetamine sulfate), as well as pure standards of these drugs. We have found that by using far-red (785 nm) excitation the level of fluorescence background even in untreated seized samples is sufficiently low that there is little difficulty in obtaining good quality data with moderate 2 min data accumulation times. The spectra can be used to distinguish between even chemically-similar substances, such as the geometrical isomers MDEA and MBDB, and between different polymorphic/hydrated forms of the same drug. Moreover, these differences can be found even in directly recorded spectra of seized samples which have been bulked with other materials, giving a rapid and non-destructive method for drug identification. The spectra can be processed to give unambiguous identification of both drug and excipients (even when more than one compound has been used as the bulking agent) and the relative intensities of drug and excipient bands can be used for quantitative or at least semi-quantitative analysis. Finally, the simple nature of the measurements lends itself to automatic sample handling so that sample throughputs of 20 samples per hour can be achieved with no real difficulty.

A new tablet brittleness index.

Science.gov (United States)

Gong, Xingchu; Sun, Changquan Calvin

2015-06-01

Brittleness is one of the important material properties that influences the success or failure of powder compaction. We have discovered that the reciprocal of diametrical elastic strain at fracture is the most suitable tablet brittleness indices (TBIs) for quantifying brittleness of pharmaceutical tablets. The new strain based TBI is supported by both theoretical considerations and a systematic statistical analysis of friability data. It is sufficiently sensitive to changes in both tablet compositions and compaction parameters. For all tested materials, it correctly shows that tablet brittleness increases with increasing tablet porosity for the same powder. In addition, TBI increases with increasing content of a brittle excipient, lactose monohydrate, in the mixtures with a plastic excipient, microcrystalline cellulose. A probability map for achieving less than 1% tablet friability at various combinations of tablet tensile strength and TBI was constructed. Data from marketed tablets validate this probability map and a TBI value of 150 is recommended as the upper limit for pharmaceutical tablets. This TBI can be calculated from the data routinely obtained during tablet diametrical breaking test, which is commonly performed for assessing tablet mechanical strength. Therefore, it is ready for adoption for quantifying tablet brittleness to guide tablet formulation development since it does not require additional experimental work. Copyright © 2015 Elsevier B.V. All rights reserved.

Biowaiver monograph for immediate-release solid oral dosage forms: bisoprolol fumarate.

Science.gov (United States)

Charoo, Naseem A; Shamsher, Areeg A A; Lian, Lai Y; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James; Shah, Vinod P; Dressman, Jennifer

2014-02-01

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing bisoprolol as the sole active pharmaceutical ingredient (API) are reviewed. Bisoprolol is classified as a Class I API according to the current Biopharmaceutics Classification System (BCS). In addition to the BCS class, its therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability problems are taken into consideration. Qualitative compositions of IR tablet dosage forms of bisoprolol with a marketing authorization (MA) in ICH (International Conference on Harmonisation) countries are tabulated. It was inferred that these tablets had been demonstrated to be bioequivalent to the innovator product. No reports of failure to meet BE standards have been made in the open literature. On the basis of all these pieces of evidence, a biowaiver can currently be recommended for bisoprolol fumarate IR dosage forms if (1) the test product contains only excipients that are well known, and used in normal amounts, for example, those tabulated for products with MA in ICH countries and (2) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving with similarity of the dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Formulation and optimisation of raft-forming chewable tablets containing H2 antagonist.

Science.gov (United States)

Prajapati, Shailesh T; Mehta, Anant P; Modhia, Ishan P; Patel, Chhagan N

2012-10-01

The purpose of this research work was to formulate raft-forming chewable tablets of H2 antagonist (Famotidine) using a raft-forming agent along with an antacid- and gas-generating agent. Tablets were prepared by wet granulation and evaluated for raft strength, acid neutralisation capacity, weight variation, % drug content, thickness, hardness, friability and in vitro drug release. Various raft-forming agents were used in preliminary screening. A 2(3) full-factorial design was used in the present study for optimisation. The amount of sodium alginate, amount of calcium carbonate and amount sodium bicarbonate were selected as independent variables. Raft strength, acid neutralisation capacity and drug release at 30 min were selected as responses. Tablets containing sodium alginate were having maximum raft strength as compared with other raft-forming agents. Acid neutralisation capacity and in vitro drug release of all factorial batches were found to be satisfactory. The F5 batch was optimised based on maximum raft strength and good acid neutralisation capacity. Drug-excipient compatibility study showed no interaction between the drug and excipients. Stability study of the optimised formulation showed that the tablets were stable at accelerated environmental conditions. It was concluded that raft-forming chewable tablets prepared using an optimum amount of sodium alginate, calcium carbonate and sodium bicarbonate could be an efficient dosage form in the treatment of gastro oesophageal reflux disease.

Formulation, optimization, and evaluation of self-emulsifying drug delivery systems of nevirapine.

Science.gov (United States)

Chintalapudi, Ramprasad; Murthy, T E G K; Lakshmi, K Rajya; Manohar, G Ganesh

2015-01-01

The aim of the present study was to formulate and optimize the self-emulsifying drug delivery systems (SEDDS) of nevirapine (NVP) by use of 2(2) factorial designs to enhance the oral absorption of NVP by improving its solubility, dissolution rate, and diffusion profile. SEDDS are the isotropic mixtures of oil, surfactant, co-surfactant and drug that form oil in water microemulsion when introduced into the aqueous phase under gentle agitation. Solubility of NVP in different oils, surfactants, and co-surfactants was determined for the screening of excipients. Pseudo-ternary phase diagrams were constructed by the aqueous titration method, and formulations were developed based on the optimum excipient combinations with the help of data obtained through the maximum micro emulsion region containing combinations of oil, surfactant, and co-surfactant. The formulations of SEDDS were optimized by 2(2) factorial designs. The optimum formulation of SEDDS contains 32.5% oleic acid, 44.16% tween 20, and 11.9% polyethylene glycol 600 as oil, surfactant, and co-surfactant respectively. The SEDDS was evaluated for the following drug content, self-emulsification time, rheological properties, zeta potential, in vitro diffusion studies, thermodynamic stability studies, and in vitro dissolution studies. An increase in dissolution was achieved by SEDDS compared to pure form of NVP. Overall, this study suggests that the dissolution and oral bioavailability of NVP could be improved by SEDDS technology.

Preparation and biological efficacy of haddock bone calcium tablets

Science.gov (United States)

Huo, Jiancong; Deng, Shanggui; Xie, Chao; Tong, Guozhong

2010-03-01

To investigate the possible use of waste products obtained after processing haddock, the present study prepared haddock bone calcium powder by NaOH and ethanol soaking (alkalinealcohol method) and prepared haddock bone calcium tablets using the powder in combination with appropriate excipients. The biological efficacy of the haddock bone calcium tablets was investigated using Wistar rats as an experiment model. Results show that the optimal parameters for the alkalinealcohol method are: NaOH concentration 1 mol/L, immersion time 30 h; ethanol concentration 60%, immersion time 15 h. A mixture of 2% polyvinylpyrrolidone in ethanol was used as an excipient at a ratio of 1:2 to full-cream milk powder, without the use of a disintegrating agent. This process provided satisfactory tablets in terms of rigidity and taste. Animal studies showed that the haddock bone calcium tablets at a dose of 2 g·kg-1·d-1 or 5g·kg-1·d-1 significantly increased blood calcium and phosphorus levels and bone calcium content in rats. Therefore, these tablets could be used for calcium supplementation and prevent osteoporosis. Although the reasons of high absorption in the rats fed with haddock bone calcium tablets are unclear, it is suggested that there are some factors, such as treatment with method of alkaline-alcohol or the added milk, may play positive roles in increasing absorption ratio.

Novel approaches to vaginal delivery and safety of microbicides: biopharmaceuticals, nanoparticles, and vaccines.

Science.gov (United States)

Whaley, Kevin J; Hanes, Justin; Shattock, Robin; Cone, Richard A; Friend, David R

2010-12-01

The HIV-1 epidemic remains unchecked despite existing technology; vaccines and microbicides in development may help reverse the epidemic. Reverse transcriptase inhibitors (RTIs) formulated in gels tenofovir (TFV) and IVRs (dapivirine) are under clinical development. While TFV or similar products may prove successful for HIV-1, alternatives to RTIs may provide additional benefits, e.g., broader STI prevention. Biopharmaceutical agents under development as microbicides include cyanovirin, RANTES analogues, commensals, and Mabs. Cost of manufacturing biopharmaceuticals has been reduced and they can be formulated into tablets, films, and IVRs for vaginal delivery. Nanotechnology offers a novel approach to formulate microbicides potentially leading to uniform epithelial delivery. Delivery through vaginal mucus may be possible by controlling nanoparticle size and surface characteristics. Combining prevention modalities may be the most effective means of preventing STI transmission, importantly, codelivery of microbicides and vaccines has demonstrated. Finally, the safety of microbicide preparations and excipients commonly used can be assessed using a mouse/HSV-2 susceptibility model. Screening of new microbicide candidates and formulation excipients may avoid past issues of enhancing HIV-1 transmission. This article forms part of a special supplement covering several presentations on novel microbicide formulations from the symposium on "Recent Trends in Microbicide Formulations" held on 25 and 26 January 2010, Arlington, VA. Copyright © 2010 Elsevier B.V. All rights reserved.

Zinc oxide as a new antimicrobial preservative of topical products: interactions with common formulation ingredients.

Science.gov (United States)

Pasquet, Julia; Chevalier, Yves; Couval, Emmanuelle; Bouvier, Dominique; Bolzinger, Marie-Alexandrine

2015-02-01

Zinc oxide (ZnO) appears as a promising preservative for pharmaceutical or cosmetic formulations. The other ingredients of the formulations may have specific interactions with ZnO that alter its antimicrobial properties. The influence of common formulation excipients on the antimicrobial efficacy of ZnO has been investigated in simple model systems and in typical topical products containing a complex formulation. A wide variety of formulation excipients have been investigated for their interactions with ZnO: antioxidants, chelating agents, electrolytes, titanium dioxide pigment. The antimicrobial activity of ZnO against Escherichia coli was partially inhibited by NaCl and MgSO4 salts. A synergistic influence of uncoated titanium dioxide has been observed. The interference effects of antioxidants and chelating agents were quite specific. The interactions of these substances with ZnO particles and with the soluble species released by ZnO were discussed so as to reach scientific guidelines for the choice of the ingredients. The preservative efficacy of ZnO was assessed by challenge testing in three different formulations: an oil-in-water emulsion; a water-in-oil emulsion and a dry powder. The addition of ZnO in complex formulations significantly improved the microbiological quality of the products, in spite of the presence of other ingredients that modulate the antimicrobial activity. Copyright © 2014 Elsevier B.V. All rights reserved.

Nasal Absorption of Macromolecules from Powder Formulations and Effects of Sodium Carboxymethyl Cellulose on Their Absorption.

Directory of Open Access Journals (Sweden)

Akiko Tanaka

Full Text Available The nasal absorption of macromolecules from powder formulations and the effect of sodium carboxymethyl cellulose (CMC-Na as a pharmaceutical excipient on their absorption were studied. Model macromolecules were fluorescein isothiocyanate-labeled dextran (average molecular weight of 4.4kDa, FD4 and insulin. The plasma concentration of FD4 after application of the powder containing 50% starch (control was higher than that after application of the solution, and the absorption from 50% starch powder was enhanced by the substitution of starch with CMC-Na. The fractional absorption of FD4 after administration of the CMC-Na powder formulation was 30% and 40% higher than that after administration from the solution and the starch powder, respectively. The nasal absorption of insulin from the powder and the effect of CMC-Na were similar with those of FD4. The effective absorption of FD4 and insulin after application of powder with CMC-Na could be due to the increase in the nasal residence of FD4 and insulin. No damage in the nasal mucosa or dysfunction of the mucociliary clearance was observed after application of the drug powder and CMC-Na. The present findings indicate that nasal delivery of powder formulations with the addition of CMC-Na as an excipient is a promising approach for improving the nasal absorption of macromolecules.

Using a mass balance to determine the potency loss during the production of a pharmaceutical blend.

Science.gov (United States)

Mackaplow, Michael B

2010-09-01

The manufacture of a blend containing the active pharmaceutical ingredient (API) and inert excipients is a precursor for the production of most pharmaceutical capsules and tablets. However, if there is a net water gain or preferential loss of API during production, the potency of the final drug product may be less than the target value. We use a mass balance to predict the mean potency loss during the production of a blend via wet granulation and fluidized bed drying. The result is an explicit analytical equation for the change in blend potency a function of net water gain, solids losses (both regular and high-potency), and the fraction of excipients added extragranularly. This model predicts that each 1% gain in moisture content (as determined by a loss on drying test) will decrease the API concentration of the final blend at least 1% LC. The effect of pre-blend solid losses increases with their degree of superpotency. This work supports Quality by Design by providing a rational method to set the process design space to minimize blend potency losses. When an overage is necessary, the model can help justify it by providing a quantitative, first-principles understanding of the sources of potency loss. The analysis is applicable to other manufacturing processes where the primary sources of potency loss are net water gain and/or mass losses.

Risperidone oral disintegrating mini-tablets: A robust-product for pediatrics.

Science.gov (United States)

El-Say, Khalid M; Ahmed, Tarek A; Abdelbary, Maged F; Ali, Bahaa E; Aljaeid, Bader M; Zidan, Ahmed S

2015-12-01

This study was aimed at developing risperidone oral disintegrating mini-tablets (OD-mini-tablets) as age-appropriate formulations and to assess their suitability for infants and pediatric use. An experimental Box-Behnken design was applied to assure high quality of the OD-mini-tablets and reduce product variability. The design was employed to understand the influence of the critical excipient combinations on the production of OD-mini-tablets and thus guarantee the feasibility of obtaining products with dosage form uniformity. The variables selected were mannitol percent in Avicel (X1), swelling pressure of the superdisintegrant (X2), and the surface area of Aerosil as a glidant (X3). Risperidone-excipient compatibilities were investigated using FTIR and the spectra did not display any interaction. Fifteen formulations were prepared and evaluated for pre- and post-compression characteristics. The prepared OD-mini-tablet batches were also assessed for disintegration in simulated salivary fluid (SSF, pH 6.2) and in reconstituted skimmed milk. The optimized formula fulfilled the requirements for crushing strength of 5 kN with minimal friability, disintegration times of 8.4 and 53.7 s in SSF and skimmed milk, respectively. This study therefore proposes the risperidone OD-mini-tablet formula having robust mechanical properties, uniform and precise dosing of medication with short disintegration time suitable for pediatric use.

Application of water-insoluble polymers to orally disintegrating tablets treated by high-pressure carbon dioxide gas.

Science.gov (United States)

Ito, Yoshitaka; Maeda, Atsushi; Kondo, Hiromu; Iwao, Yasunori; Noguchi, Shuji; Itai, Shigeru

2016-09-10

The phase transition of pharmaceutical excipients that can be induced by humidifying or heating is well-known to increase the hardness of orally disintegrating tablets (ODTs). However, these conditions are not applicable to drug substances that are chemically unstable against such stressors. Here, we describe a system which enhances the hardness of tablets containing water-insoluble polymers by using high-pressure carbon dioxide (CO2). On screening of 26 polymeric excipients, aminoalkyl methacrylate copolymer E (AMCE) markedly increased tablet hardness (+155N) when maintained in a high-pressure CO2 environment. ODTs containing 10% AMCE were prepared and treatment with 4.0MPa CO2 gas at 25°C for 10min increased the hardness to +30N, whose level corresponded to heating at 70°C for 720min. In addition, we confirmed the effects of CO2 pressure, temperature, treatment time, and AMCE content on the physical properties of ODTs. Optimal pressure of CO2 gas was considered to be approximately 3.5MPa for an AMCE formula, as excessive pressure delayed the disintegration of ODTs. Combination of high-pressure CO2 gas and AMCE is a prospective approach for increasing the tablet hardness for ODTs, and can be conducted without additional heat or moisture stress using a simple apparatus. Copyright © 2016 Elsevier B.V. All rights reserved.

Weak interactions in clobazam-lactose mixtures examined by differential scanning calorimetry: Comparison with the captopril-lactose system

Energy Technology Data Exchange (ETDEWEB)

Toscani, S. [Departement de Chimie - UMR 6226, Faculte des Sciences, Universite de Rennes 1, Batiment 10B, 263 avenue du General Leclerc, F-35042 Rennes Cedex (France); Cornevin, L. [Universite de Rennes 1, Faculte de Pharmacie, 2 Avenue Leon Bernard, F-35043 Rennes Cedex (France); Burgot, G., E-mail: Gwenola.burgot@univ-rennes1.fr [Universite de Rennes 1, Faculte de Pharmacie, Laboratoire de Chimie Analytique, EA 1274 ' Mouvement, sports, sante' , 2 Avenue Leon Bernard, F-35043 Rennes Cedex (France); CHGR Rennes, Pole Medico-Technique Pharmacie, F-35703 Rennes Cedex (France)

2012-09-10

Highlights: Black-Right-Pointing-Pointer Thermodynamic and kinetic parameters of weak interactions in binary systems by DSC. Black-Right-Pointing-Pointer Energy-barrier decrease for lactose dehydration induced by clobazam. Black-Right-Pointing-Pointer Recrystallisation of metastable liquid clobazam induced by anhydrous alpha lactose. Black-Right-Pointing-Pointer Decrease of lactose dehydration temperature in binary mixtures with captopril. Black-Right-Pointing-Pointer Increase of lactose dehydration enthalpy in binary mixtures with captopril. - Abstract: The thermal behaviour of binary mixtures of two drugs (clobazam and captopril, respectively) and a pharmaceutical excipient (lactose monohydrate) was measured with differential scanning calorimetry to determine thermodynamic and kinetic parameters (dehydration and melting enthalpies and dehydration and glass-transition activation energies) which might be affected by intermolecular interactions. A kinetic study showed that lactose dehydration is not a single-step conversion and that clobazam contributed to reduce the energy barrier for the bulk dehydration of the excipient. On the other hand, the physical interactions between metastable liquid clobazam and crystalline anhydrous {alpha}-lactose obtained from monohydrate dehydration gave rise to the recrystallisation of clobazam. In the captopril-lactose system, the liquid captopril influenced the lactose dehydration: a sharp increase of the dehydration enthalpy and a concurrent reduction of the dehydration temperature were observed. Finally, it turned out that solid-phase transitions were enhanced by the contact with a liquid phase.

Artificial neural network combined with principal component analysis for resolution of complex pharmaceutical formulations.

Science.gov (United States)

Ioele, Giuseppina; De Luca, Michele; Dinç, Erdal; Oliverio, Filomena; Ragno, Gaetano

2011-01-01

A chemometric approach based on the combined use of the principal component analysis (PCA) and artificial neural network (ANN) was developed for the multicomponent determination of caffeine (CAF), mepyramine (MEP), phenylpropanolamine (PPA) and pheniramine (PNA) in their pharmaceutical preparations without any chemical separation. The predictive ability of the ANN method was compared with the classical linear regression method Partial Least Squares 2 (PLS2). The UV spectral data between 220 and 300 nm of a training set of sixteen quaternary mixtures were processed by PCA to reduce the dimensions of input data and eliminate the noise coming from instrumentation. Several spectral ranges and different numbers of principal components (PCs) were tested to find the PCA-ANN and PLS2 models reaching the best determination results. A two layer ANN, using the first four PCs, was used with log-sigmoid transfer function in first hidden layer and linear transfer function in output layer. Standard error of prediction (SEP) was adopted to assess the predictive accuracy of the models when subjected to external validation. PCA-ANN showed better prediction ability in the determination of PPA and PNA in synthetic samples with added excipients and pharmaceutical formulations. Since both components are characterized by low absorptivity, the better performance of PCA-ANN was ascribed to the ability in considering all non-linear information from noise or interfering excipients.

Formulation and evaluation of orally disintegrating clopidogrel tablets

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Gamal Mohamed Mahrous

Full Text Available ABSTRACT Recent advances in drug delivery systems have aimed to achieve better patient compliance. One of these advances is the formulation of orally disintegrating tablets (ODTs that dissolve instantaneously, releasing drugs within a few seconds without the need of water. The main objective of this paper was to prepare and develop ODTs of clopidogrel. The ODTs were prepared by direct compression. The effect of three superdisintegrants, namely crospovidone, croscarmellose sodium, and sodium starch glycolate, using three different disintegration times on the dissolution rate was investigated. The prepared tablets were evaluated for hardness, friability, disintegration time and in vitro drug release. Furthermore, the interaction of clopidogrel with the formulation excipients was studied using differential scanning calorimetry (DSC. DSC studies revealed that there were no interactions between the drug and the excipients used. All tablets had hardness values in the range 4.0-5.2 kp and friability lower than 1%. The weight and drug content uniformity of all formulations was within official limits according to BP. In vitro drug release studies of the ODTs showed that more than 90% of the drug was released within ten minutes. A palatability test in human volunteers showed acceptable taste and mouth feel. Thus, the obtained results conclusively demonstrated successful rapid disintegration of the formulated tablets and acceptable palatability.

Effect of binders on 500mg metformin hydrochloride tablets produced by wet granulation

Directory of Open Access Journals (Sweden)

LUCIANA CATIA BLOCK

2009-12-01

Full Text Available Metformin hydrochloride (MH is an oral hypoglycemic agent and a high-dose drug that has poor flow and compression properties. In this study, the feasibility of developing adequate, low cost 500mg tablets of metformin hydrochloride by wet granulation was tested with several binders (Starch / PVP K30®; Starch 1500® /PVP K30®, PVP K30® and PVP K90® in a simple tablet press of the type used in small pharmaceutical laboratories. The drug powder was tested for ability to flow, by determining Carr’s Index (CI and the Hausner ratio (HR. Differential scanning calorimetry and thermogravimetric analysis were carried out on isolated MH and 1:1 (w/w binary mixtures with the excipients. The size distribution, friability, flow properties and drug content of the granules were analyzed, as were the hardness, friability, disintegration, dissolution and uniformity of the dosage form. The drug powder showed CI > 22% and HR > 1.25, characteristic of a poor flow powder, and no significant incompatibilities with the excipients. All the granules showed adequate flow properties and were suitable for pressing into tablets, all of which complied with pharmacopeial specifications. The starch /PVP K30® and starch 1500® /PVP K30® mixtures were best for producing 500 mg MH tablets. Keywords: Metformin hydrochloride. Tablets. Wet granulation. Binders.

Multifunctional liposomes for nasal delivery of the anti-Alzheimer drug tacrine hydrochloride

DEFF Research Database (Denmark)

Corace, Giuseppe; Angeloni, Cristina; Malaguti, Marco

2014-01-01

. This approach was chosen in order to obtain at the same time two positive results: an enhanced drug permeation through nasal mucosa and a concomitant neuroprotective effect. Several liposome formulations were prepared using the Reverse Phase Evaporation technique followed by membrane filter extrusion......Abstract The purpose of this study was the development of multifunctional liposomes for nasal administration of tacrine hydrochloride. Liposomes were prepared using traditional excipients (cholesterol and phosphatidylcholine), partly enriched with α-tocopherol and/or Omega3 fatty acids...

Application of a colorimetric technique in quality control for printed pediatric orodispersible drug delivery systems containing propranolol hydrochloride

DEFF Research Database (Denmark)

Vakili, Hossein; Nyman, Johan O; Genina, Natalja

2016-01-01

and the excipients. The inkjet printing technique deposited precise and uniform escalating doses (0.08-3.16mg) of the active pharmaceutical ingredient onto the substrates (R(2)≥0.9934). A disintegration test with clear end-point detection confirmed that all the substrates meet the requirements of the Ph. Eur....... to disintegrate within 180s. The colorimetric technique proved to be a reliable method to distinguish the small color differences between formulations containing an escalating dose of propranolol hydrochloride....

Quantitative Evaluation of Acetaminophen in Oral Solutions by Dispersive Raman Spectroscopy for Quality Control

OpenAIRE

Borio, Viviane G.; Vinha, RubensJr.; Nicolau, Renata A.; de Oliveira, Hueder Paulo M.; de Lima, Carlos J.; Silveira, LandulfoJr.

2012-01-01

This work used dispersive Raman spectroscopy to evaluate acetaminophen in commercially available formulations as an analytical methodology for quality control in the pharmaceutical industry. Raman spectra were collected using a near-infrared dispersive Raman spectrometer (830 nm, 50 mW, 20 s exposure time) coupled to a fiber optic probe. Solutions of acetaminophen diluted in excipient (70 to 120% of the commercial concentration of 200 mg/mL) were used to develop a calibration model based on p...

ROLE OF NATURAL POLYMER IN SUSTAINED AND CONTROLLED RELEASE

OpenAIRE

Vaishali S. Kadam, G. R. Shendarkar

2017-01-01

Now a day there has been an important development in different dosage forms for existing and newly designed drugs and natural products, and synthetic as well as semi-synthetic excipients always need to be used for a variety of purposes. Gums and mucilages are widely used as natural materials for conventional and novel dosage forms. With the increasing interest in polymers of natural origin, the pharmaceutical world has compliance to use most of them in their formulations. Moreover, the tremen...

Chemical imaging and solid state analysis at compact surfaces using UV imaging

DEFF Research Database (Denmark)

Wu, Jian X.; Rehder, Sönke; van den Berg, Frans

2014-01-01

and excipients in a non-invasive way, as well as mapping the glibenclamide solid state form. An exploratory data analysis supported the critical evaluation of the mapping results and the selection of model parameters for the chemical mapping. The present study demonstrated that the multi-wavelength UV imaging......Fast non-destructive multi-wavelength UV imaging together with multivariate image analysis was utilized to visualize distribution of chemical components and their solid state form at compact surfaces. Amorphous and crystalline solid forms of the antidiabetic compound glibenclamide...

Comparative investigations of tablet crushing force testers

DEFF Research Database (Denmark)

Sonnergaard, Jørn; Jensen, C.G.; Poulsen, L.

2005-01-01

The performance of 16 tablet breaking force testers was evaluated in terms of accuracy, reproducibility and repeatability. Three tablet formulations with different plastic or brittle deformation mechanisms and with target breaking forces of 50, 100 and 150 N were tested. Statistically significant...... by the concept of components of variance was 5-7 % depending on the model tablet excipient. The standard deviation within testers (repeatability) was affected by the type of model formulation showing increasing variability with increasing brittleness of the compressed material. No specific effect of altering...

Use of low-frequency Raman spectroscopy and chemometrics for the quantification of crystallinity in amorphous griseofulvin tablets

DEFF Research Database (Denmark)

Mah, Pei T.; Fraser, Sara J.; Reish, Matthew E.

2015-01-01

in stored amorphous samples earlier than the mid-frequency 785 nm Raman system. Overall, this study suggests that low-frequency Raman spectroscopy has at least equally good performance compared to mid-frequency Raman for quantitative analysis of crystallinity in the pharmaceutical setting. More generally......Low-frequency Raman spectroscopy, which directly probes phonon lattice modes of crystal structures, has much unexplored potential for sensitive qualitative and quantitative analysis of crystallinity in drugs and excipients. In this study, the level of crystallinity in tablets containing amorphous...

Lipid-based formulations for oral administration of poorly water-soluble drugs

DEFF Research Database (Denmark)

Mu, Huiling; Holm, René; Müllertz, Anette

2013-01-01

Lipid-based drug delivery systems have shown great potentials in oral delivery of poorly water-soluble drugs, primarily for lipophilic drugs, with several successfully marketed products. Pre-dissolving drugs in lipids, surfactants, or mixtures of lipids and surfactants omits the dissolving....../dissolution step, which is a potential rate limiting factor for oral absorption of poorly water-soluble drugs. Lipids not only vary in structures and physiochemical properties, but also in their digestibility and absorption pathway; therefore selection of lipid excipients and dosage form has a pronounced effect...

The development of composition and technology for the capsulated drug based on bee pollen and honey powder. Announcement 3.

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B. Т. Kudrik

2016-12-01

Full Text Available Aim. To develop experimentally and to substantiate theoretically both in pharmaceutical and industrial conditions the technology of manufacturing for capsules with the immunomodulatory action (provisional name «Api-Immuno-Vit» basing on pharmacotechnological and physical-chemical studies. Also to study the effect of excipients, the residual moisture and the particle size of capsules on technological parameters of mixtures quality, as well as to substantiate the choice of the size for solid gelatin capsules. Material and methods. The study objects were the experimental samples of the mixtures of «Api-Immuno-Vit» capsules with such active pharmaceutical ingredients (API as bee pollen (DSTU 7074:2009, GOST 31776-2012 and honey powder (TU U 10.8-39834691-001:2015, as well as aerosil and mannitol, which were used as excipients. Results. The pharmacotechnological tests of the experimental samples of the mixtures (particle size distribution, moisture content, fluidity, bulk density and tapped density, angle of repose, uniformity of mixing were carried out using the conventional methods given in the State Pharmacopoeia of Ukraine. The influence of particle size distribution of the granulate on technological parameters of the mixture quality in capsules has been studied. It has been found that the increase of residual moisture leads to decrease of fluidity, and therefore, the residual moisture of the mixture for encapsulation should be less than 1.5%. It has been also noted that during the experiment the presence of large and medium fractions is important for the particle size distribution since fluidity and the bulk density of the mixtures significantly reduce if the fine fraction in more than 30% in amount. Сonclusions. The results of the experimental studies were used in developing the flowchart of «Api-Immuno-Vit» capsules manufacturing. Taking into account the physical-chemical properties and the pharmacotechnological tests the flowchart of

The technology development for the complex Api-phyto product “Apised” in the form of capsules with the restorative and sedative action

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O. S. Shpychak

2017-12-01

Full Text Available The aim of the study is to substantiate and experimentally develop the technology for the complex api-phyto product “Apised” (which is used to treat nervous disorders and the psycho-emotional stress in extreme conditions, in particular in sports medicine in the form of gelatin capsules in pharmacy conditions and in conditions of industrial production based on the pharmaceutical-technological and physical-chemical studies. Materials and methods. As the research objects the experimental samples of “Apised” capsules, as well as their mixtures of masses for encapsulation were used. These mixtures contain such active pharmaceutical ingredients (API as a standardized substance of powdered honey (PH, medicinal plant raw material (Melissa herb, hop cones, true lavender flowers and the following excipients (antifriction substances: aerosil (anhydrous colloidal silicon dioxide or the mixture of aerosil and calcium stearate (3:1 in the amount of 2 %, as well as a wetting agent – 5 % solution of Plasdone K29/32. Results. The obtained results of the experimental studies were used when developing the flowcharts of the manufacturing process for “Apised” capsules in pharmacy conditions and in conditions of the standard operating procedure for the drug. Taking into account the physical-chemical properties of API included in the composition of the drug the flowchart of the manufacturing process for the complex api-phyto product in conditions of industrial production and the project of the specification were developed, the technological parameters of its manufacturing were substantiated, the optimal amount of excipients and a wetting agent required for performing the proper technological process was calculated, as well as the control over the sequence of mixing of active substances and excipients, moisturizing and obtaining of wet granules, drying and sizing of granules, obtaining of the encapsulated mass and other control parameters affecting the

Preparation and investigation of novel gastro-floating tablets with 3D extrusion-based printing.

Science.gov (United States)

Li, Qijun; Guan, Xiaoying; Cui, Mengsuo; Zhu, Zhihong; Chen, Kai; Wen, Haoyang; Jia, Danyang; Hou, Jian; Xu, Wenting; Yang, Xinggang; Pan, Weisan

2018-01-15

Three dimensional (3D) extrusion-based printing is a paste-based rapid prototyping process, which is capable of building complex 3D structures. The aim of this study was to explore the feasibility of 3D extrusion-based printing as a pharmaceutical manufacture technique for the fabrication of gastro-floating tablets. Novel low-density lattice internal structure gastro-floating tablets of dipyridamole were developed to prolong the gastric residence time in order to improve drug release rate and consequently, improve bioavailability and therapeutic efficacy. Excipients commonly employed in the pharmaceutical study could be efficiently applied in the room temperature 3D extrusion-based printing process. The tablets were designed with three kinds of infill percentage and prepared by hydroxypropyl methylcellulose (HPMC K4M) and hydroxypropyl methylcellulose (HPMC E15) as hydrophilic matrices and microcrystalline cellulose (MCC PH101) as extrusion molding agent. In vitro evaluation of the 3D printed gastro-floating tablets was performed by determining mechanical properties, content uniformity, and weight variation. Furthermore, re-floating ability, floating duration time, and drug release behavior were also evaluated. Dissolution profiles revealed the relationship between infill percentage and drug release behavior. The results of this study revealed the potential of 3D extrusion-based printing to fabricate gastro-floating tablets with more than 8h floating process with traditional pharmaceutical excipients and lattice internal structure design. Copyright © 2017. Published by Elsevier B.V.

Incomplete copolymer degradation of in situ chemotherapy.

Science.gov (United States)

Bourdillon, Pierre; Boissenot, Tanguy; Goldwirt, Lauriane; Nicolas, Julien; Apra, Caroline; Carpentier, Alexandre

2018-02-17

In situ carmustine wafers containing 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) are commonly used for the treatment of recurrent glioblastoma to overcome the brain-blood barrier. In theory, this chemotherapy diffuses into the adjacent parenchyma and the excipient degrades in maximum 8 weeks but no clinical data confirms this evolution, because patients are rarely operated again. A 75-year-old patient was operated twice for recurrent glioblastoma, and a carmustine wafer was implanted during the second surgery. Eleven months later, a third surgery was performed, revealing unexpected incomplete degradation of the wafer. 1H-Nuclear Magnetic Resonance was performed to compare this wafer to pure BCNU and to an unused copolymer wafer. In the used wafer, peaks corresponding to hydrophobic units of the excipient were no longer noticeable, whereas peaks of the hydrophilic units and traces of BCNU were still present. These surprising results could be related to the formation of a hydrophobic membrane around the wafer, thus interfering with the expected diffusion and degradation processes. The clinical benefit of carmustine wafers in addition to the standard radio-chemotherapy remains limited, and in vivo behavior of this treatment is not completely elucidated yet. We found that the wafer may remain after several months. Alternative strategies to deal with the blood-brain barrier, such as drug-loaded liposomes or ultrasound-opening, must be explored to offer larger drug diffusion or allow repetitive delivery.

Downstream processing of a ternary amorphous solid dispersion: The impacts of spray drying and hot melt extrusion on powder flow, compression and dissolution.

Science.gov (United States)

Davis, Mark T; Potter, Catherine B; Walker, Gavin M

2018-06-10

Downstream processing aspects of a stable form of amorphous itraconazole exhibiting enhanced dissolution properties were studied. Preparation of this ternary amorphous solid dispersion by either spray drying or hot melt extrusion led to significantly different powder processing properties. Particle size and morphology was analysed using scanning electron microscopy. Flow, compression, blending and dissolution were studied using rheometry, compaction simulation and a dissolution kit. The spray dried material exhibited poorer flow and reduced sensitivity to aeration relative to the milled extrudate. Good agreement was observed between differing forms of flow measurement, such as Flow Function, Relative flow function, Flow rate index, Aeration rate, the Hausner ratio and the Carr index. The stability index indicated that both powders were stable with respect to agglomeration, de-agglomeration and attrition. Tablet ability and compressibility studies showed that spray dried material could be compressed into stronger compacts than extruded material. Blending of the powders with low moisture, freely-flowing excipients was shown to influence both flow and compression. Porosity studies revealed that blending could influence the mechanism of densification in extrudate and blended extrudate formulations. Following blending, the powders were compressed into four 500 mg tablets, each containing a 100 mg dose of amorphous itraconazole. Dissolution studies revealed that the spray dried material released drug faster and more completely and that blending excipients could further influence the dissolution rate. Copyright © 2018 Elsevier B.V. All rights reserved.

Effect of amino acids on the stability of spray freeze-dried immunoglobulin G in sugar-based matrices.

Science.gov (United States)

Emami, Fakhrossadat; Vatanara, Alireza; Najafabadi, Abdolhosein Rouholamini; Kim, Yejin; Park, Eun Ji; Sardari, Soroush; Na, Dong Hee

2018-07-01

The purpose of this study was to prepare spray freeze-dried particles of immunoglobulin G (IgG) using various combinations of trehalose and different amino acids (leucine, phenylalanine, arginine, cysteine, and glycine), and investigate the effect of the amino acids on the stability of IgG during the spray freeze-drying (SFD) process and storage. The morphology and structural integrity of the processed particles were evaluated by physical and spectroscopic techniques. SFD-processed IgG without any excipient resulted in the formation of aggregates corresponding to approximately 14% of IgG. In contrast, IgG formulations stabilized using an optimal level of leucine, phenylalanine, or glycine in the presence of trehalose displayed aggregates <2.2%. In particular, phenylalanine combined with trehalose was most effective in stabilizing IgG against shear, freezing, and dehydration stresses during SFD. Arginine and cysteine were destabilizers displaying aggregation and fragmentation of IgG, respectively. Aggregation and fragmentation were evaluated by dynamic light scattering, ultraviolet spectrophotometry, size-exclusion chromatography, and microchip capillary gel electrophoresis. The IgG formulations prepared with leucine, phenylalanine, or glycine in the presence of trehalose showed good stability after storage at 40 °C and 75% relative humidity for 2 months. Thus, a combination of the excipients trehalose and uncharged, nonpolar amino acids appears effective for production of stable SFD IgG formulations. Copyright © 2018 Elsevier B.V. All rights reserved.

Oral transmucosal delivery of domperidone from immediate release films produced via hot-melt extrusion technology.

Science.gov (United States)

Palem, Chinna Reddy; Kumar Battu, Sunil; Maddineni, Sindhuri; Gannu, Ramesh; Repka, Michael A; Yamsani, Madhusudan Rao

2013-02-01

The objective of the study was to prepare and characterize the domperidone (DOM) hot-melt extruded (HME) buccal films by both in vitro and in vivo techniques. The HME film formulations contained PEO N10 and/or its combination with HPMC E5 LV or Eudragit RL100 as polymeric carriers, and PEG3350 as a plasticizer. The blends were co-processed at a screw speed of 50 rpm with the barrel temperatures ranging from 120-160°C utilizing a bench top co-rotating twin-screw hot-melt extruder using a transverse-slit die. The HME films were evaluated for drug content, drug excipient interaction, in vitro drug release, mechanical properties, in vivo residence time, in vitro bioadhesion, swelling and erosion, ex vivo permeation from HME films and the selected optimal formulation was subjected for bioavailability studies in healthy human volunteers. The extruded films demonstrated no drug excipient interaction and excellent content uniformity. The selected HME film formulation (DOM2) exhibited a tensile strength (0.72 Kg/mm(2)), elongation at break (28.4% mm(2)), in vivo residence time (120 min), peak detachment force (1.55 N), work of adhesion (1.49 mJ), swelling index (210.2%), erosion (10.5%) and in vitro drug release of 84.8% in 2 h. Bioavailability from the optimized HME buccal films was 1.5 times higher than the oral dosage form and the results showed statistically significant (p buccal-adhesive films with improved bioavailability characteristics.

Comparative Solid-State Stability of Perindopril Active Substance vs. Pharmaceutical Formulation

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Valentina Buda

2017-01-01

Full Text Available This paper presents the results obtained after studying the thermal stability and decomposition kinetics of perindopril erbumine as a pure active pharmaceutical ingredient as well as a solid pharmaceutical formulation containing the same active pharmaceutical ingredient (API. Since no data were found in the literature regarding the spectroscopic description, thermal behavior, or decomposition kinetics of perindopril, our goal was the evaluation of the compatibility of this antihypertensive agent with the excipients in the tablet under ambient conditions and to study the effect of thermal treatment on the stability of perindopril erbumine. ATR-FTIR (Attenuated Total Reflectance Fourier Transform Infrared spectroscopy, thermal analysis (thermogravimetric mass curve (TG—thermogravimetry, derivative thermogravimetric mass curve (DTG, and heat flow (HF and model-free kinetics were chosen as investigational tools. Since thermal behavior is a simplistic approach in evaluating the thermal stability of pharmaceuticals, in-depth kinetic studies were carried out by classical kinetic methods (Kissinger and ASTM E698 and later with the isoconversional methods of Friedman, Kissinger-Akahira-Sunose and Flynn-Wall-Ozawa. It was shown that the main thermal degradation step of perindopril erbumine is characterized by activation energy between 59 and 69 kJ/mol (depending on the method used, while for the tablet, the values were around 170 kJ/mol. The used excipients (anhydrous colloidal silica, microcrystalline cellulose, lactose, and magnesium stearate should be used in newly-developed generic solid pharmaceutical formulations, since they contribute to an increased thermal stability of perindopril erbumine.

Novel algorithm for simultaneous component detection and pseudo-molecular ion characterization in liquid chromatography–mass spectrometry

Energy Technology Data Exchange (ETDEWEB)

Zhang, Yufeng; Wang, Xiaoan; Wo, Siukwan [School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong (China); Ho, Hingman; Han, Quanbin [School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong (China); Fan, Xiaohui [College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 (China); Zuo, Zhong, E-mail: joanzuo@cuhk.edu.hk [School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong (China)

2015-01-01

Highlights: • Novel stepwise component detection algorithm (SCDA) for LC–MS datasets. • New isotopic distribution and adduct-ion models for mass spectra. • Automatic component classification based on adduct-ion and isotopic distributions. - Abstract: Resolving components and determining their pseudo-molecular ions (PMIs) are crucial steps in identifying complex herbal mixtures by liquid chromatography–mass spectrometry. To tackle such labor-intensive steps, we present here a novel algorithm for simultaneous detection of components and their PMIs. Our method consists of three steps: (1) obtaining a simplified dataset containing only mono-isotopic masses by removal of background noise and isotopic cluster ions based on the isotopic distribution model derived from all the reported natural compounds in dictionary of natural products; (2) stepwise resolving and removing all features of the highest abundant component from current simplified dataset and calculating PMI of each component according to an adduct-ion model, in which all non-fragment ions in a mass spectrum are considered as PMI plus one or several neutral species; (3) visual classification of detected components by principal component analysis (PCA) to exclude possible non-natural compounds (such as pharmaceutical excipients). This algorithm has been successfully applied to a standard mixture and three herbal extract/preparations. It indicated that our algorithm could detect components’ features as a whole and report their PMI with an accuracy of more than 98%. Furthermore, components originated from excipients/contaminants could be easily separated from those natural components in the bi-plots of PCA.

Analysis of low active-pharmaceutical-ingredient signal drugs based on thin layer chromatography and surface-enhanced Raman spectroscopy.

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Li, Xiao; Chen, Hui; Zhu, Qingxia; Liu, Yan; Lu, Feng

2016-11-30

Active pharmaceutical ingredients (API) embedded in the excipients of the formula can usually be unravelled by normal Raman spectroscopy (NRS). However, more and more drugs with low API content and/or low Raman scattering coefficient were insensitive to NRS analysis, which was for the first time defined as Low API-Signal Drugs (LASIDs) in this paper. The NRS spectra of these LASIDs were similar to their dominant excipients' profiles, such as lactose, starch, microcrystalline cellulose (MCC), etc., and were classified into three types as such. 21 out of 100 kinds of drugs were screened as LASIDs and characterized further by Raman microscopic mapping. Accordingly, we proposed a tailored solution to the qualitation and quantitation problem of these LASIDs, using surface-enhanced Raman spectroscopic (SERS) detection on the thin layer chromatographic (TLC) plate both in situ and after-separation. Experimental conditions and parameters including TLC support matrix, SERS substrate, detection mode, similarity threshold, internal standard, etc., were optimized. All LASIDs were satisfactorily identified and the quantitation results agreed well with those of high performance liquid chromatography (HPLC). For some structural analogues of LASIDs, although they presented highly similar SERS spectra and were tough to distinguish even with Raman microscopic mapping, they could be successfully discriminated from each other by coupling SERS (with portable Raman spectrometer) with TLC. These results demonstrated that the proposed solution could be employed to detect the LASIDs with high accuracy and cost-effectiveness. Copyright © 2016 Elsevier B.V. All rights reserved.

Novel algorithm for simultaneous component detection and pseudo-molecular ion characterization in liquid chromatography–mass spectrometry

International Nuclear Information System (INIS)

Zhang, Yufeng; Wang, Xiaoan; Wo, Siukwan; Ho, Hingman; Han, Quanbin; Fan, Xiaohui; Zuo, Zhong

2015-01-01

Highlights: • Novel stepwise component detection algorithm (SCDA) for LC–MS datasets. • New isotopic distribution and adduct-ion models for mass spectra. • Automatic component classification based on adduct-ion and isotopic distributions. - Abstract: Resolving components and determining their pseudo-molecular ions (PMIs) are crucial steps in identifying complex herbal mixtures by liquid chromatography–mass spectrometry. To tackle such labor-intensive steps, we present here a novel algorithm for simultaneous detection of components and their PMIs. Our method consists of three steps: (1) obtaining a simplified dataset containing only mono-isotopic masses by removal of background noise and isotopic cluster ions based on the isotopic distribution model derived from all the reported natural compounds in dictionary of natural products; (2) stepwise resolving and removing all features of the highest abundant component from current simplified dataset and calculating PMI of each component according to an adduct-ion model, in which all non-fragment ions in a mass spectrum are considered as PMI plus one or several neutral species; (3) visual classification of detected components by principal component analysis (PCA) to exclude possible non-natural compounds (such as pharmaceutical excipients). This algorithm has been successfully applied to a standard mixture and three herbal extract/preparations. It indicated that our algorithm could detect components’ features as a whole and report their PMI with an accuracy of more than 98%. Furthermore, components originated from excipients/contaminants could be easily separated from those natural components in the bi-plots of PCA

Controlled Release of Lysozyme from Double-Walled Poly(Lactide-Co-Glycolide (PLGA Microspheres

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Rezaul H. Ansary

2017-10-01

Full Text Available Double-walled microspheres based on poly(lactide-co-glycolide (PLGA are potential delivery systems for reducing a very high initial burst release of encapsulated protein and peptide drugs. In this study, double-walled microspheres made of glucose core, hydroxyl-terminated poly(lactide-co-glycolide (Glu-PLGA, and carboxyl-terminated PLGA were fabricated using a modified water-in-oil-in-oil-in-water (w1/o/o/w2 emulsion solvent evaporation technique for the controlled release of a model protein, lysozyme. Microspheres size, morphology, encapsulation efficiency, lysozyme in vitro release profiles, bioactivity, and structural integrity, were evaluated. Scanning electron microscopy (SEM images revealed that double-walled microspheres comprising of Glu-PLGA and PLGA with a mass ratio of 1:1 have a spherical shape and smooth surfaces. A statistically significant increase in the encapsulation efficiency (82.52% ± 3.28% was achieved when 1% (w/v polyvinyl alcohol (PVA and 2.5% (w/v trehalose were incorporated in the internal and external aqueous phase, respectively, during emulsification. Double-walled microspheres prepared together with excipients (PVA and trehalose showed a better control release of lysozyme. The released lysozyme was fully bioactive, and its structural integrity was slightly affected during microspheres fabrication and in vitro release studies. Therefore, double-walled microspheres made of Glu-PLGA and PLGA together with excipients (PVA and trehalose provide a controlled and sustained release for lysozyme.

The Impact of Amorphisation and Spheronization Techniques on the Improved in Vitro & in Vivo Performance of Glimepiride Tablets

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Rana Refaat Makar

2017-12-01

Full Text Available Purpose: Triple solid dispersion adsorbates (TSDads and spherical agglomerates (SA present new techniques that extensively enhance dissolution of poorly soluble drugs. The aim of the present study is to hasten the onset of hypoglycemic effect of glimepiride through enhancing its rate of release from tablet formulation prepared from either technique. Methods: Drug release from TSDads or SA tablets with different added excipients was explored. Scanning electron microscopy (SEM and effect of compression on dissolution were illustrated. Pharmacodynamic evaluation was performed on optimized tablets. Results: TSDads & SA tablets with Cross Povidone showed least disintegration times of 1.48 and 0.5 min. respectively. Kinetics of drug release recorded least half-lives (54.13 and 59.83min for both techniques respectively. Cross section in tablets displayed an organized interconnected matrix under SEM, accounting for the rapid access of dissolution media to the tablet core. Components of tablets filled into capsules showed a similar release profile to that of tablets after compression as indicated by similarity factor. The onset time of maximum reduction in blood glucose in male albino rabbits was hastened to 2h instead of 3h for commercial tablets. Conclusion: After optimization of tablet excipients that interacted differently with respect to their effect on drug release, we could conclude that both amorphisation and spheronization were equally successful in promoting in vitro dissolution enhancement as well as providing a more rapid onset time for drug action in vivo.

Application of instrumented nanoindentation in preformulation studies of pharmaceutical active ingredients and excipients

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Egart Mateja

2016-09-01

Full Text Available Nanoindentation allows quantitative determination of a material’s response to stress such as elastic and plastic deformation or fracture tendency. Key instruments that have enabled great advances in nanomechanical studies are the instrumented nanoindenter and atomic force microscopy. The versatility of these instruments lies in their capability to measure local mechanical response, in very small volumes and depths, while monitoring time, displacement and force with high accuracy and precision.

SYNTHESIS AND EVALUATION OF β-CYCLODEXTRIN-EPICHLOROHYDRIN INCLUSION COMPLEX AS A PHARMACEUTICAL EXCIPIENT

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K. N. Poornima

2015-05-01

Full Text Available A water soluble Beta-cyclodextrin-epichlorohydrin complex (Beta-CDEPI was synthesized by one-step condensation polymerization. Drug- Beta-CDEPI inclusion complexes were prepared and characterized. Inclusion complexes prepared using lyophilization technique was used to formulate orodispersible tablets. Compatibility studies showed no interaction and characterization proved substantial inclusion complex formation. Drug content was found between 97-99%. In-vitro disintegration time was found to be less than 3 minutes and all the formulations showed complete drug release of 100% within 15 minutes. The formulations were found to be stable for a period of 6 months. Beta-CDEPI polymer enhances the solubility and thus effectively can be utilized to improve the aqueous solubility of poorly water soluble drugs.

In vitro and in vivo activities of antibiotic PM181104

Digital Repository Service at National Institute of Oceanography (India)

Mahajan, G.B.; Thomas, B.; Parab, R.; Patel, Z.E.; Kuldharan, S.; Yemparala, V.; Mishra, P.D.; Ranadive, P.; DeSouza, L.; Pari, K.; Sivaramkrishnan, H.

assigned into 7 different treatment groups (6 mice per group) and infected intra-peritoneally with 0.1mL of MRSA strain E710 culture containing 108 -109 cfu of bacteria. PM181104 prepared in formulation was administered at 1.25, 2.5, 5 and 10mg/kg intra-venous... and 10mg/kg intra-venous (i.v.) dose immediately post infection to 3 different groups. One group received formulation excipients (vehicle control) by i.v. route and one group received 25mg/kg standard antibiotic linezolid by intra-peritoneal (i...

Natural and Synthetic Polymers as Inhibitors of Drug Efflux Pumps

Science.gov (United States)

2007-01-01

Inhibition of efflux pumps is an emerging approach in cancer therapy and drug delivery. Since it has been discovered that polymeric pharmaceutical excipients such as Tweens® or Pluronics® can inhibit efflux pumps, various other polymers have been investigated regarding their potential efflux pump inhibitory activity. Among them are polysaccharides, polyethylene glycols and derivatives, amphiphilic block copolymers, dendrimers and thiolated polymers. In the current review article, natural and synthetic polymers that are capable of inhibiting efflux pumps as well as their application in cancer therapy and drug delivery are discussed. PMID:17896100

An in vitro analysis of disintegration times of different formulations of olanzapine orodispersible tablet: a preliminary report.

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Hobbs, David; Karagianis, Jamie; Treuer, Tamas; Raskin, Joel

2013-12-01

Orodispersible tablets (ODTs) are tablet or wafer forms of medication that disintegrate in the mouth, aided only by saliva. ODTs rely on different fast dissolve/disintegration manufacturing technologies. Disintegration time differences for several olanzapine ODT forms were investigated. Risperdal M-Tab(®) was included as a non-olanzapine ODT comparator. Eleven olanzapine ODT examples and orodispersible risperidone strengths were evaluated in vitro for formulation composition, manufacturing method, disintegration and dissolution characteristics, and formulation differences in comparison with freeze dried Zydis(®) ODT. Automated dissolution test equipment captured ODT dissolution rates by measuring real-time release of active ingredient. A high-speed video camera was used to capture tablet disintegration times in warm simulated saliva. The main outcome measure was the disintegration and dissolution characteristics of the ODT formulations. The ODT manufacturing method was associated with time to disintegrate; the fastest were freeze dried tablets, followed by soft compressed tablets and then hard/dense tablets. Olanzapine Zydis(®) was the only ODT that completely disintegrated in less than 4 s for all strengths (5, 10, 15, and 20 mg), followed by 5-mg Prolanz FAST(®) (12 s) and then risperidone ODT 4 mg (40 s). Reasons for slow dissolution of the olanzapine generics may include low product potency, excipient binding, excipient solubility, active ingredient particle size and incomplete disintegration. Differences in the formulation and manufacturing process of olanzapine ODTs appear to have a strong influence on the disintegration time of the active compound; differences that may potentially impact their use in clinical practice.

Pharmaceutical applications of cyclodextrins: basic science and product development.

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Loftsson, Thorsteinn; Brewster, Marcus E

2010-11-01

Drug pipelines are becoming increasingly difficult to formulate. This is punctuated by both retrospective and prospective analyses that show that while 40% of currently marketed drugs are poorly soluble based on the definition of the biopharmaceutical classification system (BCS), about 90% of drugs in development can be characterized as poorly soluble. Although a number of techniques have been suggested for increasing oral bioavailability and for enabling parenteral formulations, cyclodextrins have emerged as a productive approach. This short review is intended to provide both some basic science information as well as data on the ability to develop drugs in cyclodextrin-containing formulations. There are currently a number of marketed products that make use of these functional solubilizing excipients and new product introduction continues to demonstrate their high added value. The ability to predict whether cyclodextrins will be of benefit in creating a dosage form for a particular drug candidate requires a good working knowledge of the properties of cyclodextrins, their mechanism of solubilization and factors that contribute to, or detract from, the biopharmaceutical characteristics of the formed complexes. We provide basic science information as well as data on the development of drugs in cyclodextrin-containing formulations. Cyclodextrins have emerged as an important tool in the formulator's armamentarium to improve apparent solubility and dissolution rate for poorly water-soluble drug candidates. The continued interest and productivity of these materials bode well for future application and their currency as excipients in research, development and drug product marketing. © 2010 The Authors. Journal compilation © 2010 Royal Pharmaceutical Society of Great Britain.

Promotores de permeação para a liberação transdérmica de fármacos: uma nova aplicação para as ciclodextrinas Permeation enhancers in transdermal drug delivery systems: a new application of cyclodextrins

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Maria Rita Fernandes Morais Martins

2002-03-01

Full Text Available No presente trabalho é feita uma breve revisão sobre promotores de permeação cutânea, descrevendo-se os seus mecanismos de ação e alguns exemplos. Abordam-se as vias de permeação de fármacos através da pele e liberação transdérmica. São também focadas as ciclodextrinas e seus derivados, a sua estrutura e propriedades físico-químicas, formação de complexos de inclusão e o seu papel como excipientes em sistemas transdérmicos. As ciclodextrinas constituem um grupo de excipientes que têm um papel de grande importância em formulação farmacêutica. Uma das mais extraordinárias propriedades destas moléculas é a sua capacidade de incrementar a liberação de fármacos através da pele sem, no entanto, afetar a sua função barreira.The present work is a short revision about transdermal permeation enhancers, their mechanism of action including some examples. Routes of permeation across the skin and transdermal delivery are also described. We focus cyclodextrins and their derivatives, structure, chemical properties, formation of inclusion complexes and their action as excipients in transdermal drug delivery systems. Cyclodextrins are a very important group of excipients used in pharmaceutical technology. One of the most extraordinary properties of cyclodextrins is their ability to increase transdermal drug delivery without affecting the barrier function of the skin.

[Efficient Pharmaceutical Formulation Designs and Their Development Using Mathematical and Statistical Analysis].

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Iwao, Yasunori

2015-01-01

With the aim of directly predicting the functionality and mechanism of pharmaceutical excipients, we investigated an analysis method based on available surface area (S(t)), which is the surface area of a drug in direct contact with the external solvent during dissolution. First, to study the effect of lubricant concentration on the dissolution rate of acetaminophen (APAP), the dissolution behaviors as well as the change over time in S(t) of APAP tablets were examined. In the dissolution tests, a retarded dissolution of APAP was not observed with new lubricant triglycerin full behenate (TR-FB), whereas magnesium stearate (Mg-St) retarded the dissolution. The S(t) profiles for APAP with Mg-St at>0.5% showed downward curvature indicating a gradual decrease in surface area over time. Conversely, with TR-FB, even when its concentration was increased, the S(t) profile for APAP had a maximum value. The differences between Mg-St and TR-FB could be explained by the differences in extensibility deriving from their morphology. Next, we evaluated the effect of disintegtant concentration using five disintegrants. When disintegrant was added to ethenzamide tablet formulation, an increase in the dissolution rate and S(t) dependent on disintegrant concentration was observed, according to the type of disintegrant. It was found that the water absorption ability of disintegrants had strong correlations with the parameters of S(t). Taken together, this study demonstrates that analysis of S(t) can directly provide useful information, especially about the functionality of pharmaceutical excipients.

3D extrusion printing of high drug loading immediate release paracetamol tablets.

Science.gov (United States)

Khaled, Shaban A; Alexander, Morgan R; Wildman, Ricky D; Wallace, Martin J; Sharpe, Sonja; Yoo, Jae; Roberts, Clive J

2018-03-01

The manufacture of immediate release high drug loading paracetamol oral tablets was achieved using an extrusion based 3D printer from a premixed water based paste formulation. The 3D printed tablets demonstrate that a very high drug (paracetamol) loading formulation (80% w/w) can be printed as an acceptable tablet using a method suitable for personalisation and distributed manufacture. Paracetamol is an example of a drug whose physical form can present challenges to traditional powder compression tableting. Printing avoids these issues and facilitates the relatively high drug loading. The 3D printed tablets were evaluated for physical and mechanical properties including weight variation, friability, breaking force, disintegration time, and dimensions and were within acceptable range as defined by the international standards stated in the United States Pharmacopoeia (USP). X-ray Powder Diffraction (XRPD) was used to identify the physical form of the active. Additionally, XRPD, Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR) and differential scanning calorimetry (DSC) were used to assess possible drug-excipient interactions. The 3D printed tablets were evaluated for drug release using a USP dissolution testing type I apparatus. The tablets showed a profile characteristic of the immediate release profile as intended based upon the active/excipient ratio used with disintegration in less than 60 s and release of most of the drug within 5 min. The results demonstrate the capability of 3D extrusion based printing to produce acceptable high-drug loading tablets from approved materials that comply with current USP standards. Copyright © 2018 Elsevier B.V. All rights reserved.

Artifactual degradation of secondary amine-containing drugs during accelerated stability testing when saturated sodium nitrite solutions are used for humidity control.

Science.gov (United States)

Sluggett, Gregory W; Zelesky, Todd; Hetrick, Evan M; Babayan, Yelizaveta; Baertschi, Steven W

2018-02-05

Accelerated stability studies of pharmaceutical products are commonly conducted at various combinations of temperature and relative humidity (RH). The RH of the sample environment can be controlled to set points using humidity-controlled stability chambers or via storage of the sample in a closed container in the presence of a saturated aqueous salt solution. Herein we report an unexpected N-nitrosation reaction that occurs upon storage of carvedilol- or propranolol-excipient blends in a stability chamber in the presence of saturated sodium nitrite (NaNO 2 ) solution to control relative humidity (∼60% RH). In both cases, the major products were identified as the corresponding N-nitroso derivatives of the secondary amine drugs based on mass spectrometry, UV-vis and retention time. These degradation products were not observed upon storage of the samples at the same temperature and humidity but in the presence of saturated potassium iodide (KI) solution (∼60% RH) for humidity control. The levels of the N-nitrosamine derivatives varied with the pH of various NaNO 2 batches. The presence of volatile NOx species in the headspace of a container containing saturated NaNO 2 solution was confirmed via the Griess assay. The process for formation of the N-nitrosamine derivatives is proposed to involve volatilization of nitric oxide (NO) from aqueous nitrite solution into the headspace of the container followed by diffusion into the solid drug-excipient blend and subsequent reaction of NOx with the secondary amine. Copyright © 2017 Elsevier B.V. All rights reserved.

Active intestinal drug absorption and the solubility-permeability interplay.

Science.gov (United States)

Porat, Daniel; Dahan, Arik

2018-02-15

The solubility-permeability interplay deals with the question: what is the concomitant effect on the drug's apparent permeability when increasing the apparent solubility with a solubility-enabling formulation? The solubility and the permeability are closely related, exhibit certain interplay between them, and ongoing research throughout the past decade shows that treating the one irrespectively of the other may be insufficient. The aim of this article is to provide an overview of the current knowledge on the solubility-permeability interplay when using solubility-enabling formulations for oral lipophilic drugs, highlighting active permeability aspects. A solubility-enabling formulation may affect the permeability in opposite directions; the passive permeability may decrease as a result of the apparent solubility increase, according to the solubility-permeability tradeoff, but at the same time, certain components of the formulation may inhibit/saturate efflux transporters (when relevant), resulting in significant apparent permeability increase. In these cases, excipients with both solubilizing and e.g. P-gp inhibitory properties may lead to concomitant increase of both the solubility and the permeability. Intelligent development of such formulation will account for the simultaneous effects of the excipients' nature/concentrations on the two arms composing the overall permeability: the passive and the active arms. Overall, thorough mechanistic understanding of the various factors involved in the solubility-permeability interplay may allow developing better solubility-enabling formulations, thereby exploiting the advantages analyzed in this article, offering oral delivery solution even for BCS class IV drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Torsemide Fast Dissolving Tablets: Development, Optimization Using Box-Bhenken Design and Response Surface Methodology, In Vitro Characterization, and Pharmacokinetic Assessment.

Science.gov (United States)

El-Shenawy, Ahmed A; Ahmed, Mahmoud M; Mansour, Heba F; Abd El Rasoul, Saleh

2017-08-01

The present study planed to develop new fast dissolving tablets (FDTs) of torsemide. Solid dispersions (SDs) of torsemide and sorbitol (3:1) or polyvinylpyrrolidone (PVP) k25 were prepared. The prepared SDs were evaluated for in-vitro dissolution. Fourier transform infrared spectroscopy and differential scanning calorimetry for SDs revealed no drug/excipient interactions and transformation of torsemide to the amorphous form. Torsemide/sorbitol SD was selected for formulation of torsemide FDTs by direct compression method. Box-Bhenken factorial design was employed to design 15 formulations using croscarmellose sodium and crospovidone at different concentrations. The response surface methodology was used to analyze the effect of changing these concentrations (independent variables) on disintegration time (Y 1 ), percentage friability (Y 2 ), and amount torsemide released at 10 min. The physical mixtures of torsemide and the used excipients were evaluated for angle of repose, Hausner's ratio, and Carr's index. The prepared FDTs tablets were evaluated for wetting and disintegration time, weight variation, drug content, percentage friability, thickness, hardness, and in vitro release. Based on the in-vitro results and factorial design characterization, F10 and F7 were selected for bioavailability studies following administration to Albino New Zealand rabbits. They showed significantly higher C max and (AUC 0-12 ) and shorter T max than those obtained after administration of the corresponding ordinary commercial Torseretic ® tablets. Stability study was conducted for F10 that showed good stability upon storage at 30°C/75% RH and 40°C/75% RH for 3 months.