In Vitro Dissolution of Generic Immediate-Release Solid Oral Dosage Forms Containing BCS Class I Drugs: Comparative Assessment of Metronidazole,Zidovudine, and Amoxicillin Versus Relevant Comparator Pharmaceutical Products in South Africa and India

Biowaivers are recommended for immediate-release solid oral dosage forms using dissolution testing as a surrogate for in vivo bioequivalence studies. Several guidance are currently available (the World Health Organization (WHO), the US FDA, and the EMEA) where the conditions are described. In this study, definitions, criteria, and methodologies according to the WHO have been applied. The dissolution performances of immediate-release metronidazole, zidovudine, and amoxicillin products purchased in South African and Indian markets were compared to the relevant comparator pharmaceutical product (CPP)/reference product. The dissolution performances were studied using US Pharmacopeia (USP) apparatus 2 (paddle) set at 75 rpm in each of three dissolution media (pH1.2, 4.5, and 6.8). Concentrations of metronidazole, zidovudine, and amoxicillin in each dissolution media were determined by HPLC. Of the 11 metronidazole products tested, only 8 could be considered as very rapidly dissolving products as defined by the WHO, whereas 2 of those products could be considered as rapidly dissolving products but did not comply with the f₂ acceptance criteria in pH 6.8. All 11 zidovudine products were very rapidly dissolving, whereas in the case of the 14 amoxicillin products tested, none of those products met any of the WHO criteria. This study indicates that not all generic products containing the same biopharmaceutics classification system (BCS) I drug and in similar strength and dosage form are necessarily in vitro equivalent. Hence, there is a need for ongoing market surveillance to determine whether marketed generic products containing BCS I drugs meet the release requirements to confirm their in vitro bioequivalence to the respective reference product.KEY WORDS: BCS, dissolution testing, generic drug, immediate-release solid oral dosage forms, WHO criteria     

Challenges and Opportunities to Use Biowaivers to Compare Generics in China

Biowaivers for class I drugs according to the biopharmaceutics classification system (BCS) were first introduced in 2000. The in vitro equivalence can be used to document bioequivalence between products. This study compared the in vitro dissolution behavior of two BCS class I drugs, amoxicillin and metronidazole, which are sold in China. Identifying a reference product on the Chinese domestic market was impossible. Three 250-mg and two 500-mg amoxicillin capsules and four metronidazole tablet products were tested. None of the amoxicillin products and three of the four metronidazole tablets were found to be equivalent to each other when the same strengths were compared. The bioequivalence of products that fail the in vitro test can be established via in vivo clinical studies which are expensive and time consuming. Establishing nationally or globally accepted reference products may provide regulatory agencies with an efficient mechanism approving high quality generics.     

In Vitro–In Vivo Correlation of Efavirenz Tablets Using GastroPlus®

The aim of the present work was to use GastroPlus™ software for the prediction of pharmacokinetic profiles and in vitro–in vivo correlation (IVIVC) as tools to optimize the development of new generic medications. GastroPlus™ was used to simulate the gastrointestinal compartment and was based on the advanced compartmental absorption and transit model. Powder dissolution and efavirenz tablet dissolution studies were carried out to generate data from which correlation was established. The simulated plasma profile, based on the physicochemical properties of efavirenz, was almost identical to that observed in vivo for biobatches A and B. A level A IVIVC was established for the dissolution method obtained for the generic candidate using the Wagner–Nelson (r² = 0.85) and for Loo–Riegelman models (r² = 0.92). The percentage of fraction absorbed indicated that 0.5% sodium lauryl sulfate may be considered a biorelevant dissolution medium for efavirenz tablets. The simulation of gastrointestinal bioavailability and IVIVC obtained from immediate-release tablet formulations suggests that GastroPlus™ is a valuable in silico method for IVIVC and for studies directed at developing formulations of class II drugs.KEY WORDS: bioavailability, computational simulation, efavirenz, GastroPlus™, in vivo–in vitro correlation     

A novel formulary: collaboration between health care professionals,seniors, private sector and government in Nova Scotia

A novel formulary has been developed in Nova Scotia with the objective of providing quality treatment with needed medications at affordable cost. Creation of the formulary has involved collaboration among health care professionals, seniors, the Department of Health and pharmaceutical companies. This is the first Canadian formulary to use the Anatomic, Therapeutic, Chemical system. Drug listing is comprehensive rather than exclusive. Colour-coded recommendations on use assist physicians with drug choice. Relative costs are indicated within each therapeutic grouping. Listings indicate drugs approved for reimbursement, interchangeable medications, maximum allowable cost, drug identification number and manufacturer code. Treatment summaries provide brief overviews of therapeutic advice. Updates on new products and new or modified treatment summaries are provided every 6 months. The formulary will be the focus of coordinated educational activities on treatment for seniors and health care professionals.     

Naproxen Microparticulate Systems Prepared Using <Emphasis Type="Italic">In Situ</Emphasis> Crystallisation and Freeze-Drying Techniques

Poor drug solubility and dissolution rate remain to be one of the major problems facing pharmaceutical scientists, with approximately 40% of drugs in the industry categorised as practically insoluble or poorly water soluble. This in turn can lead to serious delivery challenges and poor bioavailability. The aim of this research was to investigate the effects of the surfactants, poloxamer 407 (P407) and caprol® PGE 860 (CAP), at various concentrations (0.1, 0.5, 1 and 3% w/v) on the enhancement of the dissolution properties of poorly water-soluble drug, naproxen, using in situ micronisation by solvent change method and freeze-drying. The extent at which freeze-drying influences the dissolution rate of naproxen microcrystals is investigated in this study by comparison with desiccant-drying. All formulations were evaluated and characterised using particle size analysis and morphology, in vitro dissolution studies, differential scanning calorimetry (DSC), and Fourier transform infra-red (FT-IR) spectroscopy. An increase in poloxamer 407 concentration in freeze-dried formulations led to enhancement of drug dissolution compared to desiccator-dried formulations, naproxen/caprol® PGE 860 formulations and untreated drug. DSC and FT-IR results show no significant chemical interactions between drug and poloxamer 407, with only very small changes to drug crystallinity. On the other hand, caprol® PGE 860 showed some interactions with drug components, alterations to the crystal lattice of naproxen, and poor dissolution profiles using both drying methods, making it a poor choice of excipient.     

Complex origin of Trinitario-type Theobroma cacao (Malvaceae) from Trinidad and Tobago revealed using plastid genomics

Trinidad and Tobago has a long history of producing high-quality cacao (Theobroma cacao L.). Cacao genotypes in Trinidad and Tobago are of a highly distinctive kind, the so-called “Trinitario” cultivar group, widely considered to be of elite quality. The origin of Trinitario cacao is unclear, although it is generally considered to be of hybrid origin. We used massive parallel sequencing to identify polymorphic plastidic single nucleotide polymorphisms (cpSNPs) and polymorphic plastidic simple sequence repeats (cpSSRs) in order to determine the origin of the Trinitario cultivar group by comparing patterns of polymorphism to a reference set of ten completely sequenced chloroplast genomes (nine T. cacao and one outgroup, T. grandiflorum (Willd. ex Spreng.) Schum). Only three cpSNP haplotypes were present in the Trinitario cultivars sampled, each highly distinctive and corresponding to reference genotypes for the Criollo (CRI), Upper Amazon Forastero (UAF) and Lower Amazon Forastero (LAF) varietal groups. These three cpSNP haplotypes likely represent the founding lineages of cacao to Trinidad and Tobago. The cpSSRs were more variable with eight haplotypes, but these clustered into three groups corresponding to the three cpSNP haplotypes. The most common haplotype found in farms of Trinidad and Tobago was LAF, followed by UAF and then CRI. We conclude that the Trinitario cultivar group is of complex hybrid origin and has derived from at least three original introduction events.     

Low-Viscosity Hydroxypropylcellulose (HPC) Grades SL and SSL: Versatile Pharmaceutical Polymers for Dissolution Enhancement, Controlled Release, and Pharmaceutical Processing

Hydroxypropylcellulose (HPC)-SL and -SSL, low-viscosity hydroxypropylcellulose polymers, are versatile pharmaceutical excipients. The utility of HPC polymers was assessed for both dissolution enhancement and sustained release of pharmaceutical drugs using various processing techniques. The BCS class II drugs carbamazepine (CBZ), hydrochlorthiazide, and phenytoin (PHT) were hot melt mixed (HMM) with various polymers. PHT formulations produced by solvent evaporation (SE) and ball milling (BM) were prepared using HPC-SSL. HMM formulations of BCS class I chlorpheniramine maleate (CPM) were prepared using HPC-SL and -SSL. These solid dispersions (SDs) manufactured using different processes were evaluated for amorphous transformation and dissolution characteristics. Drug degradation because of HMM processing was also assessed. Amorphous conversion using HMM could be achieved only for relatively low-melting CBZ and CPM. SE and BM did not produce amorphous SDs of PHT using HPC-SSL. Chemical stability of all the drugs was maintained using HPC during the HMM process. Dissolution enhancement was observed in HPC-based HMMs and compared well to other polymers. The dissolution enhancement of PHT was in the order of SE > BM > HMM > physical mixtures, as compared to the pure drug, perhaps due to more intimate mixing that occurred during SE and BM than in HMM. Dissolution of CPM could be significantly sustained in simulated gastric and intestinal fluids using HPC polymers. These studies revealed that low-viscosity HPC-SL and -SSL can be employed to produce chemically stable SDs of poorly as well as highly water-soluble drugs using various pharmaceutical processes in order to control drug dissolution.KEY WORDS: controlled release formulations, hydroxypropylcellulose, melt extrusion, solid dispersion     

Biopharmaceutics Classification System-Based Biowaivers for Generic Oncology Drug Products: Case Studies

Establishing bioequivalence (BE) of drugs indicated to treat cancer poses special challenges. For ethical reasons, often, the studies need to be conducted in cancer patients rather than in healthy volunteers, especially when the drug is cytotoxic. The Biopharmaceutics Classification System (BCS) introduced by Amidon (1) and adopted by the FDA, presents opportunities to avoid conducting the bioequivalence studies in humans. This paper analyzes the application of the BCS approach by the generic pharmaceutical industry and the FDA to oncology drug products. To date, the FDA has granted BCS-based biowaivers for several drug products involving at least four different drug substances, used to treat cancer. Compared to in vivo BE studies, development of data to justify BCS waivers is considered somewhat easier, faster, and more cost effective. However, the FDA experience shows that the approval times for applications containing in vitro studies to support the BCS-based biowaivers are often as long as the applications containing in vivo BE studies, primarily because of inadequate information in the submissions. This paper deliberates some common causes for the delays in the approval of applications requesting BCS-based biowaivers for oncology drug products. Scientific considerations of conducting a non-BCS-based in vivo BE study for generic oncology drug products are also discussed. It is hoped that the information provided in our study would help the applicants to improve the quality of ANDA submissions in the future.KEY WORDS: Biopharmaceutics Classification System, bioequivalence, biowaiver, cancer, oncology     

An Investigation into the Influence of Experimental Conditions on In Vitro Drug Release from Immediate-Release Tablets of Levothyroxine Sodium and Its Relation to Oral Bioavailability

The aim of this study was to investigate the influence of experimental conditions on levothyroxine sodium release from two immediate-release tablet formulations which narrowly passed the standard requirements for bioequivalence studies. The in vivo study was conducted as randomised, single-dose, two-way cross-over pharmacokinetic study in 24 healthy subjects. The in vitro study was performed using various dissolution media, and obtained dissolution profiles were compared using the similarity factor value. Drug solubility in different media was also determined. The in vivo results showed narrowly passing bioequivalence. Considering that levothyroxine sodium is classified as Class III drug according to the Biopharmaceutics Classification System, drug bioavailability will be less sensitive to the variation in its dissolution characteristics and it can be assumed that the differences observed in vitro in some of investigated media probably do not have significant influence on the absorption process, as long as rapid and complete dissolution exists. The study results indicate that the current regulatory criteria for the value of similarity factor in comparative dissolution testing, as well as request for very rapid dissolution (more than 85% of drug dissolved in 15 min), are very restricted for immediate-release dosage forms containing highly soluble drug substance and need further investigation. The obtained results also add to the existing debate on the appropriateness of the current bioequivalence standards for levothyroxine sodium products.KEY WORDS: bioequivalence, dissolution, immediate release, levothyroxine sodium, solubility     

Determining the Polymer Threshold Amount for Achieving Robust Drug Release from HPMC and HPC Matrix Tablets Containing a High-Dose BCS Class I Model Drug: In Vitro and In Vivo Studies

It is challenging to achieve mechanically robust drug-release profiles from hydrophilic matrices containing a high dose of a drug with good solubility. However, a mechanically robust drug release over prolonged period of time can be achieved, especially if the viscosity and amount of the polymer is sufficiently high, above the “threshold values.” The goal of this research was to determine the hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) polymer threshold amount that would enable robust drug release from matrix tablets containing a high dose of levetiracetam as a class I model drug according to the Biopharmaceutical Classification System (BCS). For this purpose, formulations containing HPC or HPMC of similar viscosity range, but in different amounts, were prepared. Based on the dissolution results, two final formulations were selected for additional in vitro and in vivo evaluation to confirm the robustness and to show bioequivalence. Tablets were exposed to various stress conditions in vitro with the use of different mechanically stress-inducing dissolution methods. The in vitro results were compared with in vivo results obtained from fasted and fed bioequivalence studies. Under both conditions, the formulations were bioequivalent and food had a negligible influence on the pharmacokinetic parameters C_max and area under the curve (AUC). It was concluded that the drug release from both selected formulations is mechanically robust and that HPC and HPMC polymers with intrinsic viscosities above 9 dL/g and in quantities above 30% enable good mechanical resistance, which ensures bioequivalence. In addition, HPC matrices were found to be more mechanically robust compared to HPMC.KEY WORDS: HPC, HPMC, matrix tablets, mechanically robust dissolution, threshold amount     

Impact of Vibration and Agitation Speed on Dissolution of USP Prednisone Tablets RS and Various IR Tablet Formulations

Dissolution testing is an in vitro procedure which is widely used in quality control (QC) of solid oral dosage forms and, given that real biorelevant test conditions are applied, can also be used as a predictive tool for the in vivo performance of such formulations. However, if a dissolution method is intended to be used for such purposes, it has to deliver results that are only determined by the quality of the test product, but not by other variables. In the recent past, more and more questions were arising on how to address the effects of vibration on dissolution test results. The present study was performed to screen for the correlation of prednisone dissolution of USP Prednisone Tablets RS with vibration caused by a commercially available vibration source as well as to investigate how drug release from a range of immediate release formulations containing class 1–4 drugs of the biopharmaceutical classification scheme is affected by vibration when performing dissolution experiments at different agitation rates. Results of the present study show that the dissolution process of oral drug formulations can be affected by vibration. However, it also becomes clear that the degree of which a certain level of vibration impacts dissolution is strongly dependent on several factors such as drug properties, formulation parameters, and the design of the dissolution method. To ensure the establishment of robust and predictive dissolution test methods, the impact of variation should thus be considered in method design and validation.KEY WORDS: dissolution, USP prednisone calibrator tablets, variability, vibration meter, vibration source     

A comparative study of the prevalence of the metabolic syndrome and its components in type 2 diabetic patients in two Caribbean islands using the new International Diabetes Federation definition

BACKGROUND AND AIM: Tobago and Trinidad are two Caribbean islands with distinct genetic background and lifestyles; while Tobago is serene and a tourist centre, Trinidad is characterized by a hustling and bustling lifestyle. The study was aimed at determining and comparing the prevalence of the metabolic syndrome (MetS) and its critical components in type 2 diabetic patients using the new International Diabetes Federation (IDF) definition. METHODS: Four hundred and thirteen (166 Tobago, 247 Trinidad) type 2 diabetic patients visiting 10 lifestyle disease clinics were studied. Blood pressure, anthropometric parameters (height, weight, body mass index and waist circumference) and overnight fasting blood samples were taken. Plasma glucose and serum triglycerides, total cholesterol, LDL- and HDL-cholesterol, insulin, and adiponectin were determined. Insulin resistance (IR) was determined using the HOMA method. RESULTS: The patients in Tobago were significantly older than patients in Trinidad (p < 0.001) but the duration of diabetes (9.4 +/- 0.5 vs. 11.1 +/- 0.7 yr), medications, generalized (31.7 vs. 38.8%) and central (78.5 vs. 83.7%) obesity were similar (p > 0.05). In comparison with patients in Tobago, diabetic patients in Trinidad, irrespective of gender, had significantly higher prevalence of IDF critical components such as raised BP, raised triglycerides and reduced HDL-cholesterol (all, p < 0.001). Thus, while more patients in Trinidad were diagnosed with MetS based on three or four components, more patients in Tobago were diagnosed based on two components (p < 0.001). CONCLUSIONS: There were high prevalence rates of the components of the MetS in both the islands of Tobago and Trinidad. Quantitatively, the aggregation of the components is higher in patients in Trinidad, which constitute greater risk for adverse cardiovascular outcome. Controlling central obesity should be the target in preventing MetS in the two islands.     

Ditosylate Salt of Itraconazole and Dissolution Enhancement Using Cyclodextrins

Salt formation has been a promising approach for improving the solubility of poorly soluble acidic and basic drugs. The aim of the present study was to prepare the salt form of itraconazole (ITZ), a hydrophobic drug to improve the solubility and hence dissolution performance. Itraconazolium ditolenesulfonate salt (ITZDITOS) was synthesized from ITZ using acid addition reaction with p-toluenesulfonic acid. Salt characterization was performed using ¹H NMR, mass spectrometry, Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The particle size and morphology was studied using dynamic light scattering technique and scanning electron microscopy, respectively. The solubility of the salt in water and various pharmaceutical solvents was found multifold than ITZ. The dissolution study exhibited 5.5-fold greater percentage release value in 3 h of ITZDITOS (44.53%) as compared with ITZ (8.54%). Results of in vitro antifungal studies using broth microdilution technique indicate that ITZDITOS possessed similar antifungal profile as that of ITZ when tested against four fungal pathogens. Furthermore, the physical mixtures of ITZDITOS with two cyclodextrins, β-cyclodextrin (β-CD), and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) were prepared in different molar ratios and were evaluated for in vitro release. It was observed that in only 30 min of dissolution study, about 74 and 81% of drug was released from 1:3 molar ratios of ITZDITOS with β-CD and ITZDITOS with HP-β-CD, respectively, which was distinctly higher than the drug released from ITZ commercial capsules (70%). The findings warrant further preclinical and clinical studies on ITZDITOS so that it can be established as an alternative to ITZ for developing oral formulations.KEY WORDS: antifungal, BCS class II, dissolution rate, insoluble, itraconazole     

Development and Validation of a Discriminative Dissolution Method for Atorvastatin Calcium Tablets using in vivo Data by LC and UV Methods

A dissolution method to analyze atorvastatin tablets using in vivo data for RP and test pilot (PB) was developed and validated. The appropriate conditions were determined after solubility tests using different media, and sink conditions were established. The conditions used were equipment paddle at 50 rpm and 900 mL of potassium phosphate buffer pH 6.0 as dissolution medium. In vivo release profiles were obtained from the bioequivalence study of RP and the generic candidate PB. The fraction of dose absorbed was calculated using the Loo–Riegelman method. It was necessary to use a scale factor of time similar to 6.0, to associate the values of absorbed fraction and dissolved fraction, obtaining an in vivo–in vitro correlation level A. The dissolution method to quantify the amount of drug dissolved was validated using high-performance liquid chromatography and ultraviolet spectrophotometry, and validated according to the USP protocol. The discriminative power of dissolution conditions was assessed using two different pilot batches of atorvastatin tablets (PA and PB) and RP. The dissolution test was validated and may be used as a discriminating method in quality control and in the development of the new formulations.     

Influence of Hydroxypropyl Methylcellulose on Metronidazole Crystallinity in Spray-Congealed Polyethylene Glycol Microparticles and Its Impact with Various Additives on Metronidazole Release

The purpose of this study was to investigate the effect of a hydrophilic polymer, hydroxypropyl methylcellulose (HPMC), on the crystallinity and drug release of metronidazole (MNZ) in spray-congealed polyethylene glycol (PEG) microparticles and to further modify the drug release using other additives in the formulation. HPMC has been used in many pharmaceutical formulations and processes but to date, it has not been employed as an additive in spray congealing. Crystallinity of a drug is especially important to the development of pharmaceutical products as active pharmaceutical ingredients (APIs) are mostly crystalline in nature. A combination of X-ray diffractometry, differential scanning calorimetry, Raman spectroscopy and Fourier transform-infrared spectroscopy (FT-IR) spectroscopy was employed to investigate the degree of crystallinity and possible solid-state structure of MNZ in the microparticles. The microparticles with HPMC were generally spherical. Spray congealing decreased MNZ crystallinity, and the presence of HPMC reduced the drug crystallinity further. The reduction in MNZ crystallinity was dependent on the concentration of HPMC. Smaller HPMC particles also resulted in a greater percentage reduction in MNZ crystallinity. Appreciable modification to MNZ release could be obtained with HPMC. However, this was largely attributed to the role of HPMC in forming a diffusion barrier. Further modification of drug release from spray-congealed PEG-HPMC microparticles was achieved with the addition of 5% w/w dicalcium phosphate but not with magnesium stearate, methyl cellulose, polyvinylpyrrolidone, silicon dioxide and sodium oleate/citric acid. Dicalcium phosphate facilitated formation of the diffusion barrier.KEY WORDS: crystallinity, drug release, hydroxypropyl methylcellulose, metronidazole, spray congealing     

Albendazole Microcrystal Formulations Based on Chitosan and Cellulose Derivatives: Physicochemical Characterization and <Emphasis Type="Italic">In Vitro</Emphasis> Parasiticidal Activity in <Emphasis Type="Italic">Trichinella spiralis</Emphasis> Adult Worms

The oral route has notable advantages to administering dosage forms. One of the most important questions to solve is the poor solubility of most drugs which produces low bioavailability and delivery problems, a major challenge for the pharmaceutical industry. Albendazole is a benzimidazole carbamate extensively used in oral chemotherapy against intestinal parasites, due to its extended spectrum activity and low cost. Nevertheless, the main disadvantage is the poor bioavailability due to its very low solubility in water. The main objective of this study was to prepare microcrystal formulations by the bottom-up technology to increase albendazole dissolution rate, in order to enhance its antiparasitic activity. Thus, 20 novel microstructures based on chitosan, cellulose derivatives, and poloxamer as a surfactant were produced and characterized by their physicochemical properties and in vitro biological activity. To determine the significance of type and concentration of polymer, and presence or absence of surfactant in the crystals, the variables area under the curve, albendazole microcrystal solubility, and drug released (%) at 30 min were analyzed with a three-way ANOVA. This analysis indicated that the microcrystals made with hydroxyethylcellulose or chitosan appear to be the best options to optimize oral absorption of the active pharmaceutical ingredient. The in vitro evaluation of anthelmintic activity on adult forms of Trichinella spiralis identified system S10A as the most effective, of choice for testing therapeutic efficacy in vivo.     

Comparison of In Vitro Release Rates of Acyclovir from Cream Formulations Using Vertical Diffusion Cells

Acyclovir, indicated in the treatment of herpes labialis (“cold sores”), is formulated as semisolid topical dosage forms and marketed in numerous countries. Since the formulations of the various acyclovir products may differ from country to country, this study was undertaken to compare the in vitro release of acyclovir from various generic cream products available on the South African and Indian markets using the respective brand/innovator product as the reference product. The in vitro studies were carried out using vertical diffusion cells with a diffusional surface area of 1.767 cm² and various commercially available membranes. Normal saline was used as receptor fluid and the temperature maintained at 32 ± 0.5°C. The in vitro release comparisons were based on the recommendations described in the US Food and Drug Administration Draft Guidance for acyclovir ointment and the SUPAC-SS Guidance for non-sterile semisolid dosage forms. The release rates (slope) of the test (T) and the relevant reference product (R) were monitored and compared. The comparative release of acyclovir from the various generic formulations compared with the reference product was found to be within the limits of 75–133.33% with a 90% confidence interval. These experiments indicate that the generic acyclovir cream formulations exhibited release rates that were comparable to the innovator product and could be considered to be bioequivalent.KEY WORDS: acyclovir cream, FDA Guidance, in vitro release, membranes, vertical diffusion cells     

Comparative In Vitro Study of Six Carbamazepine Products

The purpose of present study was to evaluate commercial preparations of carbamazepine tablets with respect to drug release through a defined sequence of experiments using Minitab software. The compliance of products with respect to United States Pharmacopeia (USP) dissolution test and comparison of the products with respect to drug release in different dissolution conditions is reported in the present paper. The different dissolution conditions studied include dissolution medium (1% SLS in purified water, 0.1 N HCl), volume (900 and 1,000 ml), rpm (50 rpm, 75 rpm). Studies indicated that all six products complied with USP dissolution criteria. However, the extent of influence of dissolution conditions on drug release was varied among the products. Distinct dissolution profiles were observed and there was no correlation with disintegration time in certain products. The in vitro dissolution experimentation helped in identifying the discriminatory dissolution conditions and also the formulations that were unaffected with change of dissolution variables. In summary, commercial preparations of carbamazepine vary widely in their dissolution behavior in multi dissolution run experimentation. Identifying this behavior of the products was essential as an in vitro tool for screening a good and a bad formulation.     

Application of microbiological assay to determine pharmaceutical equivalence of generic intravenous antibiotics

Background

Demonstration of equivalent amounts of the same active pharmaceutical ingredient (API) between generic and innovator products (pharmaceutical equivalence) is a basic requirement of regulatory agencies for intravenous generic drugs prior to clinical use, and constitutes the pivotal point to assume therapeutic equivalence. Physicochemical methods are preferred instead of biological assays to determine concentration of drugs in biological fluids, but it does not permit direct quantification of potency. Here, we report a microbiological assay using large plates designed to determine potency and concentration of pharmaceutical-grade antibiotics for injection and a statistical method to assess the in vitro equivalence of generic products with respect to the innovator.

Methods

The assay is based on the concentration-dependent variation of the inhibitory effect of antibiotics on reference bacteria (B. subtilis ATCC 6633, S. aureus ATCC 6538p and S. epidermidis ATCC 12228) in a seeded agar (Difco? Antibiotic Media), producing a concentration-response linear relationship with two parameters: y-intercept (concentration) and slope (potency). We compared the parameters of 22 generic products (amikacin 4, gentamicin 15, and vancomycin 3 products) against the innovator and the reference powder by Overall Test for Coincidence of the Regression Lines (Graphpad Prism 5.0).

Results

The validation method yielded excellent results for linearity (r² ≥ 0.98), precision (intra-assay variation ≤ 11%; inter-assay variation ≤ 10%), accuracy, and specificity tests according to international pharmacopoeial requirements. Except for one generic of vancomycin that had 25% more API (P _y-intercept = 0.001), the pharmaceutical equivalence was demonstrated in 21 generics with undistinguishable slopes and intercepts (P > 0.66). Potency estimates were 99.8 to 100.5, 99.7 to 100.2 and 98.5 to 99.9% for generic products of amikacin, gentamicin and vancomycin, respectively.

Conclusion

The proposed method allows rapid, cost-saving, precise, and accurate determination of pharmaceutical equivalence of drugs in pharmaceutical dosage-form, and may be used as a technique for testing generic antibiotics prior to their approval for human use.     

The Biopharmaceutical Properties of Solid Dosage Forms: I. An Evaluation of 23 Brands of Phenylbutazone Tablets

The potency, disintegration and dissolution characteristics of 23 brands of phenylbutazone tablets were determined. Five (21.7%) of the 23 brands failed to comply with the minimum requirements of the compendia or the regulations appended to the Food and Drugs Act. The in vitro characteristics of four brands were substantially different from those that disintegrated and released the drug satisfactorily. The in vivo characteristics of three of the four brands were compared with those observed for a pharmaceutically acceptable product. The latter product released the drug to the blood quickly, but the former products released the drug only after the tablets had been in the body for six to eight hours and, in the case of one product, released quantities much below those that would be acceptable to the physician. These results show that different products containing the same drug are not necessarily equivalent. This is contrary to the generic equivalency hypothesis which assumes that all products comply with specifications and, therefore, must be clinically effective.