Dissolution profile of different brands of low solubility drugs available in the Nigerian and Brazilian pharmaceutical markets / Dissolution profile of different brands of low solubility drugs available in the Nigerian and Brazilian pharmaceutical markets

The purpose of this work was to elaborate a diagnosis of the dissolution test in Africa in comparison with Brazil, evaluating the dissolution profile of low solubility drugs such as albendazole, ibuprofen, furosemide, glibenclamide, hydrochlorothiazide and carvedilol to ascertain their quality. The dissolution profiles were evaluated by utilizing the United States Pharmacopeia (USP). The glibenclamide medicine was evaluated according to the Food and Drug Administration (FDA), while a dissolution method was developed for the carvedilol medicine. A filter selection test for all the drugs showed that cannula is suitable for all, except for carvedilol, which is centrifuged. The various brands of Nigerian and Brazilian medicines tested showed some statistical differences. The suitable conditions that allowed the dissolution of carvedilol to be determined were the USP type II apparatus at 75 rpm containing 900 mL of acetate buffer, pH 4.5. The results of the dissolution test showed that out of the 17 different brands of Brazilian medicines and 17 different products from Nigeria, 94.12% and 58.82% passed respectively

O objetivo deste trabalho foi elaborar um diagnóstico do teste de dissolução na África em comparação ao Brasil, avaliando o perfil de dissolução de medicamentos de baixa solubilidade como albendazol, ibuprofeno, furosemida, glibenclamida, hidroclorotiazida e carvedilol para verificar sua qualidade.Os perfis de dissolução foram avaliados utilizando a Farmacopeia dos Estados Unidos (USP). O medicamento glibenclamida foi avaliado de acordo com a Food and Drug Administration (FDA), enquanto um método de dissolução foi desenvolvido para o medicamento carvedilol.Um teste de seleção de filtro para todos os medicamentos mostrou que a cânula é adequada para todos, exceto para o carvedilol, que é centrifugado. As diversas marcas de medicamentos Nigerianos e Brasileiros testadas apresentaram algumas diferenças estatísticas. As condições adequadas que permitiram a determinação da dissolução do carvedilol foram o aparelho USP tipo II a 75 rpm contendo 900 mL de tampão acetato, pH 4,5. Os resultados do teste de dissolução mostraram que das 17 diferentes marcas de medicamentos brasileiros e 17 diferentes produtos da Nigéria, 94,12% e 58,82% foram aprovados, respectivamente

Use of biorelevant dissolution media in dissolution tests as a predictive method of oral bioavailability

Abstract Dissolution is a key step in the uptake of oral drugs. In order to compare the behaviour of the dissolution of two formulations, the dissolution profile test was used. This assay must be discriminative and should mimic in vivo conditions. Many dissolution media described in pharmacopoeias are not predictive of bioavailability. Due to this, biorelevant media are used as an alternative to solve this problem. The objective of this work is to evaluate the relevance of biorelevant dissolution media to predict in vivo drug dissolution. For this, a bibliographic search was carried out in scientific databases. The search was first performed for articles verifying the physicochemical properties of human gastrointestinal fluids. Subsequently, a comparison was made between the properties of gastrointestinal fluids and those of biorelevant and pharmacopoeial media. Finally, the results of bioequivalence studies and dissolution profile tests in biorelevant media described in the literature were compared. The results revealed that there are a few publications that have analysed some physicochemical properties of gastrointestinal fluids. In addition, high variability was observed for some properties. Regarding the comparison of these properties with pharmacopoeial media and biorelevant media, the analysis showed that the biorelevant media are more similar to gastrointestinal fluids than the pharmacopoeial media. Finally, the in vitro dissolution profile results were similar to the results obtained in vivo. Thus, biorelevant media may be useful for analysing dissolution profiles.

Comparator product issues for biowaiver implementation: the case of Fluconazole

The aim of this work was to assess if the commercially available Fluconazole drug products (Reference, Generic and Similar) would meet the biowaiver criteria from Food and Drug Administration (FDA) and Brazilian Agency for Health Surveillance (ANVISA) agencies. All formulations were evaluated considering the dissolution profile carried out in Simulated Gastric Fluid (SGF) pH 1.2, Acetate Buffer (AB) pH 4.5 and Simulated Intestinal Fluid (SIF) pH 6.8. The results demonstrated that all formulations fulfilled the 85% of drug dissolved at 30 min criterion in SGF pH 1.2. However, in AB pH 4.5 and SIF pH 6.8, some formulations, including the comparator, did not achieve this dissolution percentage. The discrepant dissolution profiles also failed the ƒ2 similarity factor analysis, since none of the formulations showed values between 50 and 100 in the three dissolution media. Comparative dissolution profiles were not similar, considering that the main issues concerning the dissolution were evidenced for the comparator product. Hence, a revision in the regulatory norms in order to establish criteria to switch the comparator could result in an increased application of drugs based on biowaiver criteria

Equivalencia terapéutica in vitro de tabletas de enalapril maleato 20 mg de producción nacional / In vitro therapeutic equivalence of 20 mg enalapril maleate tablets of national production

Los ensayos de equivalencia terapéutica tienen como objetivo demostrar que los medicamentos genéricos aportan la misma cantidad de principio activo en comparación con el medicamento innovador. El objetivo de la investigación fue evaluar la equivalencia terapéutica del medicamento enalapril maleato en tabletas de 20 mg, según la clasificación biofarmacéutica que le corresponde, ya que este es un medicamento representativo de la clase III, para demostrar que tienen un perfil de tolerabilidad adecuado y que son eficaces para su prescripción médica. Por otro lado, al demostrarse la equivalencia terapéutica se puede recurrir con toda seguridad al medicamento genérico y reducir los costos de los tratamientos, con lo cual la población tendrá una oferta de medicamentos confiables, seguros y a precios económicos. Se utilizó un medicamento innovador y tres de los ocho medicamentos genéricos de fabricación y comercialización nacional, a los cuales se les determinó perfiles de disolución (F2: 45.41, 92.42, 71.04), uniformidad de contenido (AV: 7.37, 2.97, 2.50) y valoración de principio activo (%: 107.14, 98.89, 101.71) para determinar la cantidad de principio activo en las muestras. Los análisis se realizaron con base en los criterios establecidos en la Farmacopea de los Estados Unidos. Se aplicó un modelo estadístico independiente, y se estableció que dos de los tres lotes analizados de los medicamentos genéricos son equivalentes terapéuticos con el lote del medicamento innovador. Con las pruebas de disolución in vitro realizadas a lo largo de este estudio, se puede concluir que los tres lotes analizados de dos medicamentos genéricos pueden ser considerados intercambiables con respecto al lote del medicamento innovador.

The therapeutic equivalence essays to demonstrate that generic medicine can provide the same amount of active ingredient compared to the innovative medicine. The objective of this research was to evaluate the therapeutic equivalence of enalapril maleate 20 mg, according to the biopharmaceutical classification, given that this is a representative class III drug. This to demonstrate that it has an acceptable tolerability profile and that it is effective for medical prescription. Once the therapeutic equivalence is stablished, the use of therapeutic bioequivalence products can reduce treatment costs, so that the general public can have access to reliable, safe and affordable medicines. For this study an innovative medicine and three of the eight generic medicines of national manufacture and commercialization were used for each medicine, the dissolucion profiles (F2: 45.41, 92.42, 71.04), the uniformity of content (AV: 7.37, 2.97, 2.50) and percentage of active ingredient (%: 107.14, 98.89, 101.71) were determined. The essays were performed based on the criteria established in The United States Pharmacopeia and were satisfactory in all the analyzed batches. An independent statistical model was carried out it was established, that two of the three analyzed batches for generic medicine are therapeutic equivalents with the batch of the innovative drug. In vitro dissolution tests obtained throughout this study, concluded that the three analyzed batches of two generic medicines can be considered interchangeable in respect to the batch of the innovative medicine.

Equilibrium solubility study to determine fexofenadine hydrochloride BCS class and challenges in establishing conditions for dissolution profiles applied to suspension

The aim of this work was to perform solubility studies for fexofenadine hydrochloride and establish dissolution conditions for this drug in oral suspension dosage form. The solubility study was executed through the shake-flask method, below 37 ºC±1 ºC, at 100 rpm stirring for 12 h in three buffer solutions: hydrochloric acid pH 2.0, acetate pH 4.5 and phosphate pH 6.8. The dissolution test was developed in vessels containing 900 mL of the same buffer, employing the paddle apparatus in speed of 25 and 50 rpm, below 37 ºC±0.5 ºC. The drug was classified as low solubility according to the Biopharmaceutics Classification System, since the dose/solubility ratio was higher than 250 mL in all media tested (326.55 mL in buffer pH 2.0; 2,456.33 mL in buffer pH 4.5 and 1,021.16 mL in buffer pH 6.8). The dissolution test showed that a release of 85% in 30 min could be established. The rotation speed of 25 rpm, media volume of 900 mL and insertion of the samples through weighted syringes are adequate. The buffered media pH 2.0 could be chosen as dissolution media.

Combinação dose fixa de hidroclorotiazida (12, 5 mg) e valsartana (160 mg): Desenvolvimento de metodologia de dissolução in vitro e in silico para avaliar os perfis de dissolução dos produtos comercializados no Brasil e Peru / Fixed dose combination of hydrochlorothiazide (12. 5 mg) and valsartan (160 mg): Development of in vitro and in silico dissolution methodology to evaluate the dissolution profiles of products marketed in Brazil and Peru

Hidroclorothiazida (HTZ) e valsartana (VAL) são fármacos pouco solúveis em meio aquoso e pertencem às classes IV e II do Sistema de Classificação Biofarmacêutica (SCB), respectivamente. O objetivo deste trabalho foi desenvolver um método para avaliar o perfil de dissolução de formas farmacêuticas sólidas de dose fixa combinada contendo HTZ (12,5 mg) e VAL (160 mg) usando ferramentas in silico para avaliar os perfis de dissolução de produtos comercializados no Brasil e Peru. O presente trabalho foi dividido em 4 capítulos. No Capítulo I, foi determinada a solubilidade da HTZ e VAL pelo método shake-flask e potenciométrico, no qual foi possível demonstrar que existe correlação entre ambos os métodos e que HTZ e VAL são solúveis em tampão fosfato pH 6,8. No Capítulo II, um método cromatográfico em HPLC foi desenvolvido com base em Quality by Design (QbD), com auxílio do software Fusion®, no qual foi estabelecido uma zona de confiança dos parâmetros, que garantiu a robustez do método. O Capítulo III descreve o desenvolvimento de um método de dissolução utilizando ferramenta in silico (DDDplus®) na qual foi definido um delineamento experimental do tipo fatorial completo 33 usando como fatores a formulação, utilização de âncora e velocidade de agitação. Para os ensaios de dissolução in vitro, foi proposto um outro delineamento fatorial 3(3-1) com o intuito de obter as constantes de calibração das simulações in silico. Através de uma análise estatística das eficiências de dissolução obtidas nas simulações, foram avaliados os efeitos e as interações entre os fatores. Assim, as condições finais do método de dissolução estabelecidas foram: 900 mL de tampão fosfato pH 6,8 como meio de dissolução, 75 rpm de velocidade de agitação, e utilização de âncora para evitar a flutuação das formulações. O método desenvolvido foi empregado, no contexto do Capítulo IV, para avaliar o perfil de dissolução dos produtos contendo HTZ e VAL comercializados no Brasil e no Peru. Por análise multivariada, a eficiência de dissolução (ED), tempo médio de dissolução (MDT) e as porcentagens de dissolução de 5 até 60 minutos foram utilizadas para agrupar as formulações em grupos distintos. Embora os perfis de dissolução mostrem similaridade entre todas as formulações avaliadas, o produto referência se destacou por apresentar uma maior ED comparado com as outras formulações, devido à maior liberação nos primeiros 5 minutos de ensaio. Concluiu-se que o método proposto, além de garantir a liberação total de HTZ e VAL a partir das formulações, possui adequado poder discriminativo

Hydrochlorothiazide (HTZ) and valsartan (VAL) are poorly soluble drugs in aqueous medium and belong to classes IV and II of the Biopharmaceutical Classification System (BCS), respectively. The objective of this study was to develop a dissolution method to evaluate the dissolution profile of solid pharmaceutical forms of combined dose containing HTZ (12.5 mg) and VAL (160 mg) using in silico tools to evaluate the dissolution profiles of products sold in Brazil and Peru. The present study was divided into four chapters. In Chapter I, the HTZ and VAL solubility were determined by the shake-flask and potentiometric methods, in which it was possible to demonstrate that there is a correlation between both methods and that HTZ and VAL are soluble in pH 6.8 phosphate buffer. In Chapter II, a chromatographic method in HPLC was developed based on Quality by Design (QbD), using the Fusion® software, in which a zone of confidence of the parameters was established, which ensured the robustness of the method. Chapter III presents the development of a dissolution method using in silico (DDDplusTM) as a tool, in which an experimental design of the complete factorial type 33 was defined using as factors: the formulation, use of sinker and agitation speed. For in vitro dissolution assays, another factor design 3(3-1) was proposed to obtain the calibration constants of the in silico simulations. Through a statistical analysis of the dissolution efficiencies obtained in the simulations, the effects and interactions between the factors were evaluated. Thus, the final conditions of the dissolution method established were: 900 mL of pH 6.8 phosphate buffer as a dissolution medium, 75 rpm of stirring speed, and use of sinker to avoid the fluctuation of the formulations. The method developed was used, in the context of Chapter IV, to evaluate the dissolution profile of HTZ and VAL products marketed in Brazil and Peru. By multivariate analysis, the dissolution efficiency (ED), mean dissolution time (MDT) and the dissolution percentages from 5 to 60 minutes were used to group the formulations in different groups. Although the dissolution profiles show a similarity between all the evaluated formulations, the reference product stood out for presenting a higher ED compared to the other formulations, due to the higher release in the first 5 minutes of the test. It was concluded that the proposed method, besides guaranteeing the total release of HTZ and VAL from the formulations, has adequate discriminatory capacity

Avaliação da equivalência farmacêutica de comprimidos de Ibuprofeno por meio do teste perfil de dissolução / Evaluation of the pharmaceutical equivalence of ibuprofen tablets by dissolution profile test

Introdução: Em formas farmacêuticas sólidas orais como comprimidos, o perfil de dissolução comparativo representa o principal teste de avaliação da equivalência farmacêutica. Objetivo: comparar os perfis de dissolução de comprimidos de ibuprofeno 600mg nas formas de referência, genérico e similar. Material e método: Uma curva de calibração de ibuprofeno foi construída com cinco pontos (2, 3, 5, 10 e 15 ppm) com o objetivo de se obter os coeficientes linear, angular e de correção. A partir disto, foram realizados os ensaios de perfil de dissolução em sextuplicata, segundo parâmetros farmacopéicos com 900 mL de tampão fosfato pH 7,2, cesta como aparato, velocidade de rotação de 150 rpm e amostras coletadas em intervalos de 5, 10, 15, 20 e 30 minutos. As alíquotas obtidas foram filtradas e diluídas para a concentração adequada e analisadas em comprimento de onda de 221 nm, para a determinação da porcentagem de dissolução em cada intervalo de tempo amostrado. Resultados: Todos os tipos de medicamentos estavam de acordo com as especificações farmacopeias quanto à porcentagem de dissolução (mínimo 60%) em até 30 minutos. Além disso, segundo os parâmetros da RDC nº 31 de 11 de agosto de 2010 da Agência Nacional de Vigilância Sanitária, os valores de coeficiente de variação no tempo de 10 minutos não excederam a 10%, indicando assim equivalência farmacêutica entre as amostras avaliadas. Conclusão: Com base nos resultados obtidos através dos valores de coeficiente de variação, conclui-se que há equivalência farmacêutica entre as amostras.

Introduction: in solid oral dosage forms as tablets, the comparative dissolution profile represents the main test for the evaluation of pharmaceutical equivalence. Objective: compare the dissolution profiles of ibuprofen 600mg tablets in reference, generic and similar forms. Material and method: a calibration curve of ibuprofen was constructed with five points (2, 3, 5, 10 and 15 ppm) in order to obtain the linear, angular and correction coefficients. From this, dissolution profile assays were carried out in sixfold, according to pharmacopoeial parameters with 900 mL of pH 7.2 phosphate buffer, basket as apparatus, rotation speed of 150 rpm and samples collected at intervals of 5, 10, 15 , 20 and 30 minutes. The obtained aliquots were filtered and diluted to the appropriate concentration and analyzed at a wavelength of 221 nm to determine the percent dissolution at each sampled time interval. Results: all drug types were in accordance with the pharmacopoeial specifications for percent dissolution (minimum 60%) within 30 minutes. In addition, according to the parameters of the RDC nº 31 of August 11, 2010 of the National Agency of Sanitary Surveillance the values of coefficient of variation in the time of 10 minutes did not exceed 10%, thus indicating pharmaceutical equivalence among the evaluated samples. Conclusion: based on the results obtained through the coefficient of variation values, it is concluded that there is a pharmaceutical equivalence between the samples.

Preliminary Prediction of Bioequivalence of Leflunomide Tablets Based on Analysis of Solublility and Permeability / 中国药学杂志

OBJECTIVE: To discuss whether the difference in dissolution profile in vitro may cause different bioavailability in vivo and investigate the effects of the key quality parameters of leflunomide on bioavailability. METHODS: Using SANOFI product as the reference preparation and domestic product as the test preparation, the disintegration solution of leflunomide tablets was analyze by Morphologi G3-ID automated measurement to get the paricile size and size distribution of the API; using pH 6.5 FaSSIF solution without adding ox-gall sulfonic acid sodium and lecithin as the dissolution medium, the dissolution and permeation profiles of the reference and test preparations and raw material were compared at 37 ℃ with rotate speed of 150 r•min-1. The influence of quality parameters on the process of API's release and absorption was investigated, then the difference between the reference and test preparations were compared to preliminarily predict the bioavailability and bioequivalence. RESULTS: The particle size Dv(50)of domestic leflunomide tablets was 79.80 μm, while the particle size Dv(50)of the reference product was 17.60 μm; the dissolution rate and penetration rate of the test preparation were about 70% of the reference preparation, the tmax was basically identical,but the ρmax and AUC0-t were lower than the reference preparation. The bioavailability of the test preparation was about 90% of the reference preparation. CONCLUSION: Though the dissolution profile of domestic leflunomide tablets is not identical to the reference preparation, but the two products were predicted to be bioequivalent.

Preparation of irbesartan tablets and consistency study of their dissolubility / 药物评价研究

Objective To prepare generic irbesartan tablets and to evaluate its consistency of dissolution tests.Methods Using the original drugs (irbesartan) as reference drug,the single factor experiments were applied to investigating the type and amount of adhesive,tablet hardness,water content of tablets,and coating weight.ZRS-8G Dissolution Tester was used to conduct the dissolution tests which were carried on four different dissolution media.Then the similar factor (f2) was adopted to evaluate the similarity of dissolution between the original drug and generic drug.Results As the stabilizer,3％ HPMC-E5 was more stable than 5％ PVP K30.It had no difference of dissolution between original and generic drugs when the amount of adhesive,tablets hardness and water content were within the range of investigation.And the coating weight was 2％ to 3％.Moreover,the f2 values of original drug and generic drug were all greater than 50 in different dissolution media.Conclusion Thef2 results indicate a similarity in the dissolution behavior of reference drug and generic irbesartan tablets prepared by the single factor experiments.And the preparation process of generic irbesartan tablets is stable.

Similarity Investigation on Dissolution Curves of Metronidazole Tablets from Different Manufacturers / 医药导报

Objective To compare the dissolution curves of metronidazole tablets from 38 national manufactures and original drugs of Britain in four dissolution mediums,and provide the reference for the quality and clinical effect consistency evaluation of metronidazole tablets.Methods Paddle method was adopted at 50 r · min-1 in four dissolution mediums with the volume of 900 mL.The dissolution profiles were determined by ultraviolet spectrophotometry.The cumulative dissolution percentages were calculated and the dissolution curves were drawn.Similarity factor (f2)was used for comparing of the differences between dissolution curves.Results The dissolution profiles of 4 manufactures in pH 1.2 and 9 manufactures in pH 4.5 were similar (f2 ≥ 50)to that of original drugs,only 1 and 3 were similar to original drugs in water and pH 6.8,respectively.There are no companies whose dissolution curve were similar to that of original drugs in 4 dissolution mediums.Conclusion Great difference exists between domestic manufactures and pharmaceutical enterprises of origin in dissolution behaviors of metronidazole tablets.In order to ensure the consistency between the metronidazole tablets generics and original drugs of Britain in quality and clinical effect.It is advisable for the relevant companies to improve their product quality by improving the formulation and preparation.

Analysis of spironolactone polymorphs in active pharmaceutical ingredients and their effect on tablet dissolution profiles

ABSTRACT Spironolactone (SPR) is a steroidal drug administered as a potassium-sparing diuretic for high blood pressure treatment. The drug shows incomplete gastrointestinal absorption due to its poor aqueous solubility. The physicochemical properties of SPR in crystal forms I and II suggest that differences in their aqueous solubility may lead to a lack of bioequivalence between solid-state formulations. In this study, SPR polymorphs in five batches of active pharmaceutical ingredients (APIs) from three manufacturers were characterized using powder X-ray diffraction, infrared spectroscopy, thermal analysis, and solubility measurements. SPR tablets (50 mg) were manufactured in our laboratory using API in pure form II, and API in form II contaminated with form I, which was found in a commercial batch. Physicochemical quality evaluations of the manufactured tablets, along with five SPR tablets marketed in Brazil, were performed, and results indicated differences in their dissolution profiles. In the manufactured tablets, differences were associated with the increased solubility of API in form II contaminated with form I compared to API in pure form II. In the marketed SPR tablets, the formulation composition demonstrated an important role in the dissolution rate of the drug, leading to lack of pharmaceutical equivalence among the drug products.

In-vitro bioequivalence, physicochemical and economic benefits study for marketed innovator and generic ciprofloxacin hydrochloride tablets in Saudi Arabia.

The objective of the present study was to compare and evaluate the economic benefits and in-vitro bioequivalence of different marketed generic ciprofloxacin tablets against the innovator tablet formulation that are present in the local market of Saudi Arabia. The comparative bioequivalence and physicochemical study of five ciprofloxacin marketed tablets were performed through the assessment of the uniformity of weight, hardness, disintegration, dissolution, and content assay of the products. In order to compare the dissolution profiles of all generic tablet formulations and the innovator, a model independent approach of similarity factor (f2) and difference factor (f1) was employed in the in vitro dissolution studies. Deviations were noted in two generic products, these deviations caused significant differences in disintegration time and dissolution profile in only one of the generic products. All tested generic products passed USP monograph dissolution testing except one product which failed to pass both similarity factor (f2) and difference factor (f1) tests required by FDA bioequivalence testing. The majority of generic products in Saudi Arabia which had lower prices showed comparable quality to innovator.

Functionality of Benecel K4M/Carbopol 971P NF matrices in direct compression tablets for controlled release.

The aim of this work is the assessment of the eventual enhancing effects of Carbopol 971P NF on the performance of Benecel K4M as a controlled release agent and its impact on other technological properties such as compactibility and powder flowability. The effect of Carbopol 971P NF and Benecel K4M in the performance of metronidazole tablets with controlled release was assessed using dissolution and compactibility profiles and the flowability of powders. Benecel K4M produces release profiles with an average exponent n=0.711 while Carbopol 971P NF displays average values of n=1.19. The values for tablets containing equal parts of Carbopol 971P NF and Benecel K4M was an average of n=0.947. Metronidazole tablets containing the Benecel K4M/Carbopol 971P NF blend shows a compactibility 2-3 times higher than tablets containing only Benecel K4M. Metronidazole/Benecel K4M blends flow sufficiently at all studied polymer proportions (≤ 30%) while admixtures of metronidazole/Benecel K4M with Carbopol 971P NF flow sufficiently only at polymer proportions ≤ 17%. Carbopol 971P NF enhances the overall performance of Benecel K4M in the same way as Noveon AA1 does, it reduces better the drug release and improves the compactibility, although decreases the flowability.

Quality Evaluation and Study of Dissolution Determination for Compound Norethisterone Tablet / 中国药房

OBJECTIVE:To evaluate the inherent quality differences of different batches of Compound norethisterone tablet from different domestic enterprises by researching its in vitro dissolution,to provide reference for improving relevant standards in pharmacopoeia and optimizing production processes in drug manufacturers. METHODS:Orthogonal test was adopted to screen its dissolving conditions,small glass method was finally confirmed by detecting rotating speed,sampling time and dissolution medi-um,sampling determination was conducted with the dissolution medium of 0.5% sodium dodecyl sulfonate and rotating speed of 50 r/min and 45 min. And HPLC was adopted to simultaneously determine the in vitro dissolution of norethindrone and ethinyl estra-diol,then AV value method was adopted to detect the similarity of dissolution profiles of 8 batches of products from 2 domestic en-terprises. RESULTS:The dissolution profiles and similarity of AV value method showed the cumulative dissolution of 8 batches of Compound norethisterone tablet from 2 domestic enterprises had no significant difference at different time points,overall similarity was relatively high;but the ethinyl estradiol had certain difference,overall similarity was relatively low. CONCLUSIONS:The dif-ference of dissolution profiles of Compound norethisterone tablet may has effect on the drug efficacy,the production process and quality in domestic enterprises should be managed strictly. Meanwhile,the current method of dissolution is weak to distinguish from the quality,which needs to be improved urgently.

Comparative Study on Dissolution Profiles of Ibuprofen Suspension from Different Pharmaceutical Manu-facturers / 中国药师

Objective:To compare the similarity of dissolution curves of domestic ibuprofen suspension and the imported prepara-tion to provide the basis for the comprehensive quality evaluation of ibuprofen suspension. Methods: The in vitro dissolution of the products from four different manufacturers was investigated in pH 7. 2 phosphate buffer solution. The similarity of dissolution behavior was compared with that of the imported preparation in pH 1. 2 hydrochloric acid solution, pH 4. 5 acetate buffer solution, pH 6. 8 phos-phate buffer solution, pH 7. 2 phosphate buffer solution and water, respectively. Results:The dissolution rate of ibuprofen suspension from the four different manufacturers reached above 80% in 60 min. The dissolution profiles of ibuprofen suspension from two different manufacturers were similar with that of the imported preparation. Conclusion: The dissolution behavior of ibuprofen suspension from different manufacturers is significantly different.

Quality Consistency Evaluation of Omeprazole Enteric-coated Capsules / 中国药师

Objective:To establish a method for the determination of omeprazole delayed release capsules and investigate the be-havior of reference preparations to provide experimental basis for generic drugs quality consistency evaluation. Methods:According to the first dissolution method (basket method) stated in 0. 931 of Chinese Pharmacopeia (2015 edition), the type of release media, solu-bility and stability of omeprazole in different media, effect of different treatment methods on the drug adsorption in the solution, differ-ent rotation speed and the methodology of ultraviolet spectrophotometry were investigated. Results:The rotation speed was 75 r·min-1 with the dissolution medium volume of 900 ml. The dissolution profiles of omeprazole delayed release capsules in three different media ( pH 6. 0 phosphate buffer, pH 6. 8 phosphate buffer and water containing 3% Tween-80) were determined with online filteration. The solubility of omeprazole in the different media was 0. 123, 0. 078 and 0. 275 mg·ml-1 , respectively. The results showed that ome-prazole was degraded 44%, 8% and 14% in 2 h in the above three release media, and degraded up to 43% in 6 h in water containing 3% Tween-80. The linear of omeprazole was 0. 209 4-20. 94, 0. 204 8-20. 48 and 0. 2016-20. 16 μg·ml-1 with the average recovery of 99.3% (RSD=0.7%,n=12), 99.7% (RSD=0.9%,n=12) and 99.5% (RSD=0.6%,n=12) respectively in the three media. Conclusion:The method is accurate and reliable, which can be used to study the quality consistency of omeprazole delayed re-lease capsules.

Amiodarone hydrochloride: enhancement of solubility and dissolution rate by solid dispersion technique

abstract Amiodarone HCl is an antiarrhythmic agent, which has low aqueous solubility and presents absorption problems. This study aimed to develop inclusion complexes containing hydrophilic carriers PEG 1500, 4000 and 6000 by fusion and kneading methods in order to evaluate the increase in solubility and dissolution rate of amiodarone HCl. The solid dispersion and physical mixtures were characterized by X-ray diffraction, FT-IR spectra, water solubility and dissolution profiles. Both methods and carriers increased the solubility of drug, however PEG 6000 enhanced the drug solubility in solid dispersion better than other carriers. Different media were evaluated for the solubility study, including distilled water, acid buffer pH 1.2, acetate buffer pH 4.5 and phosphate buffer pH 6.8 at 37 ºC. Based on the evaluation of the results obtained in the study phase solubility carriers PEG 4000 and PEG 6000 were selected for the preparation of the physical mixture and solid dispersion. All formulations were prepared at drug-carrier ratios of 1:1 to 1:10(w/w). The results of in vitro release studies indicated that the solid dispersion technique by fusion method in proportion of 1:10 (w/w) increased significantly the dissolution rate of the drug. X-ray diffraction studies showed reduced drug crystallinity in the solid dispersions. FT-IR demonstrated interactions between the drug and polymers.

resumo Cloridrato de amiodarona é um agente antiarrítmico que possui baixa solubilidade aquosa e apresenta problemas de absorção. Este estudo teve como objetivo desenvolver complexos de inclusão contendo carreadores hidrofílicos PEG 1500, 4000 e 6000 através dos métodos de fusão e amassamento para avaliar o aumento da solubilidade e taxa de dissolução do cloridrato de amiodarona. As dispersões sólidas e misturas físicas foram caracterizadas por difração de raios-X, espectroscopia no infravermelho com transformada de Fourier, solubilidade em água e perfis de dissolução. Ambos os métodos e carreadores aumentaram a solubilidade do fármaco, no entanto o PEG 6000 aumentou a solubilidade do fármaco na dispersão sólida mais que os outros carreadores. Diferentes meios foram avaliados para o estudo de solubilidade, incluindo água destilada, tampão ácido pH 1,2, tampão acetato pH 4,5 e tampão fosfato pH 6,8. Com base na avaliação dos resultados obtidos no estudo de solubilidade de fases, os carreadores PEG 4000 e PEG 6000 foram selecionados para a preparação das misturas físicas e dispersões sólidas. Todas as formulações foram preparadas nas razões fármaco-carreador de 1:1 a 1:10 (p/p). Os resultados de liberação in vitro que a técnica de dispersão sólida pelo método de fusão na proporção 1:10 (p/p) aumentou significativamente a taxa de dissolução do fármaco. Estudos de difração de raios-X mostraram redução da cristalinidade do fármaco na dispersão sólida. Análise por espectroscopia no infravermelho mostrou interações entre o fármaco e o carreador.

Influence of different types of lactose on powder flow and tablets dissolution.

The objective of this study was the evaluation of different types of lactose on the powders flow properties and dissolution of tablets of formulations with captopril and amoxicillin. Data of powders flow rate, compressibility index and dissolution profiles of tablets are presented. The powders flow rate showed higher sensitivity to small changes in their properties, compared to compressibility index. SuperTabs 21AN and 24AN flow at least 20 times faster than Lactopress and lactose NF. Lubrication increases the flow rate, maintaining the observed comparative differences. Dilution of lactoses with 50% captopril or amoxicillin reduces drastically the powder flow, producing also an equalizing effect. The greater flowability of SuperTabs, compared to other types of lactose, practically disappears. Dissolution of lubricated and unlubricated lactose tablets show a much faster dissolution of SuperTab 21AN tablets followed by Lactopress, lactose NF and SuperTab 24AN tablets. Dilution of lactoses with 50% captopril displays a quite smaller dissolution rate with a comparative similar behavior as observed before while dilution with amoxicillin show an equalizing effect of drug dissolution with minor differences between lactoses. The effect of lactose excipients on dissolution is attributed in a greater extent to mechanical properties of their tablets than to differences in solubility and dissolution.

Formulation design and characterization of a non-ionic surfactant based vesicular system for the sustained delivery of a new chondroprotective agent

Diacerein is used for symptomatic relief and cartilage regeneration in osteoarthritis. Due to gastrointestinal side effects, poor aqueous solubility and low bioavailability, its clinical usage has been restricted. The objective of the present study was to enhance its dissolution profile and to attain sustained release by designing a novel delivery system based on niosomes. Five niosomal formulations (F1-F5) with non-ionic surfactant (sorbitan monostearate) and cholesterol in varying ratios of 5:5, 6:4, 7:3, 8:2 and 9:1 were developed by the reverse-phase evaporation technique. The size and polydispersivity index (PDI) were found in the range of 0.608 µm to 1.010 µm and 0.409 to 0.781, respectively. Scanning electron microscopy (SEM) of the selected formulation (F3) revealed spherical vesicles, and 79.8% entrapment was achieved with F3 (7:3). Dissolution studies using the dialysis method showed sustained release behaviour for all formulations. The optimized surfactant-to-cholesterol concentration (7:3) in formulation F3sustained the drug-release time (T50%) up to 10 hours. Kinetic modelling exhibited a zero-order release (R2=0.9834) and the release exponent 'n' of the Korsmayer-Peppas model (n=0.90) confirmed non-fickian and anomalous release. The results of this study suggest that diacerein can be successfully entrapped into niosomes using sorbitan monostearate and that these niosomes have the potential to deliver diacerein efficiently at the absorption site.

A diacereína é usada para o alívio sintomático e para a regeneração da cartilagem na osteoartrite. Devido aos efeitos adversos gastrointestinais, baixa solubilidade aquosa e biodisponibilidade, o seu uso clínico tem sido restrito. O objetivo do presente estudo foi melhorar o perfil de dissolução deste fármaco e obter liberação prolongada através do planejamento de um novo sistema de liberação designado de niossoma. Cinco formulações distintas de niossomas (F1 a F5) contendo tensoativos não iônicos (monoestearato de sorbitano) e colesterol, em diferentes proporções, de 5:5, 6:4, 7:3, 8:2 e 9:1, foram desenvolvidas através da técnica de evaporacão de fase reversa. Os tamanhos e índices de polidispersibilidade (PDI) obtidos variam entre 0,608 e 1,01 µm e entre 0,409 e 0,7781, respectivamente. Imagens de microscopia electrônica de varrimento (SEM) da formulação selecionada (F3) revelaram vesículas esféricas. Obteve-se encapsulação de 79,8% com a formulação F3 (7:3). Estudos de dissolução usando o método de diálise demonstraram padrão de liberacão prolongada para todas as formulações. A proporção de tensoativo e colesterol (7:3) na formulacão F3 prolongou o tempo de liberação do fármaco (T50%) até 10 horas. Estudos de modelação cinética demonstraram ordem de liberacão zero (R2=0,9834) e o expoente de liberação "n" do modelo de Korsmayer-Peppas (n=0.90) confirmou a liberação não-fickiana e anômala. Os resultados deste estudo sugerem que a diacereína pode ser encapsulada com sucesso no interior de niossomas, utilizando monostearato de sorbitano, o qual tem potencial para liberar, eficientemente, a diacereína no local de absorção.

Application of drug release model in design of tacrolimus sustained-release pellets prescription / 中国药学杂志

OBJECTIVE: To design tacrolimus sustained-release pellets formula by surface degradation and erosion model, and improve the design accuracy and pertinence. METHODS: The relationship between the prescription and the surface degradation rate constant K was determined by simplex centroid design. The relationship between dissolution prediction and formulation was established and used to direct the formulation design according to the requirements of the expected dissolution. The dissolution profiles obtained by the model prediction and actual experiment were compared through hot-melt coating technology. RESULTS: The dissolution profile similarity factor f2 was over 75 between the measured and predicted dissolution profiles, and the single point error of dissolution was below 5%. CONCLUSION: Using the established model, the formula of tacrolimus sustained-release pellets can be quickly and accurately designed according to the dissolution requirement.