Dissolution test for oral suspension: an overview about use and importance

Abstract This work aims to ascertain the comprehensiveness of dissolution tests for oral suspensions registered in Brazil and the USA. After consulting literature since 1994, a paucity of information about dissolution methods for suspensions was detected. It makes it difficult to establish the most appropriate test parameters. In January, 2019, there were 46 drugs registered in Anvisa (Brazil) as oral suspension, being 47 reference, 173 generic and 114 interchangeable similar (IS) medicines; while in the USA, 90 drugs were registered as oral suspension by FDA, 235 Abreviatted New Drug Application and 111 New Drug Application medicines. Out of 46 and 90, only six and 15 drugs as oral suspension had a pharmacopeial dissolution test, corresponding to 70 (20.9%) and 82 (23.7%) products in Brazil and the USA, respectively. Dissolution studies were found for 17 drugs as oral suspension in the non-compendial literature. Dissolution test conditions were established to few marketable oral suspension drugs, most of which are BCS class II or IV. Thus, investing in dissolution studies could subsidize the registration of these products by regulators, especially for generic and IS drugs, by comparing dissolution profiles, and predicting their in vivo behavior to avoid exposure of healthy individuals to clinical research.

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.

A qualidade, o custo e a dispensação de sinvastatina cápsulas em farmácias magistrais / Quality, cost and dispensing of simvastatin capsules at compounding pharmacies

Com base na RDC/ANVISA 67/2007, avaliou-se o serviço prestado na dispensação de sinvastatina cápsulas em farmácias magistrais. Vinte e quatro (16%) das 150 farmácias magistrais foram aleatoriamente selecionadas nas regiões de Belo Horizonte-MG, observando a distribuição geográfica. A qualidade do produto, os aspectos da dispensação e o custo foram considerados em estudos de correlação. Os resultados foram submetidos a análises estatísticas descritivas e inferenciais. Em apenas 25% destas farmácias, o fax da prescrição foi solicitado. Todos os pedidos foram entregues no prazo, porém sem comprovação da dispensação. Em uma das entregas, o medicamento era o incorreto. Seis (25%) dos produtos apresentaram rotulagem incompleta (ausência de posologia 16,3% ou de identificação do médico/paciente 8,7%). Apenas 11 (45,8%) das amostras apresentaram qualidade satisfatória. O custo do medicamento manipulado variou entre R$20,40 e R$44,00 com valor médio R$31,18. Não se observou associação entre a qualidade do medicamento e os aspectos do custo, prazo de entrega e localização geográfica. Verifica-se que a maioria das farmácias magistrais ainda precisa adequar-se à legislação para garantir à população uma assistência farmacêutica de qualidade.

The aim of the present study was to evaluate the dispensing of simvastatin capsules at compounding pharmacies in light of Brazilian public health regulations (RDC/ANVISA 67/2007). Twenty-four (16%) out of 150 compounding pharmacies were randomly selected in the city of Belo Horizonte based on geographic distribution among the different districts. Dispensing services, quality and cost were considered in the correlation studies. The results were submitted to descriptive and inferential statistical analyses. The prescription fax was requested in only 25% of the pharmacies. All orders were delivered on time, but without proof of dispensing. The medication was incorrect in one of the deliveries. Six (25%) product labels were incomplete (16.3% for absence of drug regimen; 8.7% for absence of physician/patient identification). Only 11 (45.8%) of the samples exhibited satisfactory quality. The cost of the compounded drug ranged from R$20.40 to R$44.00 (mean: R$31.18). No association was found between drug quality and cost, delivery or geographic location. In conclusion, the majority of compounding pharmacies need to make adjustments in order to meet the requirements of Brazilian legislation and ensure the quality of pharmaceutical services offered to the population.

Quality evaluation of simvastatin compounded capsules / Avaliação da qualidade de cápsulas manipuladas de sinvastatina

Simvastatin is commercially available as tablets and compounded capsules in Brazil. Very few reports regarding these capsules' quality, and consequently their efficacy, are available. The pharmaceutical quality of 30 batches of 20 mg simvastatin capsules from the market was evaluated by weight determination, content uniformity, disintegration (Brazilian Pharmacopeia), assay and dissolution test (USP32 tablet monograph). A HPLC method was developed for assay, content uniformity and dissolution test, and specifications were also established. Out of the 30 batches evaluated, 29 showed capsule disintegration within 45 min and individual weight variation was within ±10 percent or ±7.5 percent relative to average weight, for < or > 300 mg, respectively. Only 27 batches met dissolution test criteria with values >80 percent of the labeled amount in 45 min; 21 batches showed simvastatin content between 90.0-110.0 percent of the labeled amount and 19 batches had at least 9 out of 10 capsules with content uniformity values between 85.0-115.0 percent of the labeled amount with RSD<6.0 percent. Only 14 of all (30) batches fully met pharmacopeial quality standards. The establishment of test conditions and specification parameters for simvastatin capsules showed that there are relevant pharmacopeial quality differences between batches compounded by different pharmacies. For 53.33 percent of the tested products hypercholesterolemic treatment efficacy may be compromised.

No Brasil, a sinvastatina está comercialmente disponível na forma de comprimidos e cápsulas manipuladas. Poucos relatos estão disponíveis sobre a qualidade e, consequentemente, a eficácia dessas cápsulas. A qualidade de 30 lotes de sinvastatina 20 mg cápsulas do mercado foi avaliada através da determinação de peso, uniformidade de conteúdo, desintegração (Farmacopéia Brasileira), doseamento e teste de dissolução (monografia comprimidos USP32). Método por CLAE foi desenvolvido para o doseamento, uniformidade de conteúdo e teste de dissolução; além disso, especificações foram estabelecidas. Dos 30 lotes avaliados, 29 apresentaram desintegração da cápsula até 45 min e a variação do peso individual foi ± 10 por cento ou ± 7,5 por cento em relação ao peso médio, se < ou > 300 mg, respectivamente. Apenas 27 lotes preencheram os critérios do teste de dissolução com valores > 80 por cento da quantidade rotulada, em 45 min, 21 lotes apresentaram conteúdo de sinvastatina entre 90,0-110,0 por cento do valor rotulado e 19 lotes apresentaram pelo menos 9 em 10 cápsulas, com valores de uniformidade de conteúdo entre 85,0 -115,0 por cento da quantidade rotulada com RSD < 6,0 por cento. Apenas 14 de todos os lotes (30) atenderam completamente os padrões de qualidade farmacopéicos. O estabelecimento das condições para os testes e de especificações para os parâmetros das cápsulas de sinvastatina mostrou que houve diferenças relevantes na qualidade farmacopeica entre os lotes das cápsulas manipuladas por distintas farmácias. A eficácia do tratamento hipercolesterolêmico poderia estar comprometida para 53,33 por cento dos produtos testados.