Leon Rosmery Merma, Issa Michele Georges, Duque Marcelo Dutra, Daniel Josiane Souza Pereira, Ferraz Humberto Gomes
Department of Pharmacy, Faculty of Pharmaceutical Sciences, Universidade de São Paulo-USP, Av. Prof. Lineu Prestes, 580, São Paulo 05508-080, SP, Brazil.
Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo-UNIFESP, Rua São Nicolau, 210 Centro, Diadema 09913-030, SP, Brazil.
Pharmaceutics. 2023 Jun 14;15(6):1735. doi: 10.3390/pharmaceutics15061735.
Hydrochlorothiazide (HTZ) and Valsartan (VAL) are poorly soluble drugs in BCS classes IV and II. This study aimed to develop a method to assess the dissolution profile of tablets containing HTZ (12.5 mg) and VAL (160 mg) as a fixed-dose combination, using in silico tools to evaluate products marketed in Brazil and Peru. Firstly, in vitro dissolution tests were performed using a fractional factorial design 3. Then, DDDPlus™ was used to carry out experimental design assays of a complete factorial design 3. Data from the first stage were used to obtain calibration constants for in silico simulations. The factors used in both designs were formulation, sinker use, and rotation speed. Finally, effects and factor interaction assessment was evaluated based on a statistical analysis of the dissolution efficiency (DE) obtained from simulations. Thus, the established final conditions of the dissolution method were 900 mL of phosphate buffer pH 6.8, 75 rpm of rotation speed, and sinker use to prevent formulation floating. The reference product stood out because of its higher DE than other formulations. It was concluded that the proposed method, in addition to ensuring total HTZ and VAL release from formulations, has adequate discriminative power.
氢氯噻嗪（HTZ）和缬沙坦（VAL）属于BCS分类中的IV类和II类难溶性药物。本研究旨在开发一种方法，以评估含有HTZ（12.5毫克）和VAL（160毫克）的固定剂量复方片剂的溶出曲线，并使用计算机模拟工具评估在巴西和秘鲁销售的产品。首先，采用部分因子设计3进行体外溶出试验。然后，使用DDDPlus™进行全因子设计3的实验设计分析。第一阶段的数据用于获取计算机模拟的校准常数。两种设计中使用的因素包括处方、使用沉降片和转速。最后，基于对模拟得到的溶出效率（DE）的统计分析，评估效应和因子相互作用。因此，所建立的溶出方法的最终条件为900毫升pH 6.8的磷酸盐缓冲液、75转/分钟的转速以及使用沉降片以防止处方漂浮。参比产品因其DE高于其他处方而脱颖而出。得出的结论是，所提出的方法除了能确保制剂中HTZ和VAL的完全释放外，还具有足够的区分能力。
