Development of a Discriminative Dissolution Method, Using In-Silico Tool for Hydrochlorothiazide and Valsartan Tablets

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 3³⁻¹. Then, DDDPlus™ was used to carry out experimental design assays of a complete factorial design 3³. 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.

2.1. Materials

Valsartan (101.2% purity on a dry basis) and hydrochlorothiazide (100.1% purity on a dry basis) were kindly provided by Aché Laboratórios SA (Guarulhos, São Paulo, Brazil). Purified water was obtained using the Milli-Q filtration system (Merck Millipore, Darmstadt, Germany), and the reagents 0.15 M potassium chloride (KCl), 0.5 M potassium hydroxide (KOH) and methanol (LabSynth, Diadema, Brazil) were used in the solubility assay. Purified water and polysorbate 80 (Sigma Aldrich, São Paulo, Brazil) were used in the particle size analysis. Formulations for the dissolution method development were prepared using the following excipients: PH 200 microcrystalline cellulose—Avicel PH 200 LM NF (FMC Corporation, Philadelphia, PA, USA), PH 302 microcrystalline cellulose—Avicel PH 302 NF (FMC Corporation, Philadelphia, PA, USA), croscarmellose sodium (Blanver Farmoquímica LTDA, Taboão da Serra, Brazil), colloidal silicon dioxide—Aerosil 200 (Henrifarma Produtos Químicos e Farmacêuticos Ltd., São Paulo, Brazil), lactose monohydrate—Tablettose^® 70 (Meggle Pharma, Wasserburg, Germany), magnesium stearate (Meggle Pharma, Wasserburg, Germany). The reagents used in tablet content analysis were purified water by Milli-Q system (Merck Millipore, Darmstadt, Germany), ammonium formate (97%) (Sigma Aldrich, São Paulo, Brazil), acetonitrile and high-performance liquid chromatography (HPLC)-grade methanol (Merck, São Paulo, Brazil). Dissolution media were prepared using purified water obtained by reverse osmosis, monobasic potassium phosphate (LabSynth, Diadema, Brazil) and sodium hydroxide (LabSynth, Diadema, SP, Brazil). Formulations containing VAL (160 mg) + HTZ (12.5 mg) in tablet and capsule presentations were purchased at drugstores in Brazil and Peru. The drug products were designated as Reference drug products, B1 and B2 (coated tablets marketed in Brazil) and P2 (coated tablets), and C1 and P1 (capsules) from Peru.

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Leon, R.M.; Issa, M.G.; Duque, M.D.; Daniel, J.S.P.; Ferraz, H.G. Development of a Discriminative Dissolution Method, Using In-Silico Tool for Hydrochlorothiazide and Valsartan Tablets. Pharmaceutics 2023, 15, 1735.
https://doi.org/10.3390/pharmaceutics15061735

excipients formulation