Dissolution Rate and Stability Improvement of Hydrochlorothiazide and Valsartan by Co‐Amorphous Formulation

The current study aimed to improve the dissolution rate and physical stability of two antihypertensive drugs, hydrochlorothiazide, and valsartan, through the development of a co‐amorphous system. A co‐amorphous system was successfully prepared at molar ratios of 1:1, 1:2, and 1:6 employing rotary evaporation technique. Characterization of the formulations was performed using powder X‐ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, and thermogravimetric analysis. Powder X‐ray diffraction confirmed the amorphous nature of all samples, which remained physically stable under ambient dry conditions for at least 8 months. Differential scanning calorimetry confirmed the formation of a single‐phase system. The experimental glass transition temperature values revealed a negative deviation from those calculated by the Gordon–Taylor equation, indicating nonideal mixing and intermolecular interactions. Fourier transform infrared spectroscopy spectra supported these findings, showing peak broadening in regions corresponding to the functional groups of the parent drugs. The thermogravimetric analysis demonstrated that the samples were thermally stable, with no degradation observed up to 100°C. Dissolution studies performed in phosphate buffer (pH 6.8, 25°C) revealed significant enhancements in the dissolution rates of both hydrochlorothiazide and valsartan from the co‐amorphous formulations compared to their unprocessed forms and corresponding physical mixtures. A validated high‐performance liquid chromatography method was developed for the simultaneous analysis of hydrochlorothiazide and valsartan using a Shimadzu LC‐2030C 3D Plus system with a photodiode array detector. Separation was achieved on a Waters C18 column (250 × 4.6 mm, 5 μm) using a mobile phase of acetonitrile, methanol, and ammonium acetate buffer (20:50:30, v/v) at a flow rate of 0.70 mL/min. Detection wavelengths were set at 271 nm for hydrochlorothiazide and 249 nm for valsartan. The method showed good linearity in the range from 0.0033 to 0.0670 mM (3.3–67.0 μM), precision (RSD < 2%), and reproducibility, with hydrochlorothiazide and valsartan eluting at 3.5 and 7.2 min, respectively. At the first minute, hydrochlorothiazide release increased by approximately 8.5‐, 8.7‐, and 7.1‐fold from the 1:1, 1:2, and 1:6 co‐amorphous systems relative to the unprocessed drug, and by 4.5‐, 4.8‐, and 2.4‐fold, respectively, compared to the corresponding physical mixtures. For valsartan, the co‐amorphous systems showed 2.9‐, 2.6‐, and 1.9‐fold improvements over the unprocessed drug, and 1.5‐, 1.8‐, and 1.5‐fold improvements over the matching physical mixtures at the same molar ratios. Calcium carbonate was physically mixed with all samples to minimize gelation upon aqueous exposure. These results suggest that co‐amorphous formulation is a promising strategy for enhancing the dissolution rate and physical stability of hydrochlorothiazide and valsartan.