Creation of Hydrochlorothiazide Pharmaceutical Cocrystals Via Hot-Melt Extrusion for Enhanced Solubility and Permeability

Crystal engineering is an emerging tool for altering the physicochemical properties of drug candidates. The objective of the current investigation was to develop cocrystals of hydrochlorothiazide (HCT) with coformers such as nicotinamide (NIC), resorcinol (RSL), and catechol (CAT) using hot-melt extrusion (HME) technology. The liquid-assisted grinding (LAG) method was used to prepare cocrystals by grinding the drug and coformer in a definite molar ratio as a reference and to check the feasibility of cocrystal formation. Cocrystals were prepared using HME and evaluated with differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffractometry, and scanning electron microscopy and compared with LAG cocrystals. Barrel temperature was the critical process parameter for producing high-quality cocrystals in HME. All cocrystals exhibited improved solubility compared to the native drug, and HCT-NIC cocrystals showed a two-fold increase in solubility. Similarly, HCT-RSL and HCT-CAT showed higher solubility profiles and improved diffusion/permeability characteristics compared to that of the pure HCT due to the drug-coformer interactions in the cocrystals. In this study, the solubility of the coformer was the key factor determining cocrystal solubilization. However, hot-melt extrusion is an alternative technology for creating pharmaceutical cocrystals and has potential for industrial scale-up.