Mechanochemical synthesis of hydrochlorothiazide-nicotinamide cocrystal: from batch-based ball-milling to scale-up ready hot melt extrusion

Pharmaceutical cocrystals are increasingly recognised for their ability to enhance the physicochemical and mechanical properties of active pharmaceutical ingredients. Despite their advancements, conventional cocrystal production methods pose significant limitations, including environmental concerns due to solvent use, inefficiencies in batch processing, and challenges in scalability and quality control. As a result, there is a growing shift toward continuous, solvent-free manufacturing methods. This study investigates the application of hot melt extrusion, as a heat-assisted mechanochemical approach, for the synthesis of cocrystals of relatively less explored sulphonamide-containing drugs, focusing on hydrochlorothiazide, a diuretic used in hypertension treatment. The research aims to optimize the extrusion process for forming equimolar hydrochlorothiazide-nicotinamide cocrystals. It addresses the limitations of previous studies involving the same cocrystal parent reagents, which relied on non-quantitative indicators for example, the absence of a melting point, to confirm cocrystal formation. Instead, this study presents a quantitative assay to accurately measure the extent of cocrystal conversion, enabling a more rigorous evaluation of how different extrusion parameters affect the kinetics and efficiency of the process. By advancing the understanding of HME-based mechanochemical cocrystallisation between hydrochlorothiazide and nicotinamide, this work contributes to the development of more robust, scalable, and environmentally sustainable pharmaceutical manufacturing methods for sulphonamide drugs.