Influence of Drug–Polymer Interactions on Dissolution of Thermodynamically Highly Unstable Cocrystal

Abstract

Solubility advantage of thermodynamically highly unstable cocrystals, which undergo solution-mediated phase transformation (SMPT) in less than 1 minute, does not translate to enhanced dissolution. The present study was aimed to understand the impact of polymeric additives on dissolution of thermodynamically highly unstable cocrystal with specific emphasis on influence of drug-polymer interactions. Exemestane-maleic acid was selected as a model cocrystal with SMPT time of PVP. The molecular basis of the differential dissolution performance was investigated using infrared spectroscopy, solution-state nuclear magnetic resonance spectroscopy and nuclear Overhauser effect spectroscopy (NOESY). The polymers with stronger interactions with drug in the cocrystal (HPMCAS and HPC) displayed higher dissolution rate as compared with that of no intermolecular interaction (PVP). The study also highlighted that despite no influence of the polymers on the cocrystal SMPT, dissolution enhancement was achieved. This was attributed to small-sized API crystals (1-3 microns) generated from the supersaturated-mediated crystallization and improved solvation due to drug-polymer interaction. These findings have implications on development of drug products using thermodynamically unstable cocrystals.