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

摘要

Solubility advantage of thermodynamically highly unstable cocrystals, which undergo solution-mediated phase transformation (SMPT) in less than 1 min, 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 30 s and eutectic constant (K-eu) of 75475. Hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyvinylpyrrolidone (PVP) were selected as polymers for a dissolution study based on measurement of induction time using precipitation study. In the presence of 0.2% w/v of HPC, the cocrystal showed significantly higher drug release (similar to 3-fold) as compared with the cocrystal in the absence of predissolved polymers. Differential dissolution profiles of the cocrystal were observed with each polymer and the order of increasing dissolution rate was found to be HPC approximate to HPMCAS 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 drug crystals (1-3 mu m) generated from the supersaturation-mediated crystallization and improved solvation due to drug-polymer interactions. These findings have implications on development of drug products using thermodynamically unstable cocrystals.