In pharmaceutical development, understanding interactions and phase behavior of drug in different environments such as in solvent or in complex formulation is essential in designing drug products to meet desired criteria. Amorphous solid dispersion (ASD) is a formulation technique often used to improve solubility of poorly water-soluble drugs. ASDs typically consist of amorphous drug embedded in hydrophilic polymer environment. Studies have shown that ASD dissolution behavior is governed by interactions of the drug with itself, the polymer, water, and phase separation. In this work, molecular simulation is employed to elucidate the impact of interactions and phase separation on dissolution of ASDs. Model drugs were investigated with Copovidone, a typical pharmaceutical polymer. It was observed that increasing drug-drug interactions, resulting in phase separation, were key drivers of the ASDs dissolution. These observations and consequential effect on dissolution performance of the ASDs were experimentally validated. This study demonstrates that the complementarity information gained from molecular simulation and experiment provides a valuable and more complete understanding of the impact of drug interactions and phase separation on ASD dissolution.
