Diverse Solvent Selection for Polymorph Landscape Investigation Based on Specific API-Solvent Interactions

摘要

Selection of a diverse set of solvents is important for systematic investigation of polymorph landscape and quick identification of the stable polymorph. The diversity of selected solvents is usually defined by solvent properties only, such as solvent functional groups, polarity, and hydrogen bonding capabilities. It is desired to customize solvent selection based on API (active pharmaceutical ingredients) molecular structures, especially API-solvent interactions related to crystallization behaviors. In this study, the crystallization related API-solvent interactions were profiled using the relative conformer distributions in solutions, which was visualized as conformer solvent maps to guide solvent selection for polymorph landscape investigation. Quantum mechanics and COSMO-SAC methods were utilized to calculate the relative distributions of representative conformers of API molecules in solutions. The interplay between relative conformer distribution and the API molecular cluster in solution was studied using molecular dynamics, where virtual supersaturated solutions were simulated using large numbers of API and solvent molecules. The results suggested that relative conformer distribution could influence the structure of API molecular clusters and subsequent crystallization processes. Systematically varying the relative conformer distribution may be a practical and novel strategy for effective and efficient polymorph landscape investigation, complementary to existing solvent diversifying strategies.