Selective Nucleation of Polymorphs Induced by Multiple Conformations and Self-Association

Abstract

In an attempt to understand the relationship between solution chemistry and polymorphic nucleation, the flexible molecule chlorpropamide is used as a model compound to study its cooling crystallization behavior in four solvent systems. Online ATR-FTIR spectra proved the existence of dimers and solvated monomers in the solution. 2D nuclear overhauser effect spectroscopy and molecular dynamics simulations further revealed the molecular preassembled species in the solution. The results show that, in ethanol, ethanol/n-heptane, and ethyl acetate/n-heptane solvents, the solute molecules exist in the form of solvated monomers in multiple conformations. The stable formation of metastable form γ in ethyl acetate/n-heptane shows that, compared to conformational flexibility, the desolvation process plays a crucial role in overall self-assembly during the nucleation process. While in ethyl acetate, the solute molecules mainly exist as dimers and the rearrangement of the “wrong conformation” dimers becomes a key step to the nucleation rate and leads to the formation of stable form α. As a result, the self-association mode and conformational distribution of chlorpropamide in the solution work together to affect the nucleation process and polymorphic outcome.