(30g) Molecular Modeling of Crystallization of Flexible Organic Molecules

Crystallization is an extremely important unit operation the food, chemical, and pharmaceutical industries, among others. However, understanding the molecular-level details of nucleation and polymorph selection in molecular crystals remains a challenging problem. On the one hand, the stochastic nature of nucleation, and the fact that is usually involves only a few molecules, make it very hard to probe it experimentally. On the other hand, the time scales involved are well beyond the reach of traditional molecular simulation methods.

In this work, we present some recently developed methods for modeling the nucleation of molecular crystals, and for predicting possible crystalline polymorphs. Nucleation is modeled by constructing minimum free energy paths in a space of order parameters constructed to be sensitive to the structure of a particular polymorph. These minimum free energy paths are constructed using the string method in collective variables, and free energy barriers are then estimated using milestoning with Voronoi tesselations. Finally, we discuss how to construct plausible crystal structures for unknown polymorphs by using a global optimization method coupled with an ab initio potential.