(588b) Diabat Method for Polymorph Free Energies

Polymorphs are different crystal structures for the same molecule or compound. Many molecules can crystallize into several different polymorphs, each with different solubility and growth/dissolution kinetics. Polymorphism is especially important in pharmaceuticals as many drugs are administered as crystalline solids. Relative stability of polymorphs affects solubility which consecutively affects the bioavailability of the solid form. Ab initio calculations typically infer stability from static energies or harmonically approximate the entropy. Polymorphs of organic molecular crystals may be separated by small free energy differences and hence it is important to account for the entropy exactly. Classical force field based approaches enable complete free energy calculations with advanced sampling methods. These methods, however, typically use thermodynamic integration and are expensive multi-stage simulations.

In this talk we discuss a method to directly yield the polymorph free energy differences. The framework combines ideas from the well-established lattice-switch Monte Carlo procedure and relationships that have been previously used in the electron transfer literature. We briefly discuss the method and its previous applications to atomic solids. Recently, we generalized and extended the framework to yield relative stability of organic molecular crystals. We demonstrate the method for benzene polymorphs and all five experimentally reported polymorphs of pharmaceutically relevant carbamazepine.