Discriminating and understanding molecular crystal polymorphism

Polymorph discrimination for a molecular crystal has long been a challenging task, which, nonetheless, is a major concern in the pharmaceutical industry. In this work, we have investigated polymorph discrimination on three different molecular crystals, tetrolic acid, oxalic acid, and oxalyl dihydrazide, covering both packing polymorphism and conformational polymorphism. To gain more understanding, we have performed energy decomposition analysis based on many-body expansion, and have compared the results from the XO-PBC method, that is, the eXtended ONIOM method (XO) with the periodic boundary condition (PBC), with those from some commonly used dispersion corrected density functional theory (DFT-D) methods. It is shown here that, with the XYG3 doubly hybrid functional chosen as the target high level to capture the intra- and short-range intermolecular interactions, and the periodic PBE as the basic low level to take long range interactions into account, the XO-PBC(XYG3:PBE) method not only obtains the correct experimental stability orderings, but also predicts reasonable polymorph energy ranges for all three cases. Our results have demonstrated the usefulness of the present theoretical methods, in particular XO-PBC, while highlighted the importance of a better treatment of different kinds of interactions to be beneficial to polymorph control.