Inaccurate Conformational Energies Still Hinder Crystal Structure Prediction in Flexible Organic Molecules
Chandler Greenwell, Gregory J. O. Beran
Abstract
Crystal structure prediction driven by density functional theory has become an increasingly useful tool for the pharmaceutical industry and others interested in understanding and controlling organic molecular crystal packing. However, delocalization error in widely used density functionals leads to problematic conformational energies that can cause incorrect predictions of polymorph stabilities. In five examples ranging from small molecules to the polymorphically challenging pharmaceuticals axitinib and galunisertib, the present work demonstrates how inexpensively correcting the intramolecular conformational energies with higher-level electronic structure methods leads to polymorph stability predictions that agree far better with experiment. This approach also provides a valuable diagnostic for when skepticism about predicted polymorph stabilities is warranted.