(524a) Advances in Crystal Structure Prediction for Conformationally Flexible Molecules

Crystal structure prediction of active pharmaceutical ingredients and other real-world species is frequently complicated by conformational flexibility. One particular challenge stems from delocalization error in commonly used density functionals, which can systematically bias predictions in certain classes of conformational polymorphs. Combining periodic density functional theory with intramolecular conformational energy corrections computed at a higher level of theory can substantially improve polymorph energy rankings. A number of examples of this problematic behavior and how it can be overcome will be presented, with applications ranging from energy ranking select groups of known polymorphs to refining entire crystal energy landscapes. In addition, a new, approximate strategy for estimating vibrational free energy contributions will be discussed.