(231b) A Simple Fix Addresses Severe Density Functional Theory Polymorph Ranking Problems in Pharmaceuticals

Knowledge of the solid form landscape is key during the pharmaceutical development process. Crystal structure prediction is increasingly used to help survey these landscape, and density functional theory (DFT) has established a successful track record of predicting the most stable crystal structures for a variety of species. However, a few significant limitations of the widely used functionals have recently become apparent. Typical density functionals predict the polymorph stabilities poorly in certain conformationally flexible pharmaceuticals, for example. In other cases, these functionals incorrectly predict salt formation in are actually neutral co-crystals. More accurate correlated wavefunction methods can overcome these limitations, albeit at a much higher computational cost. The origins of these deficiencies will be discussed, and a simple, computationally inexpensive approach that can overcome the difficulties in conformational polymorphs will be presented. Examples will include prolific polymorph formers ROY, Axitinib, and Galunisertib.