QTAIM application in drug development: prediction of relative stability of drug polymorphs from experimental crystal structures.

Prediction of the most stable crystal form based on the strongest intermolecular hydrogen bonds (HBs) only, was successfully applied to ten polymorphic drug systems, using the Quantum Theory of Atoms in Molecules (QTAIM). The results of the predictions were demonstrated to be superior to the thermodynamic stability ranking based on molecular mechanical (COMPASS forcefield), DFT and DFT-D calculations, as well as on the QTAIM predictions based on the total intermolecular HBing interactions strength. The obtained results support the validity of the best donor/best acceptor hierarchical approach for polymorph stability analysis of drug-like molecules: weak interactions are not as important for stability ranking as the strongest HBs. In addition, the proposed QTAIM approach allowed a reasonable ranking of the relative stability of multiple polymorphic crystalline forms of two test systems, axitinib and sulfathiazole.