From polymorphs to cocrystals and salts: successfully predicting axitinib's challenging crystal forms

The experimental development of cancer drug axitinib was disrupted by two surprise discoveries of new, more stable crystal polymorphs. Organic crystal structure prediction can help de-risk against such occurrences, but previous attempts failed to predict the theoretically challenging axitinib conformational polymorph lattice energies reliably. Here, we demonstrate how modern crystal structure prediction methodologies can not only successfully predict the problematic axitinib crystal structures, but how they can also accurately distinguish between salt and cocrystal forms in three axitinib multi-component crystals, which has been a long-standing challenge for organic crystal modeling. These successes derive from addressing the density-driven delocalization error found in commonly-used generalized gradient approximation density functional theory models through the application of intramolecular energy corrections and/or hybrid density functionals. Notably, the simultaneous combination of both approaches provides more robust lattice energy predictions than either individual approach.