The results of the sixth blind test of organic crystal structure prediction methods are presented and discussed, highlighting progress for salts, hydrates and bulky flexible molecules, as well as on-going challenges.

A computational study of 1061 experimentally determined crystal structures of 508 polymorphic organic molecules has been performed with state-of-the-art lattice energy minimisation methods, using a hybrid method that combines density functional theory intramolecular energies with an anisotropic atom-atom intermolecular model. Rigid molecule lattice dynamical calculations have also been performed to estimate the vibrational contributions to lattice free energies. Distributions of the differences in lattice energy, free energy, zero point energy, entropy and heat capacity between polymorphs are presented. Polymorphic lattice energy differences are typically very small: over half of polymorph pairs are separated by less than 2 kJ/mol and lattice energy differences exceed 7.2 kJ/mol in only 5% of cases. Unsurprisingly, vibrational contributions to polymorph free energy differences at ambient conditions are dominated by entropy differences. The distribution of vibrational energy differences is narrower than lattice energy differences, rarely exceeding 2 kJ/mol. However, these relatively small vibrational free energy contributions are large enough to cause a re-ranking of polymorph stability below, or at, room temperature in 9% of the polymorph pairs.

The solid form screening of galunisertib produced many solvates, prompting an extensive investigation into possible risks to the development of the favored monohydrate form. Inspired by crystal structure prediction, the search for neat polymorphs was expanded to an unusual range of experiments, including melt crystallization under pressure, to work around solvate formation and the thermal instability of the molecule. Ten polymorphs of galunisertib were found; however, the structure predicted to be the most stable has yet to be obtained. We present the crystal structures of all ten unsolvated polymorphs of galunisertib, showing how state-of-the-art characterization methods can be combined with emerging computational modeling techniques to produce a complete structure landscape and assess the risk of lateappearing, more stable polymorphs. The exceptional conformational polymorphism of this prolific solvate former invites further development of methods, computational and experimental, that are applicable to larger, flexible molecules with complex solid form landscapes.

Because of excessive electron delocalization, the polymorphs of ROY constitute a surprisingly challenging system for crystal structure prediction.