Validation of a search technique for crystal structure prediction of flexible molecules by application to piracetam

A new approach to the crystal structure prediction of flexible molecules is presented. It is applied to piracetam, whose conformational polymorphs exhibit a variety of hydrogen‐bond motifs but lack the intramolecular hydrogen bond found in the gas‐phase ab initio optimized conformer. Stable crystal packing can result when favourable intermolecular interactions are made possible when the molecule distorts from the gas‐phase conformation. If the resulting intermolecular lattice energy is sufficiently favourable to compensate for the intramolecular energy penalty associated with the suboptimal gas‐phase conformation, then the crystal structure may be experimentally feasible. The new approach involves searching for low‐energy crystal structures using a large number of rigid conformers, firstly to systematically explore which regions of conformational space could give rise to low‐energy hydrogen‐bonded crystal structures, and then to refine the search using crystallographic insight to optimize particular intermolecular interactions. The timely discovery of a new polymorph (form IV) by an independent experimental team allowed this approach to be validated by way of a `blind test' of crystal structure prediction. Form IV was successfully identified as the most favourable computed crystal structure with a conformation very distinct from that in the previously known polymorphs.