Organic molecules, such as pharmaceuticals, agro-chemicals and pigments, frequently form several crystal polymorphs with different physicochemical properties. Finding polymorphs has long been a purely experimental game of trial-and-error. Here we utilize in silico polymorph screening in combination with rationally planned crystallization experiments to study the polymorphism of the pharmaceutical compound Dalcetrapib, with 10 torsional degrees of freedom one of the most flexible molecules ever studied computationally. The experimental crystal polymorphs are found at the bottom of the calculated lattice energy landscape, and two predicted structures are identified as candidates for a missing, thermodynamically more stable polymorph. Pressure-dependent stability calculations suggested high pressure as a means to bring these polymorphs into existence. Subsequently, one of them could indeed be crystallized in the 0.02 to 0.50 GPa pressure range and was found to be metastable at ambient pressure, effectively derisking the appearance of a more stable polymorph during late-stage development of Dalcetrapib.

Two novel sodium salts of the antibiotic ciprofloxacin were crystallised at pressures of 0.25 and 0.6 GPa and subsequently recovered to ambient pressure. The structures are the first reported examples of ciprofloxacin chelating a Group IA monovalent cation. Ambient-pressure crystallisation of the same solution used for high-pressure experiments, yielded crystals of the known hexahydrate. In a parallel study, the previously unknown structure of anhydrous ciprofloxacin was determined from powder diffraction data. The structures are described and compared using the XPac method.

The solid-state polymorphism of the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate, [bmim][PF₆], has been investigated via low-temperature and high-pressure crystallisation experiments. The samples have been characterised by single-crystal X-ray diffraction, optical microscopy and Raman spectroscopy. The solid-state phase behaviour of the compound is confirmed and clarified with respect to previous phase diagrams. The structures of the previously reported γ-form, which essentially exhibits a G′T cation conformation, as well as those of the elusive β- and α-forms, are reported. Crystals of the β-phase are twinned and the structure is heavily disordered; the cation conformation in this form is predominantly TT, though significant contributions from other less frequently encountered conformers are also observed at low temperature and high pressure. The cation conformation in the α-form is GT; the presence of the G′T conformer at 193 K in this phase can be eliminated on cooling to 100 K. Whilst X-ray structural data are overall in good agreement with previous interpretations based on Raman and NMR studies, they also reveal a more subtle interplay of intermolecular interactions, which give rise to a wider range of conformers than previously considered.

A monohydrate form of the neurotransmitter γ-amino butyric acid (GABA) has been crystallised in the 0.4–0.8 GPa pressure range, recovered to ambient pressure and then used as a seed. Theoretical calculations have been used to rationalise the experimental observations and gain an insight into thermodynamic stability.

High-pressure crystallisation of an aqueous solution of the GABA analogue gabapentin at 0.8 GPa resulted in the formation of a previously unknown heptahydrate form, whose structure has been determined by in situ single-crystal X-ray diffraction. The structure and water framework of this unusually highly hydrated small molecule are described in detail.

The effects of pressure on the structure of cyanocobalamin (vitamin B12) have been investigated by compressing a single crystal grown from water together with its mother liquor to 1.0 GPa. The structure of a crystal grown from water in situ in a capillary has also been re-determined at room temperature and pressure. A conformational rearrangement of selected amide side chains, reduced displacement parameters and remarkable solvent ordering have been observed at high pressure.