Linking solid-state phenomena via energy differences in `archetype crystal structures'.

Categorization underlies understanding. Conceptualizing solid-state structures of organic molecules with `archetype crystal structures' bridges established categories of disorder, polymorphism and solid solutions and is herein extended to special position and high-Z' structures. The concept was developed in the context of disorder modelling [Dittrich, B. (2021). IUCrJ, 8, 305-318] and relies on adding quantum chemical energy differences between disorder components to other criteria as an explanation as to why disorder - and disappearing disorder - occurs in an average structure. Part of the concept is that disorder, as probed by diffraction, affects entire molecules, rather than just the parts of a molecule with differing conformations, and the finding that an R·T energy difference between disorder archetypes is usually not exceeded. An illustrative example combining disorder and special positions is the crystal structure of oestradiol hemihydrate analysed here, where its space-group/subgroup relationship is required to explain its disorder of hydrogen-bonded hydrogen atoms. In addition, we show how high-Z' structures can also be analysed energetically and understood via archetypes: high-Z' structures occur when an energy gain from combining different rather than overall alike conformations in a crystal significantly exceeds R·T, and this finding is discussed in the context of earlier explanations in the literature. Twinning is not related to archetype structures since it involves macroscopic domains of the same crystal structure. Archetype crystal structures are distinguished from crystal structure prediction trial structures in that an experimental reference structure is required for them. Categorization into archetype structures also has practical relevance, leading to a new practice of disorder modelling in experimental least-squares refinement alluded to in the above-mentioned publication.

Azulene revisited: solid-state structure, invariom modeling and lattice-energy minimization of a classical example of disorder.

The molecular and solid-state structure of azulene both raise fundamental questions. Therefore, the disordered crystal structure of azulene was re-refined with invariom non-spherical atomic scattering factors from new single-crystal X-ray diffraction data with a resolution of d = 0.45 Å. An unconstrained refinement results in a molecular geometry with Cs symmetry. Refinements constrained to fulfill C2v symmetry, as observed in the gas phase and in high-level ab initio calculations, lead to similar figures of merit and residual densities as unconstrained ones. Such models are consistent with the structures from microwave spectroscopy and electron diffraction, albeit they are not the same. It is shown that for the disorder present in azulene, the invariom model describes valence electron density as successfully as it does for non-disordered structures, although the disorder still leads to high correlations mainly between positional parameters. Lattice-energy minimizations on a variety of ordered model structures using dispersion-corrected DFT calculations reveal that the local deviations from the average structure are small. Despite the molecular dipole moment there is no significant molecular ordering in any spatial direction. A superposition of all ordered model structures leads to a calculated average structure, which explains not only the experimental determined atomic coordinates, but also the apparently unusual experimental anisotropic displacement parameters.

Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening.

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.