We report on the organization and outcome of the fourth blind test of crystal structure prediction, an international collaborative project organized to evaluate the present state in computational methods of predicting the crystal structures of small organic molecules. There were 14 research groups which took part, using a variety of methods to generate and rank the most likely crystal structures for four target systems: three single-component crystal structures and a 1:1 cocrystal. Participants were challenged to predict the crystal structures of the four systems, given only their molecular diagrams, while the recently determined but as-yet unpublished crystal structures were withheld by an independent referee. Three predictions were allowed for each system. The results demonstrate a dramatic improvement in rates of success over previous blind tests; in total, there were 13 successful predictions and, for each of the four targets, at least two groups correctly predicted the observed crystal structure. The successes include one participating group who correctly predicted all four crystal structures as their first ranked choice, albeit at a considerable computational expense. The results reflect important improvements in modelling methods and suggest that, at least for the small and fairly rigid types of molecules included in this blind test, such calculations can be constructively applied to help understand crystallization and polymorphism of organic molecules.

The computer-generation of the crystal structures of the α-amino acid valine is used as a challenging test of lattice energy modeling methods for crystal structure prediction of flexible polar organic molecules and, specifically, to examine the importance of molecular polarization on calculated relative energies. Total calculated crystal energies, which combine atom-atom model potential calculations of intermolecular interactions with density functional theory intramolecular energies, do not effectively distinguish the real (known) crystal structures from the rest of the low energy computer-generated alternatives when the molecular electrostatic models are derived from isolated molecule calculations. However, we find that introducing a simple model for the bulk crystalline environment when calculating the molecular energy and electron density distribution leads to important changes in relative total crystal energies and correctly distinguishes the observed crystal structures from the set of computer-generated possibilities. This study highlights the importance of polarization of the molecular charge distribution in crystal structure prediction calculations, especially for polar flexible molecules, and suggests a computationally inexpensive approach to include its effect in lattice energy calculations.

Electron diffraction offers advantages over X-ray based methods for crystal structure determination as it can be applied to sub-micron sized crystallites, and picogram quantities of material. With molecular organic species, however, crystal structure determination with electron diffraction is hindered by rapid crystal deterioration in the electron beam, limiting the amount of diffraction data that can be collected, and by the effect of dynamical scattering on reflection intensities. While automated electron diffraction tomography provides one possible solution, in this paper we demonstrate an alternative approach where a set of putative crystal structures of the compound of interest is generated using crystal structure prediction methods, and electron diffraction is used to determine which of these putative structures is in agreement with the available electron diffraction data. This approach enables the advantages of electron diffraction to be exploited, while avoiding the need to obtain large amounts of diffraction data or accurate reflection intensities. We demonstrate the methodology using the pharmaceutical compounds paracetamol, scyllo-inositol and theophylline.

Electron diffraction offers advantages over X-ray based methods for crystal structure determination as it can be applied to sub-micron sized crystallites, and picogram quantities of material. With molecular organic species, however, crystal structure determination with electron diffraction is hindered by rapid crystal deterioration in the electron beam, limiting the amount of diffraction data that can be collected, and by the effect of dynamical scattering on reflection intensities. While automated electron diffraction tomography provides one possible solution, in this paper we demonstrate an alternative approach where a set of putative crystal structures of the compound of interest is generated using crystal structure prediction methods, and electron diffraction is used to determine which of these putative structures is in agreement with the available electron diffraction data. This approach enables the advantages of electron diffraction to be exploited, while avoiding the need to obtain large amounts of diffraction data or accurate reflection intensities. We demonstrate the methodology using the pharmaceutical compounds paracetamol, scyllo-inositol and theophylline.

A noteworthy feature of the compound theophylline is that it forms crystals with a triangular habit, an extremely rare phenomenon for an organic molecule. Here, we investigate the formation of these crystals, comprised of the polymorph Form II (Pna2 1 ), and demonstrate that the triangles are obtained from solvents which are highly hydrophobic, or which have a hydrogen bond acceptor group and no hydrogen bond donor group. The formation of the triangular crystal habit is rationalized on the basis of the way such solvents interact with the inequivalent (001) and (00-1) polar crystal faces of Form II. Interactions are significantly stronger at one face than the other, inhibiting growth in one direction and limiting crystal growth to a single, triangle shaped, growth sector. This rationalization also enabled interesting surface features observed by atomic force microscopy to be interpreted. Furthermore, we report a second, previously unreported, type of triangular crystal of theophylline for which the angle at the tip of the triangle is obtuse rather than acute. These crystals are proposed, with the aid of transmission electron microscopy and crystal structure prediction, to be a new polymorphic form of theophylline. Kingdom A noteworthy feature of the compound theophylline is that it forms crystals with a triangular habit, an extremely rare phenomenon for an organic molecule. Here, we investigate the formation of these crystals, comprised of the polymorph Form II (Pna2 1 ), and demonstrate that the triangles are obtained from solvents which are highly hydrophobic, or which have a hydrogen bond acceptor group and no hydrogen bond donor group. The formation of the triangular crystal habit is rationalized on the basis of the way such solvents interact with the inequivalent (001) and 4 (00-1) polar crystal faces of Form II. Interactions are significantly stronger at one face than the other, inhibiting growth in one direction and limiting crystal growth to a single, triangle shaped, growth sector. This rationalization also enabled interesting surface features observed by atomic force microscopy to be interpreted. Furthermore, we report a second, previously unreported, type of triangular crystal of theophylline for which the angle at the tip of the triangle is obtuse rather than acute. These crystals are proposed, with the aid of transmission electron microscopy and crystal structure prediction, to be a new polymorphic form of theophylline.

The search for materials capable of storing small molecular species is experiencing a shift from solids with permanent porosity towards organic materials capable of the uptake and release of lowmolecular-weight guests. We demonstrate that a solid mixture of the pharmaceutical compound lamotrigine with a range of saturated and unsaturated 1,4-butanedicarboxylic acids, when in combination with a third molecule, can result in the formation of a family of isostructural materials involving a structurally persistent binary-host framework based on a hydrogen-bonded molecular salt of lamotrigine and the acid. A systematic study, based on mechanochemical screening, has revealed a remarkable robustness to subtle changes in the chemical functionality of the acid in that at least 12 different acids can be used in combination with lamotrigine to generate isostructural binary-host frameworks. Such robust isostructurality results in the important attribute that the shape, size and surface chemistry of the inclusion cavities can be fine-tuned by systematic variation of the substituents on the dicarboxylic acid.

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