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Abstract: The effect of pressure on the crystal structures of the two ambient-pressure polymorphs of the amino acid l-histidine has been investigated. Single-crystal diffraction measurements, up to 6.60 GPa for the orthorhombic form I (P212121) and 6.85 GPa for the monoclinic form II (P21), show their crystal structures undergo isosymmetric single-crystal-to-single-crystal first-order phase transitions at 4.5 and 3.1 GPa to forms I′ and II′, respectively. Although the similarity in crystal packing and intermolecular interaction energies between the polymorphs is remarkable at ambient conditions, the manner in which each polymorph responds to pressure is different. Form II is found to be more compressible than form I, with bulk moduli of 11.6(6) GPa and 14.0(5) GPa, respectively. The order of compressibility follows the densities of the polymorphs at ambient conditions (1.450 and 1.439 g cm–3 for phases I and II, respectively). The difference is also related to the space-group symmetry, the softer monoclinic form having more degrees of freedom available to accommodate the change in pressure. In the orthorhombic form, the imidazole-based hydrogen atom involved in the H-bond along the c-direction swaps the acceptor oxygen atom at the transition to phase I′; the same swap occurs just after the phase transition in the monoclinic form and is also preceded by a bifurcation. Concurrently, the H-bond and the long-range electrostatic interaction along the b-direction form a three-centered H-bond at the I to I′ transition, while they swap their character during the II to II′ transition. The structural data were interpreted using periodic-density-functional theory, symmetry-adapted perturbation theory, and semiempirical Pixel calculations, which indicate that the transition is driven by minimization of volume, the intermolecular interactions generally being destabilized by the phase transitions. Nevertheless, volume calculations are used to show that networks of intermolecular contacts in both phases are very much less compressible than the interstitial void spaces, having bulk moduli similar to moderately hard metals. The volumes of the networks actually expand over the course of both phase transitions, with the overall unit-cell-volume decrease occurring through larger compression of interstitial void space.

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Abstract: Monoacylglycerols (MAGs) are the lipids most commonly used for crystallizing membrane proteins by the in meso method. The acyl chain and glycerol components of MAGs are ester-linked at the sn-1 hydroxyl of glycerol in 1-MAGs. 1-MAGs succumb to spontaneous transacylation where the chain migrates between the sn-1 and sn-2 hydroxyls. In the mesophase formed by 1-monoolein, the most commonly used MAG, equilibrium is reached in two weeks at 6 mol% 2-monoolein. Variability in 2-MAG content appears in synthetic MAGs produced for the purpose of host lipid screening. In the interests of reproducibility, extensive purification has been implemented to minimize the 2-MAG content of newly synthesized lipid. Here we show, with two membrane proteins, that such efforts are not needed. Specifically, the initial 2-MAG content can vary over wide limits without impacting negatively on the crystallization process or on the structures obtained with those crystals. Dispensing with rounds of purification means that MAGs can be produced using protocols that are simpler, faster, less expensive and more environmentally friendly. An added feature of having 2-monoolein in the crystallization mix is that it stabilizes mesophases with bigger aqueous channels, well suited to structure determination of proteins and complexes with large extramembrane domains.

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Abstract: Variable-temperature single-crystal and powder X-ray diffraction techniques have been used to study the thermal and mechanical decomposition of the acetonitrile solvate of the co-crystal formed between piroxicam and succinic acid (PRXSA-ACN). The results show that the thermal expansion behavior of PRXSA-ACN is highly anisotropic and can be correlated with structural features of the crystal lattice. Thermally-induced desolvation of PRXSA-ACN led initially to the formation of the α-form of piroxicam and the 1:1 piroxicam:succinic acid co-crystal (PRXSA), and this can be rationalized on the basis of the crystal structure of PRXSA-ACN and its thermal expansion behavior. Subsequent decomposition of PRXSA produced amorphous succinic acid and the thermodynamically more stable β-form of piroxicam. The α- and β-forms co-existed up until the melting point of the α-form, at which point the sample recrystallized to give the β-form of piroxicam. Mechanical treatment (light grinding) of PRXSA-ACN resulted in mild structural damage to the crystal structure and this led to subsequent desolvation.

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Abstract: In this work, three new cocrystals of the nonsteroidal anti-inflammatory drug flurbiprofen with salicylamide, benzamide and picolinamide have been discovered using thermodynamic analysis of solid-liquid binary phase diagrams, and their crystal structures have been determined from the high-resolution synchrotron powder diffraction data. Solid state DFT calculations have been carried out to gain additional insight into energy differences between the cocrystal structures. The pH-solubility behavior and solubility advantage of the cocrystals have been examined via eutectic concentrations of the components, and the thermodynamic stability relationships between different solid phases have been rationalized in terms of Gibbs energies of the formation reactions. In addition, a new model has been proposed for estimating the solubility product (Ksp) of a cocrystal, based on the experimental intrinsic solubility of the drug and coformer complemented by calculated physicochemical HYBOT descriptors. The applicability of the molecular volume of cocrystal formation as a reliable parameter for clarifying the relationship between the driving force of the cocrystallization process and the structural features of participating solids has been also discussed.

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Abstract: We report the solid-state structural properties and phase transition behaviour of 1,4-dibromo-2,3,5,6-tetramethylbenzene, demonstrating that this material undergoes an order-disorder phase transition below ambient temperature (at ca. 156 K on cooling and ca. 159 K on heating). In both the high-temperature and low-temperature phases, the crystal structure is based on π-stacking of the molecules. In the high-temperature phase, the bromine and methyl groups are located with essentially equal probability in each of the six substituent positions, and it is shown by natural-abundance solid-state 2H NMR spectroscopy that, at ambient temperature, this disorder is dynamic via rapid molecular reorientation about an axis perpendicular to the aromatic ring. In the low-temperature phase, the bromine and methyl substituents occupy preferred sites within the crystal structure, with the distribution of site occupancies becoming progressively more ordered on decreasing temperature.