Mercury 4.0: from visualization to analysis, design and prediction.

The program Mercury, developed at the Cambridge Crystallographic Data Centre, was originally designed primarily as a crystal structure visualization tool. Over the years the fields and scientific communities of chemical crystallography and crystal engineering have developed to require more advanced structural analysis software. Mercury has evolved alongside these scientific communities and is now a powerful analysis, design and prediction platform which goes a lot further than simple structure visualization.

A combined model of electron density and lattice dynamics refined against elastic diffraction data. Thermodynamic properties of crystalline L-alanine.

Thermodynamic stability is an essential property of crystalline materials, and its accurate calculation requires a reliable description of the thermal motion - phonons - in the crystal. Such information can be obtained from periodic density functional theory (DFT) calculations, but these are costly and in some cases insufficiently accurate for molecular crystals. This deficiency is addressed here by refining a lattice-dynamics model, derived from DFT calculations, against accurate high-resolution X-ray diffraction data. For the first time, a normal-mode refinement is combined with the refinement of aspherical atomic form factors, allowing a comprehensive description and physically meaningful deconvolution of thermal motion and static charge density in the crystal. The small and well diffracting L-alanine system was used. Different lattice-dynamics models, with or without phonon dispersion, and derived from different levels of theory, were tested, and models using spherical and aspherical form factors were compared. The refinements indicate that the vibrational information content in the 23 K data is too small to study lattice dynamics, whereas the 123 K data appear to hold information on the acoustic and lowest-frequency optical phonons. These normal-mode models show slightly larger refinement residuals than their counterparts using atomic displacement parameters, and these features are not removed by considering phonon dispersion in the model. The models refined against the 123 K data, regardless of their sophistication, give calculated heat capacities for L-alanine within less than 1 cal mol-1 K-1 of the calorimetric measurements, in the temperature range 10-300 K. The findings show that the normal-mode refinement method can be combined with an elaborate description of the electron density. It appears to be a promising technique for free-energy determination for crystalline materials at the expense of performing a single-crystal elastic X-ray diffraction determination combined with periodic DFT calculations.

Properties of the Sodium Naproxen-Lactose-Tetrahydrate Co-Crystal upon Processing and Storage.

Co-crystals and co-amorphous systems are two strategies to improve the physical properties of an active pharmaceutical ingredient and, thus, have recently gained considerable interest both in academia and the pharmaceutical industry. In this study, the behavior of the recently identified sodium naproxen-lactose-tetrahydrate co-crystal and the co-amorphous mixture of sodium, naproxen, and lactose was investigated. The structure of the co-crystal is described using single-crystal X-ray diffraction. The structural analysis revealed a monoclinic lattice, space group P21, with the asymmetric unit containing one molecule of lactose, one of naproxen, sodium, and four water molecules. Upon heating, it was observed that the co-crystal transforms into a co-amorphous system due to the loss of its crystalline bound water. Dehydration and co-amorphization were studied using synchrotron X-ray radiation and thermogravimetric analysis (TGA). Subsequently, different processing techniques (ball milling, spray drying, and dehydration) were used to prepare the co-amorphous mixture of sodium, naproxen, and lactose. X-ray powder diffraction (XRPD) revealed the amorphous nature of the mixtures after preparation. Differential scanning calorimetry (DSC) analysis showed that the blends were single-phase co-amorphous systems as indicated by a single glass transition temperature. The samples were subsequently tested for physical stability under dry (silica gel at 25 and 40 °C) and humid conditions (25 °C/75% RH). The co-amorphous samples stored at 25 °C/75% RH quickly recrystallized into the co-crystalline state. On the other hand, the samples stored under dry conditions remained physically stable after five months of storage, except the ball milled sample stored at 40 °C which showed signs of recrystallization. Under these dry conditions, however, the ball-milled co-amorphous blend crystallized into the individual crystalline components.

Electron density, disorder and polymorphism: high-resolution diffraction studies of the highly polymorphic neuralgic drug carbamazepine.

Analysis of neutron and high-resolution X-ray diffraction data on form (III) of carbamazepine at 100 K using the atoms in molecules (AIM) topological approach afforded excellent agreement between the experimental results and theoretical densities from the optimized gas-phase structure and from multipole modelling of static theoretical structure factors. The charge density analysis provides experimental confirmation of the partially localized π-bonding suggested by the conventional structural formula, but the evidence for any significant C-N π bonding is not strong. Hirshfeld atom refinement (HAR) gives H atom positional and anisotropic displacement parameters that agree very well with the neutron parameters. X-ray and neutron diffraction data on the dihydrate of carbemazepine strongly indicate a disordered orthorhombic crystal structure in the space group Cmca, rather than a monoclinic crystal structure in space group P2(1)/c. This disorder in the dihydrate structure has implications for both experimental and theoretical studies of polymorphism.

Expanding the structural landscape of niclosamide: a high Z' polymorph, two new solvates and monohydrate H(A).

Three new crystalline phases are reported for the drug niclosamide [5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide], C13H8Cl2N2O4. A new high-Z' polymorph (denoted Form II) is described, with four molecules in the asymmetric unit in the space group P2/n. The structure exhibits pseudosymmetry, including local translations and screw-type operations. The niclosamide molecules are linked by O-H...O hydrogen bonds into chains, and the chains are packed so that the molecules form face-to-face (stacking) and end-to-end interactions within layers perpendicular to the chains. There are two different layer arrangements, giving a structure that is relatively complex. In the acetone and acetonitrile solvates, the incorporated solvent molecules accept hydrogen bonds from the OH groups of niclosamide, and the niclosamide molecules are stacked in a face-to-face manner. In the acetone solvate, C13H8Cl2N2O4·C3H6O, V-shaped arrangements are formed in which the nitrobenzene ends of the niclosamide molecules are brought into face-to-face contact. In the acetonitrile solvate, C13H8Cl2N2O4·CH3CN, stacking occurs by translation along a short axis (ca 3.8 Å) and the crystals are frequently observed to be twinned by twofold rotation around that axis. The acetonitrile molecules occupy channels in the structure. A complete structure is provided for niclosamide monohydrate, C13H8Cl2N2O4·H2O, polymorph HA, obtained by Rietveld refinement against laboratory powder X-ray diffraction data. It has been suggested that this compound is related to the methanol solvate of niclosamide [Harriss, Wilson & Radosevljevic Evans (2014). Acta Cryst. C70, 758-763], but it is found that the two are not fully isostructural: they contain isostructural two-dimensional layers, but the layers are arranged differently in the two structures. This suggests that HA may have the potential for polytypism, and features in the Rietveld difference curve indicate that a polytype fully isostructural with the methanol solvate might be present.

Experimental Electron Density and Neutron Diffraction Studies on the Polymorphs of Sulfathiazole.

High resolution X-ray diffraction data on forms I-IV of sulfathiazole and neutron diffraction data on forms II-IV have been collected at 100 K and analyzed using the Atoms in Molecules topological approach. The molecular thermal motion as judged by the anisotropic displacement parameters (adp's) is very similar in all four forms. The adp of the thiazole sulfur atom had the greatest amplitude perpendicular to the five-membered ring, and analysis of the temperature dependence of the adps indicates that this is due to genuine thermal motion rather than a concealed disorder. A minor disorder (∼1-2%) is evident for forms I and II, but a statistical analysis reveals no deleterious effect on the derived multipole populations. The topological analysis reveals an intramolecular S-O···S interaction, which is consistently present in all experimental topologies. Analysis of the gas-phase conformation of the molecule indicates two low-energy theoretical conformers, one of which possesses the same intramolecular S-O···S interaction observed in the experimental studies and the other an S-O···H-N intermolecular interaction. These two interactions appear responsible for "locking" the molecular conformation. The lattice energies of the various polymorphs computed from the experimental multipole populations are highly dependent on the exact refinement model. They are similar in magnitude to theoretically derived lattice energies, but the relatively high estimated errors mean that this method is insufficiently accurate to allow a definitive stability order for the sulfathiazole polymorphs at 0 K to be determined.

From closo to isocloso structures and beyond in cobaltaboranes with 9 to 12 vertices.

Density functional theory (DFT) studies predict the dianions CpCoB(n-1)H(n-1)(2-) (n = 9, 10, 11, 12; Cp = eta(5)-C(5)H(5)) to have structures based on the most spherical deltahedra found in the isoelectronic boranes B(n)H(n)(2-). In the CpCoB(8)H(8)(2-) dianion the non-equivalent structures with the cobalt atom at a degree 4 vertex and at a degree 5 vertex are essentially degenerate in terms of energy (within approximately 1 kcal/mol). For the CpCoB(n-1)H(n-1)(2-) dianions (n = 10, 11, 12) the cobalt atom prefers energetically the vertices of the lowest possible degree (four for n = 10 and 11, five for n = 12). Structures for the neutral species CpCoB(n-1)H(n-1) (n = 10, 11, 12) based on isocloso deltahedra with the cobalt atom at a degree 6 vertex are preferred energetically by 9, 19, and 53 kcal/mol, respectively, over alternative structures. However, for CpCoB(8)H(8) the closo tricapped trigonal prismatic structure with the cobalt atom at a degree 5 vertex is energetically preferred by approximately 9 kcal/mol over the isocloso deltahedral structure with the cobalt atom at a degree 6 vertex. The lowest energy structures predicted for the dications CpCoB(8)H(8)(2+) and CpCoB(9)H(9)(2+) are highly oblate (flattened) deltahedra with the cobalt atom at a degree 7 vertex. A complicated potential energy surface was found for CpCoB(10)H(10)(2+) including non-deltahedral structures with a single quadrilateral or pentagonal face. The predicted lowest energy structures for both CpCoB(11)H(11) and CpCoB(11)H(11)(2+) are based on the same 12-vertex deltahedron with three degree 6, six degree 5, and three degree 4 vertices, and thus topologically different from the regular icosahedron normally found in boron chemistry.

Kinetic versus thermodynamic isomers of the deltahedral cobaltadicarbaboranes.

Synthesis of the deltahedral cobaltadicarbaboranes CpCoC(2)B(n-3)H(n-1) (n = 9, 10, 11, 12) typically leads initially to kinetically stable isomers with energies up to approximately 20 kcal/mol above the lowest energy isomers. Pyrolyses of these originally produced isomers typically results in isomerization to give more thermodynamically stable isomers. In this connection the relative stabilities of the CpCoC(2)B(n-3)H(n-1) (n = 9, 10, 11, 12) isomers have been investigated using density functional theory. For CpCoC(2)B(n-3)H(n-1) (n = 9, 10, 11) the isomers with both carbon atoms at degree 4 vertices are predicted to have the lowest energies. For CpCoC(2)B(9)H(11) the icosahedron is by far the preferred polyhedron. Among the nine possible icosahedral CpCoC(2)B(9)H(11) isomers, the unique isomer with the carbon atoms in antipodal (para) positions is the global minimum. However, the four CpCoC(2)B(9)H(11) isomers with the two carbon atoms in mutual non-antipodal non-adjacent (meta) positions lie within approximately 5 kcal/mol of the global minimum. These theoretical results are in reasonable agreement with the extensive experimental work on pyrolysis of CpCoC(2)B(n-3)H(n-1) (n = 9, 10, 11, 12) derivatives, mainly in the group of Hawthorne and co-workers during the 1970s.