3-Fluoro­salicylaldoxime at 6.5 GPa

3-Fluoro­salicylaldoxime, C7H6FNO2, unlike many salicylaldoxime derivatives, forms a crystal structure containing hydrogen-bonded chains rather than centrosymmetric hydrogen-bonded ring motifs. Each chain inter­acts with two chains above and two chains below via π–π stacking contacts [shortest centroid–centroid distance = 3.295 (1) Å]. This structure at 6.5 GPa represents the final point in a single-crystal compression study

WebCSD: the online portal to the Cambridge Structural Database

The new web-based application WebCSD is introduced, which provides a range of facilities for searching the Cambridge Structural Database within a standard web browser. Search options within WebCSD include two-dimensional substructure, molecular similarity, text/numeric and reduced cell searching

The effect of pressure on the crystal structure of bianthrone

Bianthrone [10(10-oxoanthracen-9-ylidene)anthracen-9-one] consists of two tricyclic anthraceneone units connected by a carbon-carbon double bond. Crystals of the form obtained under ambient conditions are yellow and contain folded centrosymmetric conformers in which the central ring of the anthraceneone unit is non-planar. When hydrostatic pressure is applied the crystals assume a red colouration which gradually deepens as pressures increases. The colour change is limited in extent to the surface of the crystals, the bulk remaining yellow. Comparison of high-pressure, single-crystal UV-vis spectra and powder diffraction data demonstrate that the colour change is associated with the formation of a polymorph containing a conformer in which the tricyclic fragments are planar and the molecule is twisted about the central C-C bond. Single-crystal diffraction data collected as a function of pressure up to 6.5 GPa reveal the effect of compression on the yellow form, which consists of layers of molecules which stack along the [010] direction. The structure remains in a compressed form of the ambient-pressure phase when subjected to hydrostatic pressure up to 6.5 GPa, and the most prominent effect of pressure is to push the layers closer together. PIXEL calculations show that considerable strain builds up in the crystal as pressure is increased with a number of intermolecular contacts being pushed into destabilizing regions of their potentials

Optimization and comparison of statistical tools for the prediction of multicomponent forms of a molecule: the antiretroviral nevirapine as a case study

In the pharmaceutical area, to obtain structures with desired properties, one can design and perform a screening of multicomponent forms of a drug. However, there is an infinite number of molecules that can be used as co-formers. Aiming to avoid spending time and money in failed experiments, scientists are always trying to optimize the selection of co-formers with high probability to co-crystallize with the drug. Here, the authors propose the use of statistical tools from the Cambridge Crystallographic Data Centre (CCDC) to select the co-formers to be used in a pharmaceutical screening of new crystal forms of the antiretroviral drug nevirapine (NVP). The H-bond propensity (HBP), coordination values (CV), and molecular complementarity (MC) tools were optimized for multicomponent analysis and a dataset of 450 molecules was ranked by a consensus ranking. The results were compared with CosmoQuick co-crystal prediction results and they were also compared to experimental data to validate the methodology. As a result of the experimental screening, three new co-crystals – NVP–benzoic acid, NVP–3-hydroxybenzoic acid, and NVP– gentisic acid – were achieved and the structures are reported. Since each tool assesses a different aspect of supramolecular chemistry, a consensus ranking can be considered a helpful strategy for selecting coformers. At the same time, this type of work proves to be useful for understanding the target molecule and analyzing which tool may exhibit more significance in co-former selection.Consejo Superior de Investigaciones Científicas (CSIC) COOPA20094Red de Cristalografía y Cristalización "Factoría de Cristalización" (MCIU) FIS2015-71928-REDCCAPES 001MCIU/AEI/FEDER, UE PGC2018-102047-B-I00CAPE

Effect of high pressure on structural oddities

This thesis describes the effect of pressure on crystal structures that are in some way unusual. The aim was to investigate whether pressure could be used to force these ‘structural oddities’ to conform to more conventional behaviour. In many cases pressure-induced phase transitions were observed, and the driving forces of these are considered. L-serine monohydrate crystallises with layers of hydrogen bonded serine molecules. Layers are linked together by H-bonds from the donor atoms of water molecules. The orientation of the water molecules between the layers is uncommon for other layered hydrates in the CSD. A single crystal of serine hydrate undergoes a pressure-induced phase transition at 5 GPa, which is characterised by a rotation of the water molecules to an orientation which is more frequently observed. PIXEL calculations show that the transition is driven by the PV term in the equation G = U - TS + PV. An attempt to reproduce the transition in another layered hydrate with a similar topology was partially successful in the compression of S-4-sulfo-L-phenylalanine monohydrate, which undergoes a similar phase transition at 1 GPa. Methyl 2-(9H-carbazol-9-yl)benzoate crystallises unusually with eight molecules in the asymmetric unit (Z’ = 8). Compression of a single crystal results in a phase transition at ca. 5 GPa to give a Z’ = 2 polymorph. The PV term is an important contributor to the driving force of the transition. The geometries of the molecules in phase-II are significantly less stable than in phase-I, and as pressure is released on phase-II the need to adopt a more stable molecular conformation eventually outweighs the PV advantage. The Z’ = 8 structure is eventually re-established at 4.6 GPa. This work illustrates how low Z’ polymorphs of the same structure are not always the thermodynamically more stable forms. When recrystallised in situ from a 4:1 by volume solution of methanol and ethanol, a new polymorph of salicylamide is obtained at 0.2 GPa. The ambient pressure phase appears in the CSD to contain a number of abnormally short H…H contacts. We find this model to be incorrect, and have re-determined the structure to find no short H…H contacts. PIXEL and DFT calculations indicate that the high-pressure polymorph is favoured over the ambient phase by the PV term, the zero point energy and entropy. Low completeness that often occurs as a result of shading from the high-pressure cell was improved by the inclusion of multiple crystals within the sample chamber. Bianthrone changes colour from yellow to green on grinding, though this does not occur when subjected to hydrostatic pressure to 6.5 GPa. There is, however, a subtle colour change from bright yellow to dark orange as pressure is applied, and it is likely that this is caused by changes in the - stacking distances. This work highlights how a system can react differently to hydrostatic and non-hydrostatic conditions.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Fast energy minimization of the CCDC drug subset structures by molecule-in-cluster computations allows independent structure validation and model completion

Optimizing structures with computations on clusters of molecules permits generation of structure-specific restraints for refinement. Equally importantly, retrospective structure validation and addition of hydrogen atoms consistent with quantum chemistry is possible for experimental structures or the solvent molecules in them, should they be missing in earlier CIF depositions. Revisiting the drug subset structures of the CCDC demonstrates that structure validation through ab initio cluster computations is a tremendous validation tool. The time required for optimization can be similar to the time required to carry out least squares refinement for small-molecule structures, and becomes feasible for large structures. Several questions arise: is it valid to augment experimental structures with structure-specific restraints, ideally through accompanying refinement with computation? Do energy minimized structures (using the experimental determinations as a starting point) still constitute an experimental result? When re-refinement is impossible in retrospect, like for most of the drug-subset molecules, then additional value lies in completion and validation of existing structures so that they are chemically and crystallographically correct, and contain missing water or solvent hydrogen atoms. Our results suggest that retroactive validation and addition of hydrogen atoms becomes possible for the entire Cambridge Structural Database. Generation of database entries of optimized alongside existing structures will provide the flexibility needed to make full use of the information gained by computation

Combining modified CCDC tools to predict multicomponent formation: co-crystals of nevirapine and benzoic derivatives

XXV General Assembly and Congress of the International Union of Crystallography - (IUCr 2021). Prague, Czech Republic, 14-22 August 2021. .-https://journals.iucr.org/a/issues/2021/a2/00

Novel solid forms of an antiretroviral drug: solvates, cocrystals and eutectic systems

LACA 2019, Bucaramanga, Colombia, October 7th-10th, 2019. -- https://ivlaca2019.co/Nevirapine (11-Cyclopropyl-4-methyl-5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one) (NVP) is an antiretroviral used to treat HIV-1 infection [1]. According to the Biopharmaceutical Classification System (BCS) [2], NVP is classified as a class II drug [3], which means it presents low solubility and high permeability. The low solubility implies in problems during formulation and resulting in a decreasing in the bioavailability. Solid-state modifications have been used in pharmaceutical area as a strategy to improve drug properties. Among the possible modifications there is the formation of multicomponent forms, including cocrystals, solvates and eutectic systems (figure 1). Several multicomponent structures containing the NVP have been described in literature. In a screening of new multicomponent forms of NVP, four co-crystals, five solvates and two eutectic systems have been found. Characterization of materials were performed using optical microscopy, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and Raman spectroscopy. Crystalline structures were determined single X-ray diffraction (SXRD) data.This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001, Consejo Superior de Investigaciones Científicas (CSIC) (i-COOP+2015, COOPA20094) and Red de Cristalografía y Cristalización “Factoría de Cristalizacion” (FIS2015-71928-REDC)