The polymorphs of ROY: application of a systematic crystal structure prediction technique.
ABSTRACT We investigate the ability of current ab initio crystal structure prediction techniques to identify the polymorphs of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, also known as ROY because of the red, orange and yellow colours of its polymorphs. We use a methodology combining the generation of a large number of structures based on a computationally inexpensive model using the CrystalPredictor global search algorithm, and the further minimization of the most promising of these structures using the CrystalOptimizer local minimization algorithm which employs an accurate, yet efficiently constructed, model based on isolated-molecule quantum-mechanical calculations. We demonstrate that this approach successfully predicts the seven experimentally resolved structures of ROY as lattice-energy minima, with five of these structures being within the 12 lowest energy structures predicted. Some of the other low-energy structures identified are likely candidates for the still unresolved polymorphs of this molecule. The relative stability of the predicted structures only partially matches that of the experimentally resolved polymorphs. The worst case is that of polymorph ON, whose relative energy with respect to Y is overestimated by 6.65 kJ mol(-1). This highlights the need for further developments in the accuracy of the energy calculations.
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ABSTRACT: Organic molecules can crystallize in multiple structures or polymorphs, yielding crystals with very different physical and mechanical properties. The prediction of the polymorphs that may appear in nature is a challenge with great potential benefits for the development of new products and processes. A multistage crystal structure prediction (CSP) methodology is applied to axitinib, a pharmaceutical molecule with significant polymorphism arising from molecular flexibility. The CSP study is focused on those polymorphs with one molecule in the asymmetric unit. The approach successfully identifies all four known polymorphs within this class, as well as a large number of other low-energy structures. The important role of conformational flexibility is highlighted. The performance of the approach is discussed in terms of both the quality of the results and various algorithmic and computational aspects, and some key priorities for further work in this area are identified.Chemical Engineering Science 09/2014; 121. DOI:10.1016/j.ces.2014.08.058 · 2.61 Impact Factor
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ABSTRACT: We describe the automated generation of libraries for predicting the geometric preferences of druglike molecules. The libraries contain distributions of molecular dimensions based on crystal structures in the Cambridge Structural Database (CSD). Searching of the libraries is performed in cascade fashion to identify the most relevant distributions in cases where precise structural features are poorly represented by existing crystal structures. The libraries are fully comprehensive for bond lengths, valence angles and rotamers, and produce templates for the large majority of unfused and fused rings. Geometry distributions for rotamers and rings take into account any atom chirality that may be present. Library validation has been performed on a set of druglike molecules whose structures were published after the latest CSD entry contributing to the libraries. Hence, the validation gives a true indication of prediction accuracy.Journal of Chemical Information and Modeling 08/2014; 54(9). DOI:10.1021/ci500358p · 4.07 Impact Factor
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ABSTRACT: Varied multicomponent molecular assemblies of trithiocyanuric acid (TCA) with N-donor compounds are prepared by varying the reaction conditions. The rational structural features, from a basic molecular recognition pattern to three-dimensional molecular assemblies, of the obtained molecular complexes are explained in detail with the help of single crystal X-ray diffraction analysis. The structural analysis highlights, within the cocrystals, TCA with multiple hydrogen bonding groups are capable of forming variable molecular patterns on its own results in varied molecular assemblies for the individual molecular ensembles with 4,4'-bipyridine (bpy), 1,2-bis-(4-pyridyl)ethylene (bpyea), and 1,7-phenanthroline (phen).Crystal Growth & Design 09/2014; 14(9):4803-4810. DOI:10.1021/cg500961n · 4.56 Impact Factor