The polymorphs of ROY: application of a systematic crystal structure prediction technique.

Department of Chemical Engineering, Centre for Process Systems Engineering, Imperial College London, London SW7 2AZ, England.
Acta crystallographica. Section B, Structural science (Impact Factor: 1.8). 12/2012; 68(Pt 6):677-85. DOI: 10.1107/S0108768112045636
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The discovery and selective production of crystalline polymorphs, an outstanding problem in solid-state chemistry, is of great importance industrially in, for example, the manufacture of pharmaceuticals and pigments. Despite considerable efforts, no reliable method exists to produce all of the stable polymorphs of a given compound. Herein, we report methodology to control the phenomenon of crystal polymorphism through the use of diverse libraries of polymer heteronuclei including both commercially available polymers and combinatorially synthesized cross-linked polymers. This new approach for exploring polymorph space offers the advantage of high throughput crystallization to discover multiple polymorphs combined with the ability to selectively produce a given form from a single solvent and temperature condition by simply varying the nature of the polymer substrate. This technique is successfully demonstrated on the pharmaceuticals acetaminophen, sulfamethoxazole, and carbamazepine and on the pharmaceutical intermediate 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY). High throughput screening, accomplished by optical microscopy and Raman spectroscopy, identified the selective production of the two stable polymorphs of acetaminophen and all six stable forms of ROY. Furthermore, one new form of carbamazepine and two new forms of sulfamethoxazole were discovered; in these cases, single crystals were obtained enabling the structural characterization of two new tetramorphic systems.
    Journal of the American Chemical Society 05/2005; 127(15):5512-7. · 10.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The crystallographically determined bond length, valence angle, and torsion angle information in the Cambridge Structural Database (CSD) has many uses. However, accessing it by means of conventional substructure searching requires nontrivial user intervention. In consequence, these valuable data have been underutilized and have not been directly accessible to client applications. The situation has been remedied by development of a new program (Mogul) for automated retrieval of molecular geometry data from the CSD. The program uses a system of keys to encode the chemical environments of fragments (bonds, valence angles, and acyclic torsions) from CSD structures. Fragments with identical keys are deemed to be chemically identical and are grouped together, and the distribution of the appropriate geometrical parameter (bond length, valence angle, or torsion angle) is computed and stored. Use of a search tree indexed on key values, together with a novel similarity calculation, then enables the distribution matching any given query fragment (or the distributions most closely matching, if an adequate exact match is unavailable) to be found easily and with no user intervention. Validation experiments indicate that, with rare exceptions, search results afford precise and unbiased estimates of molecular geometrical preferences. Such estimates may be used, for example, to validate the geometries of libraries of modeled molecules or of newly determined crystal structures or to assist structure solution from low-resolution (e.g. powder diffraction) X-ray data.
    Journal of Chemical Information and Computer Sciences 10/2004; 44(6):2133-44.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A remarkable property of certain glass-forming liquids is that a fast mode of crystal growth is suddenly activated near the glass transition temperature, Tg, and continues in the glassy state. This mode of growth, termed GC (glass-crystal), is so fast that it is not limited by molecular diffusion in the bulk liquid. We have studied the GC growth by growing multiple crystal polymorphs from the liquid of ROY, currently the top system for the number of coexisting polymorphs of known structures. We observed a new feature of GC growth that conflicts with its current description in the literature. We found that the GC mode is not truly a new growth mode suddenly appearing near Tg but one already existing in the equilibrium liquid up to approximately 1.15 Tg, in the form of fast-growing fibers. This finding is relevant to testing different explanations for GC growth and favors the view that GC growth is enabled by molecular motions that are native to the glass but still persist in the viscous liquid.
    The Journal of Physical Chemistry B 02/2008; 112(3):661-4. · 3.61 Impact Factor