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
Article: Why don't we find more polymorphs?[Show abstract] [Hide abstract]
ABSTRACT: Crystal structure prediction (CSP) studies are not limited to being a search for the most thermodynamically stable crystal structure, but play a valuable role in understanding polymorphism, as shown by interdisciplinary studies where the crystal energy landscape has been explored experimentally and computationally. CSP usually produces more thermodynamically plausible crystal structures than known polymorphs. This article illustrates some reasons why: because (i) of approximations in the calculations, particularly the neglect of thermal effects (see §1.1); (ii) of the molecular rearrangement during nucleation and growth (see §1.2); (iii) the solid-state structures observed show dynamic or static disorder, stacking faults, other defects or are not crystalline and so represent more than one calculated structure (see §1.3); (iv) the structures are metastable relative to other molecular compositions (see §1.4); (v) the right crystallization experiment has not yet been performed (see §1.5) or (vi) cannot be performed (see §1.6) and the possibility (vii) that the polymorphs are not detected or structurally characterized (see §1.7). Thus, we can only aspire to a general predictive theory for polymorphism, as this appears to require a quantitative understanding of the kinetic factors involved in all possible multi-component crystallizations. For a specific molecule, analysis of the crystal energy landscape shows the potential complexity of its crystallization behaviour.08/2013; 69(Pt 4):313-28. DOI:10.1107/S2052519213018861
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ABSTRACT: The crystal structure of Form 4 of the drug (4-[4-(2-adamantylcarbamoyl)-5-ter-butyl-pyrazol-1-yl] benzoic acid) is determined using a protocol for NMR powder crystallography at natural isotopic abundance combining solid-state 1H NMR spectroscopy, crystal structure prediction, and DFT chemical shift calculations. This is the first example of NMR structure determination for a molecular compound of previously unknown structure, and at 422 g/mol this is the largest compound to which this method has been applied so far.Journal of the American Chemical Society 10/2013; 135(46). DOI:10.1021/ja4088874 · 11.44 Impact Factor