Issue 28, 2011

Structure prediction, disorder and dynamics in a DMSO solvate of carbamazepine

Abstract

We have applied crystal structure prediction methods to understand and predict the formation of a DMSO solvate of the anti-convulsant drug carbamazepine (CBZ), in which the DMSO molecules are disordered. Crystal structure prediction calculations on the 1 : 1 CBZ : DMSO solvate revealed the generation of two similar low energy structures which differ only in the orientation of the DMSO molecules. Analysis of crystal energy landscapes generated at 0 K suggests the possibility of solvent disorder. A combined computational and experimental study of the changes in the orientation of the DMSO within the crystal structure revealed that the nature of the disorder changes with temperature. At low temperature, the DMSO disorder is static whilst at high temperature the DMSO configurations can interconvert by a 180° rotation of the DMSO molecules within the lattice. This 180° rotation of the DMSO molecules drives a phase change from a high temperature dynamically disordered phase to a low temperature phase with static disorder. Crystallisation of a DMSO solvate of the related molecule epoxycarbamazepine resulted in a different degree of DMSO disorder in the crystal structure, despite the similarity of the carbamazepine and epoxycarbamazepine molecules. We believe consideration of disorder and its contribution to entropy and crystal free energies at temperature other than 0 K is fundamental for the accuracy of future energy rankings in crystal structure prediction calculations of similar solvated structures.

Graphical abstract: Structure prediction, disorder and dynamics in a DMSO solvate of carbamazepine

Supplementary files

Article information

Article type
Paper
Submitted
25 Mar 2011
Accepted
20 May 2011
First published
14 Jun 2011

Phys. Chem. Chem. Phys., 2011,13, 12808-12816

Structure prediction, disorder and dynamics in a DMSO solvate of carbamazepine

A. J. Cruz-Cabeza, G. M. Day and W. Jones, Phys. Chem. Chem. Phys., 2011, 13, 12808 DOI: 10.1039/C1CP20927B

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