title: 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.
authors.affiliation: The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK. cruz@ccdc.cam.ac.uk
authors.forename: Aurora J
authors.initials: AJ
authors.lastname: Cruz-Cabeza
authors.forename: Graeme M
authors.initials: GM
authors.lastname: Day
authors.forename: William
authors.initials: W
authors.lastname: Jones
mesh_terms: D002220:Carbamazepine / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004121:Dimethyl Sulfoxide / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D012997:Solvents / Q000737:chemistry*; D013696:Temperature; D013816:Thermodynamics
chemical_list: D012997:Solvents; D002220:Carbamazepine; D004121:Dimethyl Sulfoxide