The influence of disorder on polymorphism in pharmaceuticals

Polymorphism is of key importance in the pharmaceutical industry since the properties of different polymorphs of the same compound may differ considerably e.g. the rate of uptake of pharmaceutical molecules by the human body is often strongly dependent on which polymorphic form of the material is present. There are many patenting issues that arise from this. The aim of the study is to use diffuse scattering methods to investigate the crystal structures of polymorphic systems in a level of detail that goes beyond the average structures that are revealed by conventional crystallography. A particular aim is to investigate the role that molecular flexibility plays in determining crystal packing and the conformations and dynamics of the molecule that occur in different polymorphs. As a first step, we have studied the model compound p-(N-methylbenzylidene)-p-methylaniline (MeMe), which crystallises in three polymorphic forms. Two of these have orientational disorder in which the molecules are “flipped” either end-to-end and/or side-to-side, but the third appears, in conventional crystallographic studies, to be completely ordered. All three, however, show strong and highly structured diffuse scattering. A complete study of the diffuse scattering of the pharmaceutical ibuprofen has been published during 2007, and diffuse scattering data have been collected on two polymorphs of benzocaine, two polymorphs of barbital, several polymorphs of substituted sulfonamides and one polymorph of aspirin. Analyses of these systems are underway.