A strategy for predicting the crystal structures of flexible molecules: the polymorphism of phenobarbital

Abstract

A computational exploration of the low energy crystal structures of the pharmaceutical molecule phenobarbital is presented as a test of an approach for the crystal structure prediction of flexible molecules. Traditional transferable force field methods of modelling flexible molecules are unreliable for the level of accuracy required in crystal structure prediction and we outline a strategy for improving the evaluation of relative energies of large sets of crystal structures. The approach involves treating the molecule as a set of linked rigid units, whose conformational energy is expressed as a function of the relative orientations of the rigid groups. The conformational energy is calculated by electronic structure methods and the intermolecular interactions using an atomic multipole description of electrostatics. A key consideration in our approach is the scalability to more typical pharmaceutical molecules of higher molecular weight with many more atoms and degrees of flexibility. Based on our calculations, crystal structures are proposed for the as-yet uncharacterised forms IV and V, as well as further polymorphs of phenobarbital.