Are high Z' polymorphs metastable? Insight from pharmaceutical polymorphs

Abstract

High Z' polymorphs are hypothesized to be kinetically trapped products and hence less stable than their low Z' forms (Z' = number of symmetry independent molecules in a crystal structure). Although the existence of such a symmetry–stability relationship would be of fundamental importance to the structural chemistry of molecular crystals, it has yet to be supported by experimental or computational evidence. A major challenge in analyzing high Z′ crystal structures is the large number of atoms, which makes accurate quantum chemical evaluation of their lattice cohesive energies (LCEs) computationally intensive. A systematic test of this hypothesis in drug polymorphs is made feasible by the CE-B3LYP method which uses pairwise summation of interaction energies for LCE estimation. Here, we have analysed 15 drugs (49 poymorphs) of low and high Z' crystal forms in terms of lattice cohesive energies, Kitaigorodskii packing indices (KPI), in-crystal molecular volumes, and crystal densities. Our results show no direct relation between Z' and the stability of drug polymorphs.