Insights into the structure-property relationship of pharmaceutical co-crystals: Charge density and quantum chemical approaches

Abstract

A subset of co-crystal systems of the antipyretic and analgesic drug, propyphenazone, are used to probe the nature of the drug···co-former interactions. The experimental electron density distribution, based on very high-resolution single crystal diffraction, has been modelled and an analysis undertaken using Bader's Atoms in Molecules approach. Atomic charges, intermolecular interactions and their energies have been subsequently derived and compared between systems. Complementary theoretical calculations are used to derive interaction energies for intermolecular interactions beyond atom···atom contacts. These permit the deconvolution of the intermolecular interactions into their constituent energy components for a comprehensive analysis. This approach provides an insight into the factors affecting the assembly of the solid state, with the case of pharmaceutical co-crystals being highlighted in this work. Furthermore, this approach enables analysis of the effect of the co-former on various influencing factors that determine the physicochemical properties of these multi-component systems.