Exploring the CSD Drug Subset: An Analysis of Lattice Energies and Constituent Intermolecular Interactions for the Crystal Structures of Pharmaceuticals

Intermolecular (synthonic) modelling is used for a statistical analysis of crystal lattice energies, together with their contributing intermolecular interactions for the crystallographic structures selected from the CCDC's Drug Subset (https://doi.org/10.1016/j.xphs.2018.12.011). Analysis of this selected subset reveal similarities in packing compared to other organic crystals in the CSD with linear relationships between molecular weight and unit cell volume, void space, and packing coefficient. Crystal lattice energy calculations converge within a 30 Å intermolecular radius characterised by a mean lattice energy of ca. -36 kcal mol−1 with ca. 85% and 15% due to dispersive and electrostatic interactions, respectively. The distribution of the strongest synthons within the individual structures reveals an average strength of −5.79 kcal mol−1. The diversity of chemical space within the drug molecules is in agreement with the analysis of atom types across the selected subset with phenyl groups being found to contribute the highest mean energy of −11.28 kcal mol−1, highlighting the importance of aromatic interactions within pharmaceutical compounds. Despite an initial focus on Z’ = 1 structures, this automated approach enables rapid and consistent quantitative analysis of lattice energy, synthon strength and functional group contributions, providing solid-form informatics for pharmaceutical R&D and a helpful basis for further investigations.