Dittrich, Birger, Connor, Lauren, Werthmueller, Dominic, Sykes, Nicole and Udvarhelyi, Aniko (2023) Energy partitioning of pharmaceutical cocrystal structures. Cryst. Eng. Comm..

Abstract

Active pharmaceutical ingredients (APIs) and selected coformers were studied in crystalline self-environment, in selected co-crystal structures, and gas phase. To obtain comparable geometries from experimental crystal structures, we rely on fast quantum mechanical GFN2-XTB molecule-in-cluster optimizations. Optimized crystal structures are first analysed in terms of molecule-pair interaction energies, by subdividing a cluster generated from asymmetric unit content through space-group symmetry into pairs of molecules. Accurate energies are then obtained by single-point molecular orbital (MO/MO) two layer “ONIOM” energy partitioning, comparing the same molecules in different crystal environments. Clusters approximate the local environment of a crystal structure for ONIOM. The pre-processor program BAERLAUCH (Acta Cryst A 2012) was used to set up all cluster computations. Solid-state computations using dispersion-corrected density functional theory provide reference results. ONIOM partitioned energies shed light on the driving force of co-crystal formation, with the energy gain from the complementarity of molecule-pair wavefunctions in such structures being the main driving force. It follows that improving prediction of co-crystal structure formation beyond current approaches, e.g. COSMO-RS1 excess enthalpies, statistics from structural databases or full crystal structure prediction is possible by finding complementary molecule-pairs through conformational sampling, as ultimately exemplified.

Item Type:	Article
Keywords:	ONIOM, molecule-in-cluster computations, co-crystals, density-functional theory
Date Deposited:	01 Feb 2023 00:46
Last Modified:	01 Feb 2023 00:46
URI:	https://oak.novartis.com/id/eprint/46605