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Energy partitioning of pharmaceutical cocrystal structures

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


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