Importance of molecular shape for the overall stability of hydrogen bond motifs in the crystal structures of various carbamazepine-type drug molecules

Carbamazepine, a first generation anticonvulsant, is known to crystallize in various polymorphic forms, all of which exhibit an anti-carboxamide hydrogen bond dimer motif. Furthermore, unless cocrystallized with carboxylic acids, these dimers are also present in most crystal structures of the known carbamazepine solvates. On the other hand, two derivatives of the drug (oxcarbazepine and 10,11-dihydrocarbamazepine) have been reported to adopt hydrogen bond chain motifs in their crystal structures, whereas the epoxy derivative (10,11-epoxycarbamazepine) shows a third mode of hydrogen bonding, syn-dimers. In order to rationalize the differences in hydrogen bonding caused by the small changes in molecular structure, computational searches for the low-energy crystal structures of these drugs were performed and hydrogen bond patterns in both the hypothetical and experimentally determined crystal structures were analyzed. In addition, interaction energies between pairs of molecules were calculated using the SCDS-PIXEL approach, which partitions the intermolecular interaction energy into its different contributions (Coulombic, polarization, dispersion, and repulsion). The importance of overall molecular shape and the influence that this has on the hydrogen bond arrangements in these structures is emphasized.