Molecular dynamics simulations on the effect of solvent and supersaturation on the aggregation behaviour in carbamazepine

Polymorphism in carbamazepine is a well-known phenomenon that can occur due to different factors, such as solvent, supersaturation, temperature and external surface. We report molecular dynamics simulation studies on the effect of supersaturation and solvent on the formation of different types of carbamazepine (CBZ) dimers as a function of supersaturation in different solvents. The understanding of the factors that affect the formation of different types of CBZ dimers in solution could help to gain insight into factors that control the nucleation of different polymorphs of carbamazepine in solvent-dependent crystallization. We propose that the presence of different types of CBZ dimers (FI-type, FII-type and FIII-type) with different angles between the 6-membered aromatic rings of different CBZ molecules act as growth synthons for different CBZ polymorphs in solution. The simulation results show that there are four types of species depending on hydrogen bonding in the CBZ clusters - single hydrogen bond (HB), HB dimer, HB trimer and HB tetramer, based on the strength of the solvent-solvent and solvent-CBZ interactions. The HB dimers in the CBZ molecules lead to overlap between the 6-membered rings of CBZ and thus, the formation of FIII-type CBZ dimers in all the supersaturations in acetone and in the high supersaturation system in ethyl lactate. In the presence of a single HB and depending on the strength of the solvent-CBZ interactions there are two possibilities - FII-type CBZ dimers in solvents like ethanol and anisole that have similar CBZ-CBZ and solvent-CBZ interactions or FI-type CBZ dimers in <i>N</i>,<i>N</i>-dimethylformamide if the solvent-CBZ interactions are strong. Solvent-solvent interactions mainly govern the dynamics of the CBZ molecules and CBZ-solvent interactions play an important role in the size of the CBZ clusters.