Rational Design of the Carbamazepine Ternary Cocrystals

The first ternary cocrystals of carbamazepine (CBZ) were successfully identified through a large-scale screening. A design strategy involved the use of an aliphatic dicarboxylic acid to link CBZ and a third component into a hydrogen-bonded trimeric unit. Out of the 10 dicarboxylic acids tested, only malonic acid produced a positive response in the attempt to obtain the CBZ ternary cocrystals with benzamide and picolinamide. The crystal structures of the novel ternary cocrystals obtained by vapor diffusion crystallization were determined by single-crystal X-ray diffraction. Structural analysis revealed that the ternary cocrystals are isostructural and exhibit the packing of trimers into ladder-like chains. The relationship between the CBZ binary and ternary cocrystals was confirmed by comparing the crystal structures. The cocrystal solubility method was applied to estimate the thermodynamic parameters of the ternary cocrystal formation. The negative values of the Gibbs free energy, enthalpy, and entropy indicate that the reaction of ternary cocrystal formation is a thermodynamically favored process and driven by enthalpy. Despite the isostructural nature, the physicochemical properties of the ternary cocrystals, including melting point and thermodynamic solubility, are strongly influenced by the variable coformer.