Investigation of Ternary Phase Diagrams of Carbamazepine–Nicotinamide Cocrystal in Ethanol and Ethanol/Ethyl Acetate Mixtures at 298.15 K and 313.15 K

The phase diagrams for carbamazepine (CBZ) and nicotinamide (NCT) in ethanol and ethanol/ethyl acetate mixture were constructed at 298.15 K and 313.15 K under atmospheric pressure using the static method. The solubility of the 1:1 cocrystal is correlated as a function of the cocrystal former (nicotinamide) concentration by a mathematical model based on solubility product theory and the complexation process. The phase diagram of a CBZ–NCT cocrystal in pure ethanol at 298.15 K is asymmetric, which leads to an excess of coformer being needed to isolate the cocrystal. In terms of this issue, it was found that the solvent mixture can have a significant effect on the symmetry of phase diagrams. Employing solvent mixtures could make the phase diagrams of the CBZ–NCT cocrystal more symmetric and enlarge the safe operation region for the cocrystal. Additionally, in the cocrystal formation process, the nucleation of cocrystal and carbamazepine in a slurry crystallization, is a competitive relationship. For avoiding single component crystallization, the supersaturation ratio of cocrystal to drug should be increased to inhibit carbamazepine nucleation. These findings are all beneficial to the development of the cocrystallization process of the CBZ–NCT cocrystal.