The purpose of this work was to develop a mathematical model that describes the solubility of cocrystals by taking into consideration the equilibria between cocrystal, cocrystal components, and solution complexes. These models are applied to the phase diagrams of carbamazepine/nicotinamide (CBZ/NCT) cocrystal in organic solvents. The CBZ/NCT (1:1) cocrystal solubility was measured by suspending cocrystal in solutions of varying nicotinamide concentrations in ethanol, 2-propanol, or ethyl acetate. Results show that the solubility of the cocrystal decreases with increasing nicotinamide concentration. Mathematical models demonstrate that (1) the solubility of a cocrystal AB is described by the solubility product of cocrystal components and by solution complexation constants, (2) these equilibrium constants can be determined from solubility methods, and (3) graphical representation of the cocrystal solubility dependence on ligand concentration will serve as a diagnostic tool for the stoichiometry of solution complexes. CBZ/NCT cocrystal K sp values increase as the cocrystal solubility increases, while K 11 values decrease. The dependence of cocrystal solubility on solubility product and complexation constants provides a powerful approach to design cocrystal screening methods and to formulate solutions with cocrystal components where crystallization does not occur.

A mechanism for cocrystal synthesis is reported whereby nucleation and growth of cocrystals are directed by the effect of the cocrystal components on reducing the solubility of the molecular complex to be crystallized. The carbamazepine:nicotinamide cocrystal (CBZ:NCT) was chosen as a model system to study the reaction cocrystallization pathways and kinetics in aqueous and organic solvents. Fiber optic Raman spectroscopy and Raman microscopy were used for in situ monitoring of the cocrystallization in macroscopic and microscopic scales in solutions, suspensions, slurries, and wet solid phases of cocrystal components. This study demonstrates the advantages of reaction cocrystallization methods to develop rational approaches for high-throughput screening of cocrystals that can be transferable to control batch and continuous cocrystallization processes.

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