Mixing Effects on the Ternary Phase Diagram of Cocrystals and Gibbs Formation Energy Calculation

The fundamental thermodynamic property of a cocrystal is its formation energy, often referred to as Gibbs free energy of formation, Delta G(f), which is essential to provide insights into its preparation and stability. Most experimental methods of determining Delta G(f) of a cocrystal from its solubility and those of the pure components assume ideal intermolecular interactions among the components, i.e., where the strength and nature of interactions between different components are regarded identical with those in the pure components. However, in most real systems of interest, the interactions between the cocrystal components and their interactions with the solvent often deviate from ideality because of differences in polarity, hydrogen-bonding propensity, and dispersion forces, leading to nonideal mixing effects on their properties. In this article, a ternary phase diagram (TPD) is utilized to elucidate how nonideal mixing among the components affect the Delta G(f) determination of cocrystals and a simple equation is proposed to determine the same. Additionally, the use of a TPD in determining Delta G(f) values of a few cocrystals is described using this equation. The significance and limitations of the derived equation in determining Delta G(f) are also discussed.