Phase Equilibrium Thermodynamics and Quantum Chemistry for Ternary Cocrystal Systems Comprising Caffeine, Malonic/Oxalic Acid, and Ethanol/Ethyl Acetate

Abstract This paper investigates the object involving 2caffeine·oxalic/malonic acid cocrystal at a 2:1 mol ratio, employing the isothermal saturation technique to comprehensively assess mutual solubilities at 298.15, 313.15, and 328.15 K for the caffeine + oxalic/malonic acid + ethanol/ethyl acetate systems. Twelve cocrystal phase diagrams were generated. Each ternary system comprised three pure solids: caffeine, oxalic acid or malonic acid, and a caffeine cocrystal (2caffeine·oxalic/malonic acid, 2:1 mol ratio) with oxalic or malonic acid. Furthermore, each system included two invariant points and three saturation curves. Analyzing these cocrystal phase diagrams enhanced the comprehension of cocrystal crystallization behavior in solvents and found stable cocrystal positions in specific solvents. The improved model of solubility product and solution complexation was employed to mathematically correlate the solubilities alongside the crystalline curves of the 2caffeine·oxalic acid and 2caffeine·malonic acid cocrystals, resulting in a maximum relative standard deviation of 7.39%. The research on quantum chemistry indicated the beneficial interactions of hydrogen bonding and van der Waals forces in the formation of the 2caffeine·oxalic/malonic acid cocrystal. Synthesis and isolation of the 2caffeine·oxalic/malonic acid cocrystal in a solvent can be facilitated through the cocrystal phase diagram established in this study.