Investigating the Intermolecular Interactions in Concentration-Dependent Solution Cocrystallization of Caffeine and p-Hydroxybenzoic Acid

Cooling crystallization of methanol solutions of caffeine (CAF) and p-hydroxybenzoic acid (PHBA) with different initial concentration ratios has produced single-component crystals, CAF or PHBA, or cocrystals, 2(CAF)center dot PHBA or CAF center dot 2(PHBA), or mixtures of them. With high concentration ratio between PHBA and CAF, the crystal formation tendency is on the order of PHBA, CAF center dot 2(PHBA), 2(CAF)center dot PHBA, and CAP; that is, there is a higher chance to produce crystals with higher PHBA content. Rational explanation can be sought by characterizing the intermolecular interactions of CAF and PHBA molecules in solutions using pulsed gradient spin echo nuclear magnetic resonance. The relative magnitudes of the CAF-PHBA, CAF-CAF, and PHBA-PHBA pair interactions are found to vary systematically with the initial concentration ratio, PHBA/CAF. The results indicate that the tendency of growing respective single-component crystals or cocrystals shifts systematically with the concentration ratio. This contribution has shown that the microscopic intermolecular interactions determined in the solution state may serve as qualitative and predictive indicators for the final crystalline products. This novel approach can be used in conjunction with the ternary phase diagrams in depicting the regions of thermodynamic stability and predicting the potential formation of crystals/cocrystals in a multicomponent crystal system.