Caffeine and 4-Hydroxybenzoic Acid Cocrystal Hydrate: Preparation, Characterization, and Evaluation.

Caffeine is one of the most consumed stimulants with pharmaceutical benefits; however, its varied pH-dependent solubility (120-‍500 µg/mL) and moderate stability hinder bioavailability. In this study, a 1:1:1 cocrystal hydrate of caffeine with 4-hydroxybenzoic acid was crystallized and systematically reevaluated. SCXRD and PXRD revealed a triclinic system sustained by O─H···O and C─H···O hydrogen bonds. The Hirshfeld surface showed increased H···O/O···H interactions from 11.0% in caffeine to 15.7% in CAF·4HBA·H2O. Thermal analysis of CAF·4HBA·H2O showed a sharp melting endotherm at 166.7 °C with only a small mass loss (~2.46%) before melting, indicating high purity and good thermal stability. Dissolution studies showed the modulated caffeine release, with 2.8% released initially in pH 1.2, gradually increasing to 89.2% by 60 min and nearly complete release by 120 min. In pH 6.8, the CAF·4HBA·H2O achieved rapid and nearly complete release of caffeine within 60 min, compared to slightly slower release from pure caffeine. These results indicate that CAF·4HBA·H2O modulates dissolution kinetics rather than substantially increasing solubility. The present work emphasizes cocrystallization as a viable strategy to tailor dissolution behavior and stability, providing physicochemical insights relevant to oral formulation design.