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.