Enhancing the Solubility of Indomethacin: A Breakthrough with Cocrystal Formation

Background/objectives: Pharmaceutical cocrystals have emerged as a promising strategy to enhance the solubility and bioavailability of poorly water-soluble drugs. Indomethacin (IND), classified as a Biopharmaceutics Classification System (BCS) Class II drug, exhibits low solubility but high permeability. This study aims to develop a synthesis method, evaluate cocrystal solubility/stability and the physicochemical properties of the pure components, and describe cocrystal solubility using a mathematical model. Methods: Cocrystals were synthesized via solvent evaporation, using ethanol, methanol, and ethyl acetate. The pure components, IND and benzoic acid (AcBz) were dissolved in each solvent and maintained in a thermostabilizer for 24 h. Cocrystal formation was confirmed by UV-V spectroscopy, differential scanning calorimetry (DSC), and infrared (IR) spectroscopy. Results: The results showed that the solubility of the cocrystals decreased with increasing benzoic acid concentration. Mathematical modelling revealed that solubility can be expressed as the product of the solubilities of the individual components and the stability constant of the solution complex. Among the solvents tested, ethanol exhibited the highest solubility and equilibrium constant (K_eq) for IND-AcBz cocrystals, suggesting a greater molecular affinity and enhanced cocrystal formation. Conclusions: These findings demonstrate that the formation of the novel INDAcBz cocrystal significantly enhances Indomethacin solubility and thermodynamic stability. These results validate benzoic acid as an effective coformer and establish phase solubility diagrams (PSD) as predictive tools for rational cocrystal design, supporting the future development of optimized pharmaceutical formulations.