Three indomethacin cocrystals: Preparation, characterization and formation thermodynamics

The cocrystals of Indomethacin (Imc) with isonicotine (Iso), isoniazid (Inh), and salicylic acid (Sa) were prepared to improve solubility, dissolution rate, and in vivo intestinal absorption. The prepared cocrystals were characterized by X-ray diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), and Fourier infrared spectroscopy (FTIR). Subsequently, the equilibrium solubility and in vitro dissolution of the cocrystals were evaluated. The results indicate that the equilibrium solubility of the Imc-Inh cocrystal is 3.2 times that of Imc, and the maximum dissolution of the Imc-Iso cocrystal is approximately 4 times that of Imc. The mechanism underlying the formation of the Imc-Iso, Imc-Inh, and Imc-Sa cocrystals was investigated through the thermodynamics of the cocrystal formation and the calculation of DFT-D. The results demonstrate that the Gibbs free energy change (ΔG), the formation enthalpy change (ΔH) of the Imc cocrystals with Iso, Inh, and Sa are less than zero, indicating that the formation of cocrystals is spontaneous and driven by enthalpy. As the temperature rises, the values of ΔG of the cocrystals formation demonstrate a gradual increase, indicating that elevated temperatures are not favorable to cocrystal formation. In vivo single-pass intestinal perfusion experiments (SPIP) reveal that the Imc-Iso cocrystals can enhance the permeability of Imc.