Thermodynamic analysis and enthalpy–entropy compensation for the solubility of indomethacin in aqueous and non-aqueous mixtures

The solubility of indomethacin was measured at several temperatures (20–40 °C) at the polarity range provided by aqueous (ethanol–water, solubility parameter δM = 26.51–47.97 MPa1/2) and non-aqueous (ethanol–ethyl acetate δM = 26.51–18.49 MPa1/2) mixtures. The solubility curve displays a single peak in the least polar mixture (δM = 20.91 MPa1/2, 30% ethanol-in ethyl acetate). The thermodynamic functions of solution and mixing were obtained. In ethanol–water, the enthalpy of solution curve against solvent composition passes through a maximum at 50% ethanol. The solubility enhancement is entropy driven at the water-rich region (50–100% water) and enthalpy controlled at the ethanol-rich region (50–100% ethanol). In the non-aqueous mixture, the enthalpy of solution displays a minimum (30% ethanol), and the enthalpy change is the dominant mechanism. The aqueous mixture shows a parabolic enthalpy–entropy compensation relationship, and the slope change can be related to a shift of the dominant mechanism from enthalpy to entropy. For the non-aqueous mixture, there are not slope changes, indicating that a single mechanism, enthalpy, controls the solubility enhancement. The results show the usefulness of the enthalpy–entropy compensation analysis to identify changes of the mechanism of co-solvent action. A solubility model using a minimum number of solubility experiments provides excellent solubility predictions for indomethacin in aqueous and non-aqueous mixtures.