Enthalpy-entropy compensation for the solubility of drugs in solvent mixtures: Paracetamol, acetanilide, and nalidixic acid in dioxane-water

In earlier work, a nonlinear enthalpy-entropy compensation was observed for the solubility of phenacetin in dioxane-water mixtures. This effect had no t been earlier reported for the solubility of drugs in solvent mixtures. To gain insight into the compensation effect, the behavior of the apparent th ermodynamic magnitudes for the solubility of paracetamol, acetanilide, and nalidixic acid is studied in this work. The solubility of these drugs was m easured at several temperatures in dioxane-water mixtures. DSC analysis was performed on the original powders and on the solid phases after equilibrat ion with the solvent mixture. The thermal properties of the solid phases di d not show significant changes. The three drugs display a solubility maximu m against the cosolvent ratio. The solubility peaks of acetanilide and nali dixic acid shift to a more polar region at the higher temperatures. Nonline ar van't Hoff plots were observed for nalidixic acid whereas acetanilide an d paracetamol show linear behavior at the temperature range studied. The ap parent enthalpies of solution are endothermic going through a maximum at 50 % dioxane. Two different mechanisms, entropy and enthalpy, are suggested to be the driving forces that increase the solubility of the three drugs. Sol ubility is entropy controlled at the water-rich region (0-50% dioxane) and enthalpy controlled at the dioxane-rich region (50-100% dioxane). The entha lpy-entropy compensation analysis also suggests that two different mechanis ms, dependent on cosolvent ratio, are involved in the solubility enhancemen t of the three drugs. The plots of Delta H versus Delta G are nonlinear, an d the slope changes from positive to negative above 50% dioxane. The compen sation effect for the thermodynamic magnitudes of transfer from water to th e aqueous mixtures can be described by a common empirical nonlinear relatio nship, with the exception of paracetamol, which follows a separate linear r elationship at dioxane ratios above 50%. The results corroborate earlier fi ndings with phenacetin. The similar pattern shown by the drugs studied sugg ests that the nonlinear enthalpy-entropy compensation effect may be charact eristic of the solubility of semipolar drugs in dioxane-water mixtures.