The solubility of paracetamol was determined as a function of temperature in mixtures of wide polarity range (ethyl acetate:ethanol and ethanol:water) to compare the solvation effects of amphiprotic and amphiprotic-aprotic solvent systems.
The mole fraction solubility of the drug showed solubility maxima at δ1 = 14·53 (cal mL−1)1/2 (15:85 v/v, water:ethanol) and δ1 = 11·78 (cal mL−1)1/2 (30:70 v/v, ethyl acetate:ethanol) against the solubility parameter (δ1) of these solvent mixtures. The solubility peaks result from different processes, and the nature of the solvent mixture plays an important role; in the ethanol:water mixtures, the dissolution process is entropy-controlled while enthalpy is the driving force in the case of ethanol:ethyl acetate mixtures. The nature of the solute determines the solvent proportion at which the solubility peak is located in the amphiprotic-aprotic mixture.
Separate nonlinear enthalpy-entropy compensation is observed in the two solvent systems. Ethanol deviates from the general trend in the amphiprotic mixtures.