Thermodynamics of Cosolvent Action: Phenacetin, Salicylic Acid and Probenecid

The solubility of phenacetin, salicylic acid, and probenecid in ethanol-water and ethanol-ethyl acetate mixtures at several temperatures (15-40°C) was measured. The solubility profiles are related to medium polarity changes. The apparent thermodynamic magnitudes and enthalpy-entropy relationships are related to the cosolvent action. Salicylic acid and probenecid show a single peak against the solubility parameter δ1 of both solvent mixtures, at 40% (δ1 = 21.70 MPa1/2) and 30% (δ1 = 20.91 MPa1/2) ethanol in ethyl acetate, respectively. Phenacetin displays two peaks at 60% ethanol in ethyl acetate (23.30 MPa1/2) and 90% ethanol in water (δ1 = 28.64 MPa1/2). The apparent enthalpies of solution display a maximum at 30% (phenacetin and salicylic acid) and 40% (probenecid) ethanol in water, respectively. Two different mechanisms, entropy at low ethanol ratios, and enthalpy at high ethanol ratios control the solubility enhancement in the aqueous mixture. In the nonaqueous mixture (ethanol-ethyl acetate) enthalpy is the driving force throughout the whole solvent composition for salicylic acid and phenacetin. For probenecid, the dominant mechanism shifts from entropy to enthalpy as the ethanol in ethyl acetate concentration increases. The enthalpy-entropy compensation plots corroborate the different mechanisms involved in the solubility enhancement by cosolvents.