Dissociation constants (pK a ) of trazodone hydrochloride (TZD ¥ HCl) in EtOH/H 2 O media containing 0, 10,20,30,40, 50, 60, 70, and 80% (v/v) EtOH at 288.15, 298.15, 308.15, and 318.15 K were determined by potentiometric techniques. At any temperature, pK a decreased as the solvent was enriched with EtOH. The dissociation and transfer thermodynamic parameters were calculated, and the results showed that a nonspontaneous free-energy change (D diss G o > 0) and unfavorable enthalpy (D diss H o > 0) and entropy (D diss S o < 0) changes occurred on dissociation of trazodone hydrochloride. The free-energy change or pK a varied nonlinearly with the reciprocal dielectric constant, indicating the inadequacy of the electrostatic approach. The dissociation equilibria are discussed on the basis of the standard thermodynamics of transfer, solvent basicity, and solutesolvent interactions. The values of D trans G o and D trans H o increased negatively with increasing EtOH content, revealing a favorable transfer of trazodone hydrochloride from H 2 O to EtOH/H 2 O mixtures and preferential solvation of H and trazodone (TZD). Also, D trans S o values were negative and reached a minimum, in the H 2 Orich zone that has frequently been related to the initial promotion and subsequent collapse of the lattice structure of water. The pK a or D diss G o values correlated well with the Dimroth-Reichardt polarity parameter E T (30), indicating that the physicochemical properties of the solute in binary H 2 O/organic solvent mixtures are better correlated with a microscopic parameter than the macroscopic one. Also, it is suggested that preferential solvation plays a significant role in influencing the solvent dependence of dissociation of trazodone hydrochloride. The solute-solvent interactions were clarified on the basis of the linear free-energy relationships of Kamlet and Taft. The best multiparametric fit to the Kamlet-Taft equation was evaluated for each thermodynamic parameter. Therefore, these parameters in any EtOH/H 2 O mixture up to 80% were accurately derived by means of the obtained equations.