Effect of Preferential Solvation on the Thermodynamic Properties of Antidepressant Drug Trazodone in Aqueous Ethanol: Linear Free-Energy Relationships

Abstract

Dissociation constants (pKa) of trazodone hydrochloride (TZD⋅HCl) in EtOH/H2O 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, pKa decreased as the solvent was enriched with EtOH. The dissociation and transfer thermodynamic parameters were calculated, and the results showed that a non-spontaneous free-energy change (ΔdissGo>0) and unfavorable enthalpy (ΔdissHo>0) and entropy (ΔdissSo<0) changes occurred on dissociation of trazodone hydrochloride. The free-energy change or pKa 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 solute-solvent interactions. The values of ΔtransGo and ΔtransHo increased negatively with increasing EtOH content, revealing a favorable transfer of trazodone hydrochloride from H2O to EtOH/H2O mixtures and preferential solvation of H+ and trazodone (TZD). Also, ΔtransSo values were negative and reached a minimum, in the H2O-rich zone that has frequently been related to the initial promotion and subsequent collapse of the lattice structure of water. The pKa or ΔdissGo values correlated well with the Dimroth-Reichardt polarity parameter ET(30), indicating that the physicochemical properties of the solute in binary H2O/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/H2O mixture up to 80% were accurately derived by means of the obtained equations.