Transfer Thermodynamic Parameters of Local Anesthetic Lidocaine in Ethanol–Water Mixtures. Effect of Preferential Solvation

The dissociation constants of lidocaine (LH⁺) in 0%–80% (v/v) ethanol–water mixtures have been determined potentiometrically at four different temperatures. Thus, its thermodynamic parameters of dissociation and transfer from water to ethanol–water mixtures have been derived and discussed. The dissociation constant as well as the thermodynamic parameters for the dissociation of lidocaine in various ethanol–water mixtures is influenced to a greater extent by the solute-solvent interaction than by electrostatic interactions. The dissociation constants are found to be insensitive to ionic strength, increase with increasing temperature and ethanol content in ethanol–water mixtures. The dissociation processes are nonspontaneous, endothermic, and entropically unfavourable. The acidity of the drug increases with increasing ethanol content and this is due primarily to the combined effect of stability of both H⁺ and L in the mixed solvent relative to that in water. On the basis of solvent basicity, solute-solvent interactions and the standard Gibbs energies of transfer of the species present in dissociation equilibrium (H⁺, LH⁺ and L), the solvent effects have been clarified. A non-linear dependence of the dissociation thermodynamic parameters on the bulk macroscopic properties (such as the mole fraction of ethanol and the reciprocal of the dielectric constant of the solvent mixtures) was observed. Correlations of the dissociation thermodynamic parameters with the microscopic properties of solvents were also examined and were found to be much better than the corresponding correlations with macroscopic ones. The linear solvation energy relationship method was also applied to the thermodynamic parameters with the Kamlet and Taft solvatochromic parameters of ethanol–water mixtures. The relationships obtained allow the thermodynamic of dissociation and transfer of lidocaine in any ethanol–water mixtures up to 80% (v/v) ethanol to be calculated. Moreover, an overview of the effect of preferential solvation of lidocaine in ethanol–water mixtures on the values of pK_a and the thermodynamic parameters was also obtained.