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

Abstract

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.

Solvent Effects on pKa values of Some Substituted Sulfonamides in Acetonitrile−Water Binary Mixtures by the UV-Spectroscopy Method

“…The appearance of such variation (Figure ) for the p K 1 values of sulfonamides in MeCN−water mixtures might be due to the fact that these dissociation constants are dependent on solute−solvent interaction effects, and these effects vary with the structural features of the mixtures. If a solute interacts with one solvent more strongly than with the other, the solute will be preferentially solvated by the former . On the water-rich side of MeCN−water mixtures, x MeCN > 0.15, the water structure remains more or less intact, and the MeCN molecules gradually occupy the cavities between the water molecules without disrupting the water structure.…”

“…If a solute interacts with one solvent more strongly than with the other, the solute will be preferentially solvated by the former. 13 On the water-rich side of MeCN-water mixtures, x MeCN > 0.15, the water structure remains more or less intact, and the MeCN molecules gradually occupy the cavities between the water molecules without disrupting the water structure. The (v/v) % limit beyond which the MeCN can no longer be accommodated within the cavities of the structure of water depends on the pressure and is about 30 % (v/v) in MeCN.…”

“…10,11 Previously, the solvent effect on dissociation equilibria was believed to be chiefly guided by electrostatic interactions. However, recent studies [12][13][14] reveal that the change in the dielectric constant cannot be the sole factor. The variation of the pK values with the content of organic modifier can be explained by consideration of the preferential solvation of electrolytes in organic solvents such as methanol-water and acetonitrile (MeCN)-water mixtures.…”

The Conundrum of pH in Water Nanodroplets: Sensing pH in Reverse Micelle Water Pools

“…Although the pK a for a probe (such as decavanadate) solvated in the water pool domain may maintain its macroscopic value, the pK a can differ significantly for a probe located in the interfacial domain, hence in small RMs. 14,17,28 , or HV 10 O 28 5À ? In RMs formed using the anionic AOT surfactant, the H 3 O þ species are larger than Na þ counterions that balance the surfactant charge.…”

“…Similar pK a changes have been reported for other heterogeneous environments such as in aqueous organic solvents mixture and on proteins. 28 For example, Shehatta measured the pK a variation of the drug trazodone hydrochloride in waterÀethanol mixtures.…”