Thermodynamic aspects of solubility, solvation and partitioning processes of some sulfonamides

Abstract

The thermodynamic aspects of sublimation processes of three sulfonamides with the general structures C 6H 5–SO 2NH–C 6H 4–R (R = 4-NO 2) and 4-NH 2–C 6H 4–SO 2NH–C 6H 4–R (R = 4-NO 2; 4-CN) were studied by investigating the temperature dependence of vapor pressure using the transpiration method. These data together with those obtained earlier for C 6H 5–SO 2NH–C 6H 4–R (R = 4-Cl) and 4-NH 2–C 6H 4–SO 2NH–C 6H 4–R (R = 4-Cl; 4-OMe; 4-C 2H 5) were analyzed and compared. A correlation was derived between sublimation Gibbs free energies and the sum of H-bond acceptor factors of the molecules. Solubility processes of the compounds in water, phosphate buffer with pH 7.4 and n-octanol (as phases modeling various drug delivery pathways) were investigated and corresponding thermodynamic functions were calculated as well. Thermodynamic characteristics of the sulfonamides solvation were evaluated. Also in this case a correlation between solubility/solvation Gibbs free energy values and the sum of H-bond acceptor factors was observed. For the sulfonamides with various substituents at para-position the processes of transfer from one solvent (water or buffer) to n-octanol were studied by a diagram method combined with analysis of enthalpic and entropic terms. Distinguishing between enthalpy and entropy, as is possible through the present approach, leads to the insight that the contribution of these terms is different for different molecules (entropy- or enthalpy-determined). Thus, in contrast to the interpretation of only the Gibbs free energy of transfer (extensively used for pharmaceuticals in the form of the partition coefficient, log P), the analysis of thermodynamic functions of the transfer process provides additional mechanistic information. This may be important for further evaluation of the physiological distribution of drug molecules and may provide a better understanding of biopharmaceutical properties of drugs.