Journal of Chemical Thermodynamics, Vol.96, 57-66, 2016
Impact of structural modification of 1,2,4-thiadiazole derivatives on thermodynamics of solubility and solvation processes in 1-octanol and n-hexane
Influence of a structural modification on thermodynamic aspects of solubility and solvation processes of the 1,2,4-thiadiazole drug-like compounds in pharmaceutically relevant solvents n-hexane and 1-octanol was investigated. The solubility of the compounds in 1-octanol does not substantially depend on the nature and position of the substituent in the phenyl moiety. In n-hexane, however, the introduction of any substituent in the phenyl ring of the 1,2,4-thiadiazole molecule reduces the solubility in the solvent. In order to rationalize the relationships between the structure of 1,2,4-thiadiazoles and their solubility, the latter was considered in terms of two fundamental processes: sublimation and solvation. It was found that for the most of the compounds the solubility change in both solvents is a consequence of competition between the sublimation and solvation contributions, i.e. the introduction of substituents leads to growth of the sublimation Gibbs energy and increase in the solvation Gibbs energy. Thermodynamic parameters of the transfer process of the compounds from n-hexane to 1-octanol, which is a model of the blood-brain barrier (BBB), were also analyzed. (C) 2015 Elsevier Ltd. All rights reserved.