Poorly soluble drugs: disbalance of thermodynamic characteristics of crystal lattice and solvation

Abstract

The dissolution processes in aqueous media of poorly soluble drugs belonging to the classes of spiro derivatives, benzoic acid and its derivatives, sulfonamides, fenamates, and thiadiazoles were analyzed based on the data recently published by the author. The main criterion for the solubility analysis was the comparison of the thermodynamic characteristics of sublimation processes (state of the molecules in solids) and solvation (state of the molecules in solutions) under structural modification of the reference molecule. The characteristics of the processes under investigation were compared by the superposed diagram approach which allows complete information to be obtained about the thermodynamic state of the molecules in crystal and solution. A variety of thermodynamic paths of the molecules undergoing structural modification (design) was shown. The extreme solubility values were obtained for the considered classes of compounds which can be derived by structural modification of the substances. A classification of the drugs was suggested based on the analysis of the determinative steps of the dissolution processes: crystal or solvation controlled. Based on the investigation of 59 drugs belonging to five different classes of compounds, it was estimated that for 50.7% of the compounds the solubility processes were crystal controlled, whereas for the rest 49.3% – solvation controlled. Among all the considered compounds, a structural modification of the reference one led to a solubility enhancement only in 22.1% of the substances. And in 85% of the compounds, the dissolution processes were solvation controlled and in the remaining 15% – crystal controlled.