Thermodynamic analysis and correlation of solubility of candesartan cilexetil in aqueous solvent mixtures

The solubility of candesartan cilexetil (Form I) was measured by a gravimetric method in aqueous solvent mixtures (ethanol–water, acetonitrile–water and acetone–water), and the calculated values by (NIBS)/Redlich–Kister equation agreed well with the experimental data. The relationship between solubility of candesartan cilexetil (Form I) and molar fraction of organic solvents (ethanol, acetonitrile and acetone) shown unimodal curves, and this phenomenon can be explained by ΔHsol–ΔGsol compensation theory. For ethanol–water and acetonitrile–water mixture, the plot of ΔHsol–ΔGsol compensation was nonlinear with positive and negative slopes, indicating that the increases of solubility were controlled by two different mechanisms (entropy and enthalpy). However, for acetone–water mixture, the plot of ΔHsol–ΔGsol compensation was a linear curve, indicating that enthalpy is the dominant mechanism to control the solubility enhancement. These results can also be used to explain that acetone molecule played an important role in increasing the solute–solvent interactions of the candesartan cilexetil (Form I).

► The solubility of candesartan cilexetil (Form I) was measured in three aqueous solvent mixtures.
► The experimental data were correlated with (NIBS)/Redlich–Kister equation.
► The thermodynamic functions of solution and mixing were obtained from these solubility data.
► The dominant mechanism for the solubility enhancement was determined by thermodynamic analysis.