Investigation the solubility of active pharmaceutical ingredients in pure solvent and solvent mixtures

Equilibrium mole fraction solubilities of coumarin and 6-methylcoumarin in nine aqueous-ethanolic mixtures, as well as in neat water and neat ethanol, were determined at seven temperatures from (293.15 to 323.15) K. Coumarin and 6-methylcoumarin solubilities in these mixtures were correlated with well-known correlation/prediction models. Apparent thermodynamic functions, i.e. Gibbs energy, enthalpy, and entropy, for the dissolution, mixing and solvation processes, were computed by means of the van't Hoff and Gibbs equations. The enthalpy-entropy relationship for coumarin was non-linear in the plot of enthalpy vs. Gibbs energy of dissolution with negative slope from neat water to the mixture of w1 = 0.10 but positive from this mixture to neat ethanol. Similarly, the enthalpy-entropy relationship for 6-methylcoumarin was non-linear in the plot of enthalpy vs. Gibbs energy of dissolution with negative slope from neat water to the mixture of w1 = 0.20 and from the mixture of w1 = 0.90 to neat ethanol but positive in the interval of 0.20 < w1 < 0.90. Accordingly, in the first case the coumarin transfer from neat water to the mixture of w1 = 0.10 and the 6-methylcoumarin transfer from neat water to the mixture of w1 = 0.20 are entropy-driven, which could be attributed to water molecules releasing, which were originally bounded as "icebergs" around the non-polar groups of these drugs. Otherwise, enthalpy is the driving mechanism for the transfer of coumarin in w1 ≥ 0.10 mixtures and 6-methylcoumarin in 0.20 < w1 < 0.90 mixtures from more polar solvent systems to less polar ones, possibly due to better drug solvation. Moreover, by using the inverse Kirkwood-Buff integrals it is observed that coumarin and 6-methylcoumarin are preferentially solvated by water molecules in water-rich mixtures but preferentially solvated by ethanol molecules in mixtures of 0.23 < x1 < 1.00 and 0.24 < x1 < 1.00, respectively.