Enthalpy and Entropy Contributions to the Solubility of Sulphamethoxypyridazine in Solvent Mixtures Showing Two Solubility Maxima

Abstract

Abstract The solubility of sulphamethoxypyridazine was measured at several temperatures in mixtures of water: ethanol and ethanol: ethyl acetate. Sulphamethoxypyridazine was chosen as a model drug to compare the solvation effects of proton donor-proton acceptor (water and ethanol) and proton acceptor (ethyl acetate) solvents and mixtures of these solvents because this drug contains functional groups capable of Lewis acid-base interaction. A plot of the mole fraction solubility against the solubility parameter (δ1) of these solvent mixtures showed two solubility maxima, one at δ1 = 30·87 MPa1/2 (20:80 v/v water: ethanol) and another at δ1 = 20·88 MPa1/2 (30:70 v/v ethanol: ethyl acetate) at all the temperatures under study. The enthalpies and entropies of mixing as well as the enthalpies and entropies of transfer of sulphamethoxypyridazine from ethanol to water:ethanol and ethanol:ethyl acetate mixtures were calculated to compare solvation characteristics of the solvent mixtures toward the drug. As ethanol is added to water, the entropy increases and the structure of the solvent mixture became less ordered, favouring the interaction of the drug with the solvent mixture. On the other hand, in the case of the ethanol: ethyl acetate mixture, solubility is favoured by the more negative enthalpy values. This way, the same result, i.e. a solubility maximum, is obtained by different routes. In the ethanol: water mixtures, the dissolution process is entropy-controlled while enthalpy is the driving force in the case of ethanol: ethyl acetate mixtures. The two solvent systems show enthalpy-entropy compensation. Water deviates from the linear relationship due possibly to its hydrophobic effect.