Solubility and Preferential Solvation of Caffeine and Theophylline in {Methanol plus Water} Mixtures at 298.15 K

Solubility is a very important property of drugs involved in purification processes and the different pharmaceutical dosage form design stages. Otherwise, caffeine and theophylline are alkaloid drugs widely used in several solid and liquid pharmaceutical formulations. The equilibrium solubility of caffeine and theophylline were determined in {methanol + water} binary mixtures at 298.15 K by means of the shaken flask method and both mass balance and UV spectrophotometric composition analyses. Solubility is expressed in both molarity and mole fraction. Maximum solubility of both drugs is observed in a mixture of similar proportions of methanol and water instead of the neat cosolvent. All these solubility values were correlated with the Jouyban-Acree model. Preferential solvation parameters by methanol (delta x (1,3)) of these xanthines were derived from their thermodynamic solution properties by using the inverse Kirkwood-Buff integrals method. For both compounds the delta x (1,3) values are negative in water-rich and methanol-rich mixtures but positive in mixtures with almost the same proportion of methanol and water. It is conjectured that in the former case the hydrophobic hydration around non-polar groups of these drugs plays a relevant role in the solvation. Besides, the preferential solvation of these solutes by methanol in mixtures of similar cosolvent compositions could be explained in terms of the higher basicity of methanol compared to water. Finally, the preferential solvation by water in methanol-rich mixtures could be a consequence of the higher acidity of water compared to methanol.