Simultaneous Influence of Electrolytes and pH on Solubility and Distribution Coefficients of Ionizable Pharmaceuticals

Abstract

The influence of electrolytes (NaCl or KCl) and pH on solubility and octanol–water distribution was investigated for the active pharmaceutical ingredients (APIs) naproxen, ibuprofen, and lidocaine. The solubilities and partition coefficients were measured by UV/vis spectroscopy. The thermodynamically consistent framework for applying ePC-SAFT to ionizable APIs developed in previous work was expanded to account for electrolytes. Their influence on pH-dependent solubilities was fully predicted in quantitative agreement with experimental data. The octanol–water distribution coefficients of the APIs were obtained in good agreement with the experimental findings. This is noteworthy, as all model parameters were taken from the literature or determined from data on the pure components or binary subsystems. The model revealed that electrolytes decrease the degree of ionization of the APIs, which affects both their solubility and octanol–water distribution coefficients. Compared to electrolyte-free systems, the API solubility decreased by 30%, while their distribution coefficients increased 3-fold per mole of electrolyte.