Phase behaviour and pH-solubility profile prediction of aqueous buffered solutions of ibuprofen and ketoprofen

Salt formation is commonly used to increase the solubility of ionisable active pharmaceutical ingredients (APIs) and is monitored via a pH-solubility profile of the API and its salt. Due to the extremely low solubilities of many APIs in water, experiments are difficult to perform, and reliable predictive tools can be especially useful in this context. Here, we use the SAFT-gamma Mie group-contribution equation of state to predict the phase diagrams and the pH-dependent solubility of two acidic APIs: ibuprofen and ketoprofen. We consider ibuprofen and ketoprofen in basic buffer solutions of NaOH, KOH, LiOH, RbOH, Ca(OH)(2), Mg(OH)(2), n-hexylamine, n-octylamine, benzylamine and tert-butylamine, and in acidic buffer solutions of HCl and acetate. A predictive approach is developed in which the unlike interactions involving charged groups are either taken from previous work, calculated using combining rules or, in the case of groups originating from organic groups (e.g., COO-), taken to be the same as the equivalent interaction involving the neutral (uncharged) group. A new group, NH3+, is characterised for the case of amine buffers and salts. Equilibrium constants for the dissociation of the APIs and the formation of salts (pK(a) and K-sp,K-A nu AB nu B values) are also incorporated in the model using experimental values from literature. Predictions of the complete phase diagrams of the APIs in water are presented, including the vapour-liquid, liquid-liquid (oiling out), and solid-liquid (solubility) equilibria. The SAFT-gamma Mie approach is shown to provide accurate predictions of the solid-liquid solubility of the compounds, as well as of the presence of liquid-liquid separation. Furthermore, the pH-solubility profiles of the APIs at T = 298.15 K and 310.15 K for the range of buffers and salts considered are predicted in good agreement with the available experimental data. (C) 2022 Published by Elsevier B.V.