Predicting Surface pH in Unbuffered Conditions for Acids, Bases, and Their Salts - A Review of Modeling Approaches and Their Performance.

Dissolution of ionizable drugs and their salts is a function of drug surface solubility driven by the surface pH, i.e., the microenvironmental pH at the solid/liquid interface, which will deviate from bulk pH when there is an acid-base reaction occurring at the solid/liquid interface. In this work, we first present a brief overview of the modeling approaches available in the literature, classified according to the rate-determining step assumed in the dissolution process. In the second part, we present and evaluate the prediction performance of two different modeling approaches for surface pH. The first method relies only on thermodynamic equilibria, while the second method accounts for transport phenomena of charged compounds through the diffusional boundary layer using the Nernst - Planck equation. Model outcomes are compared with experimental data taken from the literature and obtained during this work. In terms of surface pH predictions, the models provide identical values for weak acids or weak bases. The models' outcomes for bases are in good agreement with experimental data in acidic conditions (bulk pH 1-4), while overpredictions are observed in the 5-7 bulk pH range in a system-dependent manner. Deviations can be related to the effect of surface dissolution (also referred to as surface reaction), which may become a controlling mechanism and slow the replenishment of the unionized drug at the surface of the crystal. Surface pH predictions for acids are generally in good agreement with experiments, with a slight underestimation for some drug examples, which could be related to errors in intrinsic solubility determination or to the assumption of thermodynamic equilibrium at the surface of the drug. A good agreement is also observed for salts with the thermodynamic model except for mesylate salts, suggesting that other phenomena, not currently included in the thermodynamic equilibrium model, may determine the surface pH.