Calculating pH-solubility profile and pHmax for monoprotic salts of poorly water-soluble weak bases

Pharmaceutical salts are a commonly used strategy to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). The selected salt form is expected to have high solubility to obtain optimal supersaturation and sufficient physical stability for adequate shelf life. In this paper, we aim to develop equations to describe critical parameters of salts, including pH-solubility profile and pHmax. The equations serve as a valuable tool to aid in the calculation of salt solubility at pH below the pHmax in the presence of common counter ions. This provides the knowledge to assess the risks of pre-selection of the salt formers without the necessity of salt synthesis. The solubilities calculated by this model demonstrate good agreement with experimental solubility results reported in the literature. Compared to the conventional approaches for salt solubility and pHmax calculation, our model stands out, especially for poorly water-soluble bases with low pKa values, which benefit the most from salt formation. Moreover, the equations are used to support the concept that salt selection should focus on finding salt forms with sufficient solubility, rather than the most soluble salt, as excessively high solubility could be detrimental to physical stability.