Measurement and Accurate Interpretation of the Solubility of Pharmaceutical Salts

Abstract

Salt formation is one of the primary approaches to improve the developability of ionizable poorly water-soluble compounds. Solubility determination of the salt candidates in aqueous media or biorelevant fluids is a critical step in salt screening. Salt solubility measurements can be complicated due to dynamic changes in both solution and solid phases. Because of the early implementation of salt screening in research, solubility measurements often are performed using minimal amount of material. Some salts have transient high solubility on dissolution. Recognition of these transients can be critical in developing these salts into drug products. This minireview focuses on challenges in salt solubility measurements due to the changes in solution caused by self-buffering effects of dissolved species and the changes in solid phase due to solid-state phase transformations. Solubility measurements and their accurate interpretation are assessed in the context of dissolution monitoring and solid-phase analysis technologies. A harmonized method for reporting salt solubility measurements is recommended to reduce errors and to align with the U.S. Pharmacopeial policy and Food and Drug Administration recommendations for drug products containing pharmaceutical salts.

Keywords: dissolution; equilibrium; pH; phase-transformation; poorly water soluble; salt; salt dissociation; solid phase; solubility; solution phase.