Intrinsic Solubility of Ionizable Compounds from pK a Shift

Aqueous solubility of pharmaceutical substances plays an important role in small molecule drug discovery and development, with ionizable groups often employed to enhance solubility. Drug candidate compounds often contain ionizable groups to increase their solubility. Recognizing that the electrostatically charged form of the compound is much more soluble than the uncharged form, this work proposes a model to explore the relationship between the pK(a) shift of the ionizable group and dissolution equilibria. The model considers three forms of a compound: dissolved-charged, dissolved-uncharged, and aggregated-uncharged. It analyzes two linked equilibria: the protonation of the ionizable group and the dissolution-aggregation of the uncharged form, with the observed pK(a) shift depending on the total concentration of the compound. The active concentration of the aggregates determines this shift. The model was explored through the determination of the pK(a) shift and intrinsic solubility of specific compounds, such as ICPD47, a high-affinity inhibitor of the Hsp90 chaperone protein and anticancer target, as well as benzoic acid and benzydamine. The model holds the potential for a more nuanced understanding of intrinsic solubility and may lead to advancements in drug discovery and development.

Automated summary

The aqueous solubility of pharmaceutical substances is crucial for small molecule drug discovery and development, and the use of ionizable groups is common to enhance solubility. This study proposes a model to explore the relationship between the pK(a) shift of ionizable groups and dissolution equilibria. By determining the pK(a) shift and intrinsic solubility of specific compounds, the model provides a more nuanced understanding of intrinsic solubility and may contribute to advancements in drug discovery and development.