Intrinsic Solubility of Ionizable Compounds from p Ka Shift

Joku Bas Preikša; Vilma Petrikaitė; Vytautas Petrauskas; Daumantas Matulis

doi:10.1021/acsomega.3c04071

Intrinsic Solubility of Ionizable Compounds from p K_a Shift

ACS Omega. 2023 Nov 13;8(47):44571-44577. doi: 10.1021/acsomega.3c04071. eCollection 2023 Nov 28.

Authors

Joku Bas Preikša^{1

2}, Vilma Petrikaitė^{3

2}, Vytautas Petrauskas², Daumantas Matulis²

Affiliations

¹ Department of Molecular Compound Physics, Center for Physical Sciences and Technology, Savanoriu Ave. 231, Vilnius, LT-02300, Lithuania.
² Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius, LT-10257, Lithuania.
³ Laboratory of Drug Targets Histopathology, Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu pr. 13, Kaunas, LT-50162, Lithuania.

Abstract

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.