Ionic resorcinarenes as drug solubilization agents in water

Abstract

Resorcinarenes are capable of host–guest complexation with small molecules, however, they are less studied as pharmaceutical drug delivery aids. This article reports on the aqueous-solubility enhancing effect of an octa-sulfonated resorcinarene and a C-hydroxybenzyl ammonium resorcinarene chloride on three hydrophobic drugs: isoniazid, caffeine, and griseofulvin. The findings are backed by dynamic light scattering, isothermal calorimetric titration, and nuclear magnetic resonance experiments in water. Aqueous mixtures of equal volumes of drug compounds and resorcinarene solutions produced a more soluble and clearer unit than solutions of pure drug compounds in water. Light scattering experiments revealed shifts in particle sizes of pure drug compounds to the range of resorcinarene hosts. ¹H NMR measurements of resorcinarene-drug mixtures confirmed interactions with shift changes ranging from −0.20 to 0.81 ppm. Binding affinities quantified through ITC experiments ranged between 0.54 and 211 mM, signifying interactions between resorcinarenes and drug compounds necessary for the solubility of the drugs. Cytotoxicity studies suggest that resorcinarenes alone, or complexed with any of the drug compounds, do not exert cytotoxicity in mammalian cells HEK-293 up to 200 μM. We herein propose a set of hydrophilic resorcinarene macrocycles as potential drug solubilizers.