Exploring the effect of bioenvironment on the ionization of drugs using the membrane mimetic properties of differently charged micelles

Abstract

Objective The membrane-mimicking approach is grounded in the idea of organizing molecules into distinct compartments within systems, which can influence reaction rates, physicochemical properties and stereochemistry of pharmacologicaly active compounds, in ways that differ from those observed in "pure" water [1]. There isn't a perfect model that can replicate all the complexities of biological membranes, but a large variety of membrane mimetics are available [2]. Among them, micellar solutions of differently charged surfactants are systems the most commonly used to mimic the desired functions of cells membranes, since their properties are well understood at the chemical level [1]. Methods The pKa values of pharmacologically active compounds, with and without the presence of anionic (SDS), cationic (CTAB) and nonionic (TX-100, Brij 35) micelles, were determined potentiometrically, under the same experimental conditions (temperature 25°C and ionic strength 0.1 M NaCl). The experimental results were analyzed in the Hyperquad program. Compounds which are distereomers are additionally analysed in RP-HPLC system using Chromolith Performance using RP-18e column and phosphate buffer pH 7.0-acetonitrile mixture as a mobile phase. Results The presence of micelles caused the most significant shifts in the protolytic equilibria (∆pKa) of amino (-2.80 to +1.44) and carboxyl groups (-0.92 to +1.90). A more pronounced effect on the change in ionization mode was observed in the presence of anionic and cationic micelles compared to nonionic micelles. A change in the distribution of equilibrium forms of investigated drugs, in the presence of micelles, was observed at biopharmaceutically significant pH values (1.2; 4.5; 6.8; 7.4), where the content of ionized forms changed in the range from -74% to +66% compared to "pure" water. Conclusions Small changes in solution conditions can significantly affect the protolytic equilibria of drugs, suggesting that the ionization of drugs under physiological conditions may be completely different than expected exclusively on the basis of the pKa values determined in “pure” water