Drug delivery in reverse micelles: Impact of hydrophilic organic solvents on micellar organization and drug retention

Reverse micelles (RM) enable encapsulation of hydrophilic compounds in lipophilic environments; however, their stability and drug retention are strongly influenced by interfacial organization and hydration. Hydrophilic organic solvents (hOS) are frequently incorporated into RM formulations, yet their impact on RM organization and delivery performance remains insufficiently understood. Here, three RM systems composed of different surfactants and oils were systematically investigated in the presence and absence of ethanol or isopropanol. Apparent reverse critical micelle concentrations (rCMC), hydrodynamic diameter, and polydispersity were determined, while time-dependent equilibrium water content was quantified by 1H NMR over 12 h. Drug release, apparent LogD values, and concentration-dependent effects of hOS were additionally evaluated using methylene blue, Safranin O, and fluorescein sodium as model compounds. hOS reduced the apparent rCMC by up to 57.6%, decreased RM diameters by up to 61%, and consistently lowered the equilibrium water content of RM systems during incubation, whereas formulations without hOS exhibited progressive water uptake. These changes were accompanied by enhanced drug retention, reduced release, and up to 2-fold higher apparent logD values. For both alcohols, 2.5-5% (v/v) represented the optimal concentration range for RM stabilization. Collectively, the results demonstrate that short-chain hydrophilic organic solvents improve RM performance through the combined influence of interfacial reorganization and altered equilibrium water distribution, thereby providing practical guidance for the rational design of RM-based drug delivery systems.