Solubilization of Sparingly Soluble Active Compounds in Lecithin-Based Microemulsions: Influence on Phase Behavior and Microstructure

Abstract

Starting from the pharmaceutically interesting Winsor III system of water, 1-propanol, soybean phosphatidylcholine, and medium-chain triglycerides (MCT), the influence of two active drug compounds, felodipine and (R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]argininamide (BIBP3226), on the phase behavior and microstructure was studied by means of phase studies, NMR self-diffusion measurements, and measurements of drug solubility in the aqueous phase and the oil phase. Felodipine, being practically insoluble in water and slightly soluble in MCT, was found to act as a nonpenetrating oil. With increasing concentration of felodipine in the oil phase, the polarity of the oil phase increases, which in turn curves the surfactant film toward water. Thus, water is expelled from the microemulsion phase, and oil is incorporated as felodipine is added. With the composition used here, the microstructure remains bicontinuous, however, even at high felodipine concentrations. The increase in the polarity of the oil phase also has the effect of increasing the partitioning of 1-propanol in the oil phase, which increases the solubility of felodipine. The maximum solubility of felodipine in the system was 9 wt %, defined as the weight percent of felodipine/(felodipine + MCT). This value should be compared to 3 wt %, which is the solubility in pure MCT. BIBP3226, on the other hand, is a charged molecule and practically insoluble in MCT but slightly soluble in water. Furthermore, it has an affinity for the lecithin monolayer and is therefore partitioned between the water phase and the surfactant film. Mainly because of solubilization of BIBP3226 in the surfactant film and the entropy of the accompanying counterions, the excess water is incorporated in the microemulsion at a very low concentration of BIBP3226. At the drug concentration at which the water phase as well as the surfactant film is saturated with drug, the microstructure has changed from a bicontinuous structure to oil-swollen micelles (oil-in-water microemulsion). At this point, approximately 60% of the drug molecules are located in the surfactant film.