Solubilization of sparingly soluble active compounds in lecithin-based microemulsions: Influence on phase behavior and microstructure

Starting from the pharmaceutically interesting Winsor III system of water, l-propanol, soybean phosphatidylcholine, and medium-chain triglycerides (MC T), the influence of two active drug compounds, felodipine and (R)-N-2-(dip henylacetyl)-N-[(4-hydroxyphenyl)methyl]argininamide (BIBP3226), on the pha se behavior and microstructure was studied by means of phase studies, NMR s elf-diffusion measurements, and measurements of drug solubility in the aque ous phase and the oil phase. Felodipine, being practically insoluble in wat er and slightly soluble in MCT, was found to act as a nonpenetrating oil. W ith increasing concentration of felodipine in the oil phase, the polarity o f the oil phase increases, which in turn curves the surfactant film toward water. Thus, water is expelled from the microemulsion phase, and oil is inc orporated as felodipine is added. With the composition used here, the micro structure remains bicontinuous, however, even at high felodipine concentrat ions. 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 practicall y insoluble in MCT but slightly soluble in water. Furthermore, it has an af finity far the lecithin monolayer and is therefore partitioned between the water phase and the surfactant film. Mainly because of solubilization of BI BP3226 in the surfactant film and the entropy of the accompanying counterio ns, the excess water is incorporated in the microemulsion at a very low con centration of BIBP3226. At the drug concentration at which the water phase as well as the surfactant film is saturated with drug, the microstructure h as changed from a bicontinuous structure to oil-swollen micelles (oil-in-wa ter microemulsion). At this point, approximately 60% of the drug molecules are located in the surfactant film.