Parameters influencing the course of passive drug loading into lipid nanoemulsions

Abstract

Passive drug loading can be used to effectively identify suitable colloidal lipid carrier systems for poorly water-soluble drugs. This method comprises incubation of preformed carrier systems with drug powder and subsequent determination of the resulting drug load of the carrier particles. Until now, the passive loading mechanism is unknown, which complicates reliable routine use. In this work, the influence of drug characteristics on the course of passive loading was investigated systematically varying drug surface area and drug solubility. Fenofibrate and flufenamic acid were used as model drugs; the carrier system was a trimyristin nanodispersion. Loading progress was analyzed by UV spectroscopy or by a novel method based on differential scanning calorimetry. While increasing drug solubility by micelle incorporation did not speed up passive loading, a large drug surface area and high water solubility were key parameters for fast loading. Since both factors are crucial in drug dissolution as described by the Noyes-Whitney equation, these findings point to a dissolution-diffusion-based passive loading mechanism. Accordingly, passive loading also occurred when drug and carrier particles were separated by a dialysis membrane. Knowledge of the loading mechanism allows optimizing the conditions for future passive loading studies and assessing the limitations of the method.