Supersaturation and Solubilization upon In Vitro Digestion of Fenofibrate Type I Lipid Formulations: Effect of Droplet Size, Surfactant Concentration and Lipid Type.

Lipid-based formulations (LBF) enhance oral drug absorption by promoting drug solubilization and supersaturation. The aim of the study was to determine the effect of the lipid carrier type, drop size and surfactant concentration on the rate of fenofibrate release in a bicarbonate-based in vitro digestion model. The effect of the lipid carrier was studied by preparing type I LBF with drop size ≈ 2 µm, based on medium-chain triglycerides (MCT), sunflower oil (SFO), coconut oil (CNO) and cocoa butter (CB). The drop size and surfactant concentration effects were assessed by studying MCT and SFO-based formulations with a drop size between 400 nm and 14 µm and surfactant concentrations of 1 or 10%. A filtration through a 200 nm filter followed by HPLC analysis was used to determine the aqueous fenofibrate, whereas lipid digestion was followed by gas chromatography. Shorter-chain triglycerides were key in promoting a faster drug release. The fenofibrate release from long-chain triglyceride formulations (SFO, CNO and CB) was governed by solubilization and was enhanced at a smaller droplet size and higher surfactant concentration. In contrast, supersaturation was observed after the digestion of MCT emulsions. In this case, a smaller drop size and higher surfactant had negative effects: lower peak fenofibrate concentrations and a faster onset of precipitation were observed. The study provides new mechanistic insights on drug solubilization and supersaturation after LBF digestion, and may support the development of new in silico prediction models.

Rotator phases in hexadecane emulsion drops revealed by X-ray synchrotron techniques.

HYPOTHESIS: Micrometer sized alkane-in-water emulsion drops, stabilized by appropriate long-chain surfactants, spontaneously break symmetry upon cooling and transform consecutively into series of regular shapes (Denkov et al., Nature 2015, 528, 392). Two mechanisms were proposed to explain this phenomenon of drop "self-shaping". One of these mechanisms assumes that thin layers of plastic rotator phase form at the drop surface around the freezing temperature of the oil. This mechanism has been supported by several indirect experimental findings but direct structural characterization has not been reported so far. EXPERIMENTS: We combine small- and wide-angle X-ray scattering (SAXS/WAXS) with optical microscopy and DSC measurements of self-shaping drops in emulsions. FINDINGS: In the emulsions exhibiting drop self-shaping, the scattering spectra reveal the formation of intermediate, metastable rotator phases in the alkane drops before their crystallization. In addition, shells of rotator phase were observed to form in hexadecane drops, stabilized by C16EO10 surfactant. This rotator phase melts at ca. 16.6 °C which is significantly lower than the melting temperature of crystalline hexadecane, 18 °C. The scattering results are in a very good agreement with the complementary optical observations and DSC measurements.