Effect of polyoxylglycerides-based excipients (Gelucire®) on ketoprofen amorphous solubility and crystallization from the supersaturated state.

Polyoxylglycerides-based solid mixtures, commercially known as Gelucire®, are excipients commonly used for bioavailability improvement of poorly water-soluble drugs. However, their effect on solutions containing hydrophobic drugs above crystalline solubility has not yet been explored. The goal of this study was to investigate the impact of a mix of two commercial Gelucire® with high HLB values (Gelucire®50/13 and Gelucire®48/16) on the amorphous solubility and crystallization from supersaturated solutions of ketoprofen, used as model drug. The results evidenced a strong interaction between Gelucire® components and the drug-rich nanodroplets generated upon liquid-liquid phase separation. This led to two important consequences: on one hand, the drug amorphous solubility was decreased, together with the amorphous-to-crystalline solubility ratio; on the other hand, the enlargement and coalescence of the drug-rich droplets were prevented. This stabilizing effect towards the drug-rich phase was comparable to, or even stronger than, that obtained with traditional amorphous polymers (PVP or HPMC) and contributed to inhibiting drug crystallization. Notably, the impact of Gelucire® on drug crystallization from the supersaturated state depended on its micellar behaviour: the monomeric form (below 50 μg/mL) accelerated the formation of crystals, whereas pre-micellar aggregates (50-500 μg/mL) and solubilizing micelles (above 500 μg/mL) inhibited drug crystallization. These findings will contribute to a better understanding of the behaviour of supersaturated drug solutions in the presence of Gelucire® and will facilitate the rational design of supersaturating drug delivery systems containing these excipients.