Freeze-drying of itraconazole-loaded nanosphere suspensions: a feasibility study

Abstract

The present study concerns the stabilization of the association of the new hydrophobic triazole derivative itraconazole within poly-ϵ-caprolactone-nanospheres by means of freeze-drying. We have investigated the freeze-drying of nanospheres, and especially the cryopreservation conditions, with the help of differential scanning calorimetry and zeta potential measurements. Five commonly used cryoprotective agents were evaluated (glucose, sucrose, trehalose, dextran, mannitol at 0, 5, 10, 20, and 30% [w/v]) after freeze-thawing and freeze-drying. The addition of carbohydrates led to a partial protection of the colloidal suspension, with leakage of 30% of itraconazole under the best cryopreservation conditions (10% of glucose or sucrose). Zeta potential measurements revealed that the main destabilization mechanism during freeze-drying was surface modifications of the nanospheres, and particularly drug desorption. Therefore, the hydrophilic surfactant adsorbed at the surface of the nanospheres played an important role in the cryopreservation. Replacing the commonly used non ionic surfactant PLURONIC®PE F68 by the anionic surfactant sodium deoxycholate resulted in a complete stabilization of itraconazole-loaded nanospheres after freeze-drying, with no drug desorption, in the presence of 10% sucrose, but not in the presence of glucose. As shown by thermal analysis, PLURONIC®PE F68 may crystallize during freezing, which could lead to surface modifications and drug desorption, whereas sodium deoxycholate may not. Moreover, the Tg′ of glucose-containing suspensions is 10°C lower than Tg′ of sucrose-containing suspensions, which may explain the shrinkage of the cake observed in the case of glucose and the homogeneous appearance of the dried product in the case of sucrose. © 1996 Wiley-Liss, Inc.