Hot-melt extrusion as a continuous manufacturing process to form ternary cyclodextrin inclusion complexes

The aim of this study was to evaluate hot-melt extrusion (HME) as a continuous process to form cyclodextrin (CD) inclusion complexes in order to increase the solubility and dissolution rate of itraconazole (ITZ), a class II model drug molecule of the Biopharmaceutics Classification System. Different CD derivatives were tested in a 1:1 (CD: ITZ) molar ratio to obtain CD ternary inclusion complexes in the presence of a polymer, namely Soluplus (R) (SOL). The CD used in this series of experiments were beta-cyclodextrin (beta CD), hydroxypropyl-beta-cyclodextrin (HP beta CD) with degrees of substitution of 0.63 and 0.87, randomly methylated beta-cyclodextrin (Rameb (R)), sulfobutylether-beta-cyclodextrin (Captisol (R)) and methyl-beta-cyclodextrin (Crysmeb (R)). Rheology testing and mini extrusion using a conical twin screw mini extruder were performed to test the processability of the different CD mixtures since CD are not thermoplastic. This allowed Captisol (R) and Crysmeb (R) to be discarded from the study due to their high impact on the viscosity of the SOL/ITZ mixture. The remaining CD were processed by HME in an 18 mm twin screw extruder. Saturation concentration measurements confirmed the enhancement of solubility of ITZ for the four CD formulations. Biphasic dissolution tests indicated that all four formulations had faster release profiles compared to the SOL/ITZ solid dispersion. Formulations of HP beta CD 0.63 and Rameb (R) even reached 95% of ITZ released in both phases after 1 h. The formulations were characterized using thermal differential scanning calorimetry and attenuated total reflectance infra-red analysis. These analyses confirmed that the increased release profile was due to the formation of ternary inclusion complexes. (C) 2016 Elsevier B.V. All rights reserved.