Enhancement of Solubility of Itraconazole by Complexation with ß Cyclodextrin Derivatives

Eda GÖKBULUT*, Nurten ÖZDEMİR** °

* Nobel Pharmaceuticals, Tahran St. 6/6 Kavaklıdere, Ankara, Turkey
** Ankara University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 06100, Ankara, Turkey

° Corresponding Author;
Phone: 03122033151
Fax: 03122131081
E-mail : nozdemir@pharmacy.ankara.edu.tr

Summary

The purpose of this study was to increase the solubility of itraconazole (IT) with inclusion complexes. For this aim, different types of ITcyclodexrin complexes were prepared by using beta cyclodextrin (βCD), hydroxypropyl beta cyclodextrin (HPβCD) and randomized methylated beta cyclodextrin (RAMEB). The phase solubility studies were made in order to determine the molar ratios of complexes and for βCD, BS type, for HPβCD and RAMEB, AL type solubility diagrams were revealed. Since the BS type diagrams indicate the complexes with limited solubility, the studies were continued with HPβCD and RAMEB. 1:1 and 1:2 molar ratio of IT:HPβCD and IT:RAMEB complexes were prepared by using physical mixture, kneading and coprecipitation method. Inclusion complexes were confirmed by the results from the studies of differential scanning calorimetry (DSC). When the solubility of complexes determined in pH 1.2, it was seen that the solubility of IT which is 4.5 μg/ml, increased to 12.39 μg/ml with HPβCD and to 14.05 μg/ml with RAMEB by using kneading method and 1:2 IT:CD molar ratio. Due to the solubility values and the stability constants which show the stability of the complexes (for HPβCD, Kc= 3 M-1, for RAMEB, Kc= 75 M-1) it was decided to prepare complexes with RAMEB in formulation studies. A water soluble polymer, polyethylene glycol 4000 (PEG 4000) were added to RAMEB complexes as solubility enhancer and it was seen that the solubility increased to 28.72 μg/ml.

Key Words :
Itraconazole, β cyclodextrin derivatives, physical mixture, kneading method, coprecipitation method, DSC