Cyclodextrin-crosslinked poly(acrylic acid): synthesis, physicochemical characterization and controlled release of diflunisal and fluconazole from hydrogels

The aim of this work was to develop mucoadhesive hydrogels with variable drug delivery properties by crosslinking poly(acrylic acid) (PAA) with cyclodextrins (CDs). CD-PAA polymers with high CD content and good inter-batch reproducibility were synthesized by activating PAA with SOCl2, then reacting PAA chloride with CD in the presence of 4-dimethylaminopyridine at 50 degrees C. Manipulation of the synthesis conditions affected the physicochemical character of the CD-PAA polymers and hydrogels in terms of CD content, the average number of ester bonds to an individual CD, viscosity, and the association and release of model drugs. Inclusion complexation of diflunisal (DIF) and fluconazole (FLZ) with CD-PAA hydrogels was assessed by F-19 NMR spectroscopy and association constants (K(a)s) for DIF were in the range 220-486 M-1 with beta CD-PAA and 1327-6055 M-1 with hydroxypropyl-beta CD-PAA. For FLZ the K-a range was 34-171 M-1 with hydroxypropyl-beta CD-PAA. The hydrogels were found to release both drugs by means of Fickian diffusion as the predominant mechanism. A slight trend toward negative correlation was found between the K-a and Higuchi k(H) values for DIF. These results highlight the potential of CD-PAA hydrogels to control the release of model drugs through inclusion complexation. (C) 2013 Elsevier B. V. All rights reserved