Weak complexation of 5-fluorouracil with β-cyclodextrin, carbonate, and dianhydride crosslinked β-cyclodextrin: in vitro and in silico studies

BACKGROUND AND PURPOSE: Several pharmaceutical formulations were investigated to improve the solubility of 5-fluorouracil to enhance bioavailability and therapeutic efficacy. This study aimed to examine the potential use of cyclodextrin-based nanosponges for the incorporation of 5-fluorouracil and to investigate the use of different crosslinking agents on the properties of the resulting drug carrier. 5-Fluorouracil complexation with β-cyclodextrin was also studied to explain the unexpected results of weak 5-fluorouracil incorporation in nanosponge. EXPERIMENTAL APPROACH: Nanosponges were synthesized by crosslinking β-cyclodextrin with two different crosslinkers; diphenyl carbonate and ethylenediaminetetraacetic dianhydride. The incorporation of 5-fluorouracil into β-cyclodextrin and the prepared nanosponges were assessed by NMR, FTIR, PXRD, DSC, and TGA. In addition, an in vitro release study was carried out to evaluate the potential use of β-cyclodextrin- based nanosponges as pharmaceutical formulations for 5-fluorouracil. FINDINGS / RESULTS: Physicochemical characterization of the dried formulations indicated the complexation of 5-fluorouracil with the β-cyclodextrin polymer. Despite that, no clear manifestation of 5-fluorouracil encapsulation in the prepared β-cyclodextrin-based nanosponge was detected. Furthermore, no significant differences were observed in the release profiles of 5-fluorouracil, β-cyclodextrin complex, and β- cyclodextrin-based nanosponge, suggesting weak complexation and instability in aqueous solutions. EDTA- crosslinked β-cyclodextrin-based nanosponge showed a slight improvement in 5-fluorouracil solubility with a faster initial rate of 5-fluorouracil release. CONCLUSION AND IMPLICATIONS: This study suggested weak complexation between 5-fluorouracil and the β- cyclodextrin polymer or nanosponges. Crosslinking of β-cyclodextrin with EDTA dianhydride crosslinker showed an enhancement in 5-fluorouracil saturation solubility combined with a faster initial rate of drug release.