Supercritical carbon dioxide assisted complexation of benznidazole: γ-cyclodextrin for improved dissolution

Abstract

Benznidazole (BZ) and nifurtimox are first-line drugs for the treatment of Chagas disease, with BZ preferred due to its moderate side effects compared to nifurtimox. However, BZ has low aqueous solubility and a low dissolution rate which potentially limit its oral bioavailability. We now report for the first time efforts to improve the aqueous dissolution of BZ via processing and γ-cyclodextrin (γ-CD) complexation using supercritical carbon dioxide (scCO2). We first investigated the solubility of BZ in scCO2 and the effect of scCO2 processing on the solid-state, particle size characteristics and dissolution behaviour of processed BZ compared to un-processed BZ. Moreover, the efficacy of scCO2 in dissolving and complexing BZ with γ-CD was studied and compared with conventional freeze-drying (FD). The solubility of BZ in scCO2 was time-dependent (1.78 × 10-6 to 3.18 × 10-5 mol. mol−1) and reached the equilibrium after 10 h. Complexation efficiency and loading capacity were in the range of 4 ± 1.4% to 54 ± 10% and 1.8 ± 0.1% to 27 ± 5%, respectively, and they varied depend on the preparation method and conditions. XRD, DSC, and FTIR results revealed that although scCO2 was able to solubilise BZ, it did not change the solid-state morphology of BZ. Contrary, FD and γ-CD complexation were shown to affect the solid-state characteristics of BZ and γ-CD. The mean particle size of processed BZ was significantly reduced from 604 ± 61.50 nm (un-processed BZ) to 257 ± 41–385 ± 36.56 nm (processed BZ). Both the dissolution rate profiles and dissolution efficiency differed depending on preparation methods, process conditions, and BZ-to-γ-CD ratio, but they were significantly increased compared to un-processed BZ. Overall, this study demonstrated that the preparation methodology had substantial effects on the solid-state particle size/morphology characteristics and aqueous dissolution behaviour of BZ, both alone or in complexes with γ-CD, with potential to develop improved formulations.