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

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 gamma-cyclodextrin (7-CD) complexation using supercritical carbon dioxide (scCO(2)). We first investigated the solubility of BZ in scCO(2 )and the effect of scCO(2) processing on the solid-state, particle size characteristics and dissolution behaviour of processed BZ compared to un-processed BZ. Moreover, the efficacy of scCO(2) in dissolving and complexing BZ with 7-CD was studied and compared with conventional freeze-drying (FD). The solubility of BZ in scCO(2) was time-dependent (1.78 x 10(-6) to 3.18 x 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 scCO(2) was able to solubilise BZ, it did not change the solid-state morphology of BZ. Contrary, FD and gamma-CD complexation were shown to affect the solid-state characteristics of BZ and gamma-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-gamma-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 gamma-CD, with potential to develop improved formulations.

Automated summary

This study reports on efforts to improve the aqueous dissolution of Benznidazole (BZ) via processing and gamma-cyclodextrin complexation. The preparation methodology had substantial effects on the solid-state particle size/morphology characteristics and aqueous dissolution behavior of BZ, both alone or in complexes with gamma-CD, with potential to develop improved formulations.