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

John Ndayishimiye; Amirali Popat; Tushar Kumeria; Mark A T Blaskovich; James Robert Falconer

doi:10.1016/j.ijpharm.2021.120240

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

Int J Pharm. 2021 Mar 1:596:120240. doi: 10.1016/j.ijpharm.2021.120240. Epub 2021 Feb 2.

Authors

John Ndayishimiye¹, Amirali Popat², Tushar Kumeria³, Mark A T Blaskovich⁴, James Robert Falconer⁵

Affiliations

¹ School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Brisbane, Queensland 4102 Australia.
² School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Brisbane, Queensland 4102 Australia; Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent St, Woolloongabba, QLD 4102, Australia.
³ School of Materials Science and Engineering, University of New South Wales, New South Wales, Australia.
⁴ Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072 Australia.
⁵ School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Brisbane, Queensland 4102 Australia. Electronic address: j.falconer@uq.edu.au.

PMID: 33540030
DOI: 10.1016/j.ijpharm.2021.120240

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.

Keywords: Benznidazole; Complexation; Dissolution; FD method; scCO(2) process; γ-cyclodextrin.

MeSH terms

Calorimetry, Differential Scanning
Carbon Dioxide
Nitroimidazoles*
Solubility
gamma-Cyclodextrins*

Substances

Nitroimidazoles
gamma-Cyclodextrins
Carbon Dioxide
benzonidazole