Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 596, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2021.120240
Keywords
Benznidazole; gamma-cyclodextrin; Complexation; Dissolution; scCO(2) process; FD method
Categories
Funding
- Australian Government
- University of Queensland
- National Health and Medical Research Council [GNT1146627]
- National Health and Medical Research Council (NHMRC) [GNT1143296]
- Australian Research Council (ARC) [DP200102723]
- Australian Research Council [DP200102723] Funding Source: Australian Research Council
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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.
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.
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