Benznidazole microcrystal preparation by solvent change precipitation and in vivo evaluation in the treatment of Chagas disease

Abstract

Benznidazole (BNZ) is traditionally used to treat Chagas disease. Despite its common use, BNZ has a poor water solubility and a variable bioavailability. The purpose of this study was to prepare BNZ microcrystals by solvent change precipitation and to study the effects of BNZ micronisation on therapeutic efficiency using a murine model of Chagas disease. The solvent change precipitation procedure was optimised in order to obtain stable and homogeneous particles with a small particle size, high yield and fast dissolution rate. The thermal and crystallographic analysis showed no polymorphic change in the microcrystals, and microscopy confirmed a significant reduction in particle size. A marked improvement in the drug dissolution rate was observed for micronised BNZ particles and BNZ tablets in comparison with untreated BNZ and commercial Rochagan. In vivo studies showed a significant increase in the therapeutic efficacy of the BNZ microparticles, corroborating the dissolution results.

Rapid and sensitive ultra‐high‐pressure liquid chromatography method for quantification of antichagasic benznidazole in plasma: application in a preclinical pharmacokinetic study

“…The LLOQ was established as 0.15 μg/mL, given the criteria of precision and accuracy (Table 2). This LLOQ was lower compared with other published methods, demonstrating that the proposed method was more sensitive for the quantification of plasma BNZ (Salomon, 2012;Maximiano et al, 2011;Morilla et al, 2002; Moreira da Silva et al, 2012; Leonardi et al, 2013;Marsón et al, 2013;Morilla et al, 2003). The recovery test also showed the acceptance criteria for precision and accuracy (Table 3), demonstrating that the method of processing the sample was suitable for the analysis of BNZ in plasma.…”

“…In the search for new formulations of BNZ, some authors have reported new pharmaceutical technologies to improve the pharmacokinetics, bioavailability and dissolution of BNZ (Salomon, 2012;Maximiano et al, 2011;Morilla et al, 2002). In some of these studies, bioanalytical methods were developed for the quantification of BNZ in plasma with application in vivo studies to evaluate the pharmacokinetics of the drug.…”

Antisolvent precipitation technique: A very promising approach to crystallize curcumin in presence of polyvinyl pyrrolidon for solubility and dissolution enhancement

“…Stabilizers have been utilized widely to prevent crystal growth by providing steric hindrance due to the absorption at the drug-solvent interface during particle precipitation [34,35,36,37].…”

First Century of Chagas' Disease: An Overview on Novel Approaches to Nifurtimox and Benznidazole Delivery Systems

“…Therefore, an in situ micronization technique without any mechanical process was developed recently by means of solvent precipitation with the addition of polymeric stabilizers in order to avoid the agglomerates 46. Maximiano et al47 described the preparation of benznidazole microcrystals by solvent change precipitation and its inclusion into tablets as an alternative solid dosage form, which is capable of overcoming that limitation and delivers the drug at optimal concentration for the desired therapeutic effect. The formation of crystals of reduced sized was carried out by means of a saturated solution of benznidazole prepared with selected organic solvents and water.…”