Organic solvent-free benznidazole nanosuspension as an approach to a novel pediatric formulation for Chagas disease

<b>Aim:</b> Benznidazole (BNZ), a class-II drug, is the primary treatment for Chagas disease, but its low aqueous solubility presents challenges in formulation and efficacy. Nanosuspensions (NS) could potentially address these issues. <b>Methods:</b> BNZ-NS were prepared using a simple, organic solvents-free nano-milling approach. Physicochemical characterizations were conducted on both NS and lyophilized solid-state BNZ-nanocrystals (NC). <b>Results:</b> BNZ-NS exhibited particle size &lt;500 nm, an acceptable polydispersity index (0.23), high Z-potential, and physical stability for at least 90 days. BNZ-NC showed tenfold higher solubility than pure BNZ. Dissolution assays revealed rapid BNZ-NS dissolution. BNZ-NC demonstrated biocompatibility on an eukaryotic cell and enhanced BNZ efficacy against trypomastigotes of <i>Trypanosoma cruzi</i>. <b>Conclusion:</b> BNZ-NS offers a promising alternative, overcoming limitations associated with BNZ for optimized pharmacotherapy. Novel nanosuspension of BNZ was produced without the use of organic solvents using a top-down method. The aqueous solubility of BNZ-NS was found to be ten-times higher than its intrinsic solubility. BNZ-NS exhibited improved <i>in vitro</i> dissolution behavior compared with crushed commercial tablets. BNZ-NS demonstrated physical stability for 90 days under refrigerator and room temperature conditions. BNZ-NS showed improved toxicity profiles and efficacy against <i>Trypanosoma cruzi</i>.