Introduction: Benznidazole (BNZ), a poorly water-soluble drug, is the first-line treatment for Chagas disease; however, long treatment periods at high doses often cause adverse effects with insufficient efficacy in the chronic phase. This study aimed to design and compare benznidazole-loaded nanoparticles (NPs) and lipid nanocapsules (LNCs) with the pure drug, focusing on dissolution enhancement and kinetic modeling to support strategies for improving oral bioavailability.

Methods: LNCs were prepared by the phase inversion technique, yielding formulations with an average diameter of 50 nm, an encapsulation efficiency between 83–92%, and drug loading between 0.66–1.04%. NPs were obtained by the liquid anti-solvent precipitation process, also with diameters of approximately 50 nm. Both systems were evaluated and compared with the pure drug by in vitro release assays in simulated gastric medium at 37 °C. The experimental data were fitted to the Lumped-Gonzo model, which provided pharmaceutically relevant parameters and showed an excellent fit to the release profiles (R² > 0.99).

Results: The pure drug exhibited very limited dissolution, requiring more than 280 minutes to reach 20% release (t_20%) and showing a mean dissolution time (MDT_20%) close to 90 minutes. In contrast, LNCs doubled the initial release rate compared with BNZ, reduced MDT_20% to around 33 minutes, and increased dissolution efficiency (DE_360min) to 26.3%. NPs showed the most remarkable performance, achieving a very fast initial release rate of 1.5701 %/min and a maximum release of 89.2%.

Conclusions: Both formulations enhanced benznidazole dissolution compared with the pure drug, with LNCs showing a moderate but sustained effect and NPs achieving the most pronounced improvement. These findings highlight the potential of nanocarriers, particularly NPs, as promising platforms for improving BNZ oral bioavailability.