Design of experiments-based optimization of nifurtimox polymeric nanoparticle formulations

Abstract

This study aimed, for the first time, to develop and optimize spray-dried nanoparticles loaded with nifurtimox to enhance drug release, using a Design of Experiments approach to evaluate the effects of key formulation and process variables. Nanoparticles were prepared via spray drying using Soluplus® as a polymeric carrier. A Box-Behnken design was employed to analyze the influence of the polymer ratio in aqueous phase (0.30–0.65 %wt), inlet temperature (110–140 °C), and feed flow rate (1–2 mL/min) on critical quality attributes, including particle size, drug loading, yield, and in vitro release profile by diffusion method. Dynamic light scattering, X-ray diffractometry, differential scanning calorimetry, and Fourier-transform infrared spectroscopy were used to study the drug in the solid state. Subsequently, in vitro drug release using the dialysis membrane, as well as the in vitro dissolution profiles, were evaluated. The optimized formulation yielded spherical nanoparticles with a mean size of approximately 370 nm, high encapsulation efficiency, and significantly improved dissolution rates compared to pure nifurtimox. Encapsulation into Soluplus® decreased the drug crystallinity, which contributed to improved solubility and dissolution behavior. The optimization approach demonstrated strong predictive capability, with statistically significant effects observed for polymer ratio and temperature on both drug release and particle morphology. In conclusion, spray drying combined with statistical optimization enabled the successful development of a fast-release nifurtimox nanoparticulate system. This approach offers a scalable strategy alternative for potentially improves its therapeutic performance in the treatment of Chagas disease.