A Comparative Study of Flash Nanoprecipitation and Sequential Nanoprecipitation: Impact of Formulation Parameters on Drug-Loaded Nanoparticle Formation.

Flash NanoPrecipitation (FNP) is a well-established method for forming core-shell drug-loaded nanoparticles that has demonstrated effectiveness for encapsulating highly hydrophobic compounds. However, certain formulation challenges persist, including size limitations and reduced encapsulation efficiency for moderately hydrophobic drugs. Sequential NanoPrecipitation (SNaP) is a novel nanoparticle synthesis process that relies on the same assembly principle as FNP, while decoupling the core formation and stabilization. Through a systematic comparison using drugs with varying hydrophobicity, we demonstrate complementary capabilities between these techniques. We showed that for the high hydrophobicity drugs such as β-carotene, both SNaP and FNP performed effectively. In the case of cinnarizine, a moderately hydrophobic drug that requires the use of hydrophobic ion pairing, good encapsulation efficiency was observed for the case of SNaP, while no encapsulation was observed with FNP. For ibuprofen, a water-soluble analgesic, low encapsulation efficiency was observed with SNaP, and no loading was observed with FNP. Release studies with itraconazole nanoparticles revealed that SNaP-produced nanoparticles exhibited approximately 50% slower release rates compared to FNP over 48 h. Additionally, SNaP enabled access to a broader size range and successful nanoparticle formation at lower solid concentrations. These findings establish SNaP as a valuable complement to FNP, particularly for applications requiring larger nanoparticles, encapsulation of moderately hydrophobic compounds, or modified release kinetics. Together, these nanoprecipitation approaches provide formulators with expanded capabilities for developing polymeric nanoparticle drug delivery systems.