Reversible pH-Driven Flocculation of Amphiphilic Polyelectrolyte-Coated Nanoparticles for Rapid Filtration and Concentration

Nanoformulating poorly water-soluble drugs is attractive for improving oral dissolution kinetics, but concentrating and drying dilute nanoparticle (NP) suspensions is a barrier to translation. This work describes a reversible, pH-driven flocculation technique for concentrating NPs stabilized with a carboxylic acid-bearing cellulose polymer. Lumefantrine NPs 150 nm in diameter stabilized by anionic hydroxypropylmethylcellulose acetate succinate, a Food and Drug Administration-approved pharmaceutical polymer excipient, are prepared using flash nanoprecipitation. Particles are then concentrated 50-fold by acid-induced flocculation at pH 2.0, separation (either filtration or centrifugation), and base-induced redispersion at pH 6.9, reducing the drying time 50-fold. Dried powders retain enhanced lumefantrine dissolution kinetics. Filtration efficiency is assessed, and flocculation is found to improve NP retention from 3 to 85% on a 2.5 μm filter. The kinetics of flocculation and the fractal nature of the flocs are studied using confocal microscopy and agree closely with a diffusion-limited aggregation model. These results demonstrate a proof of concept that reversible flocculation is a facile method for separating amphiphilic polyelectrolyte-coated NPs from suspension for advanced processing.