Flash precipitation of random copolymers in a micro-mixer for controlling the size and surface charge of nanoparticles.

Precisely controlling the size and surface chemistry of polymeric nanoparticles (P-NPs) is critical for their versatile engineering and biomedical applications. In this work, various NPs of amphipathic random copolymers were comparatively produced by the flash nanoprecipitation (FNP) method using a tube-in-tube type of micro-mixer up to 330 mg min in production scale in a kinetically controlled manner. The NPs obtained from poly(styrene--maleic acid), poly(styrene--allyl alcohol), and poly(methyl methacrylate--methacrylic acid) were concurrently controlled in the range 51-819 nm in size with narrow polydispersity index (<0.1) and -44 to -16 mV in zeta potential, by depending not only on the polymeric chemistry and the concentration but also the mixing behavior of good solvents (THF, alcohols) and anti-solvent (water) under three flow regimes (laminar, vortex and turbulence, turbulent jet). Moreover, the P(St-MA) derived NPs under turbulent jet flow conditions were post-treated in the initial solution mixture for up to 16 h, resulting in lowering of the zeta potential to -52 mV from the initial -27 mV and decreasing size to 46 nm from 50 nm by further migration of hydrophilic segments with -COOH groups on the outer surface, and the removal of THF trapped in the hydrophobic core.