(344a) Sequential Flash Nanoprecipitation for the Scalable Formulation of Stable Core-Shell Nanoparticles with Core Loadings up to 90%

Flash NanoPrecipitation (FNP) is a scalable, single-step process that uses rapid mixing to formulate nanoparticles with a hydrophobic core and amphiphilic stabilizing shell. Because the two steps of particle self-assembly – (1) core nucleation and growth and (2) adsorption of a stabilizing polymer onto the surface of the growing core – occur simultaneously during FNP, nanoparticles formulated with a weight fraction of core material above approximately 70% typically exhibit poor stability or do not form at all. In addition, a fundamental limit on the concentration of total solids that can be introduced into the FNP process has been reported previously. Both of these limits (on core loading and total input solids concentration) are believed to share a common mechanism: the entrainment of the stabilizing polymer into the growing particle core, which leads to destabilization and aggregation.

We here demonstrate a variation of the FNP technique that separates the nucleation and stabilization steps of particle formation into separate sequential mixers. This scheme allows the hydrophobic active to nucleate and grow in the first mixing chamber unimpeded by adsorption of the stabilizing polymer, which is not introduced until the growing nuclei enter the second mixer immediately downstream of the first. Using this Sequential Flash NanoPrecipitation (SNaP) technique, we formulate stable nanoparticles with up to 90% core loading by mass. We also form particles at 6-fold higher total input solids concentrations than typically reported. This approach of decoupling the nucleation and stabilization of particles produced by FNP broadens the range of loadings and solids concentrations that can be achieved by the platform without sacrificing scalability.