Inverse flash nanoprecipitation for biologics encapsulation: Nanoparticle formation and ionic stabilization in organic solvents

Inverse Flash NanoPrecipitation, or iFNP, is a recently developed scalable, controllable, and reproducible process to produce nanoparticles highly loaded with water soluble molecules, such as biologics. The nanoparticles produced by iFNP have a hydrophilic core and hydrophobic corona, and are dispersed in organic solvents. However, most nanoparticle applications, particularly biomedical applications, require that the particle be stable in aqueous environments. Here, we demonstrate that the size of these "inverted" nanoparticles can be controlled between 40 and 300nm, and that they can be stabilized by ionically gelling the poly(acrylic acid) core with metal cations. The effect of solvent and salt on crosslinking were investigated. A method to evaluate the crosslinking efficiency was developed, and a number of metals were found to be effective at crosslinking the particle core, including Ca²⁺, Zn²⁺, and Fe³⁺. Once stabilized, these particles may be further processed for applications in aqueous environments.