Sequential Flash Nanoprecipitation for the Scalable Formulation of Nanoparticles Using High Mass Concentration Mixing Streams

In the industrial scale production of pharmaceuticals, maximizing the mass concentrations of mixing streams is of economical benefit as it minimizes the volume scale/throughput required of process systems to generate a given amount of product. Flash NanoPrecipitation (FNP) is a scalable process to formulate nanoparticles with a hydrophobic core and amphiphilic stabilizing shell. Here, we demonstrate a variation of the FNP technique that separates the nucleation and stabilization steps into separate sequential mixers, allowing the hydrophobic active to nucleate and grow unimpeded by adsorption of the stabilizing polymer. Using this sequential Flash NanoPrecipitation (sFNP) technique, we can formulate stable nanoparticles in the 200-400nm range while increasing the mass concentration of the core and stabilizer streams beyond what is possible in a single mixer. This technique provides a process for nanoparticle production in a middle size range that was previously unattainable using traditional FNP. The potential of this scalable platform technology to decouple the size and core loading of particles produced by FNP could provide finer control over formulation development than previously demonstrated for turbulent mixing.