Abstract
Flash NanoPrecipitation is a scalable approach to generate polymeric nanoparticles using rapid micromixing in specially designed geometries such as a confined impinging jets mixer or a Multi-Inlet Vortex Mixer (MIVM). A major limitation of formulation screening using the MIVM is that a single run requires tens of milligrams of the therapeutic. To overcome this, we have developed a scaled-down version of the MIVM, requiring as little as 0.2 mg of therapeutic, for formulation screening. The redesigned mixer can then be attached to pumps for scale-up of the identified formulation. It was shown that Reynolds number allowed accurate scaling between the 2 MIVM designs. The utility of the small-scale MIVM for formulation development was demonstrated through the encapsulation of a number of hydrophilic macromolecules using inverse Flash NanoPrecipitation with target loadings as high as 50% by mass.
Highlights
NP size was evaluated by dynamic light scattering (DLS) at different flow rates, which were converted to mixer Reynolds number (Re) (Eq 1) and are reported in Table S2 and Figure 4a for the 3 configurations tested
The excellent agreement between stand- and pump-driven flow configurations for the micro” Multi-Inlet Vortex Mixer (mMIVM) indicates that small-scale operation scales directly to larger batch sizes
The Re based on inlet jet velocity was shown to accurately predict flow rate scale-up to the Multi-Inlet Vortex Mixer (MIVM) geometry
Summary
Nanoparticles (NPs) have received considerable interest as vehicles for hydrophobic therapeutics and imaging agents, among other applications.[1,2,3,4,5] Production of polymeric NPs in a reproducible manner is necessary for successful clinical translation, but scale-up is often difficult.[5,6] Flash NanoPrecipitation (FNP) provides a scalable solution to this challenge through a continuous rapid mixing process, which is carried out in specific geometries.[2,7] As a continuous process, scale-up entails longer run times rather than implementation in larger vessels.[8,9,10] The resultant NPs contain a Abbreviations used: FNP, Flash NanoPrecipitation; CIJ, confined impinging jets; MIVM, Multi-Inlet Vortex mixer; NP(s), nanoparticle(s); BCP, block copolymer; PSPEG (PS-b-PEG), poly(styrene)-block-poly(ethylene glycol); PS, poly(styrene); THF, tetrahydrofuran; Re, Reynolds Number; iFNP, inverse Flash NanoPrecipitation; mMIVM, micro Multi-Inlet Vortex Mixer; CHCl3, chloroform; DMSO, dimethyl sulfoxide; PS-b-PAA, poly(styrene)-block-poly(acrylic acid); DLS, dynamic light scattering; PDI, polydispersity index; OVA, ovalbumin; HRP, horseradish peroxidase.
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