Design of a Small-Scale Multi-Inlet Vortex Mixer for Scalable Nanoparticle Production and Application to the Encapsulation of Biologics by Inverse Flash NanoPrecipitation

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.

Flash NanoPrecipitation for the Encapsulation of Hydrophobic and Hydrophilic Compounds in Polymeric Nanoparticles

“…Three example formulations using FNP and iFNP are presented below. Two employ the CIJ mixer and one requires the MIVM 15,22 . The first formulation demonstrates encapsulation of a model hydrophobic compound by FNP.…”

“…A small-scale version of the MIVM (the μMIVM) with its mixer stand is shown in Figure 2. As with the CIJ, this mixer can be used to encapsulate hydrophobic or hydrophilic compounds 22 . In step 3, a protocol for the encapsulation of a hydrophilic protein, OVA, by iFNP was described.…”

Translational formulation of nanoparticle therapeutics from laboratory discovery to clinical scale

“…1b) can be used to produce any batch size by scaling production time, nanoparticle processing often involves other unit operations such as tangential flow filtration or spray drying. The mixer size should be matched to the flows and time scales of the other unit operations [9, 24]. Therefore, to avoid operating under conditions where the mixing and assembly regime has changed, a larger MIVM with a higher flow rate may be used.…”

“…Therefore, to avoid operating under conditions where the mixing and assembly regime has changed, a larger MIVM with a higher flow rate may be used. We designed the MIVM-5L to operate at a volumetric flow rate of 5 L/min at Re = 10 5 and used a modified form of the design reported by Markwalter and Prud’homme [24]. We adopted a strategy that constrained several parameters within boundaries reported by Liu et al as well as Markwalter and Prud’homme [24, 25].…”

“…We designed the MIVM-5L to operate at a volumetric flow rate of 5 L/min at Re = 10 5 and used a modified form of the design reported by Markwalter and Prud’homme [24]. We adopted a strategy that constrained several parameters within boundaries reported by Liu et al as well as Markwalter and Prud’homme [24, 25]. The MIVM-1.5L and MIVM-5L mixers are geometrically similar with the vortex chamber of the 5L design being 2.5 times larger than the 1.5L design presented by Liu et al [26].…”