Abstract Summary (Max 250 words)
Continuous antisolvent precipitation has emerged as a scalable method for producing lipid nanoparticles (LNPs), which is known to be a micro-mixing limited process. Several microfluidic devices and meso-scale devices have been developed for antisolvent precipitation. The device design and operating parameters influence local micro-mixing and thereby affect the quality attributes of LNPs – particle size, polydispersity and encapsulation efficiency. In the present work, we demonstrate the use of coiled pinched tube and vortex-based cavitation device operated in a loop configuration for continuous antisolvent precipitation of LNPs. The results are compared with once through operation of commercial microfluidic devices and coiled pinched tube. In a once-through configuration, micro-mixing is tightly coupled with capacity. In loop configuration, the micro-mixing is controlled by flow rate through recirculation loop and therefore independent of net flow rates of solvent and antisolvent streams (capacity). This offers flexibility of adjusting the throughput as per the requirements without compromising mixing efficiency. Furthermore, the use of loop configuration helps in highly concentrated LNP suspensions (up to 50 mg/mL) without jeopardising the limits on size and polydispersity which is not possible in conventional once-through configuration. These experimental results are modelled with two and three environment engulfment models to simulate interactions of micro-mixing and kinetics of LNP formation in the aforementioned devices. The presented approach of loop configuration offers effective pathway to achieve desired size and productivity of LNPs, over a broad range of feed lipid concentrations.
