Stabilized Production of Lipid Nanoparticles of Tunable Size in Taylor Flow Glass Devices with High-Surface-Quality 3D Microchannels

Abstract

Nanoparticles as an application platform for active ingredients offer the advantage of efficient absorption and rapid dissolution in the organism, even in cases of poor water solubility. Active substances can either be presented directly as nanoparticles or can be integrated in a colloidal carrier system (e.g., lipid nanoparticles). For bottom-up nanoparticle production minimizing particle contamination, precipitation processes provide an adequate approach. Microfluidic systems ensure a precise control of mixing for the precipitation, which enables a tunable particle size definition. In this work, a gas/liquid Taylor flow micromixer made of chemically inert glass is presented, in which the organic phases are injected through a symmetric inlet structure. The 3D structuring of the glass was performed by femtosecond laser ablation. Rough microchannel walls are typically obtained by laser ablation but were smoothed by a subsequent annealing process resulting in lower hydrophilicity and even rounder channel cross-sections. Only with such smooth channel walls can a substantial reduction of fouling be obtained, allowing for stable operation over longer periods. The ultrafast mixing of the solutions could be adjusted by simply changing the gas volume flow rate. Narrow particle size distributions are obtained for smaller gas bubbles with a low backflow and when the rate of liquid volume flow has a small influence on particle precipitation. Therefore, nanoparticles with adjustable sizes of down to 70 nm could be reliably produced in continuous mode. Particle size distributions could be narrowed to a polydispersity value of 0.12.

Microfluidics for pharmaceutical nanoparticle fabrication: The truth and the myth

“…Shear forces on the channel walls create relative backflows in a segmented liquid plug, which induce vortices symmetrical to the channel central axes. The mixing time can be controlled by the size of the segmented plugs, which determines the size of the precipitated nanoparticles (Erfle et al, 2019).…”

High-Efficiency Small Sample Microparticle Fractionation on a Femtosecond Laser-Machined Microfluidic Disc

“…After laser ablation, the wafer was processed in a clean environment and steeped in a glass etching solution (Phosphoric acid, Hydrofluoric acid and water, 20:6:9) for 90 s in order to smoothen the ablation facets and dissolve residual glass fragments. The ablated wafer and another blank wafer were then inserted in a wafer cleaning machine (Fairchild Convac, Neuenstadt, Germany) that sprays pressurized water and dispenses a mixture of H 2 SO 4 and H 2 O 2 for cleaning and surface activation before thermally bonding the two wafers by placing them in a muffle oven at 620 • for a duration of 6 h. The post-ablation process was adopted from an earlier work by Erfle et al [44,45]. Figure 2 shows laser microscopy images before and after dipping the wafer in glass etching solution.…”

“…surface activation before thermally bonding the two wafers by placing them in a muffle oven at 620° for a duration of 6 h. The post-ablation process was adopted from an earlier work by Erfle et al [44,45]. Figure 2 shows laser microscopy images before and after dipping the wafer in glass etching solution.…”

Protective Filtration for Microfluidic Nanoparticle Precipitation for Pharmaceutical Applications

“…Work on microfluidic mixing has contributed significantly to enabling the synthesis of nanoparticles with defined properties by antisolvent precipitation. Devices which rely on staggered herringbone mixers 7–10, flow focusing 11–14, multilamination 15, impinging jets 16–19, single droplet formation 20, Taylor flows 21, 22, or splitting the streams and recombining them to minimize the diffusion length 23, 24 have been described. Some groups added additional external power to intensify the mixing process, e.g., by using small rotors 25 or ultrasound 26–28.…”

“…To face these issues, different strategies have been aplied in microsystems like the conditioning of the stream 23, 32, conditioning of the channel surface 22, 23, 33, encasing with sheath streams 14, 34, or sonication 35–38.…”