Microfluidic Mixers for Antisolvent Precipitation of Lipid Nanoparticles

Many active pharmaceutical ingredients (APIs) exhibit low water solubility and limited possibilities for oral or parenteral application. Incorporation or attachment of APIs in or to a nanoparticulate lipid matrix can provide increased bioavailability. Defined particle sizes and narrow size distributions support controlled drug release and minimize potential side effects. Antisolvent precipitation in microfluidic systems provides a gentle and continuous process that enables the preparation of small and narrowly distributed nanoparticles but requires a rapid and homogeneous mixing. Three microfluidic systems with different mixing principles were developed for lipid nanoparticle preparation with the lipid castor oil or the hard fat Softisan® 100. The first system used a symmetrical channel design that initiated 3D flow focusing of the liquids and gas-liquid segmentation at a junction and increased mixing efficiency through vortices in the segmented sections. The second and third systems used a stretch-and-fold process through coaxial lamination and horseshoe lamination, respectively, and combined with 3D flow focusing, enabled an efficient and homogeneous mixing process. The systems provided good control of the mixing processes by adjusting the flow rates, allowing mixing times below 10 ms and realizing a selective adjustment of the particle sizes. Precipitation experiments with different lipid concentrations at different flow rate ratios and flow rates up to 800 µl/min resulted in small and narrowly distributed in some cases even monodisperse nanoparticles with sizes down to 42 nm. The systems provided a stable and continuous precipitation process that allows scalable production.