Goodbye fouling: a unique coaxial lamination mixer (CLM) enabled by two-photon polymerization for the stable production of monodisperse drug carrier nanoparticles.

Poorly soluble drugs can be incorporated in lipid carrier nanoparticles to achieve sufficient bioavailability and open up diverse routes of administration. Preparation by antisolvent precipitation in microfluidic systems enables excellent control of lipid nanoparticle size. However, particle-containing flows bear the risk of material deposition on microchannel surfaces, limiting reproducibility, prolonged continuous processing and scale-up by parallelization as required for practical use. The coaxial lamination mixer (CLM) introduced in this study can fully eliminate contact of the organic phase with the channel walls while efficiently mixing organic and aqueous phases. This unique micromixer, including a nozzle for coaxial injection, a sequence of stretch-and-fold elements and inlet filters, cannot be realized by conventional 2.5D microfabrication but only by 3D two-photon polymerization. Hydrodynamic focusing of the organic phase and fast coaxial lamination were studied in simulations and flow visualization experiments. Different concentrations of castor oil or a hard fat and polysorbate 80 dissolved in ethanol were injected and combined with purified water. Total flow rates of 100 and 200 μL min-1 and flow rate ratios of 15% or less resulted in particle sizes between 67 and 153 nm and polydispersity indices of 0.04 to 0.10. Extended preparation time revealed stable particle sizes and displayed no fouling, indicating that CLMs will even allow high throughput parallelization. Stable castor oil nanoemulsions loaded with the poorly soluble drugs fenofibrate or cannabidiol were prepared. In conclusion, the unique 3D design of the CLM enables prolonged, stable and scalable production of small as well as very narrowly distributed, in most cases even monodisperse drug-loaded lipid nanoparticles.