Optically monitored segmented flow for controlled ultra-fast mixing and nanoparticle precipitation

Abstract

Nanoparticles of drugs or colloidal carrier systems are capable of providing substantial advantages for drug bioavailability, but manufacturing nanoparticulate drugs or drug carriers remains a challenge because traditional mechanical or chemical batch mode processes might lack precise control of nanoparticle sizes. Microfluidic approaches are believed to give advantages but often do not provide chemically inert environments and lack controllable operation. Here, segmented flow devices with symmetrical design for centered organic phase injection and for nanoparticle precipitation in transparent and chemically inert glass microchannels are presented. Femtosecond laser fabrication was used to structure borosilicate glass wafers with hydrophilic microchannels of nearly circular cross section. They allow for ultra-fast mixing of solvents with aqueous fluids and subsequent precipitation of poorly water soluble drug nanoparticles or colloidal carrier particles. The best results for mixing and controlled precipitation were obtained with flow focusing and gas segmentation occurring at the same channel intersection point. In such systems, early interdiffusion of the solvent and aqueous solution before ultra-fast convective mixing in the plug is suppressed. A novel optical analysis technique revealed that the speed of mixing can be well controlled by simply adjusting the volume flow rate of the gas phase where changes in the liquid flow rate have practically no influence. In a controlled and stable Taylor flow, smallest plug volumes of 3.8 nl can be generated, which allows complete mixing in 9 ms. The production of lipid nanoparticles down to a diameter of 74 nm could already be demonstrated.