Microdevices for pharmaceutical nanoparticle precipitation, downstream processing, and analysis

The use of microfluidic systems for chemical and pharmaceutical production processes has been investigated for some time, as they can offer unique advantages through increased process control and extremely fast process steps. One example that can benefit from the use of microfluidic systems is the precipitation of lipid nanoparticles. Such particles are used as carriers for active ingredients that are difficult to dissolve in water or whose release needs to be controlled. In order to produce pharmaceutical carrier particles and to bring them into an applicable form, several process steps are required. The aim of this work was to demonstrate the closed chain of synthesis, purification, and analysis of lipid nanoparticles in pharmaceutical quality in a microfluidic system. For this purpose, several microfluidic devices were developed and combined. First, nanoparticles were synthesized in a precipitation process in which drug and lipid were dissolved in an organic solvent and afterwards mixed with water (solvent-anitsolvent precipitation). To carry out the precipitation, a multilamination mixer was used, which has proven its capability to produce nanoparticles in several experiments. However, microfluidic precipitation processes are often plagued by intensive fouling. Here this problem was solved by treating the system with ultrasound, which allowed a production cycle over several hours. In addition to the desired nanoparticles, the product contained both microparticles and the acetone used as solvent in concentrations that would prohibit pharmaceutical application of the pure precipitate. To remove the organic phase from the product, a pervaporation chip made of PDMS was developed and characterized. Experimentally, pervaporation rates were found to be significantly lower than predicted by theory. The difference could be attributed to certain factors not considered in the modeling. In order to purge the product from contamination by microparticles, the possibility of continuous purification with microfluidicintegrated filter membranes was investigated. For such a device, a reduction of the particle concentration to a safe level could be experimentally validated. The suitability for continuous operation over several hours in a modular integrated system of microfluidic precipitation and filtration was successfully demonstrated without any degradation of filtration efficiency being observed. For a production process, the consistent quality of the product must be ensured. Such a control requires a permanently working online detector that was adapted to the process. The detector used in this study measured particle size and concentration in a diverted stream. To measure only the characteristics of a single particle, the sample was passed through a small channel to reduce the average particle content in the analyzed channel section below 1. To investigate the process monitoring capability, the detector was combined with a mixer. The Experiments showed that the detector could detect changes in particle size and was able to detect perturbations in the process. In this study, a series of microsystems designed for the production of pharmaceutical carrier particles were developed. Moreover, the additional requirements that arise from a combination of systems and an application focus were demonstrated. The next step would be to integrate the individual devices to form a single system for nanoparticle synthesis and purification with continuous process and feedback control.