FDmix – Fraunhofer Dynamic Mixing Technologies

Technical mixing operations such as crystallization or precipitation reactions are part of many production processes in the pharmaceutical, chemical and biotech industries. The quality of the mixture not only determines the quality of products such as active medical ingredients and nanoparticles, but ultimately also their effectiveness. The Fraunhofer Dynamic Mixing Technologies achieve mixtures of unprecedented homogeneity with minimal mixing times and are scalable over a large volume flow range, enabling efficient and robust series production of pharmaceuticals and chemical industry products, for example.

Production of nanoparticles to encapsulate active ingredients

One application example is the production of nanoparticles, such as those used in mRNA vaccines. For these vaccines or other RNA-based drugs, the active ingredient is encapsulated in a protective coating so that it can be transported into the cells in the human body and released there.

For this purpose, the active ingredient dissolved in a buffer is mixed with another solution, e.g. a lipid or polymer solution. As soon as these two liquids are mixed together, nanoparticles are formed that encapsulate the active ingredient. The resulting particles are significantly smaller and more homogeneous, and the particle size can even be adjusted.

For laboratory use, so-called microfluidics are used, which produce a very good and fast mixing, but only allow a very low throughput. So-called impinging mixers (also known as T-mixers or Y-mixers) are available for industrial-scale applications. They enable a high throughput, but at the cost and expense of the mixing quality. This emphasizes the problem of scaling up laboratory processes to manufacture series products. The situation is very similar with nanoemulsions, in which a stable emulsion of otherwise immiscible substances, such as water and oil, is produced.

Fraunhofer IPK was able to bridge the gap between mixing quality and throughput as part of its research and development projects together with FDX Fluid Dynamix GmbH. The resulting Fraunhofer Dynamic Mixing Technologies (FDmix) platform allows a consistent mixing quality and speed from laboratory use to series production and has already been successfully tested for the production of lipid and polymer nanoparticles as well as nanoemulsions. As the tests have shown, the mixing quality of the FDmix platform is superior to many conventional systems.

The FDmix platform can be used for a wide range of mixing applications, as the system is extremely robust, delivers short mixing times, and nearly provides the same mixing quality over the entire flow range. Therefore, the system can be used quite generally for continuous flow chemistry, i.e. for chemical reactions such as precipitation processes that are not carried out in individual batch productions but in a continuous flow. In addition, the FDmix platform is suitable for the production of nanoemulsions, i.e. for creating a stable mixture of otherwise immiscible substances such as water and oil. Finally, the system can also be used to encapsulate nanoparticles, e.g. for mRNA vaccines and mRNA-based drugs.

At the heart of the FDmiX platform is an OsciJet nozzle by FDX Fluid Dynamix GmbH, as shown schematically on the right. ❶ Inside the nozzle, a jet of liquid is positioned on one of the sides of the main chamber. ❷ If you follow the jet through the main chamber, you can see that a small part of the jet is deflected into a side channel before leaving the nozzle. At the end of the side channel, it meets the main jet again and pushes it to the other side. ❸ This causes the main jet to oscillate continuously from one side to the other. ❹ shows the beam pattern as it looks in time resolution.

The illustration on the left shows an FDmix mixer. The mixer consists of a base plate with the nozzle mentioned above, a mixing chamber and a lid (not shown). The structure is sealed with screw connections to withstand even the highest pressures. The schematic diagram on the left shows how the actual mixer works: One of the fluid components to be mixed is introduced into the system at ① and then flows into the nozzle. As it flows through the nozzle, the component is caused to vibrate. The second component is introduced at ② perpendicular to the mixer and then meets the oscillating jet of the first component at ③. The high-frequency vibration now ensures that the first component interacts quasi abruptly with the second component and is then transported further into the mixing chamber. The mixture then leaves the outlet ④ further downstream of the mixing chamber.

The mixing of the FDmiX platform is based on a scalable principle. The oscillating flow of one substance through the nozzle meets the flow of the second substance perpendicularly and thus produces a good mixture very quickly. The mixing times are in the millisecond range and are therefore faster than lightning. As the mixers can be easily scaled up, laboratory processes can be adapted to production scale. In internal tests, Fraunhofer IPK and FDX Fluid Dynamix GmbH were able to demonstrate that particularly in lipid nanocapsulation, i.e. the coating of an active ingredient with a lipid shell, the resulting particles are significantly smaller and more homogeneous, and the particle size can even be adjusted. The FDmix platform is therefore particularly well suited for the production of nanoparticles and nanoparticle emulsions, for precipitation processes and many other mixing processes.

The videos show mixing experiments that were performed using the transmitted light method. In the impinging mixer, shown in the first video, you can see that the two phases collide and then flow down vertically parallel to each other. Differences in concentration can be clearly seen here.

The FDmix mixer in the second video, on the other hand, shows a much more homogeneous image.

In the course of their research, Fraunhofer IPK and FDX Fluid Dynamix GmbH have developed and tested mixers for different pressure and flow rates. The smallest mixers (FDmix XS) can operate at flow rates below one milliliter per minute and the largest (FDmix XL) at more than 5 liters per minute.

In encapsulation tests with mRNA in lipid nanoparticles with different mixers and flow rates, the FDmix XL produced smaller particles with significantly lower size distribution (PDI) compared to an impinging mixer at the same flow rate. All FDmix mixers proved in the tests that they can produce excellent nanoparticles over a wide flow range and are able to provide:

• smaller particles (~10-20% smaller than impinging mixers),
• significantly lower particle size distribution (PDI), and
• high encapsulation efficiency and particle integrity.