Our ONE FLOW concept was tested with the multistep synthesis of four pharmaceutically relevant compounds, which all had the necessity to compartmentalize subsequent reaction steps. The feasibility of ONE-FLOW was fully demonstrated for two of the four compounds. The other two compounds were especially explored to investigate the scope of the compartmentalization strategies we have implemented. The general applicability of the concept was demonstrated also for the production of sialic acid derivatives, and the ONE-FLOW synthesis of Rufinamide.
The second innovative aspect was compartmentalization. Segmented flow systems were developed in which liquid droplets were effectively separated by interspersed gas droplets. The level of control makes this process directly translatable to flow production. The spaciant flow factory, in which solubility of the reaction components is highly controlled and can be effectively varied throughout the process, was instrumental for the execution of the synthesis of Rufinamide. As the solvent of choice can be efficiently selected via computational methods, this process holds great promise for process intensification.
We successfully explored Pickering emulsions in flow. These particle-stabilized emulsions are very stable, but can, under the right circumstances be efficiently separated, allowing for effective catalyst separation and recycling. This was also the case for newly developed catalytic nanoparticles, crosslinked enzyme nano-aggregates (nCLEnA). The in-depth life cycle analysis of this process indicated how many recycling steps are required to make this form of compartmentalization economically feasible.
The final level of innovation was in the area of process control and integration, using microprocessors for control and reaction monitoring. Through a workshop and through development of the system, even more interactions were achieved. Our open-access Tutored Discourse (10.1039/C9RE00407F) further allows all interested parties to use the machine-assisted approach to aid their research. Furthermore, using the automated process control in flow, we were able to identify novel processing windows and therefore could synthesize classes of molecules that were not attainable by classic batch chemistry. Finally we constructed tailor made ONE-FLOW reactors. Using a 3D printed steel reactor, we could successfully execute part of the synthesis of one of our pharmaceutical intermediates.
The research activities have led to the publication of 34 open access research papers. Furthermore, we have presented the results of the program at a wide range of conferences (45 oral and poster presentations. Specifically worth mentioning is the dedicated session on the ONE-FLOW concept held at the 2019 Dutch chemistry conference CHAINS.
Dissemination to the non-scientific public was addressed by articles in the popular press. To achieve this more effectively, the ONE-FLOW consortium participated in the Future Tech week and prepared a youtube video explaining the ONE-FLOW concept (
https://www.youtube.com/watch?v=oV0dDMgq0FA&feature=youtu.be(s’ouvre dans une nouvelle fenêtre)). Also, via our website we have informed the general audience about our program.
The ONE FLOW concept was brought under the attention to many companies via work shops, consultations and site visits. A brochure with the main highlights on innovation within ONE FLOW was prepared and distributed among pre-selected company contacts. As part of the dissemination and innovation potential, Microinnova constructed a ONE-FLOW prototype reactor made by 3D printing in steel. This prototype can be used to demonstrate to companies in the field of the fine chemicals and pharmaceuticals sectors how continuous production with in-flow work up can be achieved.
