Periodic Reporting for period 2 - One-Flow (Catalyst Cascade Reactions in ‘One-Flow’ within a Compartmentalized, Green-Solvent ‘Digital Synthesis Machinery’ – End-to-End Green Process Design for Pharmaceuticals)
Reporting period: 2019-01-01 to 2021-06-30
WP1: ‘The Compartmentalized Smart Factory’. We developed and introduced compartmentalization approaches for flow: (i) polymersomes composed of block copolymers, (ii) Pickering emulsions stabilized by solid particles, (iii) structured microfluidic multiphases, and (iv) chemisorption-anchored catalysts.
WP2: ‘The Green-Solvent Spaciant Factory’. Pharmacy likes to largely minimize use of non-green solvents and has banned the ones with environmental damage. Our approach was to use functional green solvents, which allowed to open and close interim reaction spaces alike reactors do, but more elegantly; thus, being named spaciants.
WP3: ‘The Systemic Operations Factory’. If full orthogonality is provided alike in the (bio )chemical assembly line, unit operations of chemical engineering virtually vanish to a systemic operation in the flow cascade. We envisioned the ultimate level of harmonization to be continuous “One-Flow” processing.
WP 4: ‘The Digital Machine-to-Machine Factory’. The “Internet of Chemical Things” is poised to alter the landscape of chemical synthesis, enabling simple machine-to-machine data transfer and relegation of process monitoring to central computer systems under the oversight of chemists.
WP5: ‘The Fully Continuous Integrated Factory’. To ensure right process selection and to avoid dead-end scenarios, a process-design evaluation was performed, using life-cycle assessment and cost analysis to monitor sustainability. This together with a ‘critical process parameter map’ resulted in a foundation towards a commercial platform technology.
With the ONE-FLOW programme we demonstrated a novel approach in chemical synthesis by executing multiple processes in a continuous flow system without intermediate work up steps. The benefits for society of this approach are that processes are intensified and hence require less chemicals (such as extraction solvents) and energy (for intermediate purification). This contributes to a greener production of fine chemicals. We have shown this concept for four important intermediates used by the pharmaceutical industry. Furthermore, using smart compartmentalization techniques, we were able to enlarge the process window, which allowed novel chemical pathways which are not possible in classical batch type processes. The achieved innovations were a result of the integrative approach regarding reaction, compartmentalization and reactor design, facilitated by automation.
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). 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.