Advanced Real‐Time Process Analytics for Multistep Synthesis in Continuous Flow**

Abstract

In multistep continuous flow chemistry, studying complex reaction mixtures in real time is a significant challenge, but provides an opportunity to enhance reaction understanding and control. We report the integration of four orthogonal Process Analytical Technology tools (NMR, UV/vis, IR and UHPLC) in the multistep synthesis of an Active Pharmaceutical Ingredient, mesalazine. This synthetic route makes optimal use of flow processing for nitration, high temperature hydrolysis and hydrogenation steps, as well as three inline separations. Advanced data analysis models were developed (indirect hard modelling, deep learning and partial least squares regression), to quantify the desired products, intermediates and impurities in real time, at multiple points along the synthetic pathway. The capabilities of the system have been demonstrated by operating both steady state and dynamic experiments and represents a significant step forward in data-driven continuous flow synthesis. File list (2) download file view on ChemRxiv SI_Advanced Real-Time Process Analytics_Final.pdf (10.76 MiB) download file view on ChemRxiv MS_Advanced Real-Time Process Analytics_v2.pdf (1.33 MiB)

Sampling and Analysis in Flow: The Keys to Smarter, More Controllable, and Sustainable Fine‐Chemical Manufacturing

“…The rotor slots are designed to keep the system flowing during the load and inject configuration, making these systems appropriate for at‐line/off‐line sampling. This was demonstrated in a recent report on real‐time process analytics in continuous flow [49, 50] …”

“…The stream can be directed post‐IR analysis to a second analytical device for the evaluation of a second set of quality attributes (e.g. Raman or NMR spectroscopic analysis) [49, 50] …”

Towards 4th industrial revolution efficient and sustainable continuous flow manufacturing of active pharmaceutical ingredients

“…16,17 Process analytical technology (PAT) has found many applications and progressively played a central role in continuous flow processing, allowing real-time reaction monitoring for a variety of applications to enable process transfer, rapid optimisation, scale-up, fault-detection, process monitoring, continuous improvement and process control when needed. 9,13,18,61–64 Furthermore, it's application ensures improved knowledge of the industrial requirements to allow the best possible yield while avoiding obtaining unreacted raw materials and by-products in the continuous reactor effluent. In reaction optimisation, inline analysis systems allows for real time monitoring of variables such as temperature, reagent, equivalents of reagent and reaction time.…”

“…Sagmeister and coworkers, 63 demonstrated the incorporation of four different four real-time analytical tools (NMR, UV/vis, IR and UHPLC) in a continuous flow multistep synthesis of the API, mesalazine (Fig. 24).…”

A versatile non-fouling multi-step flow reactor platform: demonstration for partial oxidation synthesis of iron oxide nanoparticles

“…The interest in flow reactors is mostly due to 1) the advantageous synthetic conditions made possible, e.g., by fast mixing, improved heat and mass transfer, precise temperature control, and precisely timed reagent addition; 2) their inherent continuous operation mode, providing opportunities for large-scale production; 3) the reduction of manual steps reducing the operator effect on reproducibility. [1][2][3][4][5][6][7] Their ease of automation is also why flow reactors are in demand for high-throughput screening as well as self-optimising reactor platforms. [8][9][10][11][12][13] Not only for fine chemical, but also polymer as well as micro and nanoparticle synthesis, such platforms combining flow reactors, intelligent algorithms and real-time material characterisation can pave the way to fully computer aided chemical science tuning molecular or particle properties.…”