Abstract

Flow chemistry facilitates the reproducibility of chemical processes otherwise inefficient or problematic and allows not only the minimization and optimization of reaction time, but also safety improvement and easy scale up. For this reason, this widely explored technology is generally considered as green methodology. With its cost and energy efficiency, automation provided by flow chemistry is a step toward a much greater sustainability in chemistry. In addition, flow chemistry assists the progress of scalability: the optimization of reaction conditions is faster, and the scaling up of the processes is facilitated. Because of the above-mentioned characteristic, flow processes present clearly advantages over batch production. Nevertheless, not all reactions work when transferred to flow chemistry manufacturing because of solubility’s issue. An integration between batch and flow methodologies needs to be envisaged.

Finally, together with automation, digitalization is another important parameter for an efficient scale up and greener transition. The Digital Twin technology are virtual copies of the physical processes can in fact support the transition towards a more circular scale up and help companies reduce their resources and carbon footprint.

This literature review is therefore organised into two macro-areas:

1. A focus on Flow Chemistry. The first abstract presents a multistep continuous flow synthesis of an API, while in the second and third studies photo- and electro-chemistries are combined with flow chemistry to implement large scale synthesis. Finally, the last abstract presents a comparison between flow and batch production: for one selected compound, flow chemistry was successfully exploited to improve batch process limitations, while problems connected to the second compound showed that flow chemistry should not be considered a priori as a general successful approach for the synthesis of every drug.
2. A focus on Digital Twin: the first abstract provides a detailed definition of digital twin, explains its applications in the manufacturing supply chain and sustainability, and presents a sustainable digital twin implementation framework. The second one presents a novel digital twin ecosystem suitable for testing/process monitoring/remote management of an additive manufacturing machine in a simulated virtual environment. Lastly, in the final abstract digital twin applications in the bio-manufacturing industry are presented.

1 FLOW CHEMISTRY

Scientific online resources as Pubmed and Google Scholar were used to retrieve articles of interest. To screen for the most advanced research, articles were selected between the years 2020 and 2022 with the following keywords: flow chemistry, scale up, industrial application.

Advanced Real-Time Process Analytics for Multistep Synthesis in Continuous Flow

Peter Sagmeister1,2, René Lebl1,2, Ismael Castillo3, Jakob Rehrl4, Julia Kruisz4, Martin Sipek5, Martin Horn3, Stephan Sacher4, David Cantillo1,2, Jason D Williams1,2, C Oliver Kappe1,2

Affiliations:

1. Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010, Graz, Austria.
2. Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010, Graz, Austria.
3. Institute of Automation and Control, Graz University of Technology, Inffeldgasse 21b, 8010, Graz, Austria.
4. Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010, Graz, Austri ...
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