Continuous stirred tank reactors in fine chemical synthesis for efficient mixing, solids-handling, and rapid scale-up

Cherkasov, Nikolay; Adams, Samuel J.; Bainbridge, Edward G. A.; Thornton, Jonty A. M.

doi:10.1039/d2re00232a

Cited by 21 publications

(24 citation statements)

References 39 publications

(98 reference statements)

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“…Operation at steady state also improves control over reaction conditions (e. g., temperature) in order to optimize the rate of reactions within the vessel. [89] Finally, batch-to-batch variation is reduced by presenting opportunities to implement feed-forward and feed-back loops in the operation of a CSTR. These address variability from non-reactor sources such as feedstocks, environment fluctuations, etc., while simultaneously reducing losses (See Table 1).…”

Section: Continuous Stirred Tank Reactorsmentioning

confidence: 99%

“…Once steady‐state is achieved the CSTR may operate continuously for a significant duration of time before intermittent cleaning is needed, resulting in much higher throughput per operating cycle. Operation at steady state also improves control over reaction conditions ( e. g ., temperature) in order to optimize the rate of reactions within the vessel [89] . Finally, batch‐to‐batch variation is reduced by presenting opportunities to implement feed‐forward and feed‐back loops in the operation of a CSTR.…”

Section: Unit Operationsmentioning

confidence: 99%

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Continuous Manufacturing of Active Pharmaceutical Ingredients: Current Trends and Perspectives

Hyer,

Gregory,

Kay

et al. 2024

Adv Synth Catal

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The pharmaceutical industry has traditionally employed batch processing as a means of synthesizing active pharmaceutical ingredients (APIs) on a commercial scale. Batch manufacturing enables API synthesis in large quantities in order to meet regulations. Yet, this strategy remains cumbersome, is labor‐intensive, and creates complex logistical networks. In recent decades, batch API processing has gradually eroded American economic competitiveness and has led to the off‐shoring of API manufacturing from the United States. Today it is estimated that +80% of APIs are manufactured overseas. Meanwhile, disruptions from the Coronavirus Disease (SARS‐CoV‐2) have exacerbated weaknesses in the global supply chain, culminating with widespread shortages of critical life‐saving drugs. These shortages have emphasized the importance of reshoring drug manufacturing to the U.S. and fostered a regulatory landscape that seeks advanced methods of API manufacturing in order to bolster America’s supply chain resiliency. Recently, increased attention has been directed towards continuous drug manufacturing to enable nonstop API production within modular stand‐alone flow systems. Continuous manufacturing (CM) facilitates modular automation, offers new avenues towards process intensification, and even enables in‐line analytical monitoring from raw materials to packaged products. This strategy offers better conversion, increased safety, reduced waste, and overall cost savings versus traditional batch‐style processing. The rise of advanced API manufacturing, coupled with the current regulatory landscape, offers a rare window of opportunity to convert traditional batch pharmaceutical processes into continuous, streamlined production systems to on‐shore API manufacturing and eliminate drug shortages. This review will outline the current state‐of‐the‐art in the CM of APIs and will highlight the translation of chemistry and unit operations from batch processes to modular CM systems.

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Section: Continuous Stirred Tank Reactorsmentioning

confidence: 99%

Section: Unit Operationsmentioning

confidence: 99%

Continuous Manufacturing of Active Pharmaceutical Ingredients: Current Trends and Perspectives

Hyer,

Gregory,

Kay

et al. 2024

Adv Synth Catal

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“…[181] Reactants are continuously fed and the reaction mixture with the products is continuously withdrawn. Although small‐scale CSTRs exist, they are often used on a large scale [182] . They are widely used in the chemical, biological, and petrochemical industries [183] .…”

Section: Gas–solid–liquid Reactions In Continuous Flowmentioning

confidence: 99%

Multiphasic Continuous‐Flow Reactors for Handling Gaseous Reagents in Organic Synthesis: Enhancing Efficiency and Safety in Chemical Processes

Laporte,

Masson,

Zondag

et al. 2023

Angewandte Chemie

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The use of reactive gaseous reagents for the production of active pharmaceutical ingredients (APIs) remains a scientific challenge due to safety and efficiency limitations. The implementation of continuous‐flow reactors has resulted in rapid development of gas‐handling technology because of several advantages such as increased interfacial area, improved mass‐ and heat transfer, and seamless scale‐up. This technology enables shorter and more atom‐economic synthesis routes for the production of pharmaceutical compounds. Herein, we provide an overview of literature from 2016 onwards in the development of gas‐handling continuous‐flow technology as well as the use of gases in functionalization of APIs.

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“…Flow chemistry is a discipline in synthetic organic chemistry that uses a continuous stream of different reagents, which are introduced by pumps and mixed in a continuous reactor, such as plug flow reactor (PFR) or continuous-stirred tank reactor (CSTR). 1,2 Compared to conventional batch processing which is often carried out in round-bottom flasks, it offers several advantages such as enhanced mass and heat transfer, improved safety, increased reaction efficiency, reduced waste, better scalability, and improved reproducibility. 3,4 As a consequence, flow chemistry allows for precise control over reaction conditions and enables real-time monitoring and analysis of reaction kinetics, resulting in high-quality products and streamlined processes.…”

Section: Introductionmentioning

confidence: 99%

A field guide to flow chemistry for synthetic organic chemists

2023

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Continuous stirred tank reactors in fine chemical synthesis for efficient mixing, solids-handling, and rapid scale-up

Abstract: Continuous Stirred Tank Reactors (CSTRs) facilitate chemical manufacture in continuous flow and have been used for decades. They excel at solid handling and have well understood scale-up capacity. CSTRs in...

Cited by 21 publications

References 39 publications

Continuous Manufacturing of Active Pharmaceutical Ingredients: Current Trends and Perspectives

Continuous Manufacturing of Active Pharmaceutical Ingredients: Current Trends and Perspectives

Multiphasic Continuous‐Flow Reactors for Handling Gaseous Reagents in Organic Synthesis: Enhancing Efficiency and Safety in Chemical Processes

A field guide to flow chemistry for synthetic organic chemists

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