Continuous Flow Chemical Technology

• Continuous flow chemistry refers to chemical reactions occurring within a continuously flowing fluid.  Raw materials and reagents are prepared as solutions and pumped into reaction channels from separate containers, where subsequent chemical transformations occur. Commonly used reactors in continuous flow chemistry include microreactors and medium-sized reactors. Microreactors typically have a three-dimensional structure, with internal dimensions less than 1 mm, ranging from 10 to 100 microns.
  In the context of "double-carbon", "green chemistry" is advancing into the biopharmaceutical industry. Only by continuously innovating R&D technology can we open new doors to green chemistry. In recent years, Medicilon has been closely tracking the latest green chemistry research progress in the industry and is committed to transforming this research into applicable technologies to promote the green upgrading of pharmaceutical R&D.

Advantages of Continuous Flow Chemistry Technology

• 1) Safe and Stable: It can implement automated and continuous production, greatly reducing the risk of thermal runaway during reactions. The liquid holding capacity of continuous flow devices is relatively small, limiting the spread even if control is lost. 2) Energy Saving and Cost Reduction: Equivalent-sensitive reactions enable precise control of substrate dosages. Continuous flow equipment exhibits relatively high mass transfer and heat transfer efficiencies, reducing solvent usage and achieving energy conservation by minimizing utility engineering specifications or utility usage. Continuous flow equipment generally operates in a continuous closed form, minimizing various uncontrolled emissions.3) Efficiently Increase Production: It significantly enhances non-homogeneous phase reactions and facilitates control over endothermic and exothermic reactions. The reaction process maintains close to constant temperatures, with multi-stage reactions quickly adjusting to required temperatures. In addition to enhancing overall product yields by extending microreactor operating times, parallel amplification of continuous flow reactors boosts production.

Feasibility Assessment of Continuous Reactions

• Through literature research and analysis of preliminary experimental results, we have gained a comprehensive and in-depth understanding of the chemical reactions under study and their reaction mechanisms. Combined with the characteristics of continuous flow equipment, we design the continuous flow synthesis process.
  We verify the feasibility of reaction effects and trends in process optimization through continuous flow experiments.
  Based on the feasibility analysis results, we explore process optimization, synthesis route optimization and optimization of reaction conditions.
  
  Image 1. Decision diagram for flow chemistry^[1]

Reactive Types for Continuous Flow Applications

• Low Temperature Reaction (less than -20 degrees)High Temperature Reaction (greater than 150 degrees)Diazomethane ReactionOzonation ReactionPeroxide Participates in Oxidation ReactionsNitrification ReactionPhotochemical ReactionElectrochemical ReactionCatalytic Hydrogenation ReactionPreparation and Application of Organometallic ReagentsReactions such as Azide to Generate High-Energy CompoundsReactions Involving Gases (such as acetylene, ethylene, ammonia, hydrogen, etc.)

Process Development and Optimization

• Based on laboratory synthesis process research, continuous flow synthesis process research was conducted.
  
  Image 2. Zones of a standard two-feed continuous flow setup^[1]
  When studying continuous flow synthesis processes, the experimental plan is usually optimized by adjusting reaction parameters. These parameters include input parameters such as reaction time, reaction temperature, molar ratio; intrinsic parameters such as microreactor volume, stoichiometric ratio, concentration of solution; output parameters such as flow rate, microreactor temperature. In this approach, input parameters are usually chosen and intrinsic parameters are used to calculate the output parameters. The flow rates largely determine the outcomes of continuous flow experiments. Deviations in flow rate can lead to variations in the molar ratio of reaction materials and reaction time, thereby affecting experimental accuracy. This factor should be given high importance in the research of continuous flow synthesis processes.
  Design of Experiments (DoE) and one-factor rotation experiments (OFAT) are highly useful and effective methods for optimizing continuous flow reactions. Select the appropriate optimization method as needed to enhance the process of continuous flow reactions and synthesis routes.
  

• In the future, as a dedicated advocate of green chemistry, Medicilon will actively fulfill its social responsibilities, continue to innovate in green R&D technologies, and support the sustainable development of the biopharmaceutical industry.
  Reference
  [1] M. B. Plutschack, B. Pieber, K.Gilmore, P. H. Seeberger, Chem. Rev.2017,117,11796-11893.

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