Continuous Flow Chemical Technology

 The continuous flow chemistry technology service platform is one of the important technologies used by Medicilon to support green chemistry. Based on the specific reactions of the innovative drug synthesis process, we can conduct feasibility assessment of continuous reactions, process development and optimization, and continuous improvement of the process to improve the research and development efficiency of the synthesis process and reduce the development cost of innovative drugs.

• Continuous flow chemistry refers to chemical reactions taking place in a continuously flowing fluid.  Raw materials and reagents are formulated into solutions and pumped into the reaction channels from different containers, where chemical transformations subsequently occur.  Commonly used reactors in continuous flow chemistry are microreactors and medium-sized reactors. Microreactors usually refer to reactors with a three-dimensional structure, whose internal dimensions are less than 1 mm and range from 10 to 100 microns.
  In the context of "double-carbon", "green chemistry" is penetrating into the biopharmaceutical industry.  Only by continuously innovating R&D technology can we open a new door 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 these researches into applicable technologies to promote the green upgrading of pharmaceutical R&D.
  The continuous flow chemistry technology service platform is one of the important technologies used by Medicilon to support green chemistry.  Based on the specific reactions of the innovative drug synthesis process, we can conduct feasibility assessment of continuous reactions, process development and optimization, and continuous improvement of the process to improve the research and development efficiency of the synthesis process and reduce the development cost of innovative drugs.

Advantages of Continuous Flow Chemistry Technology

• 1) Safe and Stable:1) Safe and Stable:2) Energy Saving and Cost Reduction:Equivalent-sensitive reactions enable good control of substrate dosage; continuous flow equipment has relatively high mass transfer and heat transfer efficiencies, which can reduce solvent usage and achieve energy conservation and consumption reduction by reducing utility engineering specifications or reducing utility usage; continuous flow equipment is generally in a continuous closed form, which reduces various unorganized emissions.3) Efficiently Increase Production:Have obvious enhancement effect on non-homogeneous phase; easily control endothermic and exothermic reactions, the reaction process is close to constant temperature, and the temperature of different multi-stage reactions can be quickly adjusted to the temperature required by the process; parallel amplification of continuous flow reactors can increase production, in addition, extending the operating time of microreactors can also increase product production.

Feasibility Assessment of Continuous Reactions

• Through literature research and analysis of preliminary experimental results, we have a comprehensive and in-depth understanding of the studied chemical reactions and their reaction mechanisms, and combined with the characteristics of continuous flow equipment to design the continuous flow synthesis process.
  Through literature research and analysis of preliminary experimental results, we have a comprehensive and in-depth understanding of the studied chemical reactions and their reaction mechanisms, and combined with the characteristics of continuous flow equipment to design the continuous flow synthesis process.
  Verify the feasibility-reaction effect and process optimization trend through continuous flow experiments.
  Based on the feasibility analysis results, explore the process optimization content, synthesis route optimization and reaction condition optimization.
  
  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

• On the basis of laboratory synthesis process research, continuous flow synthesis process research was carried out.
  
  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 can be divided into input parameters: reaction time, reaction temperature, molar ratio; intrinsic parameters: microreactor volume, stoichiometric ratio, concentration of solution; output parameters: flow rate, microreactor temperature.  In this approach, input parameters are usually selected and intrinsic parameters are used to calculate the output parameters.  The flow rates largely determine the results of continuous flow experiments. The deviation of the flow rate leads to the deviation of the molar ratio of the reaction materials and the reaction time, which leads to the error of the experimental results. It should be highly valued in the research of the continuous flow synthesis process.
  Design of Experiments (DoE) and one-factor rotation experiment (OFAT) are very useful and effective methods in continuous flow reaction optimization.  As needed, select appropriate optimization methods to optimize the process of continuous flow reactions and synthesis routes.
  

• In the future, Medicilon, as a staunch advocate of green chemistry, will actively fulfill its social responsibilities, continue to innovate green R&D technologies, and assist 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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