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Flow Chemistry

Continuous manufacturing and the development of flow processes are specialties on which NJ Bio has focused a lot of its energy and resources. We have experts in the field of flow chemistry that have developed continuous flow processes to important compounds such as Imatinib.1 To add value to our clients’ programs, we have partnered with Amar Equipments Pvt. Ltd. and founded Amar Chemistry Pvt. Ltd., because we believe that customizing flow reactors to the chemistry is better than fitting the chemistry to the flow reactors. By not limiting our chemical development to the available flow system, we can develop the most efficient and scalable process. As an example, we are currently applying this flexible approach to a flow process for the preparation of a broad-spectrum antibiotic, with the goal of ultimately manufacturing multi-ton quantities.

Please contact us to discuss the advantages and applicability of flow chemistry to your processes!

Workflow for Continuous Flow Process Development at NJ Bio

NJ Bio’s Approach to Flow Chemistry

The first step is familiarization and initial investigation to transfer our client’s chemistry to flow by using a basic set-up consisting of syringe pumps, different flow paths, and tubings. This simple approach allows for a quick optimization of parameters before starting the process with instruments. Different flow paths, configurations, and temperatures can be quickly swapped out, guiding the design of the instrument’s components. The second part is adaptation of the work-up conditions to help telescope as many steps as possible to flow chemistry, which adds efficiency to the entire process. Finally, the entire instrument set-up is designed considering all the best conditions such as residence time, mixing type, concentration, and temperature. We can use Design of Experiments (DOE) to help ensure the flow set-up controls for the most important parameters are optimized, which will lead to an easier transition to a continuous manufacturing process. The advantages of flow chemistry are numerous, such as better heat transfer, mixing and temperature control, which all result in better and more robust chemical processes. For example, reactions can be run at high pressure to allow heating of a solvent above its boiling point safely. Residence time can be optimized for photochemical and electrochemical reactions for the best conversions while minimizing impurities. Flow chemistry is an important tool that adds value to the development and production of many pharmaceutically active ingredients.

Type of Reactions

Many reactions and processes are safer and more economical in flow, because of better conversions and lower impurity profiles.2,3 Below is a list of reactions that are routinely performed in flow and many more can be adapted.
  • Alkylation reaction
  • Amide formations
  • Buchwald-Hartwig couplings
  • Diazotization
  • Fluorinations
  • Grignard reactions
  • Lithiation/borylation reactions
  • Negishi couplings
  • Nitration
  • Nucleophilic substitutions
  • Oxidations
  • Suzuki-Miyaura couplings
  • Trifluoromethylation reactions

From Process to Production

Once all the conditions and processes are developed at NJ Bio, we can transfer the design and conditions to our clients, if desired. Alternatively, the developed process can be transferred to our affiliate Amar Chemistry Pvt. Ltd. for further scale-up and development. Amar Chemistry’s chemists have ample experience in the scale-up of flow processes. Generally, small-scale flow reactions can be adjusted more quickly to larger scales than batch processes. The reason for this easier scale-up is that the reaction parameters do not change when parallel reactors are added. With the help of our flow chemistry partners Amar Equipments and Amar Chemistry, we can support our clients’ continuous flow programs from start to finish. Even validated batch processes can be adapted to flow chemistry resulting in a more cost-effective process. This is the case for an antibiotic that we are currently adapting from batch to flow with the goal of supplying the material domestically in the USA for the same price as overseas. Flow chemistry has certainly evolved and is now able to accommodate a wide range of chemistry and processes.

Please consider using flow chemistry in your development plan!

Reactors

Due to its affiliation with Amar Chemistry and collaboration with Amar Equipments, NJ Bio has a variety of reactor types and continuous flow set-ups available. Below are representative examples of the many reactors and configurations that are available at NJ Bio and its partners. Custom set-up can be easily accommodated by placing all the proper reactors and mixers in the required configuration.

We are here to help our clients throughout the design process. Please contact us for a detailed discussion!

Flow Reactors

Amar Photochemical Reactor

Amar Automated Flow Reactor

IKA ElectraSyn Flow Reactor

ThalesNano Phoenix Flow ReactorTM

Microchannel Based Flow Reactors

Amar-1 Micromixer Used in Amar 1J Flow Reactor

Amar-1J Flow Reactor

Amar-2 Flow Reactor with Inbuilt Micromixer

Amar-2 Advance Micromixer Flow Reactor

3-D Flow Reactors

Amar-3 1 mL Micromixer Flow Reactor

Amar 3 Micromixer Flow Reactor 30 mL

Amar-3 Kilo Scale Set Up

Pinch Tube Flow Reactors

100 mL Amar-4P Pinched Tube Reactor

12 L Kilo Scale Amar-4P Pinched Tube Reactor

150 L Production Scale Amar-4P Pinched Tube Reactor

Other Types of Reactors and Equipment

Amar Slurry Flow Reactor for Solid Handling

Liquid-Liquid Separator

Amar Packed-bed Multipurpose Flow Reactor for Heterogeneous Catalyst Handling

Literature References

  1. C. Yang, D. Niu, B.P. Karsten, F. Lima and S.L. Buchwald Use of a “Catalytic” Cosolvent, N,N-Dimethyl Octanamide, Allows the Flow Synthesis of Imatinib With No Solvent Switch. Angew. Chem. Int. Ed. 2016, 55, 2531-2535. https://doi.org/10.1002/anie.201509922.
  2. Hughes, D. L. Applications of Flow Chemistry in the Pharmaceutical Industry—Highlights of the Recent Patent Literature. Organic Process Research & Development 2020, acs.oprd.0c00156. https://doi.org/10.1021/acs.oprd.0c00156.
  3. Hughes, D. L. Applications of Flow Chemistry in Drug Development: Highlights of Recent Patent Literature. Organic Process Research & Development 2018, 22 (1), 13–20. https://doi.org/10.1021/acs.oprd.7b00363.