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Why the Classic Pharma Chemist Should Consider Flow Chemistry

Edition 2 / June 2021
Small Molecules Platform > What is Flow Chemistry? A Personal Point of View

Edition 2 / June 2021

Clemens Horn, Senior Flow Chemistry Expert, CordenPharma Chenôve, headshot

Clemens Horn,

Flow Chemistry Expert
CordenPharma Chenôve

Cordenpharma white on green small molecule drug icons

What is Flow Chemistry? A Personal Point of View

Close-up of flow chemistry equipment at Continuous Manufacturing lab at CordenPharma Chenôve, France

Chemistry flows through the HEART (Heat Exchange & Advanced Reaction Technology) in the Continuous Manufacturing lab at CordenPharma Chenôve (FR).

Over the last 20 years, a new term has entered the chemical lab: Flow Chemistry.

But what really is Flow Chemistry?

First of all, is flow chemistry really new? The answer is pretty simple: No. At the most fundamental level, flow chemistry means performing a chemical reaction continuously. This has already been done for more than 100 years, for example, in Petrochemistry. Chemical engineers know three different types of reactors: a stirred tank reactor, a continuous stirred tank reactor, and a plug flow reactor. The last two are reactors for performing a reaction continuously.

What is new about Flow Chemistry?

Chemical engineers use continuous reactors to overcome challenges linked to known reactions (e.g. mechanism, energy balance). In this way, they design a reactor best suited for a specific reaction. Chemists similarly use flow chemistry to overcome synthetic challenges on a research scale, since flow chemistry can provide better control over reactions / parameters compared to standard batches. Some examples include the addition of a reagent that can be timed to the second, a reaction performed at a precise temperature, or mixing that is quasi-spontaneous – and all this is highly reproducible.

Why is Flow Chemistry not used more often?

There are several reasons. First of all education. Chemists are used to working with flasks in a batch-wise approach, not with tubes. The wording does not help either, as a look into literature will associate flow chemistry with micro reactors, micro channels. These are words that no one would associate by default with gs, kgs, tons or production. The mentality of chemists plays as well a role. When it comes to equipment, most chemists are ultra-conservative. This is pretty contradictory, since the job of a chemist is to solve problems by being inventive.

As Mark Gilligan phrased it[1], “The only thing that’s been proven to be generally useful for generations of chemists is a round-bottomed flask.” There is budget as well. A commercial flow reactor setup can cost up to 100K euro and more, which is a lot of money, especially if one is not fully convinced of its effectiveness. In short, flow chemistry for the classic chemist is an unknown, expensive solution, if one is not equipped.

How to convince chemists to do reactions in flow?

Flow chemistry is not the “answer of the ultimate question of life, the universe and everything.”[2] Forget about all those fancy high-performance flow reactors. They are good, but in most cases, a tube will do the same.
The most effective way to convince chemists of the usefulness of the tool “flow chemistry” is for them to try it themselves. It worked for me and the students in my lab. Choose a reaction that can benefit from temperature control, time (instable intermediate) or mixing. The result will be surprising. When one student, who was very skeptical concerning flow chemistry, tried a nitration in flow without any flow chemistry experience, she got much better yields than with batch. She never questioned the usefulness of flow chemistry again. “You can assemble some cool flow reactors with cheap polymer or stainless steel capillaries and reusable microfluidic fittings.”[3] And this is exactly what she did. Every undergraduate student can do this.

Two lab technicians in continuous manufacturing flow chemistry lab at CordenPharma Chenôve, France

CordenPharma’s Continuous Manufacturing Flow Chemistry lab in CordenPharma Chenôve (FR).

There are only two things which are important: time and pumps. Flow chemistry knows two kind of times: residence time and run time. Residence time refers to the time of the reaction in the flow reactor, which is a function of the reactor volume and the flow rates. Run time is how long the pumps are working, or in other words, it defines the quantity that is produced – the size of your “batch.”

Pumps are as important for flow as a balance and a stirrer are for the batch. These could be syringe pumps already on hand in the lab – they will do just fine. They can only run on a limited time, which means the “batch size” is defined by the syringe volume, not by when you have enough material produced. If there are not enough syringe pumps, one can be built for less than 50 Euros. It might sound complicated, but I promise it is not harder than assembling a classical glass aperture. The difference is instead of connecting conically tapered joints together, tubes are connected. Even this low-cost setup will show that flow chemistry is a nice solution for reactions that cause trouble in batch. This is the reason why doing flow chemistry allows one to perform a trouble-free reaction.

And if you want to go to a larger scale or production, you do not need to invest in professional material. CordenPharma can do the production for you!

Flow Chemistry at CordenPharma Chenôve

CordenPharma has installed a laboratory and pilot workshop for flow chemistry at the CordenPharma Chenôve site in France. The installation is based on a modular concept that allows for custom flow setups which address the individual needs of each reaction in the laboratory and the pilot workshop. We choose the modules for the flow setup from a pool of dosing lines (pump + flow controller), flow reactors and in/online sensors and analytic (IR, Raman, NMR, UV). The results of the laboratory can be, often with only minor adjustments, transferred to a GMP pilot workshop (20 kg/d) flow installation.

We look forward to speaking with you to demonstrate how Flow Chemistry can impact your chemistry project.

[1] M. Gilligan Chem World 9, 2019
[2] M.B. Plutschak et all Chem . Rev. 2017, 117, 11796-11893
[3] T Noel Chem World 9, 2019

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