Flow chemistry or milli- and micro reaction technology (MRT) is a platform that can offer enormous advantages in this respect. But MRT has not yet achieved the status in fine chemicals and active ingredient manufacturing that one might expect. What are the reasons for this reluctance?

CHEManager asked executives and industry experts dealing with flow che­m­istry so share their opinion on why some industry sectors are so reluctant in adopting continuous production processes. We wanted to know:

Which factors are affecting the global flow chemistry market and the implementation of flow chemistry in the industry?

André de Vries: Lately, also the fine chemical industry and the small molecule pharma arena has adopted so-called flow chemistry as one of their focus points to improve manufacturing processes. While the continuous manufacturing of bulk chemicals is state of the art, it faces some challenges in fine and pharmaceutical chemicals, which prevent its introduction on a broad basis.
 

This is due to the fact that fine, pharma, and agro chemicals are manufactured in multi-purpose plants; are complex molecules with many functionalities (many steps / unit operations); are relatively small volume compounds; and that they often have a limited life cycle.

In fact, when the first scalable process is required, in many cases there is no revenue or guaranteed market approval.

Moreover, speed to market is key for the development stages of the pharma/agro product, hence a limited process development time is critical, as well as the flow chemistry equipment being readily available. For the latter, we at Innosyn have adopted selective laser melting (SLM), or 3D metal printing, as enabling manufacturing technology to create the “best fit for purpose” flow reactors and mixers. 3D metal printing is capable of printing full dense objects in any metal that can be welded, and it provides almost an unlimited freedom of design.

Typical useful chemical reactions to perform preferably in a continuous mode can be divided into two main categories. First, for very fast, highly exothermic reactions, such as nitrations, DiBAl-H reductions, and metalorganic reactions, we have designed, “printed”, and applied flow reactors with a relative narrow zigzag channel having superb heat transfer coefficients (U up to 10.000 W/m²K). As additional feature, 3D metal printing enables to incorporate thermo couple inlets at any point of interest, and, if appropriate, also multiple injection ports of the highly reactive reagent.

Second, when applying hazardous reagents in relative slow chemistry, e.g. an S_N2 substitution with sodium azide at sterically hindered alkylbromides, we have produced rather large flow reactors (up to 500 mL) with about 1 cm wide channels containing over the full length SMXL elements to secure narrow residence time distribution.

In practice one can now design, “print”, and apply within 1 month a new tailored piece of equipment for any type of challenging chemistry, and if required get into an iterative mode to optimize the flow chemistry hardware.

The goal for the chemical process development community is to get the best process in place (for that moment). This could involve flow chemistry, especially for those highly reactive and exothermic reaction steps, and the reaction steps using hazardous reagents, but implanting flow chemistry as such is not the goal. This is one more reason why the implementation level of flow chemistry in the fine/pharma/agro arena is rather low.

Another important argument for flow chemistry is its robustness. A plant manager would be interested to use flow chemistry, provided the development team can overlay a robust process, with continuously the same quality output.