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Multi-Purpose Microreactors
A Fast Track to Optimized Processes?
Standard batch reactors have long been the workhorse for chemical ingredient and intermediate manufacturing and,
although their use is well understood, they do have a number of performance drawbacks and limitations such as poor
mixing, limited heat transfer capabilities, and lengthy scale-up phases. These limitations have led to the evaluation of
alternative production methods with microreactors, in many instances, offering a more effective solution for chemical
manufacture and great potential as a ‘fast track’ to optimized processes.

Extensive research work using microreactors has been undertaken by SAFC®. This work resulted in both the successful
execution of a number of reactions not possible in traditional batch processors and, depending on the process and batch size,
more cost-effective reactions for processes that already run well in batch reactors.

Microreactors are not new. In fact, they have been around in various forms since the end of the 19th Century. However, it is
only very recently that their full range of uses are being fully explored and employed in the production of fine chemicals on a
bulk scale. Microreactors are generally made from stainless steel or glass, and each material offers different benefits. Glass,
for example, is more chemically resistant and therefore ideal for multipurpose work, while stainless steel has better heat
conductivity, so is preferable for very exothermic reactions. Stainless steel is also more robust than glass, so in many cases it
will be the ideal choice for a production environment if the reaction is compatible.

The Nature of Microreactors

Many lab reactions are not suitable for large scale In a microreactor, as the equipment is the same throughout,
processing, the most common problems being that the the same person can be responsible for the whole process
reagents are too dangerous in bulk or the reaction requires optimization, from the first trial runs to the final production.
specific conditions, such as low temperature that are hard to The first step of this process is to identify the best solvent.
achieve in large reactors. Another problem is that, in many This is one of the most critical parameters for a continuous
cases, development chemists find that a reaction that is process, as it is essential that all the components remain in
effective at the small-scale lab level simply does translate solution throughout their time within the reactor. The ideal
to work on a large scale. Unlike batch reactors, where concentration and flow rate combination also need to be
fixed quantities of reagents are mixed together for a pre- established to maximise the yield and speed of the process.
determined length of time before the reaction is worked up, The flow rate at which the reactants are pumped through
microreactors offer continuous processing, so the production the channel is an important factor as it determines how long
of larger quantities is simple – the microreactor runs for a the chemicals remain within the microreactor chambers.
longer period of time. This is an important distinction for Too fast and the reaction will not go to completion, but if it’s
process development, as it means that the same reaction too slow productivity is poor. Once these steps have been
parameters and equipment can be easily and appropriately carried out, multi-kilogramme quantities can be manufactured.
scaled up from lab-scale to and large-scale production. Ingredients are pumped into a narrow tube or channel,
Traditional batch chemistry, on the other hand, usually which is typically around 200µm in diameter. It is here that
requires additional process development as larger batch the reaction takes place, and only very small quantities of
sizes and vessels are used. reagents are ever in the reactor at the same time.

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Figure 1: Microreation Technology

Regulation
Unit
Pressure Temperature
control control

Micro Residence
Reagent 1 Reactor Time
Unit Product

Reagent 2
0.2-2mL to 200mL

Heat Transfer

Heat transfer is one of the biggest issues when scaling up an When a reagent for an exothermic reaction is dropped into a
exothermic reaction to a large batch reactor. In a standard batch reactor, it forms a hot spot where it lands and heat is
100ml flask in the lab, for example, the surface-to-volume created by the reaction. This needs to be dissipated, and is
ratio is good, which makes it relatively straightforward to usually done so by stirring. However, the localized increase
control the temperature of an exothermic reaction by in temperature – even if it’s only a couple of degrees – can
dissipating it through the sides of the flask. However, when lead to unwanted side-products being formed because of the
this is scaled up to a 1000 litre reactor, the surface-to-volume elevated temperature. In contrast, because volumes are so
ratio drops to just 6% of that of the flask. This makes it much small in a microreactor, it is significantly easier to maintain
more difficult to remove the heat generated in the reaction. In a narrow temperature window so that the side-products that
contrast, if the reaction takes place in a typical microreactor may be formed at a higher temperature are less likely to pose
with 200µm channels, the surface-to-volume ratio is 200 times problems.
greater than for the 100ml flask, so heat transfer is unlikely to
be an issue. This increased temperature control also means
that ‘hot spots’ are less likely.

Figure 2: Heat Transfer - Optimal Mixing

Vessel Microreactor

Concentration profiles:

MRT Channel
Reactor size 1000lt Reactor 250lt Reactor 0.1lt Flask
size 200um
Surface/Volume 0.06 0.08 1 200

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Working with Hazardous Reagents Optimized Use of Space

As microreactors operate on a small scale, many reactions One final and significant advantage of continuous processing
that process development chemists would normally classify using microreactors is that the reactors themselves take up
as too dangerous or difficult to work with in a batch reactor, far less floor space than traditional batch vessels, meaning
for example those which are highly exothermic, can be that more of them could be used if required in a smaller
run safely. Microreactors also make it possible to use overall footprint, thus increasing productivity and output.
reagents that, while commonplace in the lab, are much too Although a sizeable vessel will still be required for product
dangerous on a large scale. Diketene, for example, is one collection, and further work-up and purification procedures
such substance which, although a very useful and versatile are often required, the space and equipment requirements
building block, is highly reactive and as such could only for the reactors themselves are lower. A typical microreactor
be used in batch reactors with difficulty and limitations. By used in production is about half a metre high and wide, and
carrying out reactions in a microreactor, the volume of the approximately 30cm (10”) deep. With a medium flow rate
hazardous reagent in the active reaction zone is kept to a and rapid reaction time, at SAFC this has resulted in actual
minimum. microreactor production rates of 15 tonnes per annum. Much
higher rates are also possible and, because the volumes of
Precise Temperature Controls
reagents within the reactor at any one time are so small, the
Precise temperature control permits much better process need for explosion proof cabinets is minimized.
control enhancing overall safety. It also becomes more
Perhaps the single most important advantage of
practical to use reactions that involve unstable intermediates.
microreactors is their flexibility. Known microreactor
N-Butyl lithium is a common reagent used in the lab which
productivity allows one to calculate the time required to
must be used at very low temperatures, and, when used in
manufacture the required amount of product, rather than
a batch reactor, requires cryogenic techniques with cooling
determine the most efficient batch reactor and determine
jackets used to keep the temperature at very low levels
the number of batch runs necessary for the same amount of
(usually –70°C), significantly increasing installation costs.
product.
This increased cost can be nullified by using a sequence
of microreactors instead. As an example, in the two step In conclusion, microreactors are now becoming more
substitution reaction shown in Figure 3 below, n-BuLi in important in the production of fine chemicals because of
heptane was first used to monolithiate 1,4-dibromobenzene, their flexibility, their potential for cost savings, and the ability
with the reaction completed in less than 90 seconds in the to do reactions that could not be carried out in a batch
first microreactor, where the temperature is kept at 0°C. reactor due to inherent hazards. This opens up a whole new
world of chemistry to manufacturers, and will also speed up
Figure 3: Example of a Two -Step Substitute Reaction routine development time for APIs as more applications seen
in medicinal chemistry will now be able to remain in large
BuLi F3C–CO2Et O scale synthesis. However, this will require that manufacturers
Br Br Li Br Br
re-examine the best way to have large scale fine chemicals
F3C
manufactured. Chemists are trained to think in terms of batch
Product 18550 processing, but as they get used to the possibilities of using
continuous processing in a flow reactor, microreactors are
Due to the short contact time, this elevated temperature did set to become a common tool in the manufacture of fine
not cause decomposition and also saved costs since there chemicals.
was no need for cryogenic equipment. The reaction mixture
was then transferred into a second microreactor, along with
a coupling reagent, ethyl trifluoroacetate. Again, this reaction
was carried out at 0°C, taking 60 seconds to complete.
Finally, this mixture was transferred into a ‘residence time
unit’ at room temperature to bring the reaction to completion.
Not only does this setup remove the need for expensive
cryogenic equipment, it offers several other advantages over
batch production in that it gives consistent product quality
through a reduction in batch to batch variation and limited
single-batch productivity. In addition, there were fewer side
products resulting from competing reactions such as double
lithiation and Wurtz coupling, which commonly take place at
hot spots at the drop-in site within the batch reactor.

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