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.

A Fast Track to Optimized Processes?Multi-Purpose Microreactors

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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

processing, the most common problems being that the

reagents are too dangerous in bulk or the reaction requires

specific conditions, such as low temperature that are hard to

achieve in large reactors. Another problem is that, in many

cases, development chemists find that a reaction that is

effective at the small-scale lab level simply does translate

to work on a large scale. Unlike batch reactors, where

fixed quantities of reagents are mixed together for a pre-

determined length of time before the reaction is worked up,

microreactors offer continuous processing, so the production

of larger quantities is simple – the microreactor runs for a

longer period of time. This is an important distinction for

process development, as it means that the same reaction

parameters and equipment can be easily and appropriately

scaled up from lab-scale to and large-scale production.

Traditional batch chemistry, on the other hand, usually

requires additional process development as larger batch

sizes and vessels are used.

In a microreactor, as the equipment is the same throughout,

the same person can be responsible for the whole process

optimization, from the first trial runs to the final production.

The first step of this process is to identify the best solvent.

This is one of the most critical parameters for a continuous

process, as it is essential that all the components remain in

solution throughout their time within the reactor. The ideal

concentration and flow rate combination also need to be

established to maximise the yield and speed of the process.

The flow rate at which the reactants are pumped through

the channel is an important factor as it determines how long

the chemicals remain within the microreactor chambers.

Too fast and the reaction will not go to completion, but if it’s

too slow productivity is poor. Once these steps have been

carried out, multi-kilogramme quantities can be manufactured.

Ingredients are pumped into a narrow tube or channel,

which is typically around 200µm in diameter. It is here that

the reaction takes place, and only very small quantities of

reagents are ever in the reactor at the same time.

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Heat Transfer

Heat transfer is one of the biggest issues when scaling up an

exothermic reaction to a large batch reactor. In a standard

100ml flask in the lab, for example, the surface-to-volume

ratio is good, which makes it relatively straightforward to

control the temperature of an exothermic reaction by

dissipating it through the sides of the flask. However, when

this is scaled up to a 1000 litre reactor, the surface-to-volume

ratio drops to just 6% of that of the flask. This makes it much

more difficult to remove the heat generated in the reaction. In

contrast, if the reaction takes place in a typical microreactor

with 200µm channels, the surface-to-volume ratio is 200 times

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.

When a reagent for an exothermic reaction is dropped into a

batch reactor, it forms a hot spot where it lands and heat is

created by the reaction. This needs to be dissipated, and is

usually done so by stirring. However, the localized increase

in temperature – even if it’s only a couple of degrees – can

lead to unwanted side-products being formed because of the

elevated temperature. In contrast, because volumes are so

small in a microreactor, it is significantly easier to maintain

a narrow temperature window so that the side-products that

may be formed at a higher temperature are less likely to pose

problems.

RegulationUnit

Reagent 1

Reagent 2

Pressure control

Temperature control

Product

Micro Reactor

Residence Time Unit

0.2-2mL to 200mL

Figure 1: Microreation Technology

Figure 2: Heat Transfer - Optimal Mixing

Reactor size 1000lt Reactor 250lt Reactor 0.1lt FlaskMRT Channel size 200um

Surface/Volume 0.06 0.08 1 200

Vessel Microreactor

Concentration profiles:

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Optimized Use of Space

One final and significant advantage of continuous processing

using microreactors is that the reactors themselves take up

far less floor space than traditional batch vessels, meaning

that more of them could be used if required in a smaller

overall footprint, thus increasing productivity and output.

Although a sizeable vessel will still be required for product

collection, and further work-up and purification procedures

are often required, the space and equipment requirements

for the reactors themselves are lower. A typical microreactor

used in production is about half a metre high and wide, and

approximately 30cm (10”) deep. With a medium flow rate

and rapid reaction time, at SAFC this has resulted in actual

microreactor production rates of 15 tonnes per annum. Much

higher rates are also possible and, because the volumes of

reagents within the reactor at any one time are so small, the

need for explosion proof cabinets is minimized.

Perhaps the single most important advantage of

microreactors is their flexibility. Known microreactor

productivity allows one to calculate the time required to

manufacture the required amount of product, rather than

determine the most efficient batch reactor and determine

the number of batch runs necessary for the same amount of

product.

In conclusion, microreactors are now becoming more

important in the production of fine chemicals because of

their flexibility, their potential for cost savings, and the ability

to do reactions that could not be carried out in a batch

reactor due to inherent hazards. This opens up a whole new

world of chemistry to manufacturers, and will also speed up

routine development time for APIs as more applications seen

in medicinal chemistry will now be able to remain in large

scale synthesis. However, this will require that manufacturers

re-examine the best way to have large scale fine chemicals

manufactured. Chemists are trained to think in terms of batch

processing, but as they get used to the possibilities of using

continuous processing in a flow reactor, microreactors are

set to become a common tool in the manufacture of fine

chemicals.

Working with Hazardous Reagents

As microreactors operate on a small scale, many reactions

that process development chemists would normally classify

as too dangerous or difficult to work with in a batch reactor,

for example those which are highly exothermic, can be

run safely. Microreactors also make it possible to use

reagents that, while commonplace in the lab, are much too

dangerous on a large scale. Diketene, for example, is one

such substance which, although a very useful and versatile

building block, is highly reactive and as such could only

be used in batch reactors with difficulty and limitations. By

carrying out reactions in a microreactor, the volume of the

hazardous reagent in the active reaction zone is kept to a

minimum.

Precise Temperature Controls

Precise temperature control permits much better process

control enhancing overall safety. It also becomes more

practical to use reactions that involve unstable intermediates.

N-Butyl lithium is a common reagent used in the lab which

must be used at very low temperatures, and, when used in

a batch reactor, requires cryogenic techniques with cooling

jackets used to keep the temperature at very low levels

(usually –70°C), significantly increasing installation costs.

This increased cost can be nullified by using a sequence

of microreactors instead. As an example, in the two step

substitution reaction shown in Figure 3 below, n-BuLi in

heptane was first used to monolithiate 1,4-dibromobenzene,

with the reaction completed in less than 90 seconds in the

first microreactor, where the temperature is kept at 0°C.

Due to the short contact time, this elevated temperature did

not cause decomposition and also saved costs since there

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.

BrBr Br Li Br

F3C

F3C–CO2EtBuLi O

Product 18550

Figure 3: Example of a Two -Step Substitute Reaction

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