PHARMECUTICALS
Cl |
Cl |
|
|
|
|
N |
Ph Ph
Ph
|
n-BuLi / TMEDA |
Cl |
|
|
THF , – 78 ° C |
Li |
Cl |
|
N |
Ph Ph
Ph
|
CO 2
|
HO
Cl
O
|
Cl |
N |
Ph Ph
Ph
|
4N HCl dioxane
HO
Cl
O
Cl
helps in delivering safe operations but also ensures product quality when the parameters are out of normal operating range .
QbD
Continuous flow chemistry is also more in keeping with regulatory agency demands for precise , fully documented manufacturing processes . For example , the FDA and the European Medicines Agency ( EMA ) encourage drug companies to use quality by design ( QbD ) principles in which manufacturing processes are planned in a way to ensure that products are of the highest possible quality .
Again , batch operations can follow QbD principles . Critical parameters like temperature and pressure can be monitored and controlled in such systems . However , it is not normally easy to modify these parameters while the reaction is running , because doing so would potentially invalidate the batch .
In contrast , parameters in a flow system can be modified while the process is running , with minimal impact . Any product impacted by out-of-specification parameters can be easily separated from the stream while the reaction continues . Furthermore , because continuous flow systems employ automated control processes and in-line monitoring technologies , any deviations likely to impact API quality can be rapidly detected and corrected .
1
NH
. HCl
Figure 2 – Preparation of key intermediate
API innovation
API production is a physical process as well as a chemical one . To make an intermediate or an API , raw materials and reagents must be mixed in the correct quantities , in the correct conditions , for the right length of time . Controlling this process depends entirely on the vessel in which the reaction is conducted .
In batch production , reactants are mixed in a reactor – effectively a sealed tank - and only discharged when the reaction has run its course . Such reactors involve a one-time capital investment , are simple to run and are straightforward to operate . They can be used for multiple reactions as long as they are cleaned after each use .
In contrast , continuous flow reactors can be thought of as long tubes or plates into which reactants are fed and products discharged continuously . Such reactors are custom-made or commercially available , and in most cases are dedicated to a particular intermediate or API .
Continuous flow reactors have a number of advantages for API production , the foremost being the greater range of chemistries that are possible . Reactions that require micromixing , or which use hazardous reagents , microwave energy , photochemistry , electrochemistry or sonochemistry are only possible in reaction chambers in which conditions can be precisely controlled .
For example , because of the small internal volumes and high surface- to-volume ratios in flow reactors , it is possible to conduct chemical reactions at higher temperatures and pressures more easily than can be achieved in batch reactions . Similarly , flow reactors allow for chemistries that require rapid mixing which is simply not possible in batch reactors .
Case study
Curia developed a two-step carboxylation reaction of an aryl group . The process , which involves an anion formation , followed by a quench with gaseous CO 2
, was optimised on a small scale using tubes and static mixers . The set-up was then used to process 21 kg of material in a regular lab with 88 % yield .
The incorporation of a carboxyl acid to an aryl group by the addition of CO 2 to a Grignard or lithium anion is a wellknown transformation that is widely used in chemical and pharmaceutical industries . While several major safety concerns have been reported at large scale for the formation of Grignard reagents or other organometallic species , it is still common practice to form these species in batch mode with subsequent quench with CO 2
.
Most of these reactions are carried out at cryogenic temperatures , while temperature extrusions during CO 2 quench due to inefficient mixing often leads to several by-products . Recently , there have been several reports on the generation of organometallic reagents and their subsequent additions to electrophiles under continuous flow conditions . These conditions offer a safe and efficient alternative to the current batch mode .
Compound 1 ( Figure 2 ) is an intermediate used in the preparation of an API . Several kilogram quantities of this intermediate were required to support the production of the API
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