FLOW CHEMISTRY
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Is the reaction safe in batch
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Acceptable and consistent yield in |
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batch, scale and time?
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No Is your reaction instantaneous or fast?
Is yield, selectivity and reaction tenure affected by temperature?
Is reaction involving unstable reaction intermediates / impurities or involves back-mixing of product?
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Is your reaction homogeneous or does dispersion have minimal effect on kinetics?
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Is the reaction photosensitive?
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Figure 1 – Selection criteria for flow vs. batch
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Figure 1 – Selection criteria for flow vs. batch fast or highly exothermic reactions without degradation and side reaction impurities. Similarly, flow chemistry is better than batch for photochemical reactions because it offers relatively good illumination of the entire reactor volume because more of the surface area is exposed to light.
With its minimal footprint, limited pollution and lower energy requirements, flow chemistry is a good fit for companies that are seeking to reduce the environmental impact of drug production. Other benefits include better control of mixing and side reactions and the ability to minimise reaction and degradation.
Those features and other advantages led the International Union of Pure and Applied Chemistry( IUPAC) to name flow chemistry as one of ten chemical innovations that will change our world. 1 IUPAC cited Merck & Co.’ s 100 kg-scale synthesis of a precursor and Pfizer’ s creation of a system for analyzing up to 1,500 reaction conditions / day as evidence of the power of flow chemistry. The benefits of the flow over batch reactions have been thoroughly discussed in the literature.
How to choose the right reaction
Companies can lay the foundations for successful scale-up by benchmarking batch and flow techniques in early process development. Evaluating them after completing the first proofof-concept experiments for determining a feasible synthetic route allows companies to assess how a process will perform in batch and flow reactions at each step in development, from discovery through commercial production( Figure 1).
Asking questions such as‘ Is selectivity affected by temperature?’ and‘ Is the reaction photosensitive?’ can help determine the best approach for a particular process. The answer is obvious in some cases, for example when a reaction is unsafe in batch, but the best approach can be less clear-cut for other synthesis projects. When facing uncertainty, the input of a partner with batch and flow experience and expertise at different scales is beneficial.
Early and detailed thinking about the pros and cons of batch and flow approaches supports efficient R & D but requires broad, integrated chemistry capabilities and expertise that few companies have. Ideally, the know-how, equipment and infrastructure required to make a drug at different scales will be seamlessly linked. Companies need smooth
Figure 2 – Example of flow chemistry scale-up
Note: Work to support preparation at up to kilo scale of building block( flow at c. 100-150g / hr). Materials manufacture at 0.5-1 kg scale
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