New ways to make pharmaceuticals

Flow chemistry for chemical synthesis

Organic synthesis has historically been conducted in batches, typically utilising round-bottomed flasks, test tubes, or closed vessels. However, there has been a notable shift towards continuous flow methodologies in recent years, garnering significant attention from synthetic organic chemists. Flow chemistry is a reaction process that occurs in a continuously flowing stream. The reactants are continuously pumped through a narrow flow reactor, where they mix and react under controlled conditions. Thanks to the efficient mixing within the flow reactor, reactions can be controlled to ensuring consistent conditions, and depending on the set-up, the products can be continuously removed (Plutschack et al., 2017).  

During the last decade, there has been a notable expansion in the application of flow chemistry for the synthesis of fine chemicals, including natural products and Active Pharmaceutical Ingredients (APIs), particularly within academic research. Here are some advantages of flow chemistry (Plutschack et al., 2017; Porta et al, 2016).

Efficiency

Monitoring of reaction parameters like temperature, pressure, and flow rate are typically more straightforward in continuous processes compared to batch processes. The enhanced ease of setup and process monitoring contributes to a greater level of reliability and reproducibility in a continuous production process (Newman and Jensen, 2013; Plouffe et al., 2014). The greatest advantage of a flow system lies in its remarkably efficient heat and mass transfer capabilities, which accelerates reaction rates significantly, resulting in substantially enhanced productivity compared to batch systems. This increased efficiency can lead to higher productivity and reduced waste as well as lower production costs. 

Scalability

In principle, scaling up reactions in flow reactors is more straightforward compared to batch processes. There are three primary approaches to producing larger quantities of a desired compound in flow (Anderson, 2012):  

Scaling-out: The simplest approach involves extending the duration of the process. This means running the reaction for a longer period to produce a greater quantity of the desired compound. 

Numbering-up: Another method involves using multiple microreactors in parallel. By replicating the reaction setup across several reactors simultaneously, production capacity can be increased. 

Scaling-up: Alternatively, the process can be transferred to larger continuous reactors. This involves adapting the reaction conditions and parameters to suit the scale of the larger equipment, facilitating higher production volumes. 

Each approach offers its own advantages and considerations, allowing for flexibility in scaling up production to meet varying demand.

Safety 

Flow chemistry significantly improves safety by enabling the use of hazardous chemicals in a controlled and contained environment. The continuous flow setup minimises the volume of reactive intermediates required at any given time, reducing the risk of accidents associated with the handling of dangerous substances.    

Integration of processes  

Multiple reactions or steps can be integrated into a single continuous flow system, reducing the need for intermediate purification steps, and streamlining the overall process (known as telescoping). For example, the synthesis of tamoxifen requiring 5 steps was achieved in a flow reactor yielding enough API for 900 days of patient treatment in just 80 minutes (Porta et al, 2016; Murray et al., 2013).

Another advantage is that flow systems can be designed to perform purification too, maximising mass transfer and improving purified yield (Mathieu et al, 2020).

Automation

Flow systems can be easily automated, allowing for precise control of reaction parameters and continuous monitoring of the process. This satisfies the eleventh principle of Green Chemistry: 'Analytical methodologies need to be further developed to allow for real-time, in-process monitoring and control prior to the formation of hazardous substances'. This automation can improve reproducibility and facilitate the rapid optimisation of reaction conditions in a safe environment. These methods also can generate vast libraries of API in very short times (Sagmeister et al., 2021).

Conclusion

This brief overview has presented a few possibilities for flow chemistry. Other notable advantages of flow chemistry are the high mass transfer enhancement for heterogeneous catalysis, the safer manipulation of highly reactive reagents and the integration of intensification process such as microwave heating, photochemistry or sonochemistry. Overall, flow chemistry has several advantages compared to traditional batch reactions, but some barriers exist that prevent greater adoption in the pharmaceutical industry. It is more difficult to assign batches of an API when the product is being produced continuously, which is important for product safety. This requires regulations to be adapted and 'semi-continuous' processes to be explored. Flow chemistry also requires new expertise and equipment. Synthetic chemistry is still mostly taught as batch reactions in flasks and other vessels that would be familiar to 19th century scientists. Familiarity with flow chemistry from the earliest stages of student training would help normalise flow chemistry and accelerate its adoption.