Article

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

The continuous flow method is a concrete indispensable process and an effective tool where the reaction is carried out by mixing the reagents to generate a chemical reaction. Then, this liquid or solution is allowed to go through an observation tube for further completion of the reaction process. Thus continuous-flow method also helps to monitor the kinetics of chemical reactions in solution.

The continuous flow synthesis allows combinatorial synthesis and space integration of reactions, making it the most innovative synthetic and pharmaceutical research tool. Various compounds can be synthesized sequentially using a single flow reactor and flow switch. The routes are designed for commercially synthetic processes and preparative standards than the normal batches to expand the synthetic proficiencies.

The active pharmaceutical ingredient manufacturing or synthesis in a lab is sometimes difficult for the scale-up process using the reaction equipment owing to their size and performance criteria. Hence the process optimization of the scale-up reaction is always a challenge in such cases considering the monitoring of the reaction parameters, which emphasizes that using continuous flow reactors helps understand and maintain the process requirements for the optimization techniques. Continuous flow reactors are devices that carry out synthetic transformations in a continuous flowing stream. They can be designed and customized according to the need and characteristics of the reaction. Hence customized flow reactors are available for the respective flow synthetic reaction to be carried out.

The continuous flow method gives comprehensive and additional insights into managing the flow chemistry pattern and the transformational process that makes the method a potentially competent and technically powerful tool.

It is undoubtedly one of the most widely used and enabling techniques where the specified volumes of the substrates and reagents are added into the small reactor units. This process is maintained in a controlled and reproducible manner. The regulation parameters such as heat and mass transfer are controlled. The flow reaction configuration is upgraded and customized to comply with the reaction parameters and processing requirements. The reactor is made by assembling the integrated component systems involving heating and cooling units, tubing coils, and separators. The arrangement is made so that it facilitates smooth and continuous operation. It also ensures hazardous and critical processes run smoothly without any interference and helps investigate and identify any operational difficulties that can be monitored and improved for safety concerns.

Active pharmaceutical ingredient manufacturing has been developed in a modified and innovative way to optimize and standardize the process involved. Flow synthesis of high- volume pharmaceuticals is conducted for many APIs using a microreactor. A continuous flow synthesis process is carried out where each step is optimized and standardized by taking the quality reagents for the reaction to avoid any downstream difficulties and troubles. Final purification is carried out at the end of the process of sequence.

Similarly, one of the examples of another pharmaceutical flow synthesis has been developed for the API of tyrosine kinase inhibitor Gleevec. This flow process synthesis has the key steps involving an amide formation reaction followed by a nucleophilic substitution reaction and ends with Buchwald–Hartwig coupling reaction in the flow process.

The reactors are available made with PTFE or PFA, stainless steel, microchips, or can be fixed bed or agitating microsphere reactors depending upon the length and type of the reactor required. The reactor temperature is controlled and monitored where the reagents are added through a micromixer.