The utilization of novel technologies in chemistry has significantly contributed to the development of new molecules. In contrast to batch reaction, continuous flow processes have enabled large-scale production of bioactive compounds in the pharma industry. This technique has many advantages, including reduced waste production and improved product quality.
Batch Processes vs. Continuous Flow Chemistry
Batch processes follow “cookbook” technology, where all ingredients are added at the beginning of a chemical reaction and stopped after the development of new products.1 In this process, neither additional reactants are added in the reactor, nor products are removed during the reaction. The key advantages of the batch process are low operational cost, ease of handling, and fewer control systems. Furthermore, batch systems have higher reaction rates.
The major limitation of batch systems is the development of intermediate products, which might alter the pH of the reactants. Therefore, additional steps are required to eliminate or minimize the effects of intermediate products. Furthermore, the batch system is associated with uncontrolled biological processes. Another limitation of batch reaction is insufficient heat and mass transfer.2
In continuous flow chemistry, reagents are flowed in a continuous stream into a reactor where the chemical reaction occurs. This technology requires reactors, mixers, pumps, and tubes that are optimally installed to increase productivity via chemical reactions.3 For more than 100 years, continuous flow reactors have been used industrially for the synthesis of bulk chemicals.
Continuous flow processes have gained more popularity over batch reactors as they can meet the global demand for large-scale manufacturing of organic compounds at low cost. In comparison to batch reaction, continuous flow processes require fewer steps to synthesize the target biologically active compound.
Advancements in Continuous Flow Chemistry
Continuous flow technology also allows in situ analysis by installing analytical techniques, such as mass spectroscopy (MS) and infrared and nuclear magnetic resonance (NMR) spectroscopy. Some systems are also equipped with purification systems, e.g., flash chromatography and high-performance liquid chromatography (HPLC).4
A recent implementation of novel synthetic techniques, such as artificial intelligence (AI), photochemistry, and electrochemistry, has enabled automation in continuous flow chemistry. This strategy has substantially increased process sustainability and led to a significant reduction in developmental cost and time. Continuous flow chemistry enables safer and cleaner organic synthetic transformations.
Over time, advancements in microreaction technologies have significantly improved process intensification. These advancements have ensured proper control of reaction parameters, such as temperature, reagent/reactant quantity, solvent amount, time, and mixing of ingredients in flow reactors.
Micro-structured reactors used in continuous flow systems enable the utilization of hazardous and unstable reagents for a particular chemical reaction in a safe manner. These reactors can also manage consecutive reactions of highly unstable intermediates quickly.5
In the field of flow chemistry, miniaturization has played an important role in bridging the gap between industry and academic research. The recent advancements in microreactors, particularly with the advent of new materials (e.g., perfluorinated polymers and stainless tubes), have revolutionized continuous flow systems. In contrast to conventionally used reactor materials, such as glass, ceramics, and stainless steel, the newer materials are cheaper and more durable.
Recently, a 3D-printed metal microreactor that is equipped with built-in flow distributors has been developed. This reactor was designed to produce large-scale aryl-based drug scaffolds. This technique was successfully employed in aryllithium chemistry, which plays an important role in the production of active antiplatelet compounds and breast cancer medicine letrozole.6 Looped flow processes are also extremely useful for the synthesis of complex macromolecules.
Continuous Flow Synthesis of Pharmaceutical Products
Multiple pharmaceutically important compounds are synthesized via flow chemistry. These compounds have varying core structures, such as pyrazole, triazole, piperazine, cyclic carbamate, quinoline, and tetrazole. Piperazine compounds, including trazodone, buspirone, flibanserin, and cariprazine are used for the treatment of depression, anxiety disorder, female hypoactive sexual desire disorder (HSDD), and schizophrenia.7
A total of four steps are involved in the automated continuous flow synthesis of flibanserin, a piperazine-containing compound. Flibanserin is typically used to treat anxiety disorders. Synthesis of flibanserin via continuous flow reaction involves the use of heterogenous catalysts that reduce amination and benzimidazole synthesis at high temperatures.8
Imatinib is another API used to treat chronic myelogenous leukemia and gastrointestinal stromal tumors. A promising flow synthesis methodology based on selective amidation of 4-bromo-2-chlorotoluene using benzamide has been developed. This process utilizes precatalyst and potassium phosphate at 120°C.
Aplysamines are antifungal drugs derived from the Australian marine sponge Pseudoceratina sp. This bromotyrosine-derived secondary metabolite has been synthesized using a continuous flow methodology. The key step of this new system is associated with microwave-assisted continuous-flow organic synthesis (MACOS) Heck reaction. In comparison to batch reaction, the application of continuous flow chemistry enabled a fourfold increase in aplysamines synthesis.9
Vidarabine is a synthetic analog of spongosine, which can inhibit many viruses, including poxviruses, rhabdoviruses, hepadnaviruses, herpes viruses, and RNA tumor viruses. This compound is obtained from the Caribbean sponge Cryptotethya crypta. Similar synthetic nucleosides are often synthesized via continuous-flow chemical processes. For instance, nucleoside phosphorylases have been used for a flow-catalyzed synthesis of vidarabine.9
Commercial Implementation of Continuous Flow Chemistry
Many prominent Big Pharma companies, including Novartis, Eli Lilly, Pfizer, GSK, and Janssen, have implemented continuous flow chemistry in key steps of active pharmaceutical ingredient (API) synthesis. Many of these companies have patented the methodologies for API synthesis, such as for the synthesis of brivaracetam, crizotinib, and brivaracetam. However, some protocols that include the preparation of nevirapine and abemaciclib have been published in international journals.
- Smith R, Inomata H, and Peters C. Systems, Devices and Processes. Supercritical Fluid Science and Technology. 2013; 4, 55-119. https://doi.org/10.1016/B978-0-444-52215-3.00002-7
- Orehek J, Teslić D, and Likozar B. Continuous Crystallization Processes in Pharmaceutical Manufacturing: A Review. Org. Process Res. Dev. 2021; 25, 1, 16–42
- Baumann M, Moody ST, SmythM and Wharry S. A Perspective on Continuous Flow Chemistry in the Pharmaceutical Industry. Org. Process Res. Dev. 2020; 24, 10, 1802–1813
- Sumpter B G, Hong K, Vasudevan RK, Ivanov I, and Advincula R. Autonomous continuous flow reactor synthesis for scalable atom-precision. Carbon Trends. 2023; 10, 100234. https://doi.org/10.1016/j.cartre.2022.100234
- Tanimu A, Jaenicke S, and Alhooshani K. Heterogeneous catalysis in continuous flow microreactors: A review of methods and applications. J. Chem. Eng. 2017; 327, 792-821. https://doi.org/10.1016/j.cej.2017.06.161
- Kang H, Ahn N, Lee H, Yim J, Lahore S, Lee J, Kim, H, Kim J T, and Kim P. Scalable Subsecond Synthesis of Drug Scaffolds via Aryllithium Intermediates by Numbered-up 3D-Printed Metal Microreactors. ACS Cent. Sci.2022; 8(1), 43-50. https://doi.org/10.1021/acscentsci.1c00972
- Burange A S, Osman S M, and Luque R. Understanding flow chemistry for the production of active pharmaceutical ingredients. IScience, 2022; 25(3), 103892. https://doi.org/10.1016/j.isci.2022.103892
- Bana P. et al. Flow-oriented synthetic design in the continuous preparation of the aryl piperazine drug flibanserin. React. Chem. Eng. 2019; 4.
- Peña L F, Parte L G, Escribano R, Guerra J, Barbero A, and López E. Continuous Flow Chemistry: A Novel Technology for the Synthesis of Marine Drugs. Marine Drugs. 2023; 21(7), 402. https://doi.org/10.3390/md21070402