Flow Chemistry

Approximately 2,800 active pharmaceutical ingredients (APIs) are currently marketed, 70% of which being synthetic chemical molecules. Their complexity tends to increase: among the treatments approved annually by the FDA, there is a regular increase in average molecular weight and the number of chemical functionalities.

Complex processEs for active molecule manufacturng

Today, new drugs frequently contain several heterocycles, including classical elements of the periodic table such as nitrogen, oxygen, or fluorine. Those original structures are sought after to selectively address certain biological receptors, or to influence the drugs bioavailability. Successful synthesis of these complex molecules requires a high level of chemical expertise.

More than 35% of FDA approved drugs need at least one nitration step in their manufacturing process. About 20% need a fluorination step, to mention only these two reaction families. Such chemistry handles synthetic agents that are often highly reactive. Those synthetic agents can be sometimes corrosive or toxic, such as nitric acid, sodium nitrite, azides or hydrofluoric acid. Reactions themselves are often characterized by their exothermicity, and sometimes the energetic or unstable nature of the intermediates.

Over the last 20 years, the industrialization of such reactions has become rare in Europe. Industrial plants have some difficulties of maintaining their implementation in an acceptable environmental and safety conditions with regards to local regulations. In fact, a large part of the production of APIs has been exported to Asia. A crisis such as the Covid-19 is a clear indication of the fragility of the drug supply chain in western geographical areas. Notably, several drugs under clinical trials for CoVid-19 treatment require exothermic chemistry steps.

However, a great deal of work has been done to make industrial processes safer. Largely inspired by the large-scale processes used in petrochemicals or commodity chemistry, Flow chemistry is now part of the CDMO landscape. Thois technology is considered as an essential asset for controlling sensitive chemical reactions.

Flow chemistry is now part of the CDMO landscape

Continuous operation makes it possible to minimize reaction volumes. The quantity of unstable reaction mixture in the continuous reactor at a given time is greatly reduced compared to a conventional batch process, thereby reducing safety risks. The surface/volume ratio is also much more favorable, allowing a better control of the reaction temperature and exothermicity, and a safer operation.

Flow chemistry is also characterized by a gain in chemical efficiency. Continuous plug flow or stirred-tank cascades of reactors allow a tighter residence time distribution than batch, and in many cases a better selectivity. All these elements contribute to minimizing secondary reactions and the formation of impurities. The quality of the products is correspondingly improved and the environmental footprint of such processes is reduced drastically.

Frédéric Schab, Seqens Innovation Director, explains : “The key to mastering flow chemistry processes is to combine expertise in chemistry and process engineering. The complementarity of these two disciplines is essential to efficiently industrialize, on a continuous mode, a process developed in the laboratory. “

Seqens benefits from a long experience in flow. Chemical and process engineers have been designing, optimizing, and operating continuous processes for decades, whether on large scale building blocks or active pharmaceutical ingredients (APIs), such as GMP-grade salicylic acid.

Seqens Lab will be equipped by 2022 with a new GMP pilot plant

The feasibility of Flow chemistry is systematically evaluated for all customers and internal projects of Seqens, in order to quickly identify the products that could benefit from such a technology. The experimental part is carried out in the R&D Center, Seqens Lab, in Porcheville (France), which is equipped with several reaction technologies : plate based Chemtrix Protrix™, coil based Vapourtec™ and continuous hydrogenation unit. In addition, Process Analytical Technology is used to monitor reaction and acquire appropriate data.

• Vapourtec platform is a modular system capable of either standalone operation or integration with other equipment to provide versatile automated flow chemistry, ideal for customization. The design provides ability to customize unit for specific demands by adding pumps or reactor.

• Chemtrix Protrix platform is a modular plate ceramic Flow Reactor, ideal for process development and small-scale production. The fabrication from diffusion bonded silicon carbide and the integrated heat exchange provide highest chemical compatibility and process control for challenging chemical applications. The Processes include nitrations, cyanations, lithiations, diazotisations & halogenations

• Hydrogenation platform is developed to provide fast optimization of multiple variable (temperature, pressure, flow rate, hydrogen amount, catalyst amount, concentration and solvent).

In order to complete its toolbox, Seqens’Lab will be equipped in 2022 with a new GMP pilot plant. This pilot plant will be capable of hosting nitration, diazotation or halogenation type reactions, and producing representative pre-commercial batches up to the ton scale. This flexible tool will enable to increase process robustness and accelerate scale-up and industrialization steps.

Seqens leverages its range of scientific skills to deploy Flow chemistry and benefit from its advantages in terms of safety, reagents consumption, and efficiency, which now make it possible to envisage a massive repatriation of a certain type of difficult reactions, intermediates and APIs, to Europe. This reindustrialization will ultimately secure the supply chain for many medicines in Europe, provided that this effort is supported by an appropriate investment policy.