Continuous Flow Synthesis. A Pharma Perspective

The pharmaceutical industry is going through continuouschange, and it is only by adapting to change that it can surviveand improve. Enormous pressure to deliver new and successfuldrugs to the market is impacting the research process. Newstrategies and innovative solutions on all fronts are needed toimprove and speed the journey from early discovery toproduction.

In the discovery synthetic chemistry arena there has been achange in approach and mentality in the past few years: fewercompounds are being made, and design is more focused, aidedby computational techniques and data analysis tools. As a result,synthetic chemists are being asked to deliver target compoundsmore quickly and at the same time via a synthetic route capableof delivering rapid resynthesis and supporting subsequent scaleup. Besides, they are also being asked to expand the accessiblechemical space for designers.

Synthetic chemistry plays a key part in the drug discoveryprocess. It is a vibrant science with significant research beingcarried out around the world, new reactivity patterns beingdiscovered every day, along with new reactions and applicationsof established reactions. In terms of actual lab techniques tosupport these efforts, continuous processing is emerging as oneof the techniques that can significantly impact the syntheticprocess. Several reviews1−10 have been published highlightingthe potential advantages of the technique, namely, high controlof the reaction variables, which can translate into higherproduct quality; increased safety; possibility of reactions at hightemperature and pressure (process intensification); possibilityof automation; reduced manual handling; easier reproducibility;flexibility of the production volume; possibility of in-line purification techniques and reaction telescoping; increased contactsurface between phases for biphasic and triphasic systems;bigger temporary catalyst/substrate ratio in heterogeneouslycatalyzed reactions, leading also to process intensification and asmaller footprint in a manufacturing plant.

Despite its numerousadvantages, the large majority of processes in the pharmaceuticalindustry are still run in batch. Continuous processing is,however, slowly gaining ground.In this Perspective, we give an overview of this techniquefrom the pharmaceutical industry point of view: how it iscurrently impacting in each stage of the drug discovery process,what factors are holding it from a more widespread impact, andfinally where we see its future. Far from being an exhaustivereview, this manuscript intends to provide the reader with abetter understanding of the flow technique, its potential, andchallenges. We have attempted to capture a large range ofreactions where flow has a potential advantage. However,photocatalyzed reactions11−13 and biotransformations14 havenot been included because of space constraints, despite theimportant flow potential in these areas.