Traditional manufacturing methods for pharmaceuticals utilizing standard batch-type reactors are currently being challenged globally by more innovative and enabling concepts involving continuous flow processing. This is motivated by the potential of this technology to improve control over quality, reduce costs, enhance sustainability and significantly reduce the timelines currently involved across the drug manufacturing supply chain. Although still at an early stage of development and implementation, continuous chemical processing is seen as key enabling technology for the future of the pharmaceutical manufacturing sector and is therefore strongly supported by regulatory bodies.

In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in organic synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type virtually instantaneous mixing can be achieved for all but the fastest reactions. Similarly, accumulation of heat, formation of hot-spots and dangers of thermal runaways can be prevented. Owing to the small reactor volumes, the overall safety of the process is significantly improved, even when harsh reaction conditions are applied. Thus, microreactor technology offers a unique way to perform ultrafast, exothermic reactions, and allows the execution of chemistries which proceed via highly unstable or even explosive intermediates. In addition, considerable efforts have been undertaken to devise uninterrupted multistep flow reaction sequences, and elaborate processes for the direct synthesis of complex APIs or intermediates from simple starting materials have been demonstrated.

Flow reactor (or Micro-reactor): The micro-reactor enables continuous flow reactions by employing microfabrication modules (mixer, heat exchanger, etc.) with typical lateral dimensions below 1 mm. It is used for processes such as mixing, reaction, and extracting. Surface heating/cooling area to reactor volume ratio is high. This attribute permits maintaining isothermal conditions necessary for highly exothermic reactions.

Micro-reactors are made by etching channels on a substrate such as metal, glass, or other type of ceramic. These channels are built using such techniques as lithographic (photolithography), electrical discharge machinery, or laser micromachining. The fluidic modules are made by sandwich structure of thin glass or ceramic plates with micro channels or fluid channels that have been etched into both sides. Each plate has two external layers for heat exchange fluid recirculation. This technology enables operating the reactor up to the pressure of 200 bars and temperature range between -60ºC and 350°C.  By superior mixing (in respect to flow velocity) performance in the micro-reactor enables high mass transfer between the reagents of chemical mixture with short residence time. Relatively small total volume of the micro-rector (near 90 ml) provides another safety advantage.

Microreactors or, more generally, flow reactors enable a precise control of chemical processes. This fact and the conversion of chemical processes from batch to continuous processes correlated with the use of flow reactors allow an intensification of the processes as well as the improvement of their efficiency. Often, the use of flow reactors serves to overcome limitations resulting from mass or heat transport limitations in chemical reactions. Additionally, flow reactors allow opening up novel process windows by a better control of extreme reaction and process conditions.

The reaction pathways of flow reactors are typically tube-like in design and are manufactured from non-reactive materials. Mixing methods in flow reactors can include diffusion alone, passive (or static) mixing, and more recently active mixing.

Flow reactors allow efficient control over important reaction parameters such as heat-transfer (heating and cooling), mixing (and mass-transfer) as well as reaction time (residence time). Such a level of control brings with it better potential outcomes of reaction processes, including percentage yields, purities and selectivities, whilst providing low capital costs, small reactor footprints, efficient energy use, reduced solvent use, low emissions and improved safety management.

Microreactors or, more generally, flow reactors enable a precise control of chemical processes. This fact and the conversion of chemical processes from batch to continuous processes correlated with the use of flow reactors allow an intensification of the processes as well as the improvement of their efficiency. Often, the use of flow reactors serves to overcome limitations resulting from mass or heat transport limitations in chemical reactions. Additionally, flow reactors allow opening up novel process windows by a better control of extreme reaction and process conditions.

Notably, these include handling hazardous, toxic and/or unstable reagents and gases in flow environments, many times in extreme temperature and pressure regimes reaching the near- or supercritical state. Flow processing has been executed both in monophasic or multiphasic (i.e., liquid/liquid, solid/liquid, gas/liquid, gas/liquid/solid) flow regimes using a range of reactor designs.

Advantages of Flow Chemistry

There are well-defined key advantages using flow technologies as compared to standard batch chemistry methods:

Improved heat transfer

Improved mass transfer/mixing

Reproducibility

Easier route to scale-up

Multistep (telescoping)

In-line downstream processing

Automation

Improved Safety (managing hazardous reagents and intermediates)

Smaller reactor footprint

Lower operational expenditure or running costs

Lower fugitive emissions

Lower solvent use and waste

Reaction Types

Cryogenic reactions (≤ -20ºC)

High temperature reactions (≥ 150ºC)

Diazomethane reactions

Ozonation reactions

Oxidation with peroxide

Nitration

Photochemistry

Electrochemistry

Catalytic hydrogenation reactions

Preparation and application of Grignard reagent

Hazardous reactions involving azide or hydrazine compounds

Reactions with gases including acetylene, ethylene, ammonia, etc

Process Development Solutions

Flow-chemistry feasibility assessment

Process development and optimization

Validation and up-scaling

Model design (new technology platform)

Technical package optimization

Technical transfer from lab to plant

Continuous improvement

Process optimization for all scales – lab, kilo scale, and commercial