An Overview of Flow Chemistry

Introduction to Flow Chemistry

In Flow Chemistry, a chemical reaction is set up as a continuously flowing stream.  This feature is the main differentiator between flow and batch chemical production, the other widely used method of chemical production.

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.

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

Advantages of Batch Chemistry

  • Versatile, as a batch reactor can be easily adapted to handle many different processes and campaigns.

  • Productive, as large amounts of material can be produced with each batch.

  • Established, batch technology is well known within the chemical industry and vast number of process have been designed and used in batch.

Batch processing proceeds much more slowly, and as such the overall cost of processing goes up. Start up and shut down processes of batch equipment can increase energy consumption and waste material, and the quality discrepancy between batches can be significant. This can lead to lost production and compromised quality if the batch process isn’t monitored closely.

Overall, despite the many advantages and efficiencies of flow chemistry, batch processing remains the standard within the fine chemical and pharmaceutical industries, simply because versatility, productivity and established knowhow are extremely desirable attributes that are an almost essential prerequisite when considering a route to chemical manufacture.

Flow technologies that embrace versatility and productivity will open up the possibility for their widespread use within the chemical industries, and this is the motivation and rationale for the design of the Coflore range of continuous flow reactors from AM Technology.

Active vs Passive Mixing

For the majority of flow reactors, mixing of reagents is achieved via diffusion within the reaction medium through a microchannel, or via the use of patterns or objects within a microchannel, or a combination of the two.  The latter is known as static mixing whereby the velocity of the reaction fluid is responsible for mixing efficiency.  For these methods to be of practicable use for mixing in flow, the diameter of the flow channel needs to be narrow, typically a few mm or less.

For Passive Mixing in flow, the mixing efficiency of a reaction and its residence time are intrinsically coupled; to increase the residence time, the length of the process channel will need to be increased, the flow rate reduced, or a combination of the two.  This inevitably poses restrictions upon the process in terms of reaction time, mixing efficiency, reactor length, and flow rate. Another limitation inherent with passive mixing relates to the properties of the reaction mixtures that can be used in the flow reactor.  Due to the small-sized nature of the micro-channel, they are ideally suited to single phase, liquid-liquid reaction media. Liquid-gas, solid-liquid (slurries) and solid-liquid-gas media can pose problems within the reactor, such as gas build-up and blocking or fouling of the process lines, greatly affecting the viability and outcome of a given process.

Active Mixing in flow makes use of an agitator to mechanically mix the reaction mixture, permitting the use of larger channels within the reactor (which would perform poorly under passive mixing conditions), whilst maintaining excellent heat- and mass- transfer properties of the flow reactor itself.  Such a mixing design decouples mixing and plug flow from residence time, and greatly increases the versatility of the flow reactor by allowing adjustments to be made to the flow rate or residence time, without the need to alter the reactor's configuration. As such, a single reactor with minimal configurational changes can be used for many different process applications.  Larger reaction channels increase a reactor's flexibility and facilitates the compatibility with a wider range of reaction media; liquid-gas, solid-liquid and solid-liquid-gas reaction media can be routinely used without leading to blocking, fouling or gas build-up in the process lines.  A widening of the flow channels within the flow reactor also facilitates a higher throughput of material, greatly increasing the productivity of the flow reactor in terms of chemical output for a given reaction process.

Useful Terminology in Flow Chemistry

Residence Time Distribution (RTD)​​: probability distribution of time that solid or fluid materials stay inside a continuous flow system, and is used a measure of plug flow.

Plug Flow: an important characteristic of flow reactors whereby any two molecules entering the reactor at time zero exit at a similar time.

Continuous Stirred Tank Reactor: a reactor whereby the contents are stirred so uniformly that it is assumed that no variation or concentration gradients exist within the vessel. There is a continuous stream in and out of the reactor.

Continuous Stirred Tanks in Series: a series of CSTRs is used to achieve conditions similar to plug flow. An infinite series is hydraulically equivalent to an ideal plug flow reactor.

Passive Mixing: utilises no energy input except the pressure from the pump used to drive the fluid flow at a constant rate.

Active Mixing: fluid disturbance that is applied via an external energy source, usually an agitator within the process channel.

Scale Up: migration of a process from the laboratory scale to the pilot plant scale or commercial scale.

Heat Transfer: the exchange of heat between the physical systems of a flow reactor and reaction media.

Mass Transfer: the movement of material within a flow reactor, more typically applied to the transfer of material between phases within a multi-phase process medium.

Residence Time: the time any given molecule spends in a flow reactor.

Plug Flow Reactor: is a flow reactor such that along the direction of the flow all the reaction mixture are moving along at the same speed; there is no mixing or back flow.

Microreactor:  is a device in which chemical reactions take place within a microchannel with typical lateral dimensions below 1 mm.

Microchannel: a process channel within a microreactor with typical lateral dimensions below 1 mm.

Blocking: where the reaction media impedes the flow of a process channel within a flow reactor, commonly due to a build-up of solids.

Fouling: a build-up of solids on the wetted surfaces of a flow reactor within the flow channel.

Flow Channel: the process channel within a flow reactor.

Flow Rate: a constant rate of flow of the process medium through a flow reactor.

Tubular Flow Reactor: a cylindrical reactor tube with a constant diameter, within which the reaction mixture flows continuously.

What is Plug Flow ?

Plug Flow is an important characteristic of flow reactors whereby any two molecules entering the reactor at time zero exit at a similar time. This provides an effective means of controlling the reaction time, and for optimising the separation of reactants and products. Good plug flow is essential for good performance in all but a few applications, and means that fluid travels through the reactor in a time-orderly way, and without back mixing.

Advantages of Plug Flow

  • Efficient reaction time control, as products are removed form the reactor on formation

  • Efficient utilisation of reactor volume, since reacted material is not retained within the reactor

  • Optimum reaction yield and purity, due to efficient heat and mass transfer properties and removal of products on formation, reducing by-products

  • Low start up and shut down losses, due to the smaller volumes involved

Changing Concentration

Direction of

Axial Flow

Next Volume Segment

Schematic diagram of a plug flow reactor

Fluid going through a Plug Flow Reactor may be modelled as flowing through the reactor as a series of infinitely thin coherent 'plugs', each with a uniform composition, traveling in the axial direction of the reactor, with each plug having a different composition from the ones before and after it. The key assumption is that as a plug flows through a plug flow reactor, the fluid is perfectly mixed in the radial direction but not in the axial direction (forwards or backwards). Each plug of differential volume is considered as a separate entity, effectively an infinitesimally small continuous stirred tank reactor, limiting to zero volume.

Relationship between reactants and product within a plug flow reactor (PFR)

CSTRs in Series

A Continuous Stirred Tank Reactor (CSTR) is an agitated vessel with a continuous feed of reactants and a continuous discharge of the reaction mixture (product). The feed and discharge rates are controlled to maintain constant reaction conditions (concentration, temperature, reaction rate) ensuring a consistent product stream is produced.

The behaviour of a CSTR is often approximated or modelled by that of an ideal CSTR, which assumes perfect mixing. In a perfectly mixed reactor, reagent is instantaneously and uniformly mixed throughout the reactor upon entry. Consequently, the output composition is identical to composition of the material inside the reactor, which is a function of residence time and reaction rate. The CSTR is the ideal limit of complete mixing in reactor design, which is the complete opposite of a plug flow reactor (PFR). In practice, no reactors behave ideally but instead fall somewhere in between the mixing limits of an ideal CSTR and a plug flow reactor.

Characteristics of a CSTR

  • Run at steady state with a continuous flow of reactants and products

  • Feed assumes a uniform composition throughout the reactor

  • Exit stream has the same composition as in the tank

When CSTRs are in series, the previous reactor operates at a higher concentration, therefore the rate is greater, therefore the conversion is greater than the subsequent reactor in series, which then builds on the conversion in the previous reactor.

Relationship between reactants and product within a CSTR

CSTR.png

Relationship between reactants and product within CSTRs in series

Continuous Stirred Tanks in Series Model

The continuous stirred tanks in series model is used to determine the number of theoretical stages, or 'plugs', within a flow reactor. The greater the number of theoretical stages, the nearer the flow reactor is to a true plug flow reactor.

 

It should be noted that true plug flow is a theoretical ideal that is never practically achieved, and is defined as an infinite number of theoretical stages or 'plugs'. AM Technology defines real-world plug flow behaviour within a flow reactor as ten theoretical stages or more.

“One of today's most important tools for modernizing the pharmaceutical industry is a process known as continuous manufacturing”

Director of the FDA’s Center for Drug Evaluation and Research, Janet Woodcock M.D.