AM Technology remains fully operational. We continue to wish everyone well during these difficult times.
“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.
Flow Chemistry Overview
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 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.
Active vs Passive Mixing in Flow
For the majority of flow reactors, mixing of reagents in flow 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 on the order of a few mm or less).
For passive mixing, the mixing efficiency of a reaction and its residence time are intrinsically coupled; to increase the residence time, the length of the microchannel 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. However, liquid-gas, solid-liquid (slurries) and solid-liquid-gas media can pose serious issues within the reactor such as gas build-up and blocking or fouling of the process lines, greatly affecting the outcome of a given process.
Solids Bridging in the Process Lines
Solids Settling in the Process Lines
Active mixing in flow uses 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 processes; 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.
In essence, the attributes of flow and the benefits batch have been combined with the advent of active mixing within flow reactor technology.
Solids Handling in Flow
Four common problems are associated with handling solids in flow systems: bridging, settling, accumulation and fouling. Each presents different challenges.
Bridging occurs when particles get trapped on surfaces in the flow channel and then serve to trap more particles, ultimately leading to bridging and blockage. The problem of bridging reduces as the channel size increases relative to size of the particles. As a rule of thumb, a channel diameter which is greater than ten times larger than the particle diameter has a low risk of bridging.
Settling is a common problem and is most likely to occur where the solids have high settling velocities. The settling velocity of a particle is related to its difference in density compared to the process fluid, its shape and its size. Small particles and those with a similar density to the process fluid have low settling velocities and are therefore easier to handle. Settling is counteracted by efficient and uniform mixing throughout the reactor. Solids usually travel through the flow reactor at different velocities to the process fluid. Where they travel at a lower velocity than the fluid, accumulation occurs. In serious cases, this can impair mixing, Handling solids in flow reactors leading to settling and complete blockage. The problem can be mitigated by reducing the solids concentration or employing a sloping flow path in the reactor which matches the settling direction of the solids.
Fouling occurs when solids deposit on the surfaces of the flow channel. Fluids with a tendency to foul are a serious problem for flow reactors, since the fouled material accumulates over time. This can affect the flow pattern, working volume and heat transfer characteristics of the reactor and can ultimately lead to complete blockage. Where fouling is a problem, the effects can be reduced with good mixing but fouling will always limit the cycle time of the reactor. Processes with a strong propensity to foul are generally better handled in a batch reactor.
Characteristics of Flow Reactors
In ideal plug flow, any two molecules entering a flow reactor at a given time will discharge at the same time. This provides the means for controlling reaction time and optimising 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.
The advantages of good plug flow include:
Good reaction time control
Efficient utilisation of reactor volume
Fast reaction times for nth order reactions
Optimum yield and purity
Low start up and shut down losses
It is often desirable to have plug flow operation rather than a CSTR (continuously stirred tank reactor), as plug flow gives very tight control of the processing history, leading to the following benefits:
Each element of fluid spends the same amount of time in each environment within the reactor
Unreacted and reacted material are largely separated, occupying separate areas along the reactors length
Reacted material exits the reactor soon after formation, and is therefore unable to react further to form by-products
Leading to fewer by-products and improved reaction yields
Plug Flow vs CSTRs in Series
Relationship between reactants and product within a CSTR
Relationship between reactants and product within CSTRs in series
Relationship between reactants and product within a plug flow reactor (PFR)
shortcomings of conventional equipment: the batch stirred tank: A batch stirred vessel at laboratory scale can be perfectly mixed, as it is relatively easy to operate the stirrer at a high enough rate to ensure this, i.e. a high power density is easily achieved. However, the costs of achieving this degree of mixing soon become prohibitively expensive and/or technically difficult at larger scales. In practice this means that large stirred vessels are not well-mixed, which in turn often means that the reactions are mixing-limited. These fundamental shortcomings of the stirred vessel have generated a considerable degree of uncertainty when fi ne chemical or pharmaceutical processes are being developed for full scale operation
For a stirred tank batch reactor, in the normal case of a geometrically similar scale-up, it can be readily shown that the surface area per unit reactor volume varies inversely with the vessel diameter.
Active vs Passive Mixing
Residence Time Distribution
The two extremes of behaviour in reactor engineering are the Continuously Stirred Tank Reactor (CSTR) and the Plug Flow Reactor (PFR). The CSTR is said to be ‘ fully back mixed ’ or ‘ perfectly mixed ’ , and, as such has a broad residence time distribution
PFRs, on the other hand, have an extremely narrow RTD. In fact, in an ideal PFR, the output is exactly the same as the input, as there is no axial dispersion of information along the reactor, due to its fl at velocity profile (usually due to achieving high levels of turbulence). Real reactors’ RTDs lie between these two extremes: no PFR has an infinitely narrow RTD, and no CSTR is perfectly mixed.
The feed of raw materials into the continuous reactor are tightly controlled, as is the residence time within the reactor and the temperature profile that the reacting materials are exposed to. As a result, the product flowing from the reactor tends to be more consistent as the reaction parameters are better controlled than in a batch operation whose reaction parameters must change over time. The capital costs per tonne of product of a continuous reactor are significantly lower that for a batch reactor system.
Batch reactors are, however, very process and product flexible. A batch reactor can be reconfigured from operating one process to operating another. The process is inherently inefficient.
The Coflore® ACR uses ten actively mixed reaction cells in a vertical cascade. Active mixing keeps the solids mobile and moving through the system. Short horizontal channels link the cells. Active movement of the reactor block keeps solids moving between stages. The ACR is generally suitable for solids of up to 100 microns in diameter.
The Coflore® ATR is comprised of up up to eight actively-mixed reactor tubes. Active mixing keeps solids suspended and moving through the reactor. Short vertical channels link the tubes to give gravity assisted flow in the transfer lines. The ATR is suitable for solids in the order of hundreds of microns in diameter.
The Coflore® RTR operates as a single-tube, ten-stage, actively-mixed, self-baffling continuous flow reactor. The RTR is a 100 L volume flow reactor capable of producing 30,000 L of material in a 24 hour period, for a 5 minute residence time.