Continuous reactors with easy scale-up

Continuous reactors can improve the speed and efficiency of reactions, but scale-up has always proved difficult. Now Robert Ashe, of AM Technology, says the design of the Coflore Agitated Cell Reactor overcomes such drawbacks

Continuous reactors can improve the speed and efficiency of reactions, but scale-up has always proved difficult. Now Robert Ashe, of AM Technology, says the design of the Coflore Agitated Cell Reactor overcomes such drawbacks

High value chemicals have traditionally been manufactured in batch reactors. These are large stirred tanks with cooling jackets and adequate capacity to carry the full inventory of a batch cycle. The alternative to the batch reactor is the continuous reactor - essentially a channel with a heating or cooling jacket through which reacting mixtures flow. Continuous reactors are more specialised than batch reactors and for some applications have clear advantages.

The superior heat transfer characteristics of continuous reactors enable more concentrated reaction mixtures to be used. This can improve the speed and efficiency of reactions and reduce solvent use. Continuous reactors offer better control over such conditions as reaction time, concentration profile and mixing; they also hold a lower inventory of process material (desirable when handling dangerous materials). The output from a continuous reactor can also be varied by changing the run time, providing operating flexibility.

Although the case for continuous reactors is supported by sound tech-nical and commercial arguments, they are still relatively uncommon in the pharma sector. This is surprising given that they are simple to use and often consist of little more than a jacketed pipe. One obstacle to adoption, however, relates to scale-up. The heat transfer and flow conditions in a continuous reactor are strongly influenced by channel geometry. Any change to the length or diameter of a reactor can have a dramatic effect on performance.

If a reduced scale device is used for process development, its performance may be hard to replicate at an industrial scale. If a full-scale reactor were used for development, the cost of wasted material could be significant.

A new type of reactor - the Coflore Agitated Cell Reactor - has been developed based on a continuously stirred tank reactor (CSTR), that is both flexible and allows replication of the operating conditions of large tubular reactors at very low throughputs.

Tubular reactors are arguably the most important group of continuous reactors and are essentially long tubes with cooling or heating jackets. The ideal flow condition in a tubular reactor is "plug flow". This implies that the product flows at the same velocity across the full face of the channel.

In practice, ideal plug flow does not occur as factors like wall friction, mixing and diffusion affect the velocity profile. The ability to maintain reasonably good plug flow, however, can have significant benefits. Where yield or quality is sensitive to reaction time, good plug flow permits precise control of residence time. Plug flow also results in greater separation between reacted and unreacted material. This is desirable for processes where reaction rate is affected by reactant concentration.

optimum mixing

Mixing is important, as it is instrumental in bringing reactants together and maintaining good temperature control. If good plug flow conditions are to be sustained, product mixing should be limited to material of the same age (radial mixing). In practice, however, some degree of axial mixing is inevitable and this reduces the quality of plug flow. The effects of axial mixing can be mitigated by increasing the fluid velocity and channel length.

Achieving the right combination of residence time, efficient mixing and good plug flow can result in tubular reactors that are hundreds of metres long. Tubular reactors can be divided into micro and non-micro types. Micro reactors typically have channel diameters of <1mm. The small size of these channels ensures good heat transfer capabilities and, providing the reactants are introduced into the channel in the correct ratios, diffusion can usually be relied on for mixing.

High capacity micro reactors are used for some industrial applications and these may contain hundreds or thousands of flow channels. However, in practice such applications can have issues of cost, cleaning and blockage, and pump selection can present practical problems.

larger tubes

The obvious alternative to micro channels is larger tubular reactors. Although the heat transfer characteristics are not as good as micro reactors, larger tubes offer better flow capacity, lower pressure drop and improved tolerance to solids. Where tubular reactors have a particular problem, however, is in process development.

The performance of a tubular reactor is closely linked to tube length, diameter and fluid velocity. Altering any of these parameters can have a significant impact on reaction time, pressure drop, throughput and flow conditions. This means different reaction conditions require different reactor geometries.

One response to this has been the development of tubular reactors where the reactor length can be altered by means of valves or quick couplings. Although configurable reactors have greater flexibility, they do not solve the problem of high product waste during development. Between micro reactors and large reactors, there is a need for flexible development reactors that can replicate the flow conditions and concentration gradients of large tubular reactors but operate at low throughputs.

CSTRs offer a solution to this problem. They are stirred vessels operated in continuous flow mode and can sustain turbulent conditions at very low throughput and, if multiple CSTRs are used in series, they can also replicate concentration profiles observed in plug flow reactors (see fig. 2).

In practice, reactions rarely proceed at a constant rate and if equal sized CSTR stages are used, the bulk of the reaction may take place in the first couple of reaction stages. Such a system does not provide a good comparison to a plug flow system. The solution to this is to vary the size of the stages so that the same amount of conversion is achieved in each stage (fig. 3).

Providing a reasonable number of stages are used, CSTRs can achieve similar concentration gradients to those of plug flow reactors. Their advantage, however, is that multi-stage CSTRs are more compact and flexible. They tend to have low pressure drops irrespective of throughput or viscosity and the residence time can be altered without affecting the flow conditions. They offer efficient mixing at fast or slow throughputs and can cope with mixtures of solids, liquids and gasses.

complex build

Despite these advantages, multi-stage CSTRs are relatively uncommon. There are good reasons for this. CSTRs have multiple vessels, stirrers and seals, which makes them complicated to build. Altering the volumetric profile of the reactor can be time-consuming and expensive. Where different sized jacketed vessels are used, they have different heat transfer areas. In an ideal system, each stage should have the same heat transfer area.

The final problem relates to product loss during start-up and shut-down. Unless the reaction stages are filled and emptied at the same rate and in the same sequence as the steady state operation, material processed during these periods may be wasted. Although this problem can be managed with inter-stage pumps, this adds to cost. If a buffer fluid is used to fill and purge the reactor, this will affect the reaction conditions during start-up and shut-down.

AM Technology, has spent several years developing an alternative design of multi stage CSTR. Referred to as Agitated Cell Reactors (ACR), they have been aimed at the development market. The patented design of the ACR has a number of features that simplify and increase the flexibility of multi stage CSTRs.

The standard ACR uses 10 CSTR stages. This number provides a good approximation of plug flow conditions. The first step in the design process was to eliminate the need for multiple vessels. This was achieved by having a series of reaction cells cut within a single block of PTFE. The reaction cells are linked by inter-stage channels, and by keeping the diameter of the channels small, product transfer between reaction cells is unidirectional and plug flow (Figs 1 & 4).

The reaction cells are cylindrical, giving them three working faces. The inter-stage channels are connected to the cylindrical face. On one end of the cylinder is the heat transfer face, which controls the cell temperature. At the other end is the control face. This is used for fitting chemical addition points, sampling, analytical instruments and sight glasses. (Fig 5)

Agitation is essential for the efficient operation of CSTRs. But as rotating agitators with shafts and seals add significantly to the cost and complexity, the ACR uses free-floating cylindrical weights in the cells that oscillate when the reactor is mounted on a vibrating platform. The volumetric profile of the ACR is controlled by the size of the agitation elements. This allows the volumetric profile of the reactor to be altered in minutes without changing the cell dimensions or compromising heat transfer capacity.

The final step was to devise a flow strategy that would prevent formation of gas pockets and allow full drain-down in the forward flow direction. For start-up and normal flow, the product needs to flow upwards so that gas is displaced ahead of the product. During shut-down, the product needs to be drained in the forward flow direction and without the use of buffer fluids. The solution was to orientate the reactor so that it has "up flow" and "down flow". Thus the ACR is mounted on a shaft to enable it to be rotated by 180°.

A prototype was made in mid 2007 and the first commercial machines are due for completion in October 2008. Designed as a bench-top reactor, the first commercial ACR has a nominal capacity of 100mm and is intended for throughputs of 10g to 10kg/hr. A lengthy testing programme has proved the basic functionality and reliability, and field trials are now under way with universities and end users.

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