Manufacturing

The Constant Flux Reactor

A new type of reactor not only gives better control over temperature
but, for the first time, provides a simple all-purpose tool for monitoring
the rate or progress of virtually any chemical, physical or biological process.

By Robert Ashe, Co-Founder of Ashe Morris Ltd

Robert Ashe is a Chemical Engineer with more than 30 years experience in the pharmaceutical,
chemical and food industries. He co-founded Ashe Morris Ltd in 2000 to develop Constant Flux
technology. The company has now filed more than 10 patents on Constant Flux control and
enabling technologies.

There is general recognition within the pharmaceutical
industry that greater use of analytical instruments
(within the manufacturing environment) is essential
for improving the efficiency of manufacturing
operations. The US FDA has lent their support to this
principle by promoting the Process Analytical
Technology (PAT) initiative. A UK-based company,
Ashe Morris Ltd, has developed a novel method for
controlling the temperature of batch reactors. Referred
to as Constant Flux Control, this technique relies on
variable area cooling/heating jackets to regulate
heating and cooling power.
be transformed into precision calorimeters with the
addition of a flow meter and temperature elements.
With online calorimetry, the plant operator can control
reactant accumulation, detect process end-points and
identify problems as they arise. They also have an
effective tool for monitoring and controlling
crystallisation, polymerisation and bio-reactions. For
many applications, Constant Flux reactors will not only
be faster and safer to use, but will give better yields and
improved product quality.
THE CONTINUOUSLY STIRRED TANK REACTOR

The new method not only gives better temperature
control but, for the first time, it provides plant
operators with a simple all-purpose tool for monitoring
the rate or progress of virtually any chemical, physical
or biological process. Batch vessels built or adapted to
operate on the principle of Constant Flux control can
Figure 1: A Conventional CSTR
TC T
The continuously stirred tank reactor (CSTR) is the
most common type of process equipment to be
found in a modern pharmaceutical manufacturing plant.
It is used for a wide variety of process operations such
as fermentation, chemical synthesis, polymerisation,
crystallisation, liquid/liquid extraction, mixing,
dissolution, distillation, evaporation and so on.
Frequently, the same vessel will be used for multiple
unit operations and for manufacturing a variety of
different products.
CSTRs are built of stainless steel, glass-lined steel or
exotic alloys. They vary in size from a few litres to over
100,000 litres. Most use the side walls and bottom dish
of the vessel to add or remove heat from process.
Jackets are fitted to these areas by using an outer
skin (Figure 1), or an external heat transfer coil
wrapped around the vessel surface. Heat transfer fluid
is pumped through the jacket space (or coil) to heat or
cool the vessel as required. The heating or cooling
power of a traditional reactor cooling system
is regulated by controlling the jacket temperature;
this is achieved using valves which control either

82 Innovations in Pharmaceutical Technology

the inlet temperature or the mass flow rate of the heat
transfer fluid.
THE CONSTANT FLUX REACTOR
Although CSTRs have seen many design improvements
over the past 100 years, the underlying method for
controlling product temperature has always relied on
regulating the jacket or coil temperature.
Ashe Morris Ltd are developing a new generation
of CSTRs which use a fundamentally different
temperature control philosophy. Instead of regulating
the temperature of the heating/cooling jacket, these
reactors have variable heat transfer areas. The variable
area surface is created by breaking the jacket up into
multiple independently controlled heat transfer
elements (see Figure 2). The feed and return pipes to the
individual heating/cooling elements are connected to
common manifolds, and the outlet manifold is fitted
with a motorised piston which is used to regulate the
number of heat transfer elements in service. This type of
control is referred to as Constant Flux control as the
temperature controller does not alter the heat flux of the
working elements.
PERFORMANCE ENHANCEMENTS
Constant Flux reactors have a number of valuable
advantages over traditional reactors:
Simple and Accurate Reaction Calorimetry
When a chemical, physical or biological change takes
place, heat is absorbed or released. The rate of heat
release (or absorption) reveals how fast the change is
taking place, and the total quantity of heat released (or
absorbed) can be used to determine how far the change
has progressed. The science of measuring this heat is
referred to as calorimetry.
Despite the value of thermal data, calorimetry has never
been a practical option for industrial equipment. The
problem lies in measuring the heat added or removed
from the system. In a working vessel, the thermal noise
associated with jacket temperature control totally
obscures the process heat signal. Even under perfectly
stable conditions, the heat gain/loss in the heat
transfer fluid is often too small to be measured with
standard industrial instruments. Alternative measuring
techniques, such as heat flow calorimetry and power
compensation calorimetry, have been developed for use
Innovations in Pharmaceutical Technology
Figure 2:
The Constant
Flux Reactor
The reactor uses
multiple small jacket
elements instead of
a single large jacket.
The number of jacket
elements in service
can be varied with
a motorised piston
mounted within the
inlet or outlet manifold.
in laboratories. These, however, are not practical for
industrial systems as they rely on onerous procedures and
are not reliable.
Constant Flux control eliminates the problems of
measuring heat. Thermal noise in the jacket is reduced
substantially, and even the residual noise is simple to
evaluate (since working jacket elements operate at one
temperature). The operator also has the freedom to set
the temperature shift in the heat transfer fluid at a value
which can be measured with standard industrial
instruments. Constant Flux control allows any standard
heat exchanger to be transformed into a precision
calorimeter. This gives the operator the ability to
monitor process rate and quantity of product formed.
The operator also has access to diagnostic tools for
monitoring heat and mass transfer conditions (by
monitoring the heat transfer coefficient).
Faster and More Stable Temperature Control
If large temperature shifts are applied to the heat transfer
fluid of a traditional heat exchanger, the speed of response
is increased but so is the tendency for overshoot. The
heat transfer fluid in a Constant Flux heat exchanger can
be delivered at a very large temperature difference to the
process temperature, without any increased tendency for
overshoot. As a result, Constant Flux temperature control
is inherently faster and more stable than traditional
temperature control methods.
Improved Thermal Performance
The conventional reactor jacket is not a particularly
efficient heat exchanger. It relies on high pressure drops
and high mass flows to distribute the heat transfer fluid
within the jacket. At best, fluid distribution is only
moderately good, and heat transfer coefficients are
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 generally poor. Traditional half-coil jackets do offer
better heat transfer fluid distribution, but this is achieved
at the cost of reduced heat transfer area.
The Constant Flux reactor incorporates a new concept of
reduced volume jackets. Heat transfer fluid is delivered in
very small pipes and heat is transmitted to the vessel wall
by means of heat transmission plates. These new jackets
are simple to fabricate and do not require in situ welding.
They offer exceptionally good heat transfer coefficients,
as well as very good fluid distribution without sacrificing
heat transfer area.
Ability to Control Reactor Heat Transfer Zones
A serendipitous benefit of the Constant Flux design is
that the working area of the jacket can be limited to
liquid covered surfaces in a batch reactor. This avoids the
problem of causing thermal damage to heat-sensitive
products in the splash zone above the liquid surface.
Improved Energy Efficiency
Constant Flux reactors use heat transfer fluid at one
temperature. The heat transfer fluid is also delivered at a
lower mass flow and pressure drop. These factors,
combined with better temperature control, make
Constant Flux reactors much more energy-efficient.
The Constant Flux reactor incorporates a
new concept of reduced volume jackets. Heat
transfer fluid is delivered in very small pipes
and heat is transmitted to the vessel wall by
means of heat transmission plates. These
new jackets are simple to fabricate and
do not require in situ welding. They offer
exceptionally good heat transfer coefficients,
as well as very good fluid distribution
without sacrificing heat transfer area.
PROCESS BENEFITS
In 2003, the US FDA published draft proposals for the
Process Analytical Technology Initiative (PAT). The
purpose of PAT is to promote greater use of online or at
line analytical instruments within the manufacturing
environment. Online monitoring has two major benefits
for manufacturing processes. First, better information
about the process allows manufacturers to improve and
84
optimise plant performance beyond the initial
commissioning period. Second, some processes can be
operated more effectively if key process decisions are
linked to observed changes in the process:
Detection of reaction endpoints
Constant accumulation addition control
in synthesis reactions
Prevention of hazardous accumulations in
synthesis reactions
Monitoring and control of crystallisation
Monitoring and control of bio-systems
Early detection of abnormal events in any type
of process
Calorimetry can also be used for other diagnostic
functions such as detection of fouling, icing or boiling at
the heat transfer surface or evaluation of agitation
efficiency. Constant Flux control offers a simple all-
purpose tool for online monitoring. It can be used to
improve yield, quality, throughput and safety.
STATE OF DEVELOPMENT
A 10-litre batch reactor was built in 2003 to test the
capabilities of Constant Flux control (Figure 3, page 87).
The vessel was built with a Hastelloy shell and 30
external heat transfer elements. The Constant Flux
control valve consisted of a stainless steel piston driven
by a small electric motor. Standard industrial flow meters
and temperature probes were also used. A Eurotherm
controller with proprietary Ashe Morris software was
used for control and data monitoring.
The initial tests used water as the process fluid and an
electrical heater (with an electrical power-monitoring
instrument) to simulate the exotherm. Hot and cold
water additions were also used to simulate exotherms.
Temperature Control Performance
The temperature control capabilities of Constant Flux
control have proved to be exceptionally good. At the 10
litre-scale, the temperature control is generally better
than 0.05C. Even where large and sudden heat load
changes were applied (>50 W/l), the process temperature
could be held to within 0.2C of the set point.
Innovations in Pharmaceutical Technology
Heat Monitoring Performance Figure 3: 10-Litre Hastelloy CSTR
Fluctuating heat loads (electrical) were applied to
the reactor for periods of between 30 minutes and
two hours. The correlation between the electrical
measurement and CF heat balance calorimetry was
generally better than 0.1%.

Power Monitoring Performance

In Figure 4, an exotherm was generated using a hot water
addition. A second exotherm was then simulated using
the electrical heater. As the electronic record in Figure
4 shows, heat balance calorimetry was able to follow
the events accurately and in near real time throughout
the test.

Modifying batch reactors to operate with Constant Flux

control has proved to be very simple and effective. For
processes operating at constant temperature, the
calorimetry requires no pre-calibration at all. Even where
the process temperature is changing, pre-calibration is
not required if mass and specific heat data are available.

Laboratory scale Constant Flux reactors are currently

being developed for a small number of end-users.
During 2005, lab-scale Constant Flux reaction
calorimeters will become more generally available. Full-
sized batch reactors in stainless steel, Hastelloy and
glass-lined steel will also be available in limited
Figure 4: Test Results on a 10-litre CSTR
quantities during 2005. These will be built by
established reactor manufacturers.

CONCLUSION

Although there is interest in some of the newer

manufacturing technologies, such as micro-reactors, the
ubiquitous stirred tank rector is still a long way from
retirement. Its strength lies in its versatility and it
continues to be an ideal tool for low-throughput multi-
step/multi-product processes. The FDAs PAT initiative
will however have an impact on how stirred tank
reactors are built and used. With the introduction of
PAT, process optimisation will no longer be a one-off
commissioning exercise. Process data will be collected
and used for process optimisation throughout the as NIR and UV analysis. These different instruments will
life of a manufacturing process. Some processes will find their niches within the manufacturing environment.
also use process analytical data for feedback control. From the perspective of simplicity and versatility
In the case of product drying, such systems are already however, Constant Flux calorimetry offers a unique
in operation. solution.

There are numerous types of process analytical The author can be contacted at
instruments, and many of these are optical devices such robert.ashe@ashemorris.com

Innovations in Pharmaceutical Technology 87