Chemical Industry Digest. July 2010
Scale-Up
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CMYK
CMYK
How To Minimise
Dr Trevor Laird, Managing Director and Founder of Scientific Update LLP, is an expert in organic process
R&D and scale-up of chemical processes and has been an editor-in-chief of the American Chemical Society
journal Organic Process Research and Development since its launch in 1996. With over 4 decades of
involvement with the chemical and pharmceutical industry, Trevor has consulted for companies in USA,
Canada, Australia, South Africa, Singapore, Israel and India, as well as in Western Europe. He is an
expert witness on patent cases, and is visiting professor at the University of Sussex, UK. He has authored
numerous articles and book chapters. He was educated at London and Sheffield Universities and worked
for Imperial Chemical Industries in, and Smith Kline and French, where he was in charge of the Chemical
Development Department and of the Pilot Plant.
Dr Trevor Laird
Scale-up of chemical processes,
particularly those involving batch
or semi-batch manufacture is
well-known to be a problematic
area of chemistry and chemical
engineering, and can be costly
when it goes wrong. By correctly
choosing and designing the
synthetic route to a fine chemical
or drug substance, as well as
controlling the reaction and work
up/product isolation parameters,
many of the difficulties in scale
up can be avoided. The more
complex a process is in terms of
chemistry and unit operations,
the more there is to go wrong.
This article discusses what
chemists and engineers can do
in advance, both in the laboratory
and kilo laboratory, to prevent
or at least minimise scaleup
issues.
F
or robust and efficient scale-up it is
important to choose good syntheses
and this is often the decision of the
chemist rather than the chemical engineer.
One of the failings in university education
of chemists is the teaching of organic
synthesis from a discovery rather than a
manufacturing perspective. In the latter
approach, convergent synthetic routes
using low cost raw materials, with a
minimal waste output, suitable for scale up
are designed. For the generic
pharmaceutical industry – a major moneyearner
in India – it is essential to have the
best synthesis (hopefully leading to the
best process) to maintain price
competitiveness; for the fine chemical,
agrochemical, colour chemicals and
flavour fragrance industries, this has
always been the case, so the best examples
of synthetic efficiency are often from these
industries.
A simple example from the
pharmaceutical industry is shown in
Scheme 1 for the manufacture of the key
tetralone intermediate, used in most routes
to make the Pfizer drug Sertraline, which
is now off-patent. The original synthesis
used for early manufacture compares
unfavourably with a later 1-step process
Scale UP Difficulties
Chemical Industry Digest. July 2010
Scale-Up
Choosing appropriate conditions
To avoid scale up problems, it
is important for chemists – with
expert advice from chemical
engineers – to choose the correct
conditions to scale. Many
chemists, however, believe that
reaction selectivity can only be
controlled by operating at low
temperature, often at minus 78o
C. Apart from the
expense of cooling large batches to this temperature, there
is a danger that the increased viscosity of the solvent,
coupled with the low solubility of reactants/ products/
byproducts at this temperature, leads to reaction media
which are difficult to mix on large scale and resulting in
inhomogeneity in the batch with concomitant impurity
generation. Encrustation of raw materials, intermediates
and products on the vessel walls can also be a problem
at these low temperatures.
Whilst some batches occasionally do need such low
temperatures, many processes can be operated at higher
temperatures, provided the reagent is carefully dosed in
to the process at the same rate as the
reaction is proceeding. This
ensures that the stoichiometry is
constant throughout the addition.
Correct dosing regime
Chemists are often vague about
the meaning of stoichiometry in semi-batch processes,
preferring to think only about the stoichiometry based on
the reaction equation – for example the equation might
say that 2 moles of A react with 1 mole
of B to give the product C, and
byproducts D. However, if reagent A is
being added to a solution of reaction B
in a stirred tank reactor, the
stoichiometry in the reactor varies with
time. The amount of product C formed
along with by products D will depend
on the ratio of A to B in the vessel at any
one time, and this of course depends on
the rate of addition of A, the rate of
reaction of A with B [and this depends
on the temperature, the solvent, the
solvent purity (eg water content),
concentration, pH, presence of catalysts
or inhibitors etc.] and especially the
mixing in the vessel, which may be scale
dependent. Understanding the kinetics
of the process, as chemical engineers usually want to do,
will assist in the design of the process, allowing the
correct choice of temperature along
with the optimal dosing rate for that
particular scale. For an exothermic
reaction, of course, the dosing rate
may be limited by the cooling
capacity of the vessel. So it is
important to understand exactly
when the heat is generated in the
process.
Hazards of Scale Up
When scaling up chemical processes in batch reactors,
there is always the potential for loss of control if the
reaction is exothermic, since the change in heat transfer
area per unit volume varies with scale. Whereas a
laboratory 0.5L reactor has a heat transfer area of about
0.02m2
, a production 3800L vessel has only 10.7m2
; thus
the heat transfer area per unit volume is 0.04m2
/L in the
lab and only 0.0028 m2
/L in the plant, a factor of 7
difference. The consequences of this are increased cycle
times and particularly increased addition times for
reagents. The question is usually
whether these changes affect the
yield and quality of the product – the
answer often is yes!
Even more problematic is that if
reagent addition is too fast
compared to heat removal,
accumulation can occur and can
from the much cheaper raw material α-naphthol.(6)
Scheme 1
Cl
Cl
1. succinic anhydride, AlCl3
2. sodium borohydride
Cl
Cl
O
O
benzene, AlCl3
then cyclise
Cl
Cl
O
OH
dichlorobenzene, AlCl3
1-step process
1. succinic anhydride, AlCl3
2. sodium borohydride
benzene, AlCl3
then cyclise
dichlorobenzene, AlCl3
1-step process
To avoid scale up problems, it
is important for chemists – with
expert advice from chemical
engineers – to choose the correct
conditions to scale.
Understanding the kinetics of
the process, will assist in the design
of the process, allowing the correct
choice of temperature along with
the optimal dosing rate for that
particular scale.
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Chemical Industry Digest. July 2010
Scale-Up
lead to a runaway
reaction, especially
if loss of cooling
capacity occurs,
simultaneously.
The consequences
may depend on
whether decomposition
of the
reaction mixture
then occurs
(probably with gas
evolution) and on
the boiling point of
the solvent used.
Stoessel(7)
has
defined 5 classes of
criticality with
increasing hazard
potential in his
excellent article in OPRD, and more details of this topic
can be found in this recent book(8)
. Despite the
widespread knowledge about the hazards of scale up,
particularly of compounds with potentially hazardous
groupings, such as nitro compounds, it is disturbing to
see runaways still occurring due to poor hazard testing,
and poor knowledge of the thermochemistry in the
process.
An example from 1998 at Morton International in
USA, where an explosion and fire occured during the
production of Automate Yellow 96 dye, is shown in
Scheme 2, with a picture taken from the Chemical Safety
Board report into this incident(9)
.
Hopefully lessons have been
learned from this incident that
batch (all in and heat) processes
should be replaced with semi-batch
operations (controlling the rate of
addition of one component)
whenever possible and that a
change in batch size always needs
a re-assessment of
whether it is safe to
carry out the process at
the increased scale.
Companies who
themselves have no
hazard testing equipment,
such as a reaction
calorimeter or differential
scanning
calorimeter, can
sometimes be
reluctant to
outsource the
hazard testing to
competent companies
because of
expense. They
then risk scale up
based on inadequate
knowledge.
From an accountancy
viewpoint,
destruction of a
plant facility with
possible loss of
life affects the
bottom line so
much more than
capital expenditure
on calorimetric
equipment, or a small contract for hazard evaluation.
The spin-off from these studies is a better
understanding of kinetics and by-product formation ;
calorimetric evaluation can usually pay for itself since it
usually leads to increased yield, quality or productivity.
Mass transfer issues
Chemists are often surprised when changes in
selectivity occur on scale up, owing to differences in mass
transfer across phases. An example from Merck (USA)
is the solid dosing of N-bromosuccinimide (NBS) reagent
to a heterocyclic amino derivative, where the selectivity
differences on scale up are dramatic
(Scheme 3). Solution addition of the
NBS (NB acetonitrile is often the best
solvent for this reagent) gives a
better result but still the laboratory
selectivity was not able to be
matched(10)
.
When dosing solutions of
Scheme 2
Cl
NO2
H2N n
Bu
Et NH
NO2
n
Bu
Et
+
150-153o
C
Automate Yellow 96 Dye
Morton International Inc after the explosion and fire, caused due to a
runaway reaction that released flammable materials
When scaling up chemical
processes in batch reactors, there is
always the potential for loss of
control if the reaction is exothermic,
since the change in heat transfer
area per unit volume varies with
scale.
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Chemical Industry Digest. July 2010
Scale-Up
reagents in the laboratory, chemists usually add to the
surface of the agitated liquid and this works fine on small
scale. If this is done on the plant, however, poor mixing
may occur in large reactors. The key is to add the
reagents into a region of high turbulence, such as close
to the tip of the agitator, using a dip pipe, or to add
reagents via a recirculation loop.
Ensuring that the temperature and
viscosity of the added reagent is
similar to that in the vessel will also
aid in good mixing.
Scale up of agitation can be based
on a number of factors but Paul(11)
recommends using constant power
per unit volume or mass. This mixing energy dissipation
is given by:
Ei
= NpN3
d5
/V
Where d = impeller diameter (m)
Np = power number
N = rotational speed (sec -1
)
V = volume (m3
)
Note here the dependence on the fifth power of the
impeller diameter and the third power of the rotational
speed, and it is easy to see why scale up can be
problematic. One answer is to focus on scale down, with
the mixing energy dissipa-tion being perhaps the most
useful parameter for “scale down” experiments, i.e.
mimicking the typical
plant vessel in the
laboratory at “bench”
scale. The shape (height
to diameter ratio) of
laboratory vessels should
also mimic those in the
plant.
Even if a critical
reagent is added via a dip-pipe close to the tip of the
agitator, lack of selectivity may occur in fast reactions if
the dip pipe diameter is too large, resulting in slow flow
rate from the dip pipe into the bulk solution. In the
example shown in Scheme 4 the byproduct was formed
owing to back-diffusion in the dip-pipe (12)
.
Reactions involving two liquid
phases, such as phase-transfer
catalysed reactions, can also be very
sensitive to the position of the
agitator in the vessel, as well as the
agitator type/diameter/shape, and
differences in yield and quality of
products may be seen depending on
the choice of vessel. Guidelines have been advocated for
scale up of such processes, such as “maintain the ratio
of interfacial area to total volume a constant”. Interfacial
area is also significant during product isolations
involving phase separations (13).
Solvent extraction problems on Scale Up
During extractive work-ups in the laboratory, the
chemist often does not record whether the aqueous phase
was added to the organic, or vice-versa, since in the
laboratory it usually makes no difference to the outcome
of the experiment. In the plant, if the reaction mixture is
organic and the vessel is not full, it may be convenient
to add water to it, whereas if the vessel is full and a larger
vessel needs to be used for the extractions, the water
could be added first or last, depending on preferred
NN
XX
NN
OArX
NN
OMeXArOH; NaOMe
desired
product byproduct
+
Scheme 4
N
Me
NH2Me
NBS
N
Me
NH2Me
Br
Me
NH2Me
Br
N N
Me
NH2Me
BrBr
+ +
5-bromo 3-bromo dibromo
acetone
Scheme 3
If reagent addition is too fast
compared to heat removal, accumulation
can occur and can lead to
a runaway reaction, especially if
loss of cooling capacity occurs,
simultaneously.
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Chemical Industry Digest. July 2010
Scale-Up
operations. The order of addition
can make a big difference as to
whether emulsions form, and to
the time of disengagement of the
layers, as well as their separation
efficiency. Clearly this can affect
yield, but also may impact on
product quality, since a saturated
solution of water in an organic
solvent is an excellent hydrolysis
medium for esters and other hydrolysable groups if traces
of acid base are present. At extended separation times
hydrolysis may then occur leading to greater amounts of
by-products.
For this reason the solvent ethyl acetate is a poor
choice of extraction solvent for scale up, particularly in
acid/base work-ups, since the extended times the ethyl
acetate is in contact with water when trace acids/bases
are present will initiate hydrolysis of the solvent, leading
to more acid (acetic acid) which further catalyses
hydrolysis. The high solubility of water in ethyl acetate
and vice-versa means that aqueous layers, unless heavily
salted, are rich in organics (and thus more difficult to
dispose of) whereas the ethyl acetate layers have high
water contents and may need drying before further
processing. Isopropyl acetate and butyl acetate, though
more expensive initially, may actually be more costeffective
overall in scale up, particularly since solvent
recovery is easier because the low water content in the
solvent leads to higher recoveries.
In the laboratory, liquid-liquid separations are carried
out at ambient temperature, which varies from lab to lab!
In the plant, depending on the its location and whether
it is summer or winter, extractions may be carried at
anywhere from 2-3o
C to 40o
C unless a temperature is
specified, and different results from the laboratory will
be encountered. Since extractions are more efficient at
higher temperature and separations are usually better (no
emulsions usually), it is often preferable on plant to
extract in the 50-100o
C range, if this is not detrimental to
the product quality; it is certainly
more efficient in both raw materials
usage and time.
Compatibility with glass,
stainless steel and hast-
elloy
To avoid metal contamination,
chemists mostly use glass equipment
in the laboratory, but, for many
reasons, engineers may prefer
stainless steel or Hastelloy
equipment in the plant and
corrosion testing will be necessary
to study compatibility. Many
reaction mixtures, however, are
incompatible with certain metals,
even though the individual
components may all be compatible
in use tests. It is essential,
therefore to use test the reaction
mixture as well as the individual components for
compatibility with the materials of construction of the
vessel; one company I consulted for failed to do this and
ended up with purple, rather than white product, when
the reaction intermediate picked up iron from the reactor
and formed a coloured complex!
In another case, one company failed to realise that a
CF3
group on an organic molecule may yield traces of HF
in solution, formed in small amounts in byproduct
processes. Since the reaction was being carried out in a
glass-lined reactor, this equipment then became etched,
and had to be removed from the plant and expensively
relined before it was available for manufacturing use
again and was a few months out of commission .
Crystallisation and Polymorphism
Of all the unit operations which cause difficulty on
scale up, crystallisation and drying are the most
prevalent, particularly when the intermediate or final
product is polymorphic or can form solvates(14)
. Of
course in India, the generic pharmaceutical industry is
highly active in investigating alternative crystalline
forms of drugs in order to circumvent existing patents,
or to provide new IP opportunities. However, consistent
manufacture of the desired form on large scale can be a
problem. Key parameters controlling which form is
produced, and the particle size distribution, (PSD, which
determines filterability and drying times) include the
number and level of trace impurities in solution (even as
low as 0.01%), which may vary from batch to batch.
Fine control of the
crystallisation process
(supersaturation, seeding,
cooling profile, presence of
impurities) leaves a lot to be
desired, so batch to batch
variations are expected. The
control of a crystallisation
process needs exact control of
nucleation (by seeding at a
defined supersaturation) and a
When dosing solutions of reagents in
the laboratory, chemists usually add to
the surface of the agitated liquid and this
works fine on small scale. If this is done
on the plant, however, poor mixing may
occur in large reactors. The key is to add
the reagents into a region of high
turbulence, such as close to the tip of the
agitator, using a dip pipe, or to add
reagents via a recirculation loop.
Despite the widespread knowledge
about the hazards of scale up, particularly
of compounds with potentially hazardous
groupings, such as nitro compounds, it is
disturbing to see runaways still occurring
due to poor hazard testing, and poor
knowledge of the thermochemistry in the
process.
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Chemical Industry Digest. July 2010
Scale-Up
programmed cooling programme that allows the crystals
to take up the supersaturation very slowly. Reactor or
filter/centrifuge contamination from previous batches of
the same substance may impact on the ability to produce
the correct crystal form and PSD of the product. . These
issues can also be relevant to the colour chemicals,
agrochemicals and fine chemicals industries, where
specific physical properties of the product are desired for
further processing, such as formulation, or affect the
stability of the product ( eg to oxygen or light).
The additional effect of stir out time/temperature on
crystal form content and PSD, with a subsequent
potential change during filtration/centrifugation
(depending on choice and size of equipment) and drying
(depending on dryer type, temperature, solvent removal
etc) means that batch to batch reproducibility is never
guaranteed. Only by careful laboratory studies of this
interacting factors using statistical methods such as
Design of Experiments can true manufacturing
robustness be achieved.
Optimisation using statistical methods
Many companies in India still carry out process
optimisation using one parameter at a time variations,
whereas the trend elsewhere is to use the Design of
Experiments (DoE) approach, recognising that variables
are rarely independent of each other ( eg rate of addition
and temperature). In these detailed parameter studies it
is important to study variables which affect scale up,
such as dosing time and mixing, and parameters in the
work-up and product isolation as well as in the
reactions. Only by looking at the effect of all these
interacting parameters can a truly optimised process,
which works well on scale and is efficient and robust,
be developed.
For pharmaceutical processes, regulatory authorities
are keen to see the DoE approach used in new
submissions, since it shows that “quality has been
designed into the process” and gives assurance that the
process is robust, and that the manufacturer knows the
design space in which to operate and where the edge of
failure lies. Such data is of course important and
extremely useful for a plant manager operating any
chemical process. Process understanding always leads
to better process control and usually to more successful
scale-up!
Conclusion
The best way to minimise scale up problems is by data
gathering and detailed process understanding. Having
technical staff – both chemists and engineers – who are
well trained with up-to-date knowledge of current
thinking can help with design of better processes with
fewer scale up issues. Using outside help in the form
of consultants with industry experience can be
invaluable for companies wishing to design low-cost
processes which can be easily scaled up, and in
trouble-shooting persistent manufacturing problems.
References
1. T. Laird “Development and Scale-up of Processes for the
Manufacture of Pharmaceuticals” Comprehensive
Medicinal Chemistry. Vol 1, 1989, Pergamon Press;
T. Laird, The Neglected Science of Chemical
Development, Chemistry in Britain, Dec. 1989,
p.1208
2. N.G Anderson, Practical Process Development,
Academic Press 2000
3. K.G. Gadamasetti, Process Chemistry in the
Pharmaceutical Industry, Marcel Dekker, 1999 (Vol 1)
and CRC Press 2007 (with T Braish) (Vol 2)
4. W. Hoyle, Pilot plants and Scale Up of Chemical
Processes, Royal Society of Chemistry, Vols 1 and 2,
1997 and 1999
5. S. Lee and G Robinson, Process Development: Fine
Chemicals from Grams to Kilograms, Oxford Science,
1992
6. M. Williams and G. Quallich, Chem& Ind, 1990, 315;
G Quallich, Chirality, 2005, 17, S120-S126
7. F. Stoessel, Org Process R&D, 1997, 1, 428
8. F Stoessel, Thermal Safety of Chemical Prrocesses; Risk
Assessment and Process Design, Wiley-VCH, 2008
9. www.csb.gov/assets/document/
Morton_Report.pdf
10.E.L. Paul, presentation at 2nd
International
Conference on Scale Up of Chemical Processses,
Scientific Update, 1996
11. E.L. Paul, Y.A.Atiemo-Obeng and S.M.Kresta,
Handbook of Industrial Mixing, Wiley-Interscience,
2004
12.K.J.Carpenter, Chem Eng Sci, 2001, 56, 305-322
13.J.H Atherton and K.J.Carpenter, Process Development,
Physico-Chemical Concepts, Oxford Science, 2000.
Editor’s Note:
Scientific Update LLC regularly conducts conferences and
training courses for industrial chemists and chemical
engineers in chemical development and scale-up.
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