Calorimetry Guide

Safety by Design
What do we Learn from Reaction Calorimetry?
Developing new compounds and transferring them to manufacturing requires an
understanding of the chemical route, process and all its parameters. Therefore,
knowing the scale-up as well as the safety-related parameters is equally important to
ensure a chemical process is safe at scale. Generally, the earlier critical conditions
are recognized, the easier and faster the process can be adjusted and properly
designed and implemented. The experiment results may even require scientists to
choose a different route.
Ultimately, reducing time and resources as well as speeding the chemical workflow is the
result of acquiring better information earlier.
In a simplified approach, the chemical and process development workflow begins with
Chemical Synthesis in which the chemical and physical information and chemical route
are key. Often a small quantity of the product is made for testing purposes as an integral
part of this step before the development workflow continues.
Applying traditional development tools no longer supports todays requirements. Thus,
both the technology as well as the procedure applied must be adapted to meet todays
needs in full.

Contents
1

Screening for Scalability Risks

Key Information for Moving a Process from Lab to Plant

What is the Value of Reaction Calorimetry?

Knowing the True Heat Release Pattern

Understanding Maximum Heat Release Rate and

Adiabatic Temperature Increase

Conclusions

Calorimetry Guide

1 Screening for Scalability Risks

A thorough understanding of the chemistry, physical properties of the reactants and the
reaction mass is essential. Recently, synthesis workstations have become an increasingly
common tool as they not only ensure accurate and reproducible experiments, but provide a
wealth of information at the same time.
A synthesis workstation, such as EasyMax or OptiMax, provides specifics including start and
end of a reaction and indicates the existence of induction. Information about precipitation
or crystallization during the course of the reaction is provided, along with mechanistic
information.
Looking at the temperature difference Tr - Tj (yellow curve; Figure 1), which is an indicator for
the course of the reaction, a qualitative assessment of the power of a reaction as well as the
possible accumulation of energy can be made. In addition, a wealth of other information can
be derived from the basic trends, such as start/end of a reaction, induction period or duration
of the reaction. It also becomes obvious whether or not reactants have been accumulated.
Although these are estimates and cannot be accurately quantified at this point, a number of
conclusions can be drawn identifying or even eliminating some of the scalability risks.
Broadly speaking, the process can already be separated into not critical, possibly critical
and highly critical. This means that Go/NoGo decisions can be taken early in development
saving time, eliminating waste of precious reagents, and avoiding unnecessary detours.

Reaction Duration
Accumulation

Maximum Temp.
Difference / Maximum
Flow of Engery

Temperature Difference
(Tr - Tj)

Heat loss due

to dosing

Dosing (Mr)
Temperature
(Tr)
Time
Figure 1. Information that can be obtained from an experiment looking at basic trends

Tr: Temperature of the reactor content

Tj: Temperature of the jacket
Tr - Tj (T): Temperature difference between
the reactor content and the jacket

Safety by Design

Mr: Total Mass of the Reaction

 2 Key Information for Moving a Process

from Lab to Plant
Meeting the relevant process objectives is critical for manufacturing a product successfully.
However, engineers involved in transferring processes from lab to plant understand the
importance of considering thermal risks and hazardous potential of a chemical process
more precisely.
As a reaction is scaled from lab
to plant, scalability problems
may suddenly arise for various
reasons. These are often caused
by inadequate mixing resulting in
heat or mass transfer limitations,
heat release patterns that dont
match the heat removal of a plant
vessel or sub-optimal temperature
or dosing profiles that result in
reactant accumulation (Figure 2).

Mr

qr
Figure 2. Heat flow trend with delay compared to dosing
(induction resulting in accumulation of reagent and energy)

Furthermore, crystallization, spontaneous precipitation, fouling or viscosity changes may be

identified as additional potential for hazardous situations.
The costs associated with these problems are far greater than the cost of adequately
evaluating and solving the issues during process development. Applying reaction calorimetry
means that it is possible to obtain the respective information of what is going on faster or
even allows immediate action to be taken.
In other words, examining the chemical process with a reaction calorimeter that provides
accurate and reliable information of non-scalable conditions and potential risks in a
quantitative manner is required in order to characterize the criticality of a chemical process,
and subsequently make it safe at scale.

Safety by Design

Reaction calorimetry measures the heat released from a chemical reaction or physical
process under process-like conditions and provides the fundamentals of the thermochemistry
and kinetics of a reaction.
From the basic data determined
in a simple experiment, crucial
information (such as heat transfer,
heat capacity, heat release rates,
enthalpy, conversion) can be
derived. Subsequently, these are
further processed to obtain more
specific details (i.e. accumulation
of energy, Tad and MTSR) and to
create the Runaway and Criticality
Graph (Figures 3 and 4).
But, what is learnt from
these data?
The adiabatic temperature increase
(Tad) for example is commonly
used to characterize accumulated
energy related to the hazardous
potential of a chemical reaction.
It describes the maximum
temperature increase of the reaction
mass in case of a cooling failure.
Knowing Tad we can estimate
the Maximum Temperature of the
Synthesis Reaction (MTSR) of the
desired reaction. Consequently,
possible undesired secondary
reactions and the temperature at
which Time-to-Maximum-Rate is
24 h can be evaluated.
Combining these data allow
the creation of the Runaway or
Criticality Graph that graphically
represents the hazardous potential.

Safety by Design

TD24
200.0 C

Temperature

MTSR
153.7 C

MTT
80.0 C
Tprocess
40.0 C

Criticality

Low

High

Figure 3: Criticality graph

Desired Reaction

Temperature

Calorimetry Guide

3 What is the Value of Reaction Calorimetry?

Secondary Reaction

Tad
tx (Cooling Failure)

MTSR
Tad

TMRad

Tp

Figure 4: Safety Runaway graph

Time

Lets assume a process is potentially subject to accumulating unreacted reagent which may
lead to a potentially hazardous situation. If so, control over the reaction may be lost, in case
of a cooling failure, which in the worst case leads to a runaway reaction.
Reaction calorimetry provides the ability to determine the heat flow rate as a function of the
reagent addition rate - enabling the determination of whether the reaction is controlled by
the feed (Figure 5) or if significant reactant accumulation occurs (Figure 6) that results in
increased risk of a runaway.

feed

feed

accumulation

qr

Mr

Mr
No reactant accumulation, dosing controlled
Figure 5: Immediate reaction

qr
Reactant accumulation
Figure 6: Delayed reaction

Assuming accumulation is detected in a reaction that takes place in solution, reaction

kinetics may simply be slow. Increase of temperature, changing the concentration, using a
different solvent or catalyst etc. may increase the speed of the reaction and thus, reduce the
accumulation.
If accumulation is observed and the reaction mass is heterogeneous, the reaction may be
mass transfer limited. If this is the case, increasing the stirring speed may improve mass
transfer which increases the reaction rate and reduces the accumulation.
Reducing accumulation is synonymous with reducing the hazard potential at scale.
Depending on the reaction conditions (for example whether or not the reaction produces offgas, the viscosity changes drastically, a strong heat peak is observed, precipitation occurs
spontaneously etc.), the process must be investigated more thoroughly.
While information from a synthesis workstation delivers qualitative and simpler information
(which is often sufficient), reaction calorimetry describes a chemical process in detail, and
is quantitative and accurate. As a result, reaction calorimetry is one of the most important
sources of information for scale-up, process safety screening and process safety allowing
scientists and engineers to make the appropriate decisions to create robust processes and
ensure products are manufactured safely according to plant capabilities.

Safety by Design

From a scalability point of view, it is not only a question of how much heat is released,
but also HOW the heat is released. In other words, even when enthalpy, the heat transfer
coefficient, the specific heat of the reaction mass etc. are known, the real heat release pattern
is not necessarily understood at this point.
Example
Reactant A (in excess) is in the reactor at 40 C isothermally whereas Reactant B is added
over a period of 15 minutes (green trend). After dosing was completed, a catalyst was added.
The T (blue trend) shows that only little reaction seems to take place during the addition.
200

150

1400

2000

Catalyst Added

500

1200
1000

1500

400

800

Mr (g)

600

1000

400
200

50

500
0

03:30:00

Figure 7: Course of the reaction

200

Mr

100
03:20:00

300

Tr (C)

100

qr_hf (W)

After the catalyst is added, the

reaction picks up and becomes
quite strong (visualized by the
T trend in blue). As the heat
production becomes larger it
exceeds the heat removal capacity
of the cooling system and the
excessive heat gets accumulated
in the reaction mass. Hence, the
temperature (red trend) increases
from 40 C to 96 C at a maximum
(Figure 7).

Tr-Ta (K)

Calorimetry Guide

4 Knowing the True Heat Release Pattern

03:40:00

-200

Tr
03:50:00

100

-400
04:00:00

Time (hh:mm:ss)

Once, the reaction becomes less powerful the heat release slows down and the heat removal
capacity becomes dominant over the heat production. Subsequently, the accumulated heat
is released into the jacket which causes the temperature to go back to its target value of 40
C. However, all of the above is qualitative information indicating possible issues or threats.
For more accurate, quantitative conclusions heat flow, with all its side effects, needs to be
understood (Figure 8).
2000

123.1 kJ

1000

400

800
600

Mr (g)

Tr-Tj (K)

Safety by Design

500

1200

400
200

300

Tr (C)

1400

qr_hf (W)

200
By converting the T trend into
heat flow and compensating for the
150
heat of dosing (energy consumed
1500
by heating the added reactant)
the heat removal as a function of
100
time (orange trend) is obtained.
1000
Integrating the curve between
qow
50
the start and end of the reaction
500
provides us with the reaction
T
0
Mr
enthalpy (Hr = -123.1 kJ/mol).
Tr
Figure 8 shows the way the energy
100
03:20:00
03:30:00
03:40:00
03:50:00
was flowing across the reactor
Time (hh:mm:ss)
wall with a maximum of over 400
Figure 8: Heat flow across reactor wall
W. Following the heat flow trend
(orange) it also becomes clear that the catalyst addition didnt impact the reaction at all, but
the reaction itself has a significant induction time and a huge accumulation.

200

0
-200
-400
04:00:00

100

Figure 8 provides insight into how the energy was removed by the cooling jacket and
what the overall turnover of energy is. But is this also identical to the heat evolution by the
chemical reaction?
To better understand the heat evolution of the chemical reaction, the temperature change of
the reaction mass - caused by the accumulation of heat (not identical to the accumulation of
reactants, though!) needs to be analyzed.

200

0.23568 kJ

2000

100

1000
1500

600

1000

400

qaccu decreasing

qaccu

50

500

-200

Mr

Tr

03:30:00

03:40:00

03:50:00

100

04:00:00

Time (hh:mm:ss)

Figure 9: Heat accumulation over the course of the reaction

2 Catalyst
Added

200

150

3 Accumulation
123 kJ

2000

1400

Max. Heat
5 Flow

500

1200
1000

1500

400

800
100

Heat
4 True
Flow Prole

1 Induction

600

1000

400
200

qr

50

300

Tr (C)

200

-400

qr_hf (W)

03:20:00

Mr (g)

200

300

Tr-Ta (K)

Reaction shows some induction

Catalyst, added after dosing was
completed, had no impact on the
reaction itself
Current process shows a highly
hazardous reagent accumulation
of over 87 %
True heat release pattern representing the chemical reaction
profile
Maximum heat release rate is not
400 W as the heat removal suggested, but almost 1300 W

400

800

qaccu increasing
Mr (g)

Tr-Ta (K)

150

Tr (C)

500

1200

100

Combining heat flow and heat

accumulation provides scientists
with the true heat release pattern
(Figure 10) showing that the:

1400

qr_hf (W)

As mentioned earlier, once the heat

production is dominant over heat
removal the temperature begins to
rise. The resulting accumulation is
represented in the first part of the
trend qaccu (orange). Once heat
removal becomes larger than the
heat production, accumulation
diminishes and the energy stored
is released into the jacket to finally
become zero again (Figure 9).

200

500

Mr

100
03:20:00

03:30:00

03:40:00

-200

Tr
03:50:00

100

-400
04:00:00

Time (hh:mm:ss)

This information is very different

from what was shown in the
beginning and demonstrates
how reaction calorimetry can
help identify effects that wouldnt
otherwise be seen.

Figure 10: True heat release pattern of the reaction

Safety by Design

Heat Transfer Coefcient (U)

46.188 kJ

70
800
60

2.8

Max. Heat Flow (63.2 W)

Specic
Heat (cpr)

2.6

700

Tr (C)

Mr (g)

2.4
2.3

Enthalpy (46.2 kJ)

40

2.2

A single experiment in a reaction

calorimeter (which doesnt require
much more time than a normal
experiment) provides a wealth of
information highlighting the course
of the reaction as well as the exchange of heat with the surrounding. An excerpt of the information is
listed in Table 1.

300

200

U (W)

Heat Flow (qr)

2.1

500

In this example methyl-isonicotinate

was reduced with NaBH4 in the
presence of ethanol as solvent. By
adding solid NaBH4, the reaction
immediately starts vigorously and
the heat release peaks at 63 W,
equivalent to 119 W/L (Figure 11).

400

2.5
50

600

500

2.7

qr (W)

The best way to control a reaction

depends on the scale of the reaction - and may be different between
small and large scale. At small
scale, it is often simpler to add
solids to the stirred solution of the
substrate. At large scale, the best
solution is usually starting a solid
suspension and subsequent dispensing of the substrate.

cpr (K)

Calorimetry Guide

5 Understanding Maximum Heat Release Rate and

Adiabatic Temperature Increase

Tr

30

400

2.0

Mr
03:20:00

100

1.9
03:30:00

03:40:00

03:50:00

04:00:00

Time (hh:mm:ss)

Figure 11: Heat flow pattern of reduction reaction

Methyl-isonicotinate 25.9 g (0.1851 mol)

Integral

46.19 kJ

Enthalpy

-249.54 kJ/mole High

qmax

63.2 W = 119 W/L Too High

(typically 30 W/L can be removed in plant)

Accumulation

44.65 kJ = 96.7 % Dangerous

Tad
MTSR

53 K
83 C Above boiling point of solvent

Table 1: Experiment Evaluation. Summary of relevant data.

What can be concluded from the calorimetry information obtained?

In general, batch reactions are
typically more prone to issues
than semi-batch or continuous
processes
Adding solids raises the concern
of mixing issues occurring
Because the reaction is run in
batch mode a large accumulation of more than 90 % is seen
indicating a potential safety issue
Assuming a cooling failure at
exactly the time when all the
NaBH4 is added, the adiabatic
temperature increase would
amount to around 53 K.

Safety by Design

Therefore, the Maximum

Temperature of the Synthesis
Reaction (MTSR) would result in
about 83 C which is just above
the boiling point of the solvent.
With a maximum of
approximately 119 W/L the
reaction is clearly more powerful
than a typical production vessel
can handle (approximately 30
W/L)
Heat transfer coefficient (as indicated in blue) changes by about
5 % and is, therefore, not very
significant

With a reaction time of almost

three hours the batch time is
quite long and may become a
cost issue
In other words, changing from a
batch to a semi-batch reaction,
reducing the maximum heat output, the accumulation of reagents
and the batch time are identified
targets to improve making the
process safe at scale.

 6 Conclusions
Calorimetric information is crucial when determining how chemical reactions can be
transferred safely from the lab to the plant. Along with the chemical development workflow,
reaction calorimetry provides the basic information needed for each of the individual steps
and is subsequently converted into information to evaluate the risk, scalability and criticality
of a process. Reaction calorimetry helps identify issues related to heat and mass transfer
or mixing, and allows the determination of the correct temperature, stirring or dosing profile
online. It also uncovers unexpected behavior, e.g. temporary viscosity changes, precipitation,
fouling etc and makes other scalability issues (such as reagent accumulation) visible and
quantifiable.
Depending on the development stage, different types or quality of information is required.
METTLER TOLEDO offers a range of calorimetry workstations at different volumes, temperature
ranges, and capabilities, as well as optional accessories.

Chemical Synthesis
Chemical or
Physical Event Detection

Scale-up

Lab to Plant

Process Safety

Screening for Scalability

Risks

Process Safety
Full Studies

EasyMax HFCal is typically used for calorimetric screening and to identify scalability issues
while OptiMax HFCal is ideal for scale-up and safety investigations.
The industry standard RC1e is suitable for comprehensive investigation in process safety and
is characterized by an unmatched accuracy and precision.

Safety by Design

 Sources and References

[1] F. Stoessel, Thermal Safety of Chemical Processes, Wiley-VCH, Weinheim, (2008)
[2] H. Fierz, P. Finck, G. Giger, R. Gygax, The Chemical Engineer 400, 9, (1984)
[3] F. Brogli, P. Grimm, M. Meyer, H. Zubler, Prep. 3rd Int. Symp. Safety Promotion and Loss
Prevention, Basle, 665, (1980)
[4] P. Hugo, J. Steinbach, F. Stoessel, Chemical Engineering Science, 43, 2147, (1988)

Additional Resources
Webinars
- Francis Stoessel: Avoiding Incidents at Scale-up: Is Your Process Resistant
Towards Maloperation?
- Stephen Rowe: Safe Scale-up of Chemical Processes: Holistic Strategies Supported
by Modern Tools
For a complete listing of webinars, please visit: www.mt.com/ac-webinars
Brochures
- Process Safety Brochure
To download brochures or datasheets, please visit: www.mt.com/process-safety
Websites
- Process Safety Application Website (www.mt.com/process-safety)
- Calorimetry Product Page (www.mt.com/hfcal)
Contact the Author
- Urs Groth, autochem@mt.com

Mettler-Toledo AutoChem, Inc.

7075 Samuel Morse Drive
Columbia, MD 21046 USA
Telephone +1 410 910 8500
Fax +1 410 910 8600
Email autochem@mt.com

Subject to technical changes

11/2013 Mettler-Toledo AutoChem, Inc.

www.mt.com/HFCal
For more information