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
2 Key Information for Moving a Process from Lab to Plant
3 What is the Value of Reaction Calorimetry?
4 Knowing the True Heat Release Pattern
5 Understanding Maximum Heat Release Rate and
Adiabatic Temperature Increase
6 Conclusions
 1 Screening for Scalability Risks
Calorimetry Guide

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

2 Safety by Design
 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 Mr
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 qr
vessel or sub-optimal temperature
or dosing profiles that result in
Figure 2. Heat flow trend with delay compared to dosing
reactant accumulation (Figure 2). (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 3
 3 What is the Value of Reaction Calorimetry?
Calorimetry Guide

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 TD24

in a simple experiment, crucial 200.0 C
information (such as heat transfer,
heat capacity, heat release rates, MTSR
153.7 C

Temperature
enthalpy, conversion) can be
derived. Subsequently, these are
further processed to obtain more
MTT
specific details (i.e. accumulation 80.0 C
of energy, Tad and MTSR) and to
create the Runaway and Criticality Tprocess
Graph (Figures 3 and 4). 40.0 C

Criticality Low 1 2 3 4 5 High

But, what is learnt from Figure 3: Criticality graph
these data?

The adiabatic temperature increase

Desired Reaction Secondary Reaction
(Tad) for example is commonly
used to characterize accumulated
energy related to the hazardous
Temperature

potential of a chemical reaction.

It describes the maximum Tad
temperature increase of the reaction
tx (Cooling Failure)
mass in case of a cooling failure.
Knowing Tad we can estimate
the Maximum Temperature of the
MTSR
Synthesis Reaction (MTSR) of the
desired reaction. Consequently, TMRad
possible undesired secondary Tad
reactions and the temperature at
which Time-to-Maximum-Rate is Tp
24 h can be evaluated.

Combining these data allow

the creation of the Runaway or
Criticality Graph that graphically Time
Figure 4: Safety Runaway graph
represents the hazardous potential.

4 Safety by Design
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
qr
No reactant accumulation, dosing controlled Reactant accumulation
Figure 5: Immediate reaction 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 off-
gas, 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 5
 4 Knowing the True Heat Release Pattern
Calorimetry Guide

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.

2000 1400
After the catalyst is added, the 200 500
Catalyst Added 1200
reaction picks up and becomes
1000
quite strong (visualized by the 150
1500
400
800
T trend in blue). As the heat
Tr-Ta (K)

600
production becomes larger it
Mr (g)

300

qr_hf (W)
100

Tr (C)
1000 400
exceeds the heat removal capacity
200
of the cooling system and the 50 200
0
excessive heat gets accumulated 500
T -200
in the reaction mass. Hence, the 0
Mr 100

temperature (red trend) increases Tr -400

100

from 40 C to 96 C at a maximum 03:20:00 03:30:00 03:40:00 03:50:00 04:00:00

Time (hh:mm:ss)
(Figure 7). Figure 7: Course of the reaction

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 1400

By converting the T trend into 200 500
1200
heat flow and compensating for the
heat of dosing (energy consumed 150
1500
1000 400

by heating the added reactant) 800

the heat removal as a function of 600 300

Tr-Tj (K)

100
Mr (g)

time (orange trend) is obtained.

qr_hf (W)

Tr (C)

1000 400
Integrating the curve between 50 qow 200 200
the start and end of the reaction
0
provides us with the reaction 500
T
0 -200
enthalpy (Hr = -123.1 kJ/mol). Mr 100

Tr -400
Figure 8 shows the way the energy 100

was flowing across the reactor 03:20:00 03:30:00 03:40:00 03:50:00 04:00:00
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.

6 Safety by Design
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.

As mentioned earlier, once the heat 2000 0.23568 kJ 1400

500
200
production is dominant over heat 1200
removal the temperature begins to
150 1000 400
rise. The resulting accumulation is 1500
800
represented in the first part of the qaccu increasing
600

Tr-Ta (K)
300
trend qaccu (orange). Once heat 100

Mr (g)

qr_hf (W)

Tr (C)
1000 400
removal becomes larger than the
qaccu decreasing
heat production, accumulation 50
qaccu 200 200

diminishes and the energy stored 0

500
is released into the jacket to finally 0
T -200
Mr 100
become zero again (Figure 9). Tr -400
100
03:20:00 03:30:00 03:40:00 03:50:00 04:00:00
Combining heat flow and heat Time (hh:mm:ss)
accumulation provides scientists Figure 9: Heat accumulation over the course of the reaction
with the true heat release pattern
(Figure 10) showing that the:
2 Catalyst
Added
1 Reaction shows some induction 3 Accumulation
123 kJ
2 Catalyst, added after dosing was 2000 1400
200 Max. Heat 500
completed, had no impact on the 5 Flow
1200
reaction itself 1000
150 400
3 Current process shows a highly 1500
800
hazardous reagent accumulation
4 True Heat 600
Tr-Ta (K)

100 300
of over 87 % 1 Induction Flow Prole
Mr (g)

qr_hf (W)

Tr (C)
1000 400
4 True heat release pattern repre-
senting the chemical reaction 50
qr 200 200

profile 500
0

5 Maximum heat release rate is not 0

T -200
Mr 100
400 W as the heat removal sug- Tr -400
100
gested, but almost 1300 W
03:20:00 03:30:00 03:40:00 03:50:00 04:00:00
Time (hh:mm:ss)
This information is very different Figure 10: True heat release pattern of the reaction
from what was shown in the
beginning and demonstrates
how reaction calorimetry can
help identify effects that wouldnt
otherwise be seen.

Safety by Design 7
 5 Understanding Maximum Heat Release Rate and
Calorimetry Guide
Adiabatic Temperature Increase

The best way to control a reaction Heat Transfer Coefcient (U) 46.188 kJ

depends on the scale of the reac- 70 2.8

tion - and may be different between 800

Max. Heat Flow (63.2 W) 500
2.7
Specic
small and large scale. At small 60 Heat (cpr) 2.6
scale, it is often simpler to add 400
700 2.5
solids to the stirred solution of the

qr (W)
substrate. At large scale, the best 50
Heat Flow (qr) 2.4
300

Tr (C)
Mr (g)
solution is usually starting a solid

cpr (K)
600 2.3
suspension and subsequent dis-

U (W)
40 Enthalpy (46.2 kJ) 2.2
200
pensing of the substrate.
500 2.1
Tr
In this example methyl-isonicotinate 30 2.0 100
Mr
was reduced with NaBH4 in the 400 1.9
presence of ethanol as solvent. By 03:20:00 03:30:00 03:40:00 03:50:00 04:00:00
Time (hh:mm:ss)
adding solid NaBH4, the reaction
immediately starts vigorously and Figure 11: Heat flow pattern of reduction reaction

the heat release peaks at 63 W,

equivalent to 119 W/L (Figure 11).
Methyl-isonicotinate 25.9 g (0.1851 mol)
A single experiment in a reaction Integral 46.19 kJ
calorimeter (which doesnt require Enthalpy -249.54 kJ/mole High
much more time than a normal
qmax 63.2 W = 119 W/L Too High
experiment) provides a wealth of (typically 30 W/L can be removed in plant)
information highlighting the course Accumulation 44.65 kJ = 96.7 % Dangerous
of the reaction as well as the ex- Tad 53 K
change of heat with the surround- MTSR 83 C Above boiling point of solvent
ing. An excerpt of the information is Table 1: Experiment Evaluation. Summary of relevant data.
listed in Table 1.

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 accumula-
tion of more than 90 % is seen
indicating a potential safety is-
sue
Assuming a cooling failure at
exactly the time when all the
NaBH4 is added, the adiabatic
temperature increase would
amount to around 53 K.
Therefore, the Maximum With a reaction time of almost
Temperature of the Synthesis three hours the batch time is
Reaction (MTSR) would result in quite long and may become a
about 83 C which is just above cost issue
the boiling point of the solvent.
With a maximum of In other words, changing from a
approximately 119 W/L the batch to a semi-batch reaction,
reaction is clearly more powerful reducing the maximum heat out-
than a typical production vessel put, the accumulation of reagents
can handle (approximately 30 and the batch time are identified
W/L) targets to improve making the
Heat transfer coefficient (as indi- process safe at scale.
cated in blue) changes by about
5 % and is, therefore, not very
significant

8 Safety by Design
 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 Process Safety Process Safety

Chemical or Scale-up Screening for Scalability
Lab to Plant Full Studies
Physical Event Detection Risks

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 9
 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
www.mt.com/HFCal
For more information
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.