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What do we Learn from Reaction Calorimetry?

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

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 today’s requirements. Thus, both the technology as well as the procedure applied must be adapted to meet today’s needs in full.

2 Safety by Design

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uide 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.

Temperature Difference(Tr - Tj)

Temperature(Tr)

Time

Dosing (Mr)

Accumulation

Heat loss dueto dosing

Maximum Temp.Difference / MaximumFlow of Engery

Reaction Duration

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 (ΔT): Temperature difference between the reactor content and the jacket

Mr: Total Mass of the Reaction

3Safety 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 may suddenly arise for various reasons. These are often caused by inadequate mixing resulting in heat or mass transfer limitations, heat release patterns that don’t match the heat removal of a plant vessel or sub-optimal temperature or dosing profiles that result in reactant accumulation (Figure 2).

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.

qr

Mr

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

4 Safety by Design

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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, ΔTad 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 (ΔTad) 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 ΔTad 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.

Figure 3: Criticality graph

Figure 4: Safety Runaway graph

1 2 4 5Criticality Low High

Tem

pera

ture

MTT80.0 °C

Tprocess40.0 °C

TD24200.0 °C

MTSR153.7 °C

3

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pera

ture

Time

MTSR

Tp

ΔTad

ΔTad

TMRad

Desired Reaction Secondary Reaction

tx (Cooling Failure)

5Safety by Design

Let’s 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.

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.

qr

feed

Mr

No reactant accumulation, dosing controlled

qr

feed

Mr

accumulation

Reactant accumulation

Figure 5: Immediate reaction Figure 6: Delayed reaction

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uide 4 Knowing the True Heat Release Pattern

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.

ExampleReactant 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 ΔT (blue trend) shows that only little reaction seems to take place during the addition.

After the catalyst is added, the reaction picks up and becomes quite strong (visualized by the ΔT 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).

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).

By converting the ΔT trend into heat flow and compensating for the heat of dosing (energy consumed by heating the added reactant) the heat removal as a function of time (orange trend) is obtained. Integrating the curve between the start and end of the reaction provides us with the reaction enthalpy (ΔHr = -123.1 kJ/mol). Figure 8 shows the way the energy was flowing across the reactor wall with a maximum of over 400 W. Following the heat flow trend (orange) it also becomes clear that the catalyst addition didn’t impact the reaction at all, but the reaction itself has a significant induction time and a huge accumulation.

ΔTMr

qflow

123.1 kJ

Tr

Time (hh:mm:ss)

T r-T

j (K)

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0

Mr (

g) Tr (°C)

qr _hf (W

)

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03:20:00 03:30:00 03:40:00 03:50:00 04:00:00

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ΔTMr

Catalyst Added

Tr

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Tr (°C)

qr _hf (W

)

Mr (

g)

T r-T

a (K

)

Figure 7: Course of the reaction

Figure 8: Heat flow across reactor wall

7Safety 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 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).

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

1 Reaction shows some induction2 Catalyst, added after dosing was

completed, had no impact on the reaction itself

3 Current process shows a highly hazardous reagent accumulation of over 87 %

4 True heat release pattern repre-senting the chemical reaction profile

5 Maximum heat release rate is not 400 W as the heat removal sug-gested, but almost 1300 W

This information is very different from what was shown in the beginning and demonstrates how reaction calorimetry can help identify effects that wouldn’t otherwise be seen.

ΔTMr

qr

Tr

Time (hh:mm:ss)

T r-T

a (K

)

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Mr (

g) Tr (°C)

qr _hf (W

)

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123 kJ

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CatalystAdded

3 Accumulation

4 True Heat Flow Profile

5 Max. HeatFlow

ΔTMr

qaccu increasing

qaccu

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Time (hh:mm:ss)

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a (K

)

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r (g) Tr (°C)

qr _hf (W

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0.23568 kJ

qaccu decreasing

Figure 9: Heat accumulation over the course of the reaction

Figure 10: True heat release pattern of the reaction

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Adiabatic Temperature Increase

The best way to control a reaction depends on the scale of the reac-tion - 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 dis-pensing of the substrate.

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).

A single experiment in a reaction calorimeter (which doesn’t require much more time than a normal experiment) provides a wealth of information highlighting the course of the reaction as well as the ex-change of heat with the surround-ing. An excerpt of the information is listed in Table 1.

What can be concluded from the calorimetry information obtained?

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 53 K

MTSR 83 °C – Above boiling point of solvent

Table 1: Experiment Evaluation. Summary of relevant data.

Figure 11: Heat flow pattern of reduction reaction

Time (hh:mm:ss)

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°C)

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g)

U (W)

cpr (°K)

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)

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Heat Flow (qr)

Enthalpy (46.2 kJ)

Specific Heat (cpr)

Max. Heat Flow (63.2 W)

Heat Transfer Coefficient (U) 46.188 kJ

Tr

• 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 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 indi-cated 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 out-put, the accumulation of reagents and the batch time are identified targets to improve making the process safe at scale.

9Safety 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.

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.

Chemical Synthesis Chemical or

Physical Event Detection

Scale-upLab to Plant

Process SafetyScreening for Scalability

Risks

Process SafetyFull Studies

Mettler-Toledo AutoChem, Inc.7075 Samuel Morse DriveColumbia, MD 21046 USATelephone +1 410 910 8500Fax +1 410 910 8600 Email autochem@mt.com

Subject to technical changes©11/2013 Mettler-Toledo AutoChem, Inc.

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 ResourcesWebinars

- 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

www.mt.com/HFCalFor more information