Calorimetry Guide. Safety by Design What do we Learn from Reaction Calorimetry?

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1 Calorimetry Guide 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 today s requirements. Thus, both the technology as well as the procedure applied must be adapted to meet today s 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

2 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) Dosing (Mr) Temperature (Tr) Heat loss due to dosing Time Figure 1. Information that can be obtained from an experiment looking at basic trends T r : Temperature of the reactor content T j : Temperature of the jacket T r - T j (ΔT): Temperature difference between the reactor content and the jacket : Total Mass of the Reaction 2

3 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). q r 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. 3

4 Calorimetry Guide 3 What is the Value of Reaction Calorimetry? 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? Temperature Figure 3: Criticality graph T D24. C MTSR C MTT 8. C T process 4. C Criticality Low High 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. MTSR T p Temperature Desired Reaction t x (Cooling Failure) ΔT ad Secondary Reaction TMR ad ΔT ad Combining these data allow the creation of the Runaway or Criticality Graph that graphically represents the hazardous potential. Figure 4: Safety Runaway graph Time 4

5 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. feed feed accumulation q r q r No reactant accumulation, dosing controlled Figure 5: Immediate reaction 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. 5

6 Calorimetry Guide 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. Example Reactant A (in excess) is in the reactor at 4 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 4 C to 96 C at a maximum (Figure 7). Tr-Ta (K) 15 5 Mr (g) 1 Catalyst Added ΔT T r 3:2: 3:3: 3:4: 3:5: 4:: Time (hh:mm:ss) Figure 7: Course of the reaction qr_hf (W) Tr ( C) 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 4 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 15 1 by heating the added reactant) the heat removal as a function of time (orange trend) is obtained. Integrating the curve between 5 q flow the start and end of the reaction provides us with the reaction ΔT enthalpy (ΔHr = kj/mol). T Figure 8 shows the way the energy r was flowing across the reactor Time (hh:mm:ss) wall with a maximum of over Figure 8: Heat flow across reactor wall 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. Tr-Tj (K) Mr (g) kj 3:2: 3:3: 3:4: 3:5: 4:: qr_hf (W) 3 Tr ( C) 6

7 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 1) showing that the: 1 Reaction shows some induction 2 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 representing the chemical reaction profile 5 Maximum heat release rate is not W as the heat removal suggested, but almost 13 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. Tr-Ta (K) Tr-Ta (K) Mr (g) Mr (g) q accu increasing ΔT 2 ΔT q accu Catalyst Added Induction 3:2: 3:3: 3:4: 3:5: 4:: Time (hh:mm:ss) Figure 9: Heat accumulation over the course of the reaction 3:2: 3:3: 3:4: 3:5: 4:: Time (hh:mm:ss) Figure 1: True heat release pattern of the reaction 3 Accumulation kj q accu decreasing q r T r T r 123 kj Max. Heat Flow True Heat Flow Profile qr_hf (W) qr_hf (W) 3 3 Tr ( C) Tr ( C) 7

8 Calorimetry Guide 5 Understanding Maximum Heat Release Rate and Adiabatic Temperature Increase 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. In this example methyl-isonicotinate was reduced with NaBH 4 in the presence of ethanol as solvent. By adding solid NaBH 4, the reaction immediately starts vigorously and the heat release peaks at 63 W, equivalent to 119 W/L (Figure 11). Mr (g) Tr ( C) Heat Transfer Coefficient (U) Specific Heat (cpr) Mr 3:2: 3:3: 3:4: 3:5: 4:: Time (hh:mm:ss) Figure 11: Heat flow pattern of reduction reaction Max. Heat Flow (63.2 W) Heat Flow (qr) Tr Enthalpy (46.2 kj) kj cpr ( K) 3 qr (W) U (W) 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 exchange of heat with the surrounding. An excerpt of the information is listed in Table 1. Methyl-isonicotinate Integral Enthalpy qmax Accumulation Tad MTSR 25.9 g (.1851 mol) kj kj/mole High 63.2 W = 119 W/L Too High (typically 3 W/L can be removed in plant) kj = 96.7 % Dangerous 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 9 % is seen indicating a potential safety issue Assuming a cooling failure at exactly the time when all the NaBH 4 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 3 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. 8

9 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. 9

10 Sources and References [1] F. Stoessel, Thermal Safety of Chemical Processes, Wiley-VCH, Weinheim, (8) [2] H. Fierz, P. Finck, G. Giger, R. Gygax, The Chemical Engineer, 9, (1984) [3] F. Brogli, P. Grimm, M. Meyer, H. Zubler, Prep. 3rd Int. Symp. Safety Promotion and Loss Prevention, Basle, 665, (198) [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: Brochures - Process Safety Brochure To download brochures or datasheets, please visit: Websites - Process Safety Application Website ( - Calorimetry Product Page ( Contact the Author - Urs Groth, autochem@mt.com Mettler-Toledo AutoChem, Inc. 775 Samuel Morse Drive Columbia, MD 2146 USA Telephone Fax autochem@mt.com For more information Subject to technical changes 11/213 Mettler-Toledo AutoChem, Inc.