The key objective in Process Development is to define the conditions in which the reaction should be operated to minimize possible hazards and risk. It requires an understanding of the potential sources of thermal runaway risk, building on the preliminary screening studies carried out in Discovery, and an understanding of the chemistry of the process itself. This enables the process safety chemist to classify the criticality of the reaction, and what are safe operating conditions needed to mitigate the hazards identified.
It can be split into four main areas of investigation, the first three of which are illustrated in the reaction profile in Figure 4:
1. Desired Reaction
2. Thermal Runaway of Reaction
3. Decomposition/Second Thermal Runaway?
4. How Can the Operating Conditions be Modified to Reduce the Risks Identified?
Figure 4: Key parameters to determine for assessing the criticality of a reaction
1. Desired Reaction
Here, the key pieces of information to extract are:
- What is the energy evolved in the reaction?
- What is the subsequent rise in temperature when no additional cooling is applied to keep reaction isothermal?
- What is the cooling capacity required in the manufacturing plant to deal with this and keep the reaction isothermal?
In the following example of a semi-batch esterification reaction process, acetic anhydride was added at a 2ml/minute dosing rate over 50 minutes to methanol in a 1L reactor in the Simular, a reaction calorimeter, while the temperature was held isothermally at 30 ⁰C. Figure 5 shows the:
- Reaction power (this is essentially the rate of heat generation) [pink trace]
- Energy released [blue trace]
- Feed rate [yellow trace]
Figure 5: Esterification reaction at 30 ⁰C, 2ml/min feed rate
Under these conditions, it can be seen that the reaction power reaches a maximum of 15W. This means a cooling capacity of at least 15W is required to keep this reaction isothermal. As the reaction was performed in a 1L reactor, this can be directly scaled up for a 2000 L pilot reactor, indicating that a 30kW (30,000W) cooling capacity is required for the larger system.
Thus, reaction calorimetry enables the heat evolved during the desired reaction to be measured, which is then used to calculate the reaction power and subsequently the cooling capacity required to keep the system at the desired reaction temperature, Tp.
2. Thermal Runway of Reaction
However, what happens if there is a plant failure? What is the maximum possible temperature the desired reaction will run to if, for example, the cooling used to maintain an isothermal reaction fails? The key questions to answer in this area of investigation are:
- what is the Maximum Temperature of Synthesis Reaction (MTSR)?
- what is the Time to Maximum Rate (TMRr)?
Determining these parameters, which are illustrated schematically in Figure 6, enables one to assess whether there will be enough time and sufficient emergency cooling capacity to deal with the increase in temperature.
Figure 6: Schematic illustrating the key parameters of the thermal runaway of reaction
Critical to determining these parameters is an understanding of the kinetics of the desired reaction. In a kinetics-controlled reaction there is a risk of reagent accumulation if the reaction is too slow. Effectively, this means that there is potential energy stored within the reactor, which could be released adiabatically in the event of a cooling failure. This scenario is illustrated schematically in Figure 7. This could lead to a thermal runaway if not dealt with, and perhaps trigger undesired reactions or decompositions and further thermal runaways.
Figure 7: The risk of accumulated reagent
Reaction calorimetry can also be used to determine the kinetics of the reaction, which enables the level of reagent in the reactor at any given time to be predicted. Returning to the previous example in Figure 5, it can be seen that although the reagent feed stops at 110 minutes, the energy output from the reaction continues for a further 240 minutes. The rate of heat generation does not drop to zero – signaling the end of the reaction – until the 350-minute mark. This indicates that there is unconsumed reagent in the reactor at the point the feed rate stops, which then continues to react until equilibrium is reached. Turning to the energy released, we see that only 50% (34.6 kJ) of the total energy released over the course of the reaction was released at the point the feed rate stops. We can extrapolate from this that only 50% of the reagent has been consumed at the point the feed rate stops.
The true extent of the issue posed by accumulated reagent depends at what point the plant failure occurs. Usually, the worst-case scenario is if the failure occurs just before or after the feed is stopped, as this represents the point at which the concentration of accumulated reagent is at its highest. In this particular case, this would result in the release of 34.6 kJ of energy (assuming no other reaction occurred) from the remaining unreacted reagent. From this, and a knowledge of the thermal mass of the reactants and reactor, we can calculate the temperature rise for this worst-case scenario, via the equation depicted below:
where is the energy released by the reaction of the accumulated reagent, , and is the thermal mass of the reactants and reactor. In this case, the temperature rise is determined to be 106 ⁰C.
As the temperature of the reaction (Tp) was being held isothermally at 30 ⁰C before the cooling failure, we can determine that the maximum temperature attained, or the Maximum Temperature of Synthesis Reaction (MTSR), is 136 ⁰C under these conditions (30 oC isothermal hold, plus 106 oC of temperature increase). This is summarised by the equation below:
where represents the adiabatic temperature rise for reagent accumulation, . This calculation represents the worst-case scenario for the MTSR, as it assumes that there are no heat losses from the system (i.e. it is under adiabatic conditions).
The speed of the runaway (Time to Maximum Rate – TMR) can only be estimated from reaction calorimetry, based on the heat release rate and the level of accumulated reagent. The pressure released from this thermal runaway can, similarly, only be estimated. At this stage of development, these estimates are sufficient. However, when moving to scale-up, and in particular in those cases where the calculations suggest the runaway is particularly exothermic, it is important that the magnitude of the worst-case scenario is accurately quantified.
3. Decomposition/Secondary Thermal Runaway
The next information required is whether a decomposition or secondary reaction might be triggered by the MTSR, which could lead to a secondary thermal runaway. A secondary thermal runaway is likely to occur if MTSR is greater than the onset temperature of a component in reaction mix (Td). This scenario is illustrated in Figure 8.
As previously described, MTSR is derived from reaction calorimetry, while the onset temperatures of materials are determined using thermal screening tools, such as the Thermal Screening Unit (TSu).
A more accurate value can be determined using adiabatic calorimetry, but at this stage it is often considered sufficient to use a simpler thermal screening tool. The TSu enables representative samples of the reaction mix to be screened and reliable onset temperatures determined for the reaction intermediates and products. Temporal thermal stability studies also need to take place on the reaction waste stream, which the TSu also facilitates with isothermal stability screening. Just as it is important to identify hazards during the reaction itself, it is also important to understand if there are any longer-term stability issues in the waste products formed, so that these issues can also be mitigated.
Figure 8: A decomposition or secondary reaction is triggered if MTSR is greater than Td
If it becomes apparent that there is a risk of a secondary thermal runaway occurring, it is necessary to then determine what the adiabatic temperature rise of the decomposition/secondary reaction is, and the TMRd. This allows an assessment to be made as to whether there will be sufficient time and enough emergency cooling capacity to deal with the increase in temperature.
As this reaction involves a secondary thermal runaway, it is inherently a hazardous process to scale-up. Therefore, although these parameters can be estimated from micro-calorimetry, it is advisable to use adiabatic calorimetry to get an accurate assessment.
The data collected enables the criticality of the reaction to be classified, as depicted in Figure 9
Figure 9: Classification of the criticality of a reaction
The schematic references the key reaction parameters introduced in Figure 8:
- the isothermal temperature of the reaction (Tp)
- the decomposition temperature of a component in the reaction mix (Td)
- the Maximum Temperature of the Synthesis Reaction (MTSR)
It also introduces an additional parameter, the boiling point of the solvent or active chemicals used (BP), as this is another factor that needs to be taken into account when considering the overall safety of a reaction. The relative order of these parameters in terms of temperature determine the criticality of the reaction.
- Scenario (1): the thermal order of the parameters is Tp<MTSR<BP<Td. This represents the least hazardous reaction scenario and no special measures are required as the maximum temperature of the synthesis reaction (MTSR) does not exceed that of the boiling point (BP) of the solvent, nor the decomposition temperature (Td).
- Scenario (2): as with Scenario (1), the MTSR does not exceed Td, although in this case, the boiling temperature of the solvent is higher than Td (Tp<MTSR< Td< BP). This means that, unlike Scenario (1), the boiling point will not act as a limit on the maximum temperature the reaction will attain, and heat accumulation conditions should be avoided.
- Scenario (3): the MTSR is higher than the boiling point, but less than Td (Tp< BP< MTSR<Td). This means that risk reducing measures are required, but that the boiling point of the solvent could be used as a safety mechanism for the reaction.
- Scenario (4): the MTSR is greater than Td, which means that there is a risk that the decomposition could be triggered However the boiling point of the solvent could be used as a limiting mechanism to prevent the decomposition reaction being triggered, as BP is lower than Td (Tp< BP<Td < MTSR). In this case, risk reducing measures are required.
- Scenario (5): as with Scenario (4), the MTSR is greater than Td, which means that there is a risk that the decomposition could be triggered. However, the boiling point of the solvent is also above that of Td, so it can’t be used as a safety barrier (Tp <Td < MTSR< BP). In this case, emergency control measures are also required, which may include redesigning the process
4. How Can The Operating Conditions Be Modified To Reduce The Risks Identified?
In the case of Scenarios (4) & (5) previously discussed, it is necessary to consider if the MTSR and TMRr can be reduced by altering the conditions of the reaction to reduce the levels of accumulated reagent.
There are a number of ways this could be addressed, such as:
- Increasing the temperature of the reaction
- Increasing the pressure of the reaction
- Increasing the agitation of the reaction mix
- Adding a catalyst
All of these methods will increase the rate of reaction, and thus increase the rate of consumption of the reagent. However, it must be balanced against the subsequent increase in the rate of heat evolved and so an assessment on whether the cooling capacity of the plant is able to contain this increase in heat.
Finally, reducing the feed rate of the reactants could also be considered: this will slow the total reaction time, but it will reduce the rate of reagent accumulation as it effectively allows more time for the reaction to occur and the rate-limiting reagent to be consumed before it accumulates to hazardous levels.
It is desirable to explore the impact of varying these different factors on the reaction. The Simular enables users to experiment in this way, to create a design of experiments that allows the optimum operating conditions to reduce the thermal risk to be identified.
Expanding on the example introduced earlier, in an additional study both the feed rate and process temperature were varied to understand the impact these factors would have on the level of accumulated reagent.
Reducing The Feed Rate
The effect of reducing the feed rate from 2g/min to 1g/min, whilst keeping the temperature of the process at 30 ⁰C, is illustrated in Figure 10. It reduces the accumulation of reagent to 32% at the point at which the feed stops, and it reduces the maximum reaction power from 15W to 8W. This reduction in maximum reaction power is critical, as it significantly reduces the cooling capacity required to keep the reaction isothermal and under thermal control.
Figure 10: Variation of reaction power with reagent feed rate
Increasing The Temperature
The level of accumulated reagent can be reduced further by increasing the temperature from 30 ⁰C to 40 ⁰C, whilst maintaining the slower feed rate of 1g/min. The impact of this is depicted in Figure 11. This reduces the level of reagent accumulated to 22 % at the point at which the feed is stopped, but it does result in an increase in the maximum reaction power from 8W to 10W.
Figure 11: Variation of reaction power with temperature
Cooling Capacity Considerations
Increasing the reaction temperature poses an interesting question: whilst the increase in temperature will result in less accumulated reagent, and thus a lower MTSR, should cooling fail and a thermal runaway occur, it does require a larger cooling capacity to deal with the faster rate of heat evolved. As before, if it is assumed that the 1L lab-based reactor is initially scaling up to a 2000 L reactor, the 10W reaction power for the reaction run at 40 ⁰C equates to a 20 kW cooling capacity requirement on scale-up, versus the 16 kW required for the same reaction run at 30 ⁰C. Therefore, although the 1g/min feed rate with 40 ⁰C process temperature is the desired combination from a safety point of view in terms of reagent accumulation, it may be that a lower temperature is required if the cooling capacity of the pilot plant is <20kW.
Ideally, a process should be as close to a dose-controlled reaction as possible: this means the reactant is consumed as rapidly as it is added and means that in the event of a cooling or agitation failure, it is usually sufficient to just switch off the feed to prevent a thermal runaway.
However, in cases where accumulation can’t be avoided, it is necessary to undertake a more detailed analysis of the risk.