Energy Fuels 2010, 24, 5446–5453 Published on Web 09/14/2010
: DOI:10.1021/ef100972f
)
Energy Efficiency of Conventionally-Heated Pilot Plant Reactors Compared with Microwave Reactors Darryl R. Godwin,† Simon J. Lawton, Jonathan D. Moseley,*,‡ Matthew J. Welham,† and Neil P. Weston§ )
† Development Manufacture, ‡Process Chemistry, and §Process Engineering, AstraZeneca, Process R&D, Avlon Works, Severn Road, Hallen, Bristol, BS10 7ZE, U.K., and AstraZeneca, Process R&D, Process Engineering, R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, U.K.
Received July 28, 2010. Revised Manuscript Received September 2, 2010
We report on the energy usage required for one organic reaction in two small pilot plant scale reactors of different vessel designs (both 50 L) conducted in a kilogram scale facility. The background energy consumption of the building and all supporting services was determined beforehand, and this figure used to compensate for the energy usage required for each of six pilot scale batches performed under different conditions at the 20 and 40 L scale. The energy usage data was compared between these large scale batches and with the equivalent laboratory scale batches, including several earlier microwave-heated batches (Moseley, J. D.; Woodman, E. K. Energy Fuels 2009, 23, 5438-5447). The results showed little difference in energy usage between the two pilot plant scale reactors under the different reaction conditions, except on doubling the scale which halved the energy usage per mole. However, the energy efficiency of the laboratory scale reactors was higher than the pilot scale reactors under all reaction conditions on a kilojoule/mole basis. Furthermore, the most efficient microwave reactor operating under optimal conditions was significantly more energy efficient than the pilot scale reactors even up to 40 L.
used in the Avlon Large Scale Lab (LSL) (a kilogram scale laboratory). Both reactors are nominally of 50 L capacity and made of glass-lined mild steel (GLMS). They are heated through the jacket by a heat transfer fluid (Syltherm XLT, Dow Chemicals) which in turn is heated in a temperature control module (TCM) that consists of the reactor jacket and a small loop connected to an electrical heater. The heating capacity of each TCM is 40 kW, and each can be connected to the heat transfer module (HTM) which services all the other reactors and the heating/cooling demands of the building. This uses a 4000 L Syltherm reservoir which normally runs at -29 °C; thus, the cooling capacity available to the reactors is much greater than the heating capacity. A reactor vessel and TCM is shown in schematic form in Figure 1. The operating parameters of the plant scale reactors, along with the parameters for all the laboratory scale reactors used in the previous study, are collected in Table 1. On larger pilot and production scales, the energy efficiency of conventional steam-heated plants in the medium temperature range (121-399 °C) is given by Rosen and Dincer as 90% or 65%, depending on whether the heat is generated by electricity or fossil fuel.3 Alternatively, Hulshof has recently calculated that heating by steam derived from gas is only 43% efficient.4 Others agree5-7 that at best typically only 40-65% efficiency can be expected in converting electrical energy to microwave energy and much less in some cases, especially on a
Introduction In our earlier study, we reported on a comparison of energy efficiency between microwave and conventionally heated laboratory-scale reactors, limited to the largest currently accessible scale of commercial microwave reactors (∼1-3 L).1 This was within the context of potential pharmaceutical manufacture, since it is recognized that microwave reactors and ovens can be used on much larger scales in many other industries in a commercially viable, energy efficient manner.2 The energy consumptions of four microwave reactors were compared against one another and against a conventionally heated, jacketed reaction vessel using a commercial wattmeter for four pharmaceutically relevant organic reactions performed under identical conditions. The results showed that microwave heating was more energy efficient than conventional heating under most conditions investigated, although the results were dependent on the design and operation of the microwave reactor, with significant differences being observed between them.1 They were also dependent on the scale applied, albeit only up to 3 L. Overall, the results showed that at that scale, microwave heating was generally more energy efficient than conventional heating. To further advance the debate over the energy efficiency or otherwise of microwave heating within the context of potential pharmaceutical manufacture, we have now extended this study to include two conventionally heated pilot scale reactors
(3) Rosen, M. A.; Dincer, I. Int. J. Energy Res. 2004, 28, 917–930. (4) Dressen, M. H. C. L.; van de Kruijis, B. H. P.; Meuldijk, J.; Vekemans, J. A. J. M.; Hulshof, L. A. Org. Process Res. Dev. 2010, 14, 351–361. (5) N€ uchter, M.; Ondruschka, B.; Bonrath, W.; Gum, A. Green Chem. 2004, 6, 128–141. (6) Barnard, T. M.; Leadbeater, N. E.; Boucher, M. B.; Stencel, L. M.; Wilhite, B. A. Energy Fuels 2007, 21, 1777–1781. (7) Komorowska, M.; Stefanidis, G. D.; van Gerven, T.; Stankiewicz, A. I. Chem. Eng. J. 2009, 155, 859–866.
*To whom correspondence should be addressed. Telephone: þ44 117 938 5601. Fax: þ44 117 938 5081. E-mail: jonathan.moseley@astrazeneca. com. (1) Moseley, J. D.; Woodman, E. K. Energy Fuels 2009, 23, 5438– 5447. (2) Metaxas, A. C.; Meredith, R. J. Industrial Applications and Economics. In Industrial Microwaves Heating; Peter Peregrinus Ltd for the Institute of Electrical Engineers: London, 1983 (reprinted 1993); Chapter 11, pp 296-321. r 2010 American Chemical Society
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: DOI:10.1021/ef100972f
Godwin et al. Table 1. Reactor Vessel Parameters
entry
reactor
scale
heat supply
vessel construction
1 2 3 4 5
Synthos (1400 W, sealed) MARS (1600 W, open) jacketed lab reactor LSL reactor 0103 LSL reactor 0201
lab lab lab pilot pilot
microwave microwave silicon oil Syltherm XLT Syltherm XLT
PTFE glass glass GLMS GLMS
a
reactor volume (L)
maximum heated volume (L)
minimum stirrable volume (L)
maximum temperature (°C)
maximum pressure (bar)
1.6 5.0 5.0 50 70
1.0 3.5 3.0 50 50
0.16 ∼0.5a 0.2 20 5
240a 250a,b 140b 190b 150b
40 1 1 1 1
Dependent on reaction media absorbance. b Limited by solvent boiling point.
Scheme 1
temperatures as noted),6 and there is also plenty of conventional plant capacity. Although temperatures higher than 180 °C could readily be attained by large scale microwave reactors, much of our pilot scale and production plant capacity relies on low pressure steam which is generated at 18 bar (Tsat = 207 °C) and reduced locally to 7 bar (Tsat = 165 °C). This limits the maximum reaction temperature achievable on large scale to typically ∼140-150 °C without the use of specialist equipment. Several further constraints applied to this study. Although both pilot scale reactors and personnel were available for this study (when not required to support pharmaceutical manufacturers), large scale reaction operations (charging, heating, cooling, isolation, and cleaning) take much longer than on the laboratory scale, which even with good availability of resources (plant and personnel) would limit the number of batches that could reasonably be performed. Furthermore, on this scale, availability and cost of reagents and solvents would be a significant expense. Lastly, standard chemical hazard issues, such as those associated with reduced surface area per unit volume and less efficient agitation on scale-up, could not be ignored for safety reasons. Two of the reactions under consideration from the previous study1 used potassium carbonate heated to 140-150 °C. These were discounted due to the small risk of etching the glass lining, either mechanically or due to alkaline pH at high temperatures, since the reactors were required for future GMP work. A homogeneous Heck reaction was in principle a promising option,12 but this reaction has a capricious initiation period which could have led to delayed exothermic behavior, thus raising significant safety concerns. The other problem is that when successful at high temperatures (∼140 °C), the catalyst tends to plate out as a Pd mirror onto the vessel walls. This would probably have given major problems for a post-campaign clean of the reactor for future GMP pharmaceutical projects. Fortunately, the modified Diels-Alder reaction1,8 satisfied all the criteria listed above (Scheme 1). The materials anthracene (1), maleic anhydride (2), and 1,2-dichlorobenzene (DCB) were cheap and available; there were no incompatibilities with materials of construction; there were no significant cleaning problems; and the reaction was only moderately exothermic,
Figure 1. Schematic of reactor vessel and heat transfer systems.
small scale.8,9 A recent report contemporaneous with this one, albeit of a polymerization of lactic acid, claimed an overall 70% energy saving over conventional heating when conducted on the 20 L scale and an 18-fold improvement in energy usage compared to a small scale (200 mL) microwave preparation.10 In all cases, however, this assumes all microwave energy generated can be usefully absorbed into the reaction medium.4,11 The reactions investigated in our previous study fell within the heating range 130-180 °C which was chosen to determine if microwave heating could offer any energy efficiency advantage over conventional heating. There was little value in investigating microwave heating at moderate temperatures since conventional batch reactors perform adequately below this range (Leadbeater’s report provides some data at modest (8) Razzaq, T.; Kappe, C. O. ChemSusChem. 2008, 1, 123–132. (9) Hoogenboom, R.; Wilms, T. F. A.; Erdmenger, T.; Schubert, U. S. Aust. J. Chem. 2009, 62, 236–243. (10) Nakamura, T.; Nagahata, R.; Kunii, K.; Soga, H.; Sugimoto, S.; Takeuchi, K. Org. Process Res. Dev. 2010, 14, 781–786. (11) N€ uchter, M.; M€ uller, U.; Ondruschka, B.; Tied, A.; Lautenschl€ager, W. Chem. Eng. Technol. 2003, 26, 1207.
(12) Moseley, J. D.; Woodman, E. K. Org. Process Res. Dev. 2008, 12, 967–981.
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so the chemical hazard issues were acceptable on scale-up. This reaction was ideal for comparison with microwave heating for two additional reasons. The use of a low polarity solvent (DCB, ε0 = 9.9) which couples only moderately well with microwaves (tan δ = 0.280; ε00 = 2.772) meant that this reaction would not be overly favorable to microwave heating versus conventional heating (whereas the other reactions had used strongly coupling N,N-dimethylacetamide and N-methylpyrrolidinone).13 Second, this reaction had been trialled at two temperature and time points on the 3 L scale, including the very high temperature of 180 °C for 8 min.1 One of the pilot plant reactors was capable of achieving this temperature, which meant a direct microwave/conventional heating comparison would be possible. The lower reaction time and temperature of 140 °C for 120 min was readily accessible. Figure 2. Temperature profile, energy usage, and cumulative energy usage for batch 2.
Experimental Section General Reaction Procedures. The reaction procedures from the laboratory scale microwave and conventionally heated reactors have been reported before.1 A representative example of the reaction on pilot plant scale (20 L) is given below. Reaction progress is difficult to monitor in this case but is sufficiently reliable not to require at-line analysis. Isolation and analysis of the Diels-Alder adduct (3) is confirmation of successful reaction conversion. In the large scale cases, since the product was not required and drying is a laborious process on the large scale, the damp weight of each batch was noted before discharging. A representative sample of each batch was then dried thoroughly in the laboratory and the loss-on-drying figure obtained was used to extrapolate the overall dry batch weight on the 20 L scale. Product quality was assessed on these laboratory dried samples. One large scale batch (and two previous laboratory batches) had slightly reduced yields (down by 6-8%) due to mechanical losses on removal of the product from the reactors; it can crystallize in large plates around the vessel walls and hence be difficult to remove. In the case of the pilot scale reactors, it was removed by boiling out with hot acetone. The acetone liquors were then assayed by HPLC to determine the product content and a correction factor applied if necessary to the overall yield. The results for yield and purity (and thus conversion) were very similar in every reactor as can be seen from Table 3, and the slight differences make no meaningful difference to the overall results. Reaction Procedure on 20 L Scale (Either Reactor). The reactor was inerted with nitrogen and the condenser set to -5 °C. Maleic anhydride (2) (2.50 kg, 25.2 mol) was charged to the reactor followed by anthracene (1) (4.54 kg, 25.0 mol). The agitator was started and set to 200 rpm. DCB (20.0 L) was charged to the reactor to give an off-white mobile slurry. The batch was heated to the set-point temperature (140, 160, or 180 °C) over not less than 60, 70, or 80 min, respectively, using jacket control during which time the starting materials dissolved. A comparison of the batch and jacket temperatures indicated some heat evolution in the range ∼70-90 °C (the heat of reaction), which manifested itself between ∼90 and 120 °C in the batch temperature (see Figures 2-7). The reaction was held at the set-point temperature (140, 160, or 180 °C) for 120, 30, or 8 min, respectively, on jacket control within the (3 K-band about the set-point (to avoid cooling). During this time, the product started to crystallize as a dense white solid. The batch was then step-cooled to 20-25 °C using manual jacket control to avoid thermal shock on the vessel. The product Diels-Alder adduct (3) was isolated by filtration on a 40 cm diameter polypropylene Nutsche filter. The liquors were recharged to the reactor and stirred for 5 min to rinse it out and then filtered through the product cake that was dried under vacuum. A representative
Figure 3. Temperature profile, energy usage, and cumulative energy usage for batch 3.
Figure 4. Temperature profile, energy usage, and cumulative energy usage for batch 1.
sample of damp product was washed by displacement twice with toluene and dried in a vacuum oven at 60 °C with an air bleed to yield the product as a granular white or pale yellow solid (typical dry yield calculated at ∼6.3 kg, 90-92%). Analysis for purity was taken from these samples (typically 99% by HPLC). The reactor was boiled out with acetone, the weight of the liquors noted, and a representative sample assayed for product content by HPLC, from which a corrected yield could be determined if necessary. Hazard Assessment and Calorimetry Data. The reaction was assessed for calorimetry data on a 360 mmol scale in a Mettler Toledo RC1 reaction calorimeter (RC1) and on a 5 mmol scale
(13) Hayes, B. L. Microwave Synthesis: Chemistry at the Speed of Light; CEM: Matthews, NC, 2002.
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(3) were all thermally stable with no exothermic behavior of process safety significance. Therefore, the process was deemed to be safe to scale up to 50 L in the LSL provided that the heat-up was performed in a controlled manner. Power Measurements. The power usage for the laboratory scale reactors was measured using a commercial wattmeter connected in series with the microwave reactor or the heaterchiller unit, and the data were processed with a commercial software program supplied with the wattmeter. Voltage was typically ∼245 V in our laboratory. The power usage of the ancillary equipment was not usually included unless it was essential to the operation of a particular microwave reactor, but generally it had little effect. Full details are as reported.1 Power measurements for the pilot scale reactors could not be measured in the same way because they use a 3-phase supply at 415 V from distribution boards that also power other services. The distribution boards are metered, and the energy usage from each one can be calculated using a Web-based reporting tool developed in-house which collects data points at 30 min intervals accurate to 0.5 kWh. Certain services were omitted from the energy calculations because these were deemed to be part of running the building systems and thus not directly related to the reaction (although the building needs to function for reactions to be performed, of course). These services were the 4000 L HTM system run at -29 °C and its associated pumps running with no additional process load, the condenser for the TCM (run at -5 °C), the scrubber pump, the vacuum pumps, and the room conditioning services (heating, vacuum and air-conditioning, HVAC). The power was measured with all these services running in steady state for several hours but with no additional services in use. From this, the background energy consumption of the building systems could be determined, which was then subtracted from the reaction energy data. Services that were included with the reaction were the TCM heater and circulation pump for each vessel, the additional load on the HTM from the TCM, the additional load on the vacuum pumps, and the agitator drive. In this way, we were able to log the energy consumption of each reaction without including energy usage from building services (which would essentially be identical whichever vessel was in use). In context, the background energy consumption of the building was ∼40 kW during a typical British winter. A summary of services included/excluded is given in Table 2. In addition, no losses to the environment were either measured or calculated at any scale, since we wanted the energy consumption for all reactors in their normal working environment, and environmental energy losses are in any case a feature of the overall operating efficiency and scale of operation of each reactor. Where possible, the energy used and time taken were noted for each of three periods: the heat up period, the reaction hold period, and the cool down period. Typically, most of the energy is used in the heat up period, less in the reaction hold period, and more again in the cool down period. The figures are aggregated in Table 3, but full details are given in extended table in the Supporting Information (Table S1). As noted previously,1 there are some differences in the final cool down temperature achieved in each case as this was the most difficult parameter to control, and the half-hourly energy measurements taken from the LSL were perforce somewhat coarse. However, an analysis of the data shows that only minor variations in the final figures result, which has no bearing on the overall conclusions. Active cooling was not used for the conventional laboratory scale reactor (for better comparison with the microwave reactors which have only weak cooling), but it was used on the pilot scale reactors. Although active cooling uses much more energy, it does significantly improve the batch cycle time, and importantly, this is also the normal mode of pilot/plant scale operation. However, we did try to avoid (or compensate for where we could not), the process of temperature overshoot and subsequent oscillation about the set-point, whereby the temperature controller overcompensates for the thermal lag often seen between the internal
Figure 5. Temperature profile, energy usage, and cumulative energy usage for batch 5.
Figure 6. Temperature profile, energy usage, and cumulative energy usage for batch 6.
Figure 7. Temperature profile, energy usage, and cumulative energy usage for batch 4.
in a Thermal Hazards Technology Accelerating Rate Calorimeter (ARC). Standard procedures were applied in both cases. The reaction was shown to be exothermic in both cases. Isothermal and nonisothermal RC1 tests both showed a heat of reaction of ∼109 kJ/mol which equates to an adiabatic temperature rise of ∼64 K. From the nonisothermal RC1 test, it could be shown that the exothermic behavior commenced slowly from ∼50 °C with ∼80% of the energy released during the 1 h heat up to 140 °C. An ARC test of the reaction mixture heated to 250 °C in 5 K steps showed similar results. DSC tests showed that anthracene, maleic anhydride, and the Diels-Alder adduct 5449
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: DOI:10.1021/ef100972f
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Table 2. Summary of Building Services Included/Excluded for Reactor Energy Consumptions entry
service/unit
energy included
1 2 3 4 5
agitator drive TCM heater TCM pump additional energy load on vacuum pumps additional energy load on HTM from TCM cooling/holding and condensor cooling condenser for the TCM scrubber pump vacuum pumps room conditioning services (HVAC) HTM (4000 L heat transfer fluid system and associated pumps)
yes yes yes yes yes
required for reactor in use required to heat reactor in use required to circulate heat transfer fluid in TCM required to charge reaction solvent(s) required by TCM to maintain reaction conditions
no no no no no
not required for this reaction not required for this reaction not required for this reaction required for building services whether reactor(s) in use or not required for building services whether reactor(s) in use or not
6 7 8 9 10
rationale
Table 3. Reaction Batch Operational Parameters and Results
entry
reactor
notes
temperature (°C)
1 2 3 4 5a 5b 6 7 8 9 10 11
reactor 0103 reactor 0103 reactor 0103 reactor 0201 reactor 0103 reactor 0103 reactor 0103 lab reactor MARS microwave MARS microwave MARS microwave Synthos microwave
standard reaction intermediate temp. high temperature alternative reactor repeat Bx.1 unadjusted repeat Bx.1 adjusted double scale standard reaction standard reaction high temperature reduced fill sealed vessel
140 160 180 140 140 140 140 140 140 180 180 180
a
time (min)
scale (mol)
volume (L)
total time (s)
total energy (kJ)
cool down temperature (°C)
yield (%)
purity (%)
120 30 8 120 120 120 120 120 120 8 8 8
25 25 25 25 25 25 50 2.4 2.4 2.4 1.2 1.0
20 20 20 20 20 20 40 2.5 2.5 2.5 1.3 1.0
15 360 13020 11760 13 740 14 400 14 400 18 000 10 800 11 316 4 710 2 760 2 880
275 040 268 200 246 600 302 760 334 800 262 800 252 000 9 433 8 406 2 712 1 702 3 713
29 27 35 30 40 40 33 58 58 64 nrb 49
92 91 91 90 91 91 83a 90a 92a 97 99 96
99 99 99 99 99 99 99 99 94 98 98 99
Some mechanical loss on isolation. b Not recorded.
Table 4. Energy Efficiency and Productivity Results
entry
reactor
notes
1 2 3 4 5a 5b 6 7 8 9 10 11
reactor 0103 reactor 0103 reactor 0103 reactor 0201 reactor 0103 reactor 0103 reactor 0103 lab reactor MARS microwave MARS microwave MARS microwave Synthos microwave
standard reaction intermediate temp. high temperature alternative reactor repeat Bx.1 unadjusted repeat Bx.1 adjusted double scale standard reaction standard reaction high temperature reduced fill sealed vessel
a
heating scale volume protocola (mol) (L) A B C A A A A A A C C C
25 25 25 25 25 25 50 2.4 2.4 2.4 1.2 1.0
20 20 20 20 20 20 40 2.5 2.5 2.5 1.3 1.0
total time (s)
total energy (kJ)
total total no. of no. of kJ/mol mol/kW mol/day reactorsb batchesb
15 360 13 020 11 760 13 740 14 400 14 400 18 000 10 800 11 316 4 710 2 760 2 880
275 040 268 200 246 600 302 760 334 800 262 800 252 000 9 433 8 406 2 712 1 702 3 713
11 002 10 728 9 864 12 110 13 392 10 512 5 040 3 930 3 503 1 130 1 418 3 713
1.40 1.21 1.19 1.13 1.08 1.37 3.57 2.75 3.23 4.17 1.95 0.78
141 166 184 157 150 150 240 19.2 18.3 44.0 37.6 30.0
1.07 0.90 0.82 0.95 1.00 1.00 0.63 7.81 8.19 3.41 3.99 5.00
6.0 6.0 6.0 6.0 6.0 6.0 3.0 62.5 62.5 62.5 125 150
A, 140°C for 120 minutes; B, 160°C for 30 minutes; C, 180°C for 8 minutes. b Based on a productivity of 150 mol/day.
Discussion
batch temperature and the external jacket temperature, especially on large jacketed reactors. This results in an oscillation about the set-point temperature until the batch temperature settles down to the jacket temperature. The consequence is that these cooling cycles also use energy even though the reaction is essentially at or above the desired temperature. (Microwave reactors can also experience this phenomenon, but since their active cooling is usually poor, there is little additional energy usage). With knowledge of the plant systems and careful setting of the temperature control loop, a well understood batch process can be operated on the large scale avoiding this phenomenon. This problem occurred on the first batch, and so this batch was repeated later (as batch 5). As before,1 the results are given in kilojoule/mole for comparison with data given in previous studies,6,8,10 although other studies favor percentage efficiencies.7,9 These results are also shown in mole/kilowatt, since this gives a measure of production rate. The absolute production rate in terms of mole/day (24 h working) is also given to help put these figures in context (Table 4).
The initial plan was simply to run the Diels-Alder reaction in reactor 0103 on the 20 L scale at 140 °C for 120 min and 180 °C for 8 min to get direct comparisons of energy usage and productivity with the results from the laboratory scale reactors. Reactor 0103 is not an entirely typical reactor because it was designed to provide flexibility by having an unjacketed sleeve section added to the reactor to permit operation with an increased volume. Although the sleeve was not used here, even in its normal configuration, it has relatively high environmental heat losses due to differences in insulation compared to similar-sized vessels. Reactor 0103 was used in this study because, although untypical, it was capable of attaining 190 °C internally, so a direct comparison with the high temperature microwave conditions was possible. Reactor 0201 was also available for use and is typical of many of our pilot plant 5450
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reactors, including being limited to 150 °C. Therefore, we decided to run one standard reaction (140 °C for 120 min) to get a comparison between these pilot scale reactors. From the previously determined rate plot,1 we also deduced that 30 min at 160 °C would provide an intermediate temperature/time combination which could be run in 0103. Having run these reactions, we decided to run a repeat of the first standard reaction to address issues of overheating and cooling (batch 5) and also a double scale reaction in reactor 0103 (batch 6). In total, this made six reactions, five in reactor 0103 and one in reactor 0201. The operational parameters (reaction time and temperature, scale and cool down temperature) for all six batches are summarized in Table 3, along with the total energy usage, yield, and purity. The relevant results from the laboratory scale reactions are also included for direct comparison.1 Yield and product purity results are consistent across all six batches with an estimated yield of 90-92% and product purity a consistent 99%. These results are in good agreement with the laboratory scale results. The yield is slightly reduced for batch 6 due to some mechanical losses in the reactor (additional acetone rinse washes were required to remove this material but they were not assayed and so the yield has not been corrected). For the purposes of further analysis, all yield and quality results are considered identical and no adjustment for minor differences has been made in the following discussion of energy efficiencies. Before discussing the energy consumption figures in detail, some explanation of two adjustments made to the raw data is necessary. One problem arose because these large-scale, high temperature batches took some time to reach their set-point temperatures because the TCM reduced heating on nearing the set-point. Figures 2 and 3 illustrate this and show the temperature profile, energy usage and cumulative energy usage (in half hour intervals) for batches 2 and 3. Therefore, the batches were effectively within a few degrees of the reaction temperature for several minutes (sometimes longer) when effective reaction would be occurring. This did not matter too much for the 120 min reactions, but it became more significant for the shorter, hotter reactions such as batches 2 and 3. A further problem arose for batch 1, wherein the TCM overshot the set-point of 140 °C and began active cooling (Figure 4). This used more energy as a result (the energy usage gradient continues at the same slope), even though the reaction had reached the set-point temperature. In this case, we also decided to lengthen the hold period to compensate for the time when the batch was not at the desired temperature, which used even more energy. In both cases (the slow heating rate near the set-point and excessive cooling due to oscillation about the set-point), we decided to apply a correction, since we felt that in routine manufacture on the large scale, the heating processes would be optimized in an energy efficient manner. Overall, this correction would tend to make the energy usage comparison more favorable for the pilot scale reactors. (Note, the microwave reactions did not suffer significantly from these issues due to the much smaller batch size and the sharper heating profile. Furthermore, microwave heating can be switched off instantly, and since there is no reservoir of residual heat, environmental cooling can take place immediately). Taking the slow heating rate issue first, the usual procedure in the LSL (and typically in the full-scale plant) would be to consider the temperature requirement as met once the batch was within a specified range of the set-point, typically (3 K,
which was used here. For the purposes of determining energy consumption, we therefore considered the batch as having reached temperature when it was within 3 K of the set-point and cut out the additional heat up period before the less energy-intensive hold period (e.g., see Figure 2). Since only 30 min data points were available, we used the slope of the graph at the relevant sections and calculated the energy usage pro rata on the assumption that this would be a reasonable approximation. This type of correction was applied to batches 1-4. Oscillation about the set-point is a genuine feature of dynamically controlled systems, such as these large scale batch reactors, and in fact the control system requires a difference between the measured (batch) temperature and the set-point temperature to generate an output for feedback. Furthermore, familiarity with the process and good tuning of the reactor vessel control systems can improve the energy efficiency of a process; conversely, poor tuning costs energy. However, we felt that such a large oscillation on batch 1 due to manual intervention and subsequent (energy-intensive) cooling, while representative of a real situation, was not a fair comparison with the microwave reactors since it could have been avoided. Subsequent batches performed better without manual intervention. Therefore, as a further check, we reran batch 1 (labeled as batch 5a in Tables 3 and 4), which was much improved (Figure 5). However, a small oscillation about the set-point temperature can be seen in this graph which was sufficient to significantly increase the energy usage during this period (note the ripple in the temperature plot during the hold period and the linear cumulative energy consumption plot). Because this was clearly at variance with all the other batches, we decided to apply an alternative correction to this batch by substituting the energy from the hold period of batch 1 into batch 5 (labeled as batch 5b in Tables 3 and 4). This then gave a cumulative energy consumption plot similar to the other batches and figures which we believe would be more representative of batch performance. In summary, the adjustment for batches 1-4 was to remove the heating period within 3 K of the set point temperature; the double scale batch 6 required no adjustment and heated up without overshooting the set-point and without oscillation (Figure 6). The graphical data for batch 4 is given in Figure 7. For batch 5, the unadjusted data has been included for inspection in Tables 3 and 4 as entry 5a and the adjusted data compensating for the oscillation included as entry 5b. The net result of these adjustments was a small reduction in the energy consumptions of batches 2-4 and major reductions for batches 1 and 5. In the discussion that follows, batch 5b data will be used in preference to batch 1 or unadjusted batch 5a data. The full unadjusted data for all batches is given in the Supporting Information, Table S1. Regarding the cool down temperatures, the comparisons may not seem entirely fair, since the laboratory scale reactions were stopped at higher temperatures, which gives both a shorter cycle time and uses less energy per batch. However, we decided to use the figures shown because the LSL reactors cannot be emptied while still hot (for safety reasons), whereas the laboratory scale reactions are routinely emptied at the temperatures given. The pilot scale reactors are also much more dependent on active cooling to get the batch temperature down, otherwise their batch cycle times would be much longer. It should be noted that the cumulative energy plot for each reaction (the solid purple line in Figures 2-7) follows the same pattern of steep/shallow/steep, except for the unadjusted 5451
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batch 5a (Figure 5), which agrees with the expected energy usage across the three phases of the reaction (heat up, hold, cool down). This pattern was also seen in the laboratory scale reactions.1 Even a cursory inspection of the slopes shows that cooling is as costly (in terms of energy) as is heating. This further supports the adjustment made to the batch 5a/b data. Results The detailed energy consumption figures (adjusted) for batches 1-6 and the laboratory scale comparisons are given in Table 4. Although the absolute figures have been given, the following discussion is based on the energy efficiency in terms of kilojoule/mole, since this separates the factors of productivity and time, which will be discussed individually. The following points can be observed in the data between the six pilot scale reactions, keeping in mind the precaution not to overinterpret small differences in the data given the approximations and assumptions that had to be made. There is little difference between the energy usage of the three temperature/time combinations (batches 1-3), although the high temperature procedure at 180 °C may be marginally better, probably because the hold time is shorter. The repeated standard batches (1 and 5b) at 140 °C for 120 min show good agreement, suggesting that the adjustments made in removing the final part of the heating-up phase on most batches are reasonable. Surprisingly, the energy usage was slightly worse for the standard reaction in reactor 0201 (batch 4), perhaps because not all of the jacket could be used for heating at the 20 L capacity; a larger fill might have been more efficient in this case. However, there is no doubt that working at double volume, even in reactor 0103, was much more efficient, using about half the energy required per mole on the 20 L scale (batch 6). In comparison of the large scale reactors with the microwave reactors, Table 4 shows that even in the worst case, the microwave reactors are much more energy efficient than the pilot scale reactors at 20 L and remain more efficient up to the 40 L scale (compare batches 8 and 10 with batches 5b and 6). Even when operating at 140 °C for 120 min under conditions where we and others have noted that most of the advantages of quick and hot conditions are lost in the microwave reactor compared to the conventional laboratory reactor 1,8 (cf. batches 7, 8, and 9), the laboratory reactors are still more efficient than at the pilot scale (cf. batches 7 and 8 with 5b and 6). When the microwave reactors can work under quick and hot conditions (180 °C for 8 min), the energy efficiency of the MARS microwave reactor is a step change better (batches 9 and 10). Even the Synthos, which is much less efficient than the MARS by comparison,1,9 is still much better than the pilot scale reactors under all conditions (cf. batch 11 with batches 3, 5b, and 6). When the results are examined in terms of mole/kilowatt, which does take some account of the space-time yield, the trend is similar (larger figures are now better). Only at 40 L capacity is the pilot scale reactor more efficient than most of the laboratory scale reactors, but even then the MARS microwave reactor operating at full capacity under ideal quick and hot conditions is still more efficient. It should also be borne in mind that this reaction features a relatively low microwave-absorbing reaction medium, so this is an unfavorable case and a challenge for microwave heating. There is also the possibility of solvent reflux when operating at 180 °C,
Figure 8. Graph of productivity against energy efficiency for all reactions (data from Table 4).
which has the potential to remove energy from the system through the latent heat of evaporation, although in practice no effective reflux was observed. In general terms, and in the context of organic chemistry, microwave heating cannot be compared directly to large-scale production since it is not possible to heat large reaction masses due to the limited penetration depth of microwaves into an adsorbant medium.14,15 (A direct comparison might be possible using high microwave power densities, but this still relies on heating the outer “skin” of the reaction medium and then dissipating the heat quickly by efficient mixing). Figure 8 attempts to show visually on the same plot the higher production rates (mole/day) of the pilot scale reactors and conversely, the better energy efficiencies of the laboratory scale reactors (kilojoule/mole). However, the production rates (mole/day) can be compared directly based on one reactor working an arbitrary 24 h working day (whether this is practical or not) and are given in Table 4. Clearly, the molar production rate for the pilot scale reactors is much higher than for the laboratory scale reactors, being between 3 and 8-fold greater on the 20 L scale. Interestingly, while the MARS microwave reactor is more than twice as productive running at 180 °C/8 min compared to 140 °C/120 min (compare entries 8 and 9), on the 20 L scale there is marginal difference between the three sets of conditions (compare entries 1, 2, and 3). (It should be noted that slices of both energy and time have been removed from the data for batches 1-4, for the reasons given above. In practice, this would not be possible because the reaction mixture cannot be heated instantaneously, for example, from 157 to 160 °C (cf. Figure 2). Not only does this use more energy, it also increases the cycle time and reduces the productivity. However, within the context of these numbers, the effect on these results is likely to be small so the idealized cycle times have been used). Alternatively, the comparison can also be made on the number of microwave heated (or laboratory scale) reactors operating in parallel which are required to match the productivity of a single large conventionally heated batch reaction. (14) Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J.; Mingos, D. M. P. Chem. Soc. Rev. 1998, 27, 213–223. (15) Metaxas, A. C.; Meredith, R. J. Dielectric Properties. In Industrial Microwaves Heating; Peter Peregrinus Ltd. for the Institute of Electrical Engineers: London, 1983 (reprinted 1993); Chapter 3, pp 26-69.
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: DOI:10.1021/ef100972f
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The equivalent numbers of reactors (and total batch numbers) to provide comparable productivities are also shown in Table 4. These values have been normalized for convenience at 150 mol/day, since this is typical of what the 20 L pilot scale reactions would achieve in 24 h. For the laboratory scale reactors to match this productivity, it would require nearly eight reactors working full time under the standard conditions (entries 7 and 8) or, in the best case, just over three for the MARS microwave reactor working under the quick and hot conditions (entry 9). While three MARS reactors are not excessive, the level of productivity required is 62.5 batches per day in total, which without automation is clearly not viable. The MARS reactor running at partial fill requires double this number (entry 10), and the smaller capacity Synthos needs about 150 batches from five instruments (entry 11). However, this last example disguises the total impracticality in that each Synthos “batch” actually consists of 16 small reaction vessels of ∼60 mL useful capacity, each of which has to be loaded and unloaded manually, even if the heating and cooling cycle is automated to some extent (consider also Figure 8 again). Alternatively, only three 40 L batches from one reactor working 63% of the time would achieve the same result much more readily (entry 6).
energy efficient than a conventionally heated pilot scale reactor operating at the 20 L scale under identical conditions (entry 3) and over 4 times as efficient when competing at the 40 L scale (entry 6). Although this investigation did not take the scale beyond 40 L, the approximate halving in energy usage (kilojoule/mole) on doubling the scale in reactor 0103 under standard reaction conditions (140 °C/120 min) (batches 5 and 6) allows one to speculate on a further halving of energy usage with each scaleup factor of 2. On this basis, a conventionally heated pilot scale reactor could be expected to reach energy efficiency parity with the MARS microwave reactor at the ∼150-200 L scale (assuming no change in the heating method). However, this figure disguises the impracticality of achieving a comparable rate of production in microwave-heated 3 L batches against conventionally heated 200 L batches; if it is untenable at 20 L, it will be impossible at the 200 L scale (cf. Figure 8). However, from an energy perspective, this figure does suggest that automated or continuous flow multimode microwave reactors that are capable of matching the production rate16 (and operating in a similar manner to the MARS microwave reactor) could be energy efficient up to the ∼200 L scale compared to conventional heating methods, although this assumes a number of other factors. This is within a context of pharmaceutical scale-up, and we reiterate the point that many other industries do use microwave heating economically on a large scale for low value products.2 It is also worth noting that this assumes conventional reactor performance is adequate for the transformation required; if higher temperatures cannot be reproduced conventionally, microwave heating will have a niche role irrespective of energy efficiency. Overall, these results show that under all conditions investigated up to 40 L, the microwave (and laboratory scale) reactors were more energy efficient in terms of kilojoule/mole than were pilot scale reactors operating for this specific reaction. Furthermore, when the single vessel MARS microwave reactor operated under the preferred “quick and hot” conditions, it was much more energy efficient than all types of reactors investigated here, even when only partially filled. These results continue to support the premise that microwave heating can be more energy efficient per mole than conventional heating for limited scale-up to the 40 L scale and possibly beyond.
Conclusions To achieve a worthwhile energy comparison between pilot scale and microwave (laboratory scale) reactors, certain assumptions and approximations had to be made in this study, for example, by excluding building energy usage in both cases. However, it should be remembered that all judgements were made in favor of the pilot scale reactors while trying to make a fair comparison. For example, the segments of time and energy when the reactor was nearly at the set temperature were removed from the calculations and in fact no allowance has actually been made for this additional heating time on the pilot scale, even though it would be unavoidable in practice. Similarly, corrections for oscillation about the set-point were also made. In addition, most of the comparisons are made with the less typical reactor 0103, which in this study at least looks marginally more efficient than the more typical reactor 0201. Furthermore, as the surface-area-to-volume ratio drops, more of the reaction heat remains in the vessel, again inherently favoring the larger scale reactors through additional self-heating due to smaller environmental losses. Finally, it may be argued that this reaction is not typical of pharmaceutical process chemistry, but this reaction uses two low dipole starting materials in a low microwave-absorbing solvent (DCB) and so it can hardly be considered favorable for microwave heating compared to conventional heating. It is therefore all the more impressive that the most efficient microwave reactor (Table 4, entry 9) is nearly 9 times more
Acknowledgment. We thank Tracey Meaker (AstraZeneca, Avlon) for preparation of the tables. Supporting Information Available: Photographs of reactor unit 0201 and the Avlon LSL (Photos S1-S3) and table of the corrected and uncorrected data with separate heat up, hold, and cool down times and energy usage (Table S1). This material is available free of charge via the Internet at http://pubs.acs.org. (16) Moseley, J. D.; Lawton, S. J. Chem. Today 2007, 25 (2), 16–19.
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