Safe Scale-Up of Pharmaceutical Manufacturing Processes with

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Safe Scale-Up of Pharmaceutical Manufacturing Processes with Dimethyl Sulfoxide as the Solvent and a Reactant or a Byproduct Zhe Wang,* Steven M. Richter, John R. Bellettini, Yu-Ming Pu, and David R. Hill Process Research and Development, AbbVie Inc.,1 North Waukegan Road, North Chicago, Illinois 60064, United States ABSTRACT: Thermal hazard analyses of two reactions, one with DMSO as the solvent and a reactant and one with DMSO as the solvent and a byproduct, identified low-probability but severe consequence process risks associated with violent decomposition of DMSO during heating control failure or external heating. Although DMSO cannot be totally eliminated from these reactions, using an alternative solvent to replace DMSO proved to be an effective measure in reducing the thermal hazards to allow safe scale-up.

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INTRODUCTION Dimethyl sulfoxide (DMSO) is widely used in organic synthesis as a solvent because of its high dissolution power for many organic and inorganic compounds, high boiling point, and lower relative toxicity. DMSO is also used as a reactant in some processes (e.g., oxidation reactions) and is generated as a byproduct in some reactions. Pure DMSO can decompose near its atmospheric boiling point. The presence of other chemicals such as acids, bases, or halides can reduce the onset temperature. DMSO-containing reaction mixtures can decompose more energetically and at lower temperatures than pure DMSO.1 Prolonged exposure at elevated temperature can cause accumulation of the decomposition products, which can further catalyze the decomposition. The decomposition of DMSO has been identified as a serious process safety issue.2 Severe incidents involving chemical reactions and distillations due to the decomposition of DMSO have been discussed in the literature.3−5 Two separate incidents happened in 1992 and 2003 involving explosions in DMSO manufacturing facilities that caused a total of seven fatalities, 17 injuries, and tremendous property damage.6,7 In order to scale up a process, the process safety evaluation should be performed carefully. This includes measuring the heats of reaction, screening the thermal stability of process samples, identifying the process hazards and safe operating conditions, or the development of an alternative process. Thermal stability testing can be used to obtain the onset temperatures and the severity of exothermic events. The heat of reaction can be obtained using heat-flow calorimetry. The heat of reaction can be used to determine the adiabatic temperature rise (ATR) of a reaction, which is a measure of the thermal potential of the desired reaction. The criticality index introduced by Stoessel8 classifies potential runaway reactions on the basis of relative levels of the process temperature (Tp), the maximum temperature rise of the synthesis reaction (MTSR), the boiling point of solvent (Tb), and the temperature at which the reaction mass reaches a maximum self-heating rate under adiabatic conditions in 24 h (TD24), as shown in Figure 1. The processes in classes 1 (least critical) to 3 do not have the energy to self-heat to the onset of the decomposition, and the processes in classes 4 and 5 (most critical) have the thermal © XXXX American Chemical Society

Figure 1. Criticality classification of chemical processes.

potential to self-heat to the onset temperature of decomposition. In earlier work, the risks associated with the thermal decomposition of DMSO in processes where it was used as the process solvent were studied.9 In that work, a solution was proposed to eliminate the hazard by replacing the DMSO with an alternative solvent system. In the case that DMSO is the solvent and also a reagent or a byproduct of the desired reaction, DMSO cannot be completely removed from the process. Through process safety evaluation of two reactions, a Pfitzner−Moffatt oxidation and a Corey−Chaykovsky reaction, this work demonstrates that using alternative solvents is an effective way to reduce the process hazards in scaling up reactions where DMSO is the solvent and a reactant or a byproduct.

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RESULTS AND DISCUSSION 1. Pfitzner−Moffatt Oxidation: DMSO Used as a Reactant and as the Solvent. A pharmaceutical manufactur-

Special Issue: Safety of Chemical Processes 14 Received: August 15, 2014

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dx.doi.org/10.1021/op500260n | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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DSC results for DMSO showed that although the energy released was similar, the onset temperature was 55 °C lower. It is known that in the presence of acid, autocatalytic exothermic decomposition of DMSO can occur at temperatures well below its atmospheric boiling point.3 The dichloroacetic acid in the reaction mixture is suspected to contribute to the onset temperature reduction. In order to obtain more precise onset temperature measurement and monitor pressure effects, an accelerating rate calorimeter (ARC) was selected for additional thermal stability testing for the reaction mixture (postreaction mixture from the Omnical test). As shown in Figures 3−5, an

ing step involves the synthesis of a ketone via a Pfitzner− Moffatt oxidation of an alcohol similar to the reaction shown in Scheme 1. The process temperature (Tp) for this reaction is 23 °C using DMSO activated by N-(3-(dimethylamino)propyl)N′-ethylcarbodiimide hydrochloride (EDAC) as the oxidant.10 Scheme 1

Prior to scaling up the reaction in the pilot plant, a process safety analysis was conducted. The heat of reaction, measured with the Omnical SuperCRC, was used to calculate the MTSR during a loss-of-cooling event. In the test, after thermal equilibrium at the reaction temperature was attained, EDAC was added in four equal portions over 55 min into the test cell containing the starting material, dichloroacetic acid, and DMSO (charges shown in Table A in the Experimental Section). The measured heat of reaction was −417 kJ/mol, corresponding to an ATR of 34 °C. The MTSR, calculated as the sum of the reaction temperature and ATR, is 57 °C. The Omnical SuperCRC results are shown in Figure 2. It is noted that the

Figure 3. Reaction mixture ARC test (with EDAC): temperature and pressure histories.

Figure 2. Omnical results for the Pfitzner-Moffatt oxidation.

first portion of EDAC addition is less exothermic than the other additions. The exact reason for this is not known, but it is suspected that this is due to induction or initiation of the reaction. The thermal stabilities of the starting material, EDAC, DMSO, the reaction mixture, and the product were screened via differential scanning calorimetry (DSC) testing. The results are summarized in Table 1. The test of the reaction mixture detected an exothermic event at 153 °C, which was suspected to be due to decomposition of DMSO. Comparison with the

Figure 4. Reaction mixture ARC tests: self-heat rates (with and without EDAC) and pressure rate.

exothermic event was detected near 131 °C, which propagated into a violent runaway reaction. The actual maximum temperature and pressure rise rates could be much higher than the recorded values of 585 °C/min and 140 bar/min, respectively, since the test was terminated when the pressure reached the safety limit of 70 bar. DSC testing of EDAC detected an exotherm at temperatures as low as 125 °C. An ARC test of a prereaction solution, without the addition of EDAC, was conducted to examine the impact of EDAC on the onset temperature. As shown in Figure 4, this test also exhibited a low onset temperature, which confirms that the presence of dichloroacetic acid is the most likely cause of the reduction in the onset temperature.

Table 1. DSC results sample

ΔH (J/g)

range of exotherm (°C)

starting material DMSO EDAC reaction mixture product

−133 −397 −131 −407 −63

224−300 208−266 125−200 153−207 247−299 B



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After DMAc was identified as an alternative solvent, additional testing was conducted to explore how much further DMSO could be reduced. In a reaction with the amount of DMSO reduced to 8 equiv, comparable conversion was still achieved. When the amount was reduced to 4 equiv, only 91% conversion was obtained. Doubling the reaction time failed to increase the conversion. The screening reaction results are summarized in Table 3. Table 3. Pfitzner−Moffatt oxidation reaction (3 h at 23 °C) results

Figure 5. Reaction mixture ARC tests (with EDAC): temperature/ pressure relationship.

Table 2. Temperature levels for safety analysis of the Pfitzner−Moffatt oxidation reaction mixture temperature (°C)

Tb TD24 MTSR Tp

189 118 57 23

cosolvent (7 volumes)

reaction conversion (%)

60 15 15 15 8 4

N/A DMAc NMP DMF DMAc DMAc

98 96 91 91 96 91

After it was established that 8 equiv of DMSO could be used to achieve acceptable reaction conversion, thermal stability testing was performed to determine the impact of the reduction on the decomposition of the reaction mass. The thermal stabilities of postreaction mixtures using DMAc as the solvent and 8 or 15 equiv of DMSO were tested in the ARC. As shown in Figure 6, the test results for the reaction mixture with 8 equiv

On the basis of the ARC testing data of the postreaction mixture, the calculated TD24 was determined to be ∼118 °C. From the four temperature levels required to determine the criticality class, shown in Table 2, this process is categorized as belonging to criticality class 2.

variable

equiv of DMSO

Since the reactants would only self-heat to the MTSR (57 °C), safety issues due to a cooling failure are unlikely. However, in an uncontrolled heating event, there is no safety barrier provided by the evaporation of the solvent to prevent the reaction mass from reaching the onset temperature of the decomposition. Because of the severity of the decomposition in this case, the feasibility of reducing DMSO usage was investigated. Since DMSO is the solvent as well as a reactant, total elimination of DMSO is not possible. However, by the use of an alternative solvent, the amount of DMSO can be significantly reduced to reactant quantities, potentially reducing the severity of the decomposition. Since the starting material and the product have limited solubility in nonpolar organic solvents, the search for an alternative solvent for the Pfitzner−Moffatt oxidation reaction was focused on aprotic polar solvents, including N,Ndimethylacetamide (DMAc), N-methylpyrrolidone (NMP), and N,N-dimethylformamide (DMF). The screening reactions were performed under the original reaction conditions (3 h at 23 °C) with the amount of DMSO reduced from 60 to 15 equiv, using 7 volumes of the alternative solvent to examine the performance of the Pfitzner−Moffatt oxidation reaction. The reaction proceeded using all three alternative solvents. The reaction run in DMAc was slightly more favorable among the three solvents tested, reaching 96% conversion, compared to 98% conversion when the reaction was performed in DMSO alone.

Figure 6. ARC results for the reaction mixture with 8 equiv of DMSO in DMAc: temperature and pressure histories.

of DMSO showed several very weak exothermic events between 130 and 180 °C with maximum self-heating rates near 0.04 °C/min. Although the ARC testing of the reaction mixture with 15 equiv of DMSO detected exothermic decomposition at 120 °C, the exothermic event with a maximum self-heating rate less than 1 °C/min was much weaker than that in the reaction without cosolvent. The comparison of ARC testing self-heating rates for reaction mixtures using all DMSO and 15 and 8 equiv of DMSO is shown in Figure 7. As a reactant, DMSO cannot be completely eliminated from the Pfitzner−Moffatt oxidation reaction, but using DMAc as a cosolvent and reducing the amount of DMSO to 8 equiv significantly reduces the severity of decomposition to a safe level in the event of an uncontrolled external heating. Taking C



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and summarized in Table 5. The DSC tests detected an exothermic event at 194 °C in the ylide formation mixture and an exothermic event at 175 °C in the Corey−Chaykovsky reaction mixture. The exothermic events in both mixtures were presumed to be due to the decomposition of DMSO. The decomposition energies for both mixtures were greater in magnitude than that for DMSO alone, and the onset temperatures were 10 and 30 °C lower than that of pure DMSO. It is known that in the presence of strong base or halides the exothermic decomposition of DMSO can occur at temperatures below its boiling point of 189 °C.3 The potassium tert-butoxide and/or potassium iodide in the reaction mixture were suspected to contribute to the onset temperature reduction. Additional thermal stability tests on the ylide formation and Corey−Chaykovsky cyclopropanation reaction mixtures were conducted using the more sensitive ARC to obtain accurate onset temperatures and monitor pressure effects. To avoid potential ARC test cell rupture during the energetic decomposition, both tests were performed with low material charge (∼20% full) and programmed to terminate (i.e., stop heating and cool down) at pressures exceeding 40 barg. In the ARC test of the ylide formation mixture (postreaction sample from the Omnical test), exothermic events were detected near 60, 80, and 180 °C. The mildly exothermic event near 60 °C was suspected to be due to oxidation of one of the reaction components, as suggested by the pressure drop in the test cell. The exothermic event detected near 180 °C resulted in an energetic runaway, presumably due to the exothermic decomposition of the DMSO solvent. The results are shown in Figures 9 and 10. In the ARC test of the Corey−Chaykovsky cyclopropanation reaction mixture (postreaction mixture from the Omnical test), an exothermic event detected near 170 °C resulted in an energetic runaway, likely due to the exothermic decomposition of DMSO (the solvent and a reaction byproduct). The results are shown in Figures 9 and 10. In both ARC tests, the actual severities of the runaways could have been much worse if the tests were not terminated during the exothermic events. From the temperatures shown in Table 6, both the ylide formation and Corey−Chaykovsky cyclopropanation reactions belong to criticality class 2. In the event of a cooling failure, the ylide formation reaction mixture could self-heat to the MTSR (30 °C). Safety concerns due to a cooling failure are unlikely. If cooling is not available to remove the heat generated during the Corey−Chaykovsky cyclopropanation reaction, the reaction could self-heat to the MTSR (95 °C) but could not reach the TD24. As in the case of the Pfitzner−Moffatt oxidation, a safety issue as a result of cooling failure is unlikely. However, cooling failure is not the only upset contingency. In an uncontrolled external heating event (i.e., control failure during heating or an external fire), the temperature of the ylide formation or Corey− Chaykovsky cyclopropanation reaction masses could increase to the corresponding TD24 without the benefit of the safety barrier provided by the boiling point of the solvent. Because of the potentially devastating consequences of decomposition during an uncontrolled heating, identification of an alternative solvent was explored before scaling up the process. Since DMSO is the solvent as well as a byproduct, total elimination of DMSO from the process is not possible. However, replacing DMSO with an alternative reaction solvent would be expected to reduce the severity of the decomposition.

Figure 7. Comparison of reaction mixture ARC test self-heating rates.

these measures allows the Pfitzner−Moffatt oxidation reaction to be scaled up safely. 2. Corey−Chaykovsky Reaction: DMSO Generated as a Byproduct. Cyclopropyl malonate (X), is synthesized via a Corey−Chaykovsky reaction similar to that shown in Scheme 2. At ambient temperature, the ylide is generated in situ by Scheme 2

deprotonation of trimethylsulfoxonium iodide with the base potassium tert-butoxide. The ylide then reacts with the enone to form X at 55 °C. In addition to being generated as a byproduct of the desired reaction, DMSO is typically used as the solvent in both ylide formation and Corey−Chaykovsky cyclopropanation reactions.11,12 Because of the safety concerns associated with DMSO, a detailed safety analysis was conducted before scaling up in the pilot plant. The heats of reaction measured with the Omnical SuperCRC (charges shown in Tables B and C in the Experimental Section), the calculated ATRs, and the MTSRs for the ylide formation and Corey−Chaykovsky reactions are listed in Table 4. The thermal stabilities of the enone starting material, trimethylsulfoxonium iodide, the ylide formation mixture, the Corey−Chaykovsky reaction mixture, and the product were screened via DSC testing. The results are plotted in Figure 8 Table 4. Heat of reaction measurement results for the Corey−Chaykovsky reaction reaction ylide formation Corey−Chaykovsky reaction

heat of reaction (kJ/mol)

ATR (°C)

MTSR (°C)

−23.8 −177.7

7 40

30 95

D



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Figure 8. DSC results for the Corey−Chaykovsky reaction.

Table 5. DSC results for the Corey−Chaykovsky reaction sample

ΔH (J/g)

range of exotherm (°C)

enone starting material DMSO trimethylsulfoxonium iodide ylide formation mixture Corey−Chaykovsky reaction mixture cyclopropane product

−589 −397 −337 −836 −595 −352

225−256 208−266 156−205 194−297 175−227 250−273

Figure 10. ARC results for the ylide formation and cyclopropanation reaction mixtures: temperature/pressure relationships.

Table 6. Temperature levels for safety analysis temperature levels (°C)

Figure 9. ARC results for the ylide formation and cyclopropanation reaction mixtures: self-heating rate data.

variable

ylide formation

Corey−Chaykovsky

Tb TD24 MTSR Tp

189 165 30 23

189 157 95 55

using DMF as the solvent was screened with an ARC test (charges shown in Table D in the Experimental Section). As shown in Figures 11 and 12, the exothermic decomposition detected at 170 °C in the reaction mixture using DMSO as the solvent occurred at a higher temperature of 215 °C, and the self-heating rate of the exotherm was reduced from 165 °C/min in the DMSO system to less than 0.1 °C/min. The mild exotherm at 215 °C is believed to be due to the decomposition of DMSO, the reaction byproduct.

The ylide formation and Corey−Chaykovsky cyclopropanation reactions performed using DMF as the solvent produced quality product in satisfactory yield and were identified as candidate processes to scale up. As expected, no exothermic decomposition was detected in the ARC test of the ylide formation mixture since DMSO was completely replaced as the solvent. The thermal stability of a freshly prepared reaction mixture for the Corey−Chaykovsky cyclopropanation reaction E



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scaled-up, complete removal of DMSO is unlikely. However, using an alternative solvent to replace DMSO as the solvent can reduce the severity of decomposition to a safe level so the process can be safely scaled up, accounting for a loss of cooling or an uncontrolled external heating situation. The most likely alternative solvents to replace DMSO are polar aprotic solvents such as DMAc and DMF. The issues with operator exposure and environmental restriction should be taking into consideration in selecting the alternative solvent. Another concern is the potential impact of the alternative solvent on impurity formation. Although comparable impurity profiles were obtained in both reactions in this study, this should be closely examined in selecting an alternative solvent.

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EXPERIMENTAL SECTION Equipment Used. DSC was performed with a Mettler Toledo DSC821e or DSC823e calorimeter using sealed glass ampules with a capacity of approximately 50 μL. ARC was performed using a Thermal Hazard Technology esARC calorimeter and titanium test cells. Heat-of-reaction testing was performed using an Omnical SuperCRC isothermal calorimeter. General Procedure for DSC Testing. Samples were first loaded into glass ampules, which were then sealed and ramped in the DSC furnace from 0 to 300 or 350 °C at 1−3 °C/min. General Procedure for Omnical Testing. Two 15 mL glass test cells were used per test, one for the sample and the other for the reference. Mixing was provided by a magnetic stir bar. General Procedure for ARC Testing. The sample was loaded into a Ti pressure bomb, which was then inserted into the calorimeter. The temperature and pressure of the test were recorded. The sample was heated in heat-wait-search steps of 10 °C starting at 30 °C. When self-heating was detected, the calorimeter maintained the air space around the bomb at the same temperature as the sample and tracked the exotherm to 300 °C or until a pressure of 40−70 bar was reached. Omnical Test Charges. Charges for the Omnical test of the Pfitzner−Moffatt oxidation reaction are shown in Table A.

Figure 11. ARC results for the cyclopropanation reaction mixture (using DMF as the solvent): temperature and pressure histories.

Figure 12. Comparison of reaction mixture ARC test self-heating rates.

Table A. Omnical test charges for the Pfitzner−Moffatt oxidation reaction

DMSO is generated in the Corey−Chaykovsky cyclopropanation reaction as a byproduct and hence cannot be completely eliminated. However, replacing DMSO with DMF as the solvent increases the onset temperature of decomposition during an uncontrolled external heating to above the boiling point of the solvent and reduces the severity of decomposition to a safe level. With DMF as the solvent, the Corey−Chaykovsky cyclopropanation reaction was safely scaled up to multikilogram runs.

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material

amount (equiv)

starting material EDAC dichloroacetic acid DMSO

1.0 4.1 3.2 60.5

After the reaction reached completion, 45 wt % of the reaction mixture was used in the ARC test. Charges for the Omnical test of the ylide formation reaction are shown in Table B. At the end of the Omnical test, 22 wt % of the reaction mixture was used in the ARC test. Charges for the Omnical test of the

CONCLUSIONS In the scale-up of synthesis reactions with DMSO as the solvent and a reactant or byproduct, the process safety hazards associated with DMSO should be carefully evaluated. DMSO can decompose exothermally near its boiling point. Contaminants such as strong bases, acids, or halides can reduce the onset temperature of decomposition. Since DMSO decomposition is autocatalytic, the thermal history also affects the onset temperature. In the reaction mixture, the decomposition energy can be greater in magnitude and the onset temperature or decomposition can be significantly reduced. When a reaction with DMSO as the solvent and a reactant or byproduct is

Table B. Omnical test charges for the ylide formation reaction

F

material

amount (equiv)

trimethylsulfoxonium iodide KOt-Bu DMSO

1.2 1.2 16.1



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Corey−Chaykovsky cyclopropanation reaction are shown in Table C. At the end of Omnical test, 23 wt % of the reaction mixture was used in the ARC test. Table C. Omnical test charges for the Corey−Chaykovsky reaction material

amount (equiv)

enone starting material trimethylsulfoxonium iodide KOt-Bu DMSO

1.0 1.2 1.2 20.8

ARC Test Charges. Charges for the ARC test of the Corey−Chaykovsky cyclopropanation reaction using DMF as the solvent are shown in Table D. Table D. ARC test charges for the Corey−Chaykovsky reaction using DMF as the solvent

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material

amount (equiv)

enone starting material trimethylsulfoxonium iodide KOt-Bu DMF

1.0 1.5 1.5 30.9

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was sponsored by AbbVie Inc. AbbVie contributed to the design, research, and interpretation of data and writing, reviewing, and approving the publication. All of the authors were AbbVie employees at the time that they worked on this study.

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REFERENCES

(1) Lam, T. T.; Vickery, T.; Tuma, L. J. Therm. Anal. Calorim. 2006, 85, 25−30. (2) Bollyn, M. Org. Process Res. Dev. 2006, 10, 1299−1312. (3) Hall, J. Loss Prevention Bulletin, Vol. 114, December 1993. (4) Bretherick, L. Handbook of Reactive Chemical Hazards, 6th ed.; Butterworth-Heinemann: London, 1999; p 336. (5) Report of Case Studies in the State of Tamil Nadu. http://dgfasli. nic.in/safetyhealth_info/case_studies/tamilnadu.htm. (6) Yang, X. W.; Zhang, X. Y.; Guo, Z. C.; Bai, W. S.; Hao, L.; Wei, H. Y. Thermochim. Acta 2013, 559, 76−81. (7) Zhang, Z.; Qian, X. China Saf. Sci. J. 2006, 16, 100−104. (8) Stoessel, F. Thermal Safety of Chemical Processes: Risk Assessment and Process Design; Wiley-VCH: Weinheim, Germany, 2008. (9) Wang, Z.; Richter, M. S.; Gates, D. B.; Grieme, A. T. Org. Process Res. Dev. 2012, 16, 1994−2000. (10) Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1963, 85, 3027− 3028. (11) Ivanova, O. A.; Budynina, E. M.; Chagarovskiy, A. O.; Kaplun, A. E.; Trushkov, I. V.; Melnikov, M. Y. Adv. Synth. Catal. 2011, 353, 1125−1134. (12) Dias, D. A.; Kerr, M. A. Org. Lett. 2009, 11, 3694−3697.

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Safe Scale-Up of Pharmaceutical Manufacturing Processes with

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