Continuous Flow Processing of Linezolid
Senior Design Final Design Report
Wednesday, May 11, 2016
Professor Jeremy VanAntwerp
Jeffrey Kamp
Jeremiah Daniel Rocha
Lea Wassink
Joshua Wright
(Team 13-Linezolid)
© 2016, Team Linezolid and Calvin College
5/11/16
Team 13: Linezolid
Executive Summary
Most pharmaceutical processes are conducted in batch for reasons of ease of scale-up and product
tracking as well as quick rate of return. Team 13 designed a process to make the pharmaceutical drug
Linezolid in continuous flow. Flow processes are more efficient with raw materials, reduce down time,
and produce a higher quality product more consistently than a batch process. However, flow takes longer
to implement because it requires approximately 6 more months for process development.
The objective of this project was to produce approximately 4000 kg/yr of Linezolid at a cost of $800/kg
or less to compare with the current manufacturing of Linezolid in batch. Using data from two patents, the
team converted a batch style process into flow. The reactors and separations were designed and simulated
using hand calculations and UniSim. An economic analysis of the final design resulted in a manufacturing
cost of $653.68/kg which is considerably less than the batch cost. This analysis included capital, FDA
approval, raw materials, energy annuity, waste disposal, and labor costs.
The team then looked into the implications of not manufacturing for 6 months to complete the process
development for flow. It was determined that this would result in the loss of $186.3 million of revenue,
based on current market value of $56.37. This would breakeven after 320 years with the savings of flow
over batch. The average wholesale price of Linezolid would have to decrease from $56.37 for a 600 mg
pill to $5.80 or less for the flow process to outperform the batch process, in terms of profit.
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Team 13: Linezolid
Table of Contents
Executive Summary ...................................................................................................................................... 3
Table of Contents .......................................................................................................................................... 4
Table of Figures ............................................................................................................................................ 9
Table of Tables ........................................................................................................................................... 11
1. Project Overview .................................................................................................................................... 12
1.1
1.1.1
1.2
Linezolid Overview .................................................................................................................... 12
Problem Definition.............................................................................................................. 12
Project Proposal .......................................................................................................................... 13
1.2.1
Objective ............................................................................................................................. 13
1.2.2
Target Customers ................................................................................................................ 13
1.2.3
Potential Competitors.......................................................................................................... 13
1.2.4
Differentiated Approach ..................................................................................................... 13
1.3
Team Organization...................................................................................................................... 13
1.3.1
Team Profile........................................................................................................................ 13
1.3.2
Project Contributors ............................................................................................................ 14
1.3.3
Team Management Method ................................................................................................ 15
Team Organization.................................................................................................................................. 15
1.4
Design Norms ............................................................................................................................. 16
2. Deliverables ............................................................................................................................................ 17
2.1
Posters ......................................................................................................................................... 17
2.2
PPFS............................................................................................................................................ 17
2.3
Final Design Report .................................................................................................................... 17
2.4
Team Website ............................................................................................................................. 17
2.5
Process Flow Diagram ................................................................................................................ 17
3. General Background ............................................................................................................................... 18
3.0
Background ................................................................................................................................. 18
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Team 13: Linezolid
3.1
Discovery of Linezolid................................................................................................................ 18
3.2
Significance................................................................................................................................. 18
3.2.1
Uses ..................................................................................................................................... 19
3.2.3
Dosage................................................................................................................................. 19
3.2.4
Side effects .......................................................................................................................... 19
3.4 Initial Synthesis Process ................................................................................................................... 20
3.5 Green Synthesis ................................................................................................................................ 20
4. Design Scope and Specifications ............................................................................................................ 21
5. Objectives and Constraints...................................................................................................................... 22
5.1 Reaction Kinetics .............................................................................................................................. 22
5.2 Product Purity ................................................................................................................................... 22
5.3 Capacity ............................................................................................................................................ 22
5.4 Separations ........................................................................................................................................ 23
6. Operation................................................................................................................................................. 24
7. Modeling and Simulations ...................................................................................................................... 25
8. Kinetics ................................................................................................................................................... 26
9. Reactors................................................................................................................................................... 28
9.1 Introduction ....................................................................................................................................... 28
9.2 Assumptions...................................................................................................................................... 28
9.3 Design and Optimization Strategy .................................................................................................... 28
9.4 Calculations....................................................................................................................................... 29
9.5 Results ............................................................................................................................................... 31
9.5.1 Reaction Carbam1 ...................................................................................................................... 31
9.5.2 Reaction Carbam2 ...................................................................................................................... 32
9.5.3 Reaction Carbam3 ...................................................................................................................... 34
9.5.4 Reaction A1 ............................................................................................................................... 35
9.5.5 Reaction A2 ............................................................................................................................... 36
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Team 13: Linezolid
9.5.6 Reaction B1 ................................................................................................................................ 37
9.5.7 Reaction C1 ................................................................................................................................ 38
9.5.8 Reaction C2 ................................................................................................................................ 39
9.5.9 Heat Transfer Results ................................................................................................................. 40
10. Separations ............................................................................................................................................ 41
10.1 Design Approach ............................................................................................................................ 41
10.2 Design Goals ................................................................................................................................... 41
10.3 Typical Setup .................................................................................................................................. 42
10.4 UniSim Simulation.......................................................................................................................... 42
11. Final Design .......................................................................................................................................... 43
12. Equipment ............................................................................................................................................. 49
12.1 Method for Picking and Pricing Equipment ................................................................................... 49
12.2 Reactors........................................................................................................................................... 49
12.3 Evaporators ..................................................................................................................................... 49
12.4 Crystallizers .................................................................................................................................... 50
12.5 Rinses .............................................................................................................................................. 50
12.6 Dryers.............................................................................................................................................. 51
12.7 Storage Tanks.................................................................................................................................. 51
12.8 Separation Tanks ............................................................................................................................. 51
12.9 Heat Exchangers ............................................................................................................................. 51
12.10 Pumps............................................................................................................................................ 52
12.11 Agitators........................................................................................................................................ 52
12.12 Pipes .............................................................................................................................................. 53
12.13 Valves ........................................................................................................................................... 53
13. Hazardous Operations ........................................................................................................................... 54
13.1 Waste Management ......................................................................................................................... 54
13.2 Storage ............................................................................................................................................ 56
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Team 13: Linezolid
13.3 Chemical Dangers ........................................................................................................................... 59
14. Cost Analysis ........................................................................................................................................ 63
14.1 Cost Goal ........................................................................................................................................ 63
14.2 Equipment Costs ............................................................................................................................. 63
14.3 Energy Costs ................................................................................................................................... 63
14.4 Material Costs ................................................................................................................................. 66
14.5 Other Costs...................................................................................................................................... 67
14.6 Total Production Cost ..................................................................................................................... 67
14.7 Implications..................................................................................................................................... 68
15. Sensitivity Analysis .............................................................................................................................. 70
16. Conclusion ............................................................................................................................................ 73
17. Acknowledgements ............................................................................................................................... 74
Professor Jeremy VanAntwerp ............................................................................................................... 74
Professor Michael Barbachyn ................................................................................................................. 74
Professor Wayne Wentzheimer ............................................................................................................... 74
Mark Boekeloo........................................................................................................................................ 74
Mike Dokter ............................................................................................................................................ 74
The CEAC board..................................................................................................................................... 74
Karis Kim ................................................................................................................................................ 74
18. References ............................................................................................................................................. 75
Appendix A: International Chemical Safety Cards..................................................................................... 78
Acetic Acid ............................................................................................................................................. 78
Acetone ................................................................................................................................................... 81
Ammonium Hydroxide (10%-30% solution) .......................................................................................... 83
Benzyl Alcohol ....................................................................................................................................... 85
Benzyl Chloroformate ............................................................................................................................. 87
Epichlorohydrin ...................................................................................................................................... 89
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Team 13: Linezolid
Ethyl Acetate........................................................................................................................................... 92
n-Hexane ................................................................................................................................................. 94
Hydrogen ................................................................................................................................................ 96
Hydrogen Chloride.................................................................................................................................. 98
Hydrogen Fluoride ................................................................................................................................ 100
2,2,4-Trimethylpetane ........................................................................................................................... 103
Methanol ............................................................................................................................................... 105
Methyl tert-butyl ether .......................................................................................................................... 107
Methylene Chloride .............................................................................................................................. 109
Morpholine............................................................................................................................................ 112
Nitrogen (Compressed Gas) .................................................................................................................. 115
Sodium Bicarbonate .............................................................................................................................. 116
Sodium Hydroxide ................................................................................................................................ 117
Appendix B: UniSim Process Flow Diagram ........................................................................................... 120
Stream Tables........................................................................................................................................ 124
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Team 13: Linezolid
Table of Figures
Figure 1: The chemical structure of (S) Linezolid ...................................................................................... 12
Figure 2. 2-oxazolidinone ........................................................................................................................... 18
Figure 3. Carbam 1 reaction........................................................................................................................ 31
Figure 4: Conversion as a function of volume for the Carbam1 PFR ......................................................... 31
Figure 5. Carbam II reaction ....................................................................................................................... 32
Figure 6: Results of the Ergun Equation calculation for pressure drop across the packed bed reactor,
Carbam2. ..................................................................................................................................................... 33
Figure 7. Carbam III reaction...................................................................................................................... 34
Figure 8: Conversion as a function of volume for the Carbam3 PFR ......................................................... 34
Figure 9. Reaction A1 ................................................................................................................................. 35
Figure 10: Conversion as a function of volume for the A1 PFR ................................................................ 35
Figure 11. Reaction A2 ............................................................................................................................... 36
Figure 12: Conversion as a function of volume for the A2 PFR ................................................................ 36
Figure 13. Reaction B1 ............................................................................................................................... 37
Figure 14: Conversion as a function of volume for the B1 PFR ................................................................. 37
Figure 15. Reaction C1 ............................................................................................................................... 38
Figure 16: Conversion as a function of volume for the C1 PFR ................................................................. 38
Figure 17. Reaction C2 ............................................................................................................................... 39
Figure 18: Conversion as a function of volume for the C2 PFR ................................................................. 39
Figure 19: Summary graph of the amount of heat transfer fluid required to achieve isothermal conditions
for each reactor ........................................................................................................................................... 40
Figure 20: Carbamic Acid Production Section ........................................................................................... 43
Figure 21: First Section of Linezolid Production........................................................................................ 44
Figure 22: Second Section of Linezolid Production ................................................................................... 44
Figure 23: Third Section of Linezolid Production ...................................................................................... 45
Figure 24: Full Process Flow Diagram ....................................................................................................... 46
Figure 25: Swenson-Walker continuous cooling crystallizer ..................................................................... 50
Figure 26: Percentage breakdown for producing 4300 kg of Linezolid per year ....................................... 68
Figure 27. Summary of the analysis on the effect of reactor conversion on overall production cost ......... 70
Figure 28: Production cost variance due to decreasing crystallization yield .............................................. 71
Figure 29. Summary of the analysis of the effect of percent solvent recovery on the overall production
cost .............................................................................................................................................................. 72
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Team 13: Linezolid
Figure 30:PFD first section in making Linezolid...................................................................................... 120
Figure 31: PFD section for creating carbamic acid................................................................................... 121
Figure 32: PFD second section for Linezolid production ......................................................................... 122
Figure 33: PFD third section for Linezolid production............................................................................. 123
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Team 13: Linezolid
Table of Tables
Table 1. Summary of Reaction Rate Constants .......................................................................................... 26
Table 2. Kinetics conversion extents .......................................................................................................... 27
Table 3: summary of Catalyst Information for Carbam2 ............................................................................ 32
Table 4: Heat Transfer Fluid Properties ...................................................................................................... 40
Table 5: The separation yield information used from the two synthesis patents ........................................ 42
Table 6: Equipment Summary .................................................................................................................... 47
Table 7: Summary of Final PFR Sizes and Duties...................................................................................... 48
Table 8: Results Summary for Carbam2 PBR ............................................................................................ 48
Table 9. Heat transfer coefficients used for calculating heat exchange area .............................................. 52
Table 10. Known disposal methods for chemicals in process .................................................................... 54
Table 11. Known storage methods for chemicals in process ...................................................................... 56
Table 12. Known dangers of chemicals in process ..................................................................................... 59
Table 13. Equipment Price information ...................................................................................................... 64
Table 14. Pipe and valve price information ................................................................................................ 66
Table 15. Material prices ............................................................................................................................ 66
Table 16. Solvent costs and recovery.......................................................................................................... 67
Table 17. Cost summary for producing 4300 kg of Linezolid per year ...................................................... 68
Table 18. Summary of the analysis on the effect of crystallizer yields on the overall production cost ...... 71
Table 19: Stream tables for UniSim simulations ...................................................................................... 124
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Team 13: Linezolid
1. Project Overview
1.1
Linezolid Overview
Linezolid is an antibiotic used for treatment of serious infections caused by gram-positive bacteria that
has become resistant to other antibiotics.
Figure 1: The chemical structure of (S) Linezolid
This drug is currently being manufactured by the company Pfizer under the name of Zyvox. Zyvox is
prescribed for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) as well as
“nosocomial pneumonia, community-acquired pneumonia, complicated skin and skin structure infections,
vancomycin-resistant Enterococcus faecium infections1”. As of May 2015, Pfizer’s patent on the original
chemistry for making linezolid expired, allowing the drug to be produced generically.
1.1.1
Problem Definition
Zyvox is an expensive antibiotic. The current average purchase price of Linezolid is $56.37 per pill2. This
process, like many pharmaceutical synthesis processes, is done in batch rather than continuous flow3.
Batch processes have several advantages. Batch reactors can be used for multiple products and processes;
they are easy to scale-up from bench top chemistry. Unfortunately they require human intervention at
nearly every step of the process. The reactors need to be cleaned between every run and require teams of
people working for several days to do this depending on size.
1
"ZYVOX - Linezolid Injection, Solution, Tablet, Film Coated, Suspension." Labeling.Pfizer. Pfizer, 1 July 2015.
Web. 10 Oct. 2015.
2
3
Zyvox Prices, Coupons and Patient Assistance Programs. Drugs.com, 2015. Web. 24 April 2016.
Boekeloo, Mark. Personal interview. 10 Nov. 2015.
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Team 13: Linezolid
Continuous flow processes have a few advantages over the batch process. Once they are operational, they
require little intervention because they are fully automated. Flow processes are more efficient with raw
materials and produce a higher quality product at higher consistency than a batch process.
1.2
Project Proposal
1.2.1
Objective
The proposed project was to reduce the manufacturing cost of the production of 4,000 kg of Linezolid per
year by using a continuous flow process instead of a batch process.
1.2.2
Target Customers
The target customer for this Linezolid manufacturing process was major pharmaceutical companies
looking to either enter the Linezolid market or expand by replacing their old batch Linezolid process with
our more cost-effective continuous flow process.
1.2.3
Potential Competitors
Pfizer currently holds the majority of the market for Linezolid with Zyvox which they had FDA approved
in 2000. As the patent for the original synthesis expired in 2015, more generic pharmaceutical companies
have been looking to enter the market. From May 2015 to 2016, 10 companies applied for FDA approval
to make linezolid in its tablet form. With this rise in competition, the price will be driven down and so
lower manufacturing costs will further increase profit.
1.2.4
Differentiated Approach
In the pharmaceutical industry, the most common form of processing is in batch chemistry. This is mostly
due to easy scale-up and time constraints brought on from patenting and FDA approval. Team 13’s
approach was to produce a process in flow chemistry to provide improved efficiency, more consistent
quality, and reduce the risk of contamination.
1.3
Team Organization
1.3.1
Team Profile
Jeffrey Kamp - Member
Jeffrey Kamp is a senior engineering student studying Chemical Engineering at Calvin College. He is
engaged to be married in August 2016 to his high school sweetheart Ashley. Starting in June 2016, he
will be moving to Madison, Wisconsin and will be working at Epic with the title technical services. There
he will help develop healthcare software – specializing in pharmacy software.
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Team 13: Linezolid
Jeremiah Daniel Rocha - Member
JD Rocha is a chemical engineering student at Calvin College. He interned at Master Finish Company as
part of their manufacturing projects team. During his time at Master Finish, he designed a new rinse
system for their main plating line that increased productivity by 30%. He previously worked for Professor
Wunder doing research on biofiltration and removal of nitrates in water.
Lea Wassink - Member
Lea Wassink is studying Chemical Engineering as well as Chemistry and French at Calvin College. She
has interned at Nova Chemicals, a petrochemical complex, and has experience driving heavy equipment
in the earth moving industry. She is a farmer’s daughter and musician. In the summer of 2016, she plans
to do research under Professor Michael Barbachyn working on the Design and Synthesis of Novel
Antibacterial Agents Targeting Bacterial DNA Gyrase. She will be returning to Calvin College for a fifth
year and is considering attending graduate school afterwards.
Joshua Wright - Member
Joshua Wright hails from Beaver Falls Pennsylvania and is studying Chemical Engineering with a minor
in German. He has participated in several of Calvin’s international programs including an internship at
Boehringer Ingelheim in Ingelheim am Rhein, Germany. At Boehringer, Joshua completed the analysis,
and adaptation into flow chemistry of a predefined organic synthesis. After Calvin, he will be attending
Notre Dame University for his PhD in Chemical Engineering.
1.3.2
Project Contributors
Jeremy VanAntwerp - Advisor
Jeremy VanAntwerp is a chemical engineering professor at Calvin College; he is Team 13’s advisor for
the course of this project. He went to Michigan State University to get his undergraduate degree in
chemical engineering, and he went to the University of Illinois Urbana-Champaign for his doctorate. To
complement this, he is also an editor for IEEE Control Systems Magazine.
Michael Barbachyn - Advisor
Michael Barbachyn is a chemistry professor at Calvin College. He was a member of the team at UpJohn
that developed Linezolid and introduced Team 13 to both processes for making Linezolid. He went to
Calvin College for his undergraduate and received his doctorate in organic chemistry from Wayne State
University.
Mark Boekeloo - Industrial Mentor
Mark Obtained his BS ChE from the University of Michigan in 1980. Mark Joined the Kalamazoo site
(UpJohn company) in 1981 as a Development engineer, supporting Bioprocess development. In 1985
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Team 13: Linezolid
Mark Moved to supporting the Fermentation and Isolation areas as a Production Engineer. In 1990, Mark
was promoted to Manager, Specialty Chemical production. Over the next 10 years Mark managed
multiple building is the organic synthesis plant. In 2000, Mark was promoted to Direct/TL API East
manufacture. In 2007, Mark assumed responsibility for API East and API West Manufacture, which
includes Fermentation, Isolation, Organic synthesis, and Particle Size reduction. Mark retired from Pfizer
in 2015. Mark has been married for 36 years. He and his wife Jane have 3 children.
1.3.3
Team Management Method
Team Organization
The technical work of this project was divided evenly amongst all four team members. Moreover,
organizational tasks were divided up amongst the team. The tasks listed below were not solely completed
by the team members assigned to each task, but rather were organized by the assigned team member and
completed with assistance from other team members.
Jeffrey Kamp:
Jeffrey was tasked with designing half of the separation process, as well as the economic analysis on the
design.
Jeremiah Rocha:
Jeremiah was in charge of half of the separations process, updating the website, and poster creation. He
was also in charge of creating the process flow diagram.
Lea Wassink:
Lea took on the position of research coordinator. She was responsible for combining and organizing the
resources that was assembled by the team and developed the flow process computer simulations with
Josh. She also used her connection at the Hekman Library to lead research on the chemistry, material
properties, and pricing.
Joshua Wright:
Joshua was communications officer for the team. His chief responsibilities included communication with
the team’s industrial mentor and faculty advisor. He managed the team's administrative details such as
scheduling, meeting minutes, and project organization. He also headed up creating the flow process
computer simulations and reactor design.
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1.4
Team 13: Linezolid
Design Norms
The system was designed with the following design norms: Trust, Stewardship, and Caring.
Trust means that the design should be dependable from the perspective of the user. Whoever comes into
contact with the product should be able to use it without fear of its failure or causing harm to the user. For
the design, the concept of trust manifests itself in the fact that the product will be in pharmaceutical terms
“generic.” Generic simply means that the patent owned by the discovering company has expired, and
anyone is legally permitted to produce it. Often, a stigma exists from the point of view of the consumer
that a generic pharmaceutical may not be of the same quality as its name-brand equivalent. This is
generally not true in the industry, and the team also wanted to hold to the same standard for the product.
The process was designed in such a way that the product will be of equal quality as the Pfizer-made
equivalent, giving the customer a product that will contribute to their health and wellbeing.
Stewardship involves carefully using earth’s resources frugally and thoughtfully.4 The entire theme of this
design project was encompassed by stewardship because it was attempting to produce a life-sustaining
product more efficiently through a flow process. Also, the process was designed in such a way that is not
detrimental to the environment, for example, having green side products and plant exhausts. Waste will be
properly disposed of in the most environmentally consciousness way possible.
Finally, a caring design will be one that takes into account its effects on individuals - physically, socially,
and psychologically.8Again, caring is also an integral part of the purpose of this design project. The
projects seeks to design a process that will enable more efficient and, therefore, more cost-effective
production of the active ingredient of an antibiotic. This lowers the cost of the antibiotic, giving more
patients access, improving the health, and wellbeing of people across the world.
4
Ermer, Gayle E., and Steven H. VanderLeest. "Using Design Norms to Teach Engineering Ethics." American Society
of Engineering Education. Calvin College, 2002. Google Scholar. Web. 13 Nov. 2015.
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Team 13: Linezolid
2. Deliverables
2.1
Posters
Posters were designed for presentation days as well as for engineering Fridays at Calvin. These were done
to display the progress and final results of the design process. A final poster was also designed for the
senior design presentation night and will be available for viewing in the Engineering Building for the
2016-2017 school year.
2.2
PPFS
A project proposal and feasibility study was submitted at the end of the first semester to finalize the scope
of the project as well as to present the plan moving forward.
2.3
Final Design Report
The final design report was written in order to fully document all of the design decisions and
specifications that went into the process design. It was delivered on May 11, 2016 to the team’s advisor
Professor VanAntwerp.
2.4
Team Website
A website was designed to promote the project and to update the public on the team’s progress. This is
available through the following link: http://www.calvin.edu/academic/engineering/2015-16-team13/
2.5
Process Flow Diagram
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Team 13: Linezolid
3. General Background
3.0
Background
This section outlines the technical background of the project. It discusses the entire timeline of
development of Linezolid, the proper context to fully understand what is at stake with the project.
3.1
Discovery of Linezolid
Due to the increased bacterial resistance in patients, an urgent desire to discover more antibiotics in new
classes of compounds became the goal of many pharmaceutical companies. Oxazolidinones, which was
discovered by DuPont in 19735 became an area of high interest because of its activity. The discovery of
Linezolid was a result of research done by the chemists at UpJohn (now Pfizer) into oxazolidinone
derivatives, specifically the piperazinyl derivatives which demonstrated good in vivo and in vitro activity,
water solubility, pharmacokinetics (PK) parameters, and safety profiles. Through this research, it was
found that fluorinated derivatives showed excellent antibacterial activity. This lead to the development of
two products: Eperezolid and Linezolid. In preclinical trials, Linezolid showed superior PK parameters
and bioavailability than Eperezolid. Both compounds were evaluated in Phase 1 clinical trials, however
Linezolid was chosen to move onto Phase 2 due to its PK parameters, which suggested the possibility of
taking two doses a day. It was approved by the FDA on April 18, 2000 and is now marketed as Zyvox®
by Pfizer.6
3.2
Significance
Oxazolidinones are a class of compounds containing a 2-oxazolidinone structure (a five-membered ring
containing a nitrogen and an oxygen).
Figure 2. 2-oxazolidinone7
5
Stefan, Koenig, ed. Scalable Green Chemistry. Singapore: Pan Stanford Publishing Pte. Ltd., 2013. 159. Print.
6
Barbachyn, M and Karen Joy Shaw. The oxazolidinones: past, present, and future. 2011.
http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2011.06330.x/epdf PDF
7
ChemSpider. Royal Society of Chemistry. 2015. http://www.chemspider.com/Chemical-Structure.66579.html
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Team 13: Linezolid
This particular structure has good activity against gram-positive pathogenic bacteria and is of particular
interest in antibiotics for fighting against methicillin-resistant Staphylococcus aureus (MRSA), penicillinresistant streptococci8, and vancomycin-resistant enterococci (VRE)9. Linezolid was the first member of
this oxazolidinone class to be approved for use by the FDA (US Food and Drug Administration) in
2000.10
3.2.1
Uses
Linezolid is an antibiotic for gram-positive bacteria. In order for it to be effective, Linezolid should only
be used when it is strongly suspected or proven that the infection is caused by gram-positive bacteria. The
safety of using Linezolid for longer than 28 days has not been tested and therefore it is recommended by
producing companies to not use it beyond this time period.11
3.2.3
Dosage
There are three dosage forms for Linezolid: injection, oral suspension, and tablet. The injection comes in
quantities of 200 mg, 400 mg, and 600 mg. The oral suspension is available in a quantity 100mg per 5 mL
and the tablet in a 600 mg pill.
3.2.4
Side effects
Possible side effects include myelosuppression (the “decrease in production of cells responsible for
providing immunity , carrying oxygen, and/or those responsible for normal blood clotting”12), loss of
vision, serotonin syndrome, diarrhea, elevation of blood pressure, lactic acidosis (nausea and vomiting),
convulsions, hypoglycemia (low blood glucose levels13), and development of drug-resistant bacteria.
September 16, 2015
8
Medscape. WebMD LLC. 2015. http://www.medscape.com/viewarticle/812840_9. September 16, 2015
9
antimicrobe. E-sun technologies. 2014. http://www.antimicrobe.org/d13.asp#r5 September 16, 2015
10
Barbachyn, M and Karen Joy Shaw. The oxazolidinones: past, present, and future. 2011.
http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2011.06330.x/epdf PDF
11
"ZYVOX - Linezolid Injection, Solution, Tablet, Film Coated, Suspension." Labeling.Pfizer. Pfizer, 1 July 2015.
Web. 10 Oct. 2015.
12
Bone Marrow Suppression. Wikipedia. 2015. https://en.wikipedia.org/wiki/Bone_marrow_suppression November
13, 2015
13
Hypoglycemia. American Diabetes Association. 2015. http://www.diabetes.org/living-with-diabetes/treatmentand-care/blood-glucose-control/hypoglycemia-low-blood.html?referrer=https://www.google.com/ November 13,
2015
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Team 13: Linezolid
3.4 Initial Synthesis Process
The first industrial process to produce linezolid was developed by UpJohn. Among the chemists involved
was Professor Michael Barbachyn from the Biochemistry and Chemistry department at Calvin College.
The process was patented November 17, 199814 and expired in May 2015.
3.5 Green Synthesis
Although the initial synthesis process produced a good overall yield, Pfizer decided to invest more
research and development resources into the process for making Linezolid. A team was able to develop
what is referred to in this report as the Green Synthesis which is a highly convergent 3-step process. This
process increased the overall yield by 8%, reduced waste by 56%, reduced non-recycled waste by 77%,
and reduced methylene chloride by 78% relative to the initial process. The pressurized ammonia step was
completely eliminated as well as the usage of solvents such as acetonitrile, methanol, and n-propyl
acetate15. This translated to the reduction of 1.9 million kg/year of waste and the elimination 1.7 million
kg/yr of non-recyclable waste.16 This process is still being used and is still patent protected by Pfizer17.
14
Pharmacia & UpJohn Company, 'Process To Prepare Oxazolidinones'. Patent. US5837870. 17 Nov.1998 Print.
15
Reeder, Michael. Linezolid: Process Chemistry Development of a Second Generation Process. Pfizer. Print
16
Stefan, Koenig, ed. Scalable Green Chemistry. Singapore: Pan Stanford Publishing Pte. Ltd., 2013. 157-66. Print.
17
Imbordino, Rick Joseph, Williams Roland Perrault, and Michael Robert Reeder. Process for Preparing Linezolid.
Pfizer Products Inc., assignee. Patent WO 2007/116284 A1. 18 Oct. 2007. Print
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Team 13: Linezolid
4. Design Scope and Specifications
The scope of this project was to produce a preliminary design which included both the feasibility and the
development of the flow process to make Linezolid. This included producing a process flow diagram,
equipment sizing, economic analysis, sensitivity analysis, and hazardous operations.
The process was assumed to be an addition to an already existing pharmaceutical company, rather than a
process plant built from scratch. This allowed the team to make several assumptions for systems already
in place within the plant including a solvent recovery system, an in-house waste management system, and
an incinerator.
The specifications for the process were to produce 4000 kg per year with a manufacturing cost equal to or
less than $800/kg. These conditions came from approximations of Pfizer’s production and manufacturing
of Linezolid. The process details such a reaction time, solvents, concentrations, and separations were
defined by two patents which were the basis of the entire design. The first patent is WO/2007/116284 A1
which is for the green chemistry process to make Linezolid and is held by Pfizer. The second patent is
WO 2015/068121 A1 in which a process to make one of the intermediates to make Linezolid is specified.
This patent is held by Unimark Remedies.
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5. Objectives and Constraints
For the design to be successful, it needs to be profitable and more efficient than the current batch process
that is used. The team was informed by Mark Boekeloo that the current batch production cost of Linezolid
is $800 per kilogram. This cost includes materials, equipment, energy, waste management, labor, and
FDA approval. The chemistry for making the active pharmaceutical ingredient (API), Linezolid, is
patented and is still held by Pfizer. Because of the limited information that is available, the project is
constrained by the information in the patent.
5.1 Reaction Kinetics
The patent that is being used includes many of the reaction times needed for each step of the chemistry.
These reaction times combined with the knowledge of the size of the test reactor enabled Team 13 to
calculate for the kinetic rate constants for each reaction. The reaction kinetics allow for sizing of reactors
such as plug-flow and packed bed, allowing for the scale-up of this entire process. With more research
and funding, a more robust analysis on the reaction kinetics should be completed to potentially decrease
reactor sizes which would decrease the equipment costs for the manufacturing plant.
5.2 Product Purity
Pharmaceuticals and their product purity are regulated by the FDA with tests for consistent product purity
and potency. Batch numbers provide ease of tracking, particularly in the case of a product recall. This
aspect of pharmaceutical production should be evaluated for a continuous flow process but was not
pursued in this project.
5.3 Capacity
Capacity gives a guide for equipment sizing specifications and other cost approximations for chemical
reagents and utilities. The cost approximations for this design process include capital costs as well as
energy, materials, and waste disposal.
The overall unit sales from the year 201318 averaged around 150,000 units sold per quarter. Assuming that
each unit is 10 pills and that each pill contains 600 mg of the active ingredient, the estimated amount of
Linezolid to be produced in one year is 3600 kg. To accommodate increased demand, the group decided
to have a target production capacity of 4000 kg.
18
http://www.drugs.com/price-guide/zyvox
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Team 13: Linezolid
5.4 Separations
To design the separation equipment and techniques used, solubility data was needed for each of the
compounds in solution. With limited data on the compounds and the reaction, a full and robust design of
the separations equipment was not readily possible. Instead, the group decided to assume the patent
separations yields are achievable with the proper equipment.
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Team 13: Linezolid
6. Operation
The process was designed to run for 6500 hours per year. This broke down to a cycle of three months
operation and one month down time for startup, shutdown, and equipment maintenance. This down time
was also for making sure the process would be clean according to FDA regulations. Once operational, it
would not require any personnel to operate. When the cost analysis was done, it was assumed that the
employee monitoring the controls of this operation also had responsibilities monitoring other operations
as well. For pricing purposes, it was assumed that a quarter of a person was working per shift for three
shifts since one person would be supervising several flow operations at the same time.
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Team 13: Linezolid
7. Modeling and Simulations
Model equations and simulation software were used to accurately design the equipment needed in the
process. Two different software packages were used in this project. The first software used was Polymath.
Polymath is a program authored by three accomplished individuals: Dr. Shacham, Dr. Cutlip and Michael
Elly. Polymath allowed the group to calculate reactor volumes by using the model equations for each
reactor type.
The second software used was UniSim. UniSim is a software produced by Honeywell Process Solutions,
a prominent company that specializes in process control systems. UniSim was used to simulate each
reactor to determine reactor volumes for a desired conversion. The results of these simulations were
compared to the values that were calculated by using the model equations with Polymath. UniSim was
also used to create the entire process flow diagram and simulate the entire process with all of the needed
equipment.
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8. Kinetics
Kinetic data is the most fundamental part of reactor design. Kinetic data includes the reaction rate
constant, the overall and individual orders of the reaction rate law, the Arrhenius constant, and the
activation energy. However, the kinetic data for each of the reactions to make Linezolid was not readily
available in the literature. Therefore, the team made some key assumptions based on the information
available in the patents.
Since the patent specified the process at only one set of conditions, the kinetics for each reaction were
modeled as first order in the limiting reactant at those specified conditions. This allowed the team to use
the reaction times to estimate the rate constant (k) for the reaction rates using the equation,
1
= (− ln(1 − where t is the reaction time and x is the conversion of the reaction. The k values calculated and used for
this project are shown in Table 1.
Table 1. Summary of Reaction Rate Constants
Reaction
k-value
Reaction 1-A1
0.00214
Reaction 1-A2
0.0000269
Reaction 1-B2
0.0000485
Reaction 1-C2
0.000263
Reaction 1-C3
0.00034
Carbam 1
0.000243
Carbam 2
0.000243
Carbam 3
0.000485
At this level of design, the order of magnitude of the k values was the most important information for the
process design, which was tested for its robustness in the sensitivity analysis. The analysis looked at the
range of conversions for which the order of the magnitude of the k values were valid. The results are
shown in Table 2.
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Team 13: Linezolid
Table 2. Kinetics conversion extents
Reaction
Minimum Conversion
Maximum Conversion
Reaction 1-A1
97.91%
100%
Reaction 1-A2
91.41%
100%
Reaction 1-B2
60.76%
99.94%
Reaction 1-C2
95.47%
100%
Reaction 1-C3
92.46%
100%
Carbam 1
98.01%
100%
Carbam 2
72.58%
100%
Carbam 3
84.20%
100%
In order to increase the reliability of this design, reaction kinetics would be experimentally determined in
the lab. The reactor sizing would then be adjusted to match the new kinetic data and the desired
conversion, which is usually greater than 99%.
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9. Reactors
9.1 Introduction
The process had a total of 8 reactions. 7 of these reactions were liquid phase reactions. The remaining
reaction was catalyzed using a palladium on carbon catalyst and was completed under excess hydrogen
gas.
9.2 Assumptions
Because of the limited kinetic information available, the reactors were designed to mimic the reaction
conditions given in the patent. This was done because the kinetic data available is only valid at the set of
identical reaction conditions described in the patent. Because of this, a significant number of assumptions
had to be made to make the reactor design for this process possible.
First, it was assumed that scaling up the patent process would have no effect on kinetics involved. This
assumption allowed the team to design the reactors according to the patent batch specification, and from
this design, expect results similar to the batch. If this process were to be industrially implemented, it is
recommended that further process development research be completed to ensure that there would be
minimal scaling effects on the kinetics and to further understand how the reactions change with
temperature, pressure, and varying initial concentrations.
Second, in order to best mimic the patent procedure, the reactors were designed to operate isothermally at
the temperature specified in the patent. Heat exchange was used to maintain the same temperature across
the reactor.
Pressure drop was also assumed to be negligible in each reactor that operates in liquid phase. This is a
safe assumption based on the minimal flow rates of the system. For the reactor with a gas phase, the
Ergun equation was used to calculate the pressure drop across the reactor.
Finally, it was decided to use plug flow reactors (PFRs) instead of continuous stirred tank reactors
(CSTRs). This was decided based on the scale of the process. Typically, CSTRs require much larger
volume to achieve the same conversion as a PFR. Also, from experience in reactor operation from the
team’s unit operations lab, CSTRs take much longer to achieve steady state than a PFR. Because the
process runs at very small scale with flow rates on the order of 0.1 kg/hr, the start-up time for the process
with a CSTR (typically two to three space times) would be excessive.
9.3 Design and Optimization Strategy
The reactor design for this process was completed using a design then verify strategy. First, each reactor
was designed “by hand” using the design equations for each reactor type. These equations gave the
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reactor volume required to reach 95% conversion, to match the assumption used in the initial material
balance. These calculations were used as base cases to the UNSIM simulation. The reactors were
simulated in UNISIM using the volume calculations as a starting point.
The optimization strategy was simply to maximize the conversion across each reactor. This was done
because of the large costs of the starting materials. The reactors were designed to be as large as possible
without being so large that they would not be practical when considering start up and shut down. This
condition was set to be 250 liters.
9.4 Calculations
The following equations19 were used to calculate the required volume for each PFR. The first,
=
(1)
,
is known as the PFR design equation where V is the volume of the reactor in liters, is the inlet molar
flow rate of the limiting reactant in kmol/s, − is the reaction rate in
,
∗
and X is the molar conversion
of the reaction. The rate of reaction can be expressed as a rate law in the form,
− = ,
(2)
where k is the reaction constant in and is the concentration in kmol/L of the limiting
reactant. Because the concentration of the limiting reactant is not known as every point along the
reactor, it must be represented using the equation
= (1 − ,
(3)
where is the inlet concentration of the limiting reactant in kmol/L and X is the molar conversion of
the limiting reactant across the reactor. Combining equations 1-3 above, the volume required for each
PFR in the system can be calculated. For the PBR, equation 1 is swapped out for the PBR design equation
!
=
,
19
Fogler, H. Scott. Elements of Chemical Reaction Engineering. Fourth ed. Upper Saddle River, NJ: Prentice Hall, 2006. P 143200. Print.
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Team 13: Linezolid
where W is the weight of catalyst in kg. The volume of the PBR is then solved for using the relationship
" =
!
#∗($
,
where % is the density of the catalyst in kg/L and & is the void fraction (or porosity) of the packed bed
reactor.
The Ergun equation was used to calculate the pressure drop across the packed bed reactor. This equation
was used in the form
'(
* 1 − & 150(1 − &
+
=−
.
01
+ 1.75*7
')
+,- & /
,-
where P is the pressure in kPa, z is the length of the reactor in meters, & is the void fraction (or porosity)
of the bed, ,- is the diameter of particles in the bed in meters, + is the viscosity of the gases passing
through the bed, and G is the superficial mass velocity in
8
.
9 ∗
G is defined as
* = %:,
8
where % is the density in ;, and u is the superficial velocity in m/s. The superficial velocity is equal to
the volumetric flow rate through the reactor, divided by the reactor’s cross sectional area.
Equations 4 and 5 were used to solve for the amount of heat transfer fluid required to maintain the
isothermal condition for each reactor. First, equation 4 was used to solve for the temperature of the heat
transfer fluid leaving the reactor jacket
< = =>(?@A − ?BCA ,
(4)
where Q is the total duty of the reactor taken from UniSim in watts, U is the heat transfer coefficient in
!
,
9 ∗D
A is the total heat transfer area inFG , equal to the surface area of the reactor, ?BCA is the
operating temperature of the reactor in Celsius, and ?@A is the temperature of the heat transfer fluid
coming out of the reactor jacket in Celsius. This outlet temperature was assumed to be constant because
the jacket around the vessel was assumed to be well mixed.
This temperature, ?@A was used in equation 5 to solve for the mass flow rate of heat transfer fluid
< = FH- (?IJ − ?@A ,
(5)
where Q is the total duty of the reactor taken from UniSim in watts, - is the specific heat of the heat
K
transfer fluid in 8∗D, ?@A is the temperature of the heat transfer fluid coming out of the reactor jacket in
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Celsius, ?IJ is the inlet temperature of the heat transfer fluid in Celsius, and FH is the mass flow rate of the
heat transfer fluid in g/s.
9.5 Results
9.5.1 Reaction Carbam1
This reaction is the first step in the formation of the carbamic acid intermediate. It involves the two
reactants 3,4-difluoronitrobenzene and morpholine in an aromatic substitution resulting in 4-(2-fluoro-4nitrophenyl)-morpholine.
Figure 3. Carbam 1 reaction
Figure 4 displays the results of the reactor sizing calculations for this reaction. According to the analysis,
the reactor was required to be at least 15 liters to achieve 95% conversion.
Reactor Carbam 1: PFR Conversion as a Function of Volume
100
90
Conversion (%)
80
70
60
50
Simulation
40
Design
30
20
10
0
0
10
20
30
40
50
60
Volume (L)
Figure 4: Conversion as a function of volume for the Carbam1 PFR
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9.5.2 Reaction Carbam2
The second step is the hydrogenation of 4-(2-fluoro-4-nitrophenyl)-morpholine using hydrogen gas with
palladium on activated carbon catalyst resulting in 3-fluoro-4-(4-morpholinyl)-benzenamine. Table 3
reports a summary of the catalyst properties used in the design.
Figure 5. Carbam II reaction
Table 3: summary of Catalyst Information for Carbam2
Catalyst
Particle Diameter (mm)
Sphericity
Void Fraction
Solid density (kg/m^3)
Pd/C
3.53
1
0.44
475
Carbam2 is run under excess hydrogen gas, making the flow through the reactor biphasic. Unfortunately,
at the time of design, it was not understood how to model a two-phase reaction using only hand
calculations. Therefore, this step moved directly into the validation phase and UniSim was used to
determine the volume of the reactor and the mass of the catalyst required to achieve 95% conversion.
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Figure 6 shows the result of the pressure drop calculations on the PBR for several different base cases.
The 95% conversion process has the most pressure drop across the reactor because it involves the largest
flow rates. The 100% conversion reactor has the lowest amount of pressure drop, but is too large to be
physically practical. Finally, the practical process, depicted as the red line shows the results for the
optimal design that is not too large a volume, but still achieves over 99% conversion. Because of the low
flow rates found in the process, the pressure drop does not exceed 10 kPA, which is negligible for a
packed bed reactor.
Pressure Drop Across PBR: Carbam2
203
95% Conversion
100% Conversion
Practical Process
202
Pressure (kPa)
201
200
199
198
197
0
0.1
0.2
0.3
0.4
0.5
0.6
Length of Reactor (m)
0.7
0.8
0.9
1
Figure 6: Results of the Ergun Equation calculation for pressure drop across the packed bed reactor, Carbam2.
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9.5.3 Reaction Carbam3
The final step in the formation of the carbamic intermediate is the acylation of the nucleophilic nitrogen
of 3-fluoro-4-(4-morpholinyl)-benzenamine using benzyl chloroformate, producing N-[3-fluoro-4-(4morpholinyl)phenyl]-, phenylmethyl ester carbamic acid.
Figure 7. Carbam III reaction
Figure 8 displays the results of the reactor sizing calculations for this reaction. According to the analysis,
the reactor was required to be at least 26 liters to achieve 95% conversion.
Reactor Carbam 3: PFR Conversion as a Function of Volume
100
90
80
Conversion (%)
70
60
50
Simulation
40
Design
30
20
10
0
0
10
20
30
40
50
60
70
80
90
100
Volume (L)
Figure 8: Conversion as a function of volume for the Carbam3 PFR
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9.5.4 Reaction A1
The first step in the formation of Linezolid is the formation of an imine using aqueous ammonia and 4chlorobenzaldehyde, forming 4-chloro-benzenemethanimine.
Figure 9. Reaction A1
Figure 10 displays the results of the reactor sizing calculations for this reaction. According to the analysis,
the reactor was required to be at least 1.5 liters to achieve 95% conversion.
Reactor A1: PFR Conversion as a Function of Volume
100
90
80
Conversion (%)
70
60
50
Simulation
40
Design
30
20
10
0
0
1
2
3
4
5
6
Volume (L)
Figure 10: Conversion as a function of volume for the A1 PFR
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9.5.5 Reaction A2
The resulting product from Reaction A1, 4-chloro-benzenmethanimine, then initiates an epoxide ring
opening on (S)-(+)-epichlorohydrin to form 1-chloro-3-[(E)-[(4-chlorophenyl)methylene]amino]-, (2S)2-Propanol.
Figure 11. Reaction A2
Figure 12 displays the results of the reactor sizing calculations for this reaction. According to the analysis,
the reactor was required to be at least 125 liters to achieve 95% conversion.
Reactor A2: PFR Conversion as a Function of Volume
100
90
Conversion (%)
80
70
60
50
Design
40
Simulation
30
20
10
0
0
100
200
300
400
500
Volume (L)
Figure 12: Conversion as a function of volume for the A2 PFR
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9.5.6 Reaction B1
This reaction is the combination the carbamic acid product formed in the first three reactions and 1chloro-3-[(E)-[(4-chlorophenyl)methylene]amino]-, (2S)- 2-Propanol which both undergo a
dehydrogenation. This results in 1-chloro-3-[(E)-[(4-chlorophenyl)methylene]amino]-, (2S)- 2-Propanol
forming a three member epoxide ring which is then opened by the dehydrogenated carbamic acid and
forming the oxazolidinone ring through a transesterification mechanism. This results in 5-[[(E)-[(4chlorophenyl)methylene]amino]methyl]-3-[3-fluoro-4-(4-morpholinyl)phenyl]-, (5S)- 2-Oxazolidinone.
Figure 13. Reaction B1
Figure 14 displays the results of the reactor sizing calculations for this reaction. According to the analysis,
the reactor was required to be at least 200 liters to achieve 95% conversion.
Reactor B1: PFR Conversion as a Function of Volume
100
90
Conversion (%)
80
70
60
50
Design
40
Simulation
30
20
10
0
0
100
200
300
400
500
600
700
800
900
Volume (L)
Figure 14: Conversion as a function of volume for the B1 PFR
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9.5.7 Reaction C1
5-[[(E)-[(4-chlorophenyl)methylene]amino]methyl]-3-[3-fluoro-4-(4-morpholinyl)phenyl]-, (5S)- 2Oxazolidinone combined with aqueous hydrogen chloride then undergoes a reduction to form 5(aminomethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-, (5S)- 2-Oxazolidinone.
Figure 15. Reaction C1
Figure 16 displays the results of the reactor sizing calculations for this reaction. According to the analysis,
the reactor was required to be at least 80 liters to achieve 95% conversion.
Reactor C1: PFR Conversion as a Function of Volume
100
90
Conversion (%)
80
70
60
50
Simulation
40
Design
30
20
10
0
0
50
100
150
200
250
Volume (L)
Figure 16: Conversion as a function of volume for the C1 PFR
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9.5.8 Reaction C2
The final reaction step in this process is an acylation of the nitrogen nucleophile of 5-(aminomethyl)-3-[3fluoro-4-(4-morpholinyl)phenyl]-, (5S)- 2-Oxazolidinone with acetic anhydride to form the final product
of N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]- acetamide, which is
Linezolid.
Figure 17. Reaction C2
Figure 18 displays the results of the reactor sizing calculations for this reaction. According to the analysis,
the reactor was required to be at least 45 liters to achieve 95% conversion.
Reactor C2: PFR Conversion as a Function of Volume
100
90
80
Conversion (%)
70
60
50
Simulated
40
Design
30
20
10
0
0
20
40
60
80
100
120
140
160
Volume (L)
Figure 18: Conversion as a function of volume for the C2 PFR
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9.5.9 Heat Transfer Results
Table 4 displays a summary of the properties of the two heat transfer fluids used in this process. Water
was used in every reactor except Carbam3. This reactor operates at 5°C, which is lower than the
temperature at which the cooling water is available. The heat transfer fluid syltherm, manufactured by
DOW Chemical, was used for this reaction, as it can be used from -100°C to 260°C.
Table 4: Heat Transfer Fluid Properties
Heat Transfer Fluid
Water
Syltherm
Specific
Specific Heat
Heat
(molar)
(J/g*K)
(J/mol*K)
U(W/m^2*K)
4.186
75.41
1.8
1.8
57020
45021
Figure 19 displays the results for the heat exchange calculations. These results communicate the amount
of heat transfer fluid required for each reactor to maintain its isothermal condition.
Reactor Design: Heat Exchange Summary
Heat Transfer Fluid (kg/hr)
20
18
16
14
12
10
8
6
4
2
0
Carbam1 Carbam2 Carbam3 Reactor
A1
Reactor
A2
Reactor
B1
Reactor
C1
Reactor
C2
Figure 19: Summary graph of the amount of heat transfer fluid required to achieve isothermal conditions for each reactor
20
Geankoplis, Chrisitie J. Transport Processes and Separation Process Principles. Fourth ed. Upper Saddle River, NJ: Prentice
Hall, 2003. Print. Table 4.9-2.
21
"SYLTHERM XLT Heat Transfer Fluid: Product Technical Data." Heat Transfer Fluids. Dow Chemical, Feb. 1998. Web. 10
May 2016. <http://www.dow.com/heattrans>.
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10. Separations
Separations are vital for forming pure pharmaceuticals; it is where purity standards are met as well as
where most of the product can be lost. It is vital for a design to have well designed separations if it is to be
profitable.
10.1 Design Approach
As with the reactors, the source of all separation data for this process came from the two synthesis
patents. Ideally, all separation data would be experimentally tested for in a lab; this would yield results for
solvent solubility, temperature dependent solubility, evaporation compositions, minimum rinse amounts,
and heats of mixing. Due to lack of time, funds, and materials these tests could not be done for the
compounds used at this stage of design – leaving the patent as the lone source of data. For most
operations, the patent supplied a final yield as well as the operating conditions. These were used when
possible.
10.2 Design Goals
The goal of the separations was to separate the reactor products from the solvents at high purity for use in
either the next reaction or as the final API. Where possible, the separation yields and conditions were
used as listed in the patents. With the yields given, research was conducted for equipment that could
provide those yield amounts. The equipment needed to be affordable, as well as be available in small
enough sizes for the scale of the process. If no yield information was given in the patent, a separation
between 95% and 99% yield was assumed according to the differences in the molecular structures of the
products and solvents. Table 5 shows a list of the patent yields used.
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Table 5: The separation yield information used from the two synthesis patents
Separation Unit
Patent information
Splits used
Evaporator 1
“concentrated to about half volume”22
50% solvent
Crystallizer 1
“99.7% ee by Chiral SFC”23
99.7% yield
Evaporator 2
“concentrated under vacuum to get thick slurry”24
90% acetate
95% methanol
25
Crystallizer 2
“dry weight of 180-190 gm”
Evaporator 3
“concentrated via atmospheric distillation to a total volume of
50% Acetic
3200 mL”26
80% methanol
Crystallizer 3
Nothing specified
95% yield
Evaporator 4
“volume is reduced to 1 L”27
90% solvent
Crystallizer 4
Nothing specified
98% yield
99% yield
10.3 Typical Setup
Bench top chemistry follows the same general process: reaction then separation. The separation also has a
standard procedure: separate the organic and aqueous phases if necessary – keep the desired phase,
evaporate off a portion of the solvent in order to concentrate the solution, cool the solution down in order
to lower solubility causing crystals to drop out of solution, separate these crystals from the remaining
solvent, rinse the crystals with cold solvent, and then dry them either under heat or vacuum. This same
procedure was chosen for the flow design.
10.4 UniSim Simulation
In the UniSim simulation, all separation equipment was simulated using component splitters. This was
not a rigorous simulation of the separations, but was a reasonable option for several reasons. First, all of
the large organic molecules had their physical properties estimated using UNIFAC within UniSim’s
hypotheticals tool. There was no way to tell how accurate these were, making any rigorous separation
designs extremely inaccurate. Second, the only source of separation data available was the patent yields.
The component splitter makes setting these to be the unit yields for the flow process very simple. Third,
the component splitter can have an energy stream attached; this allowed for simpler energy and heat
transfer calculations.
22
patent 116284, page 6 line 39
Patent 116284, page 7, line 2
24
Patent 068121, page 14, line 3
25
Patent 068121, page 14, line 14
26
Patent 116284, page 10, line 9
27
Patent 116284, page 11, line 7
23
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11. Final Design
The final design for the process is shown in Figures 20-24. This design was split up into four different
sections. One section was to create the carbamic acid intermediate while the other three sections were for
the main reactions to make Linezolid. The first section, shown in Figure 20, was a two-step reaction to
create the intermediate (something). The second section, shown in Figure 21, was a three-step reaction to
create the intermediate carbamic acid. The third section, shown in Figure 22, was a one-step reaction to
create the intermediate (something). The last section, shown in Figure 23, was a two-step reaction to
create the final desired product of Linezolid. Figure 24 shows the full process flow diagram.
Figure 20: Carbamic Acid Production Section
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Figure 21: First Section of Linezolid Production
Figure 22: Second Section of Linezolid Production
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Figure 23: Third Section of Linezolid Production
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Figure 24: Full Process Flow Diagram
Table 6 shows a list of estimated equipment needed to build the final plant design. This includes eight
reactors that were rigorously designed for the process.
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Table 6: Equipment Summary
Equipment
Amount Needed
Evaporators
4
Temperature Control Baths
5
Pumps
18
Screw Conveyer Belts
4
Storage/Settling Tanks
8
Tank Mixers
3
Dryers
4
Reactors
8
Pipe
Valves
Flow Manifolds
550 feet
225
4
The UniSim process flow diagram figures can be seen in Appendix B along with the stream tables for the
final design.
After establishing a base case with conversions of 95%, optimization was done to increase the size of the
reactors until achieving a larger conversion of 99%. It was found that the price of the reactors did not
have a large effect on the overall cost of the system because of the expensive starting materials.
Therefore, the reactor volumes were increased until they achieved their maximum conversion without
becoming so large that they were not physically practical. The team defined a “physically practical”
reactor as having a volume below 250 liters, where possible. Table 7 reports a summary of the optimized
reactor volumes.
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Team 13: Linezolid
Table 7: Summary of Final PFR Sizes and Duties
Carbamic 1
Carbamic 3
Reactor A1
Reactor A2
Reactor B1
Reactor C1
Reactor C2
Simulated Conversion
Volume(L) (%)
Duty (kW)
35
99.98
-0.05
60
99.96
-0.18
3
99.72
-0.05
200
99.77
-0.19
250
98.39
0.16
150
99.96
-0.08
110
99.95
-0.26
Heat
Transfer
Fluid
Water
Syltherm
Water
Water
Water
Water
Water
Heat
Transfer
fluid Flow
Rate (kg/hr)
0.65
14.4
3.5
6.3
7.09
6.5
20.4
Table 8: Results Summary for Carbam2 PBR
Weight of catalyst (kg)
226.1
Vessel Volume (L)
850
Molar Conversion
98.61
Pressure drop (kPa)
1.83
Duty (kW)
-0.31
Heat Transfer fluid
Water
Heat Transfer fluid
Flow Rate (kg/hr)
16.8
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Team 13: Linezolid
12. Equipment
12.1 Method for Picking and Pricing Equipment
With the process procedure established, equipment needed to be picked out and priced in order to
estimate the operation cost for the process. It was decided that the equipment priced out had to be
reasonably scaled for the size of this process, as well as be stainless steel for corrosion purposes. The
equipment also had to be capable of performing to the purity standards laid out within the patents. For the
pricing of the equipment, wherever possible, the CAPCOST equations laid out in Analysis, Synthesis, and
Design of Chemical Processes28 were used. These provided a reasonably accurate estimate of equipment
purchase costs. These equations are correlated over industrial scale equipment. Since the scale for this
process was substantially smaller than standard industrial scale, these equations were often not viable.
When CAPCOST was not applicable, the equipment was researched online to get various prices; an
average cost per piece of equipment was then chosen for calculating equipment cost.
12.2 Reactors
There were two types of reactors being used in this process, a packed bed reactor and the rest plug flow
reactors. The packed bed reactor is different than the plug flow reactors in that it is filled with catalyst.
These reactors were designed with heat exchange in order to achieve isothermal conditions. For pricing
these, CAPCOST equations were used; the parameters were for a jacketed reactor.
12.3 Evaporators
Each of the four main process sections has one evaporator used for concentrating the product stream prior
to being crystalized. The evaporation brings the mixture to the point of super saturation, that way the
crystals will fall out of solution as the stream temperature is lowered. Due to the small scale of this
process, typical industrial evaporators have either too harsh of conditions, or do not get small enough to
be usable. After discussing options with Calvin College’s Chemistry department lab manager Rich
Huisman, roto-evaporators were chosen. Huisman informed the team on how a typical lab evaporator can
be configured to operate continuously, and how their operating capacity falls in line with the scale of this
design. These evaporators also work well as they give precise control over vacuum operation and
operating temperature if necessary since they are heated with an electric water bath. A typical purchase
cost of a roto-evaporator was estimated as $4,500.
28
Turton, Richard, Richard C. Bailie, Wallace B. Whiting, Joseph A. Shaeiwitz, and Debangsu
Bhattacharyya. Analysis, Synthesis, and Design of Chemical Processes. fourth ed. Ann Arbor: Edwards
Brothers, 2012. 988-1016. Print.
49
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12.4 Crystallizers
There are four crystallizers within this design, each to separate the section’s main product from the
solvent at a high purity so it can be moved to the next solvent or be the final product. These units needed
to be capable of cooling the entering slurry down to near zero Celsius as well as be able to separate the
newly formed crystals from the majority of the remaining solvent. A unit that is capable of doing both of
these, as well as being available in a small enough size for this process is the Swenson-Walker
Crystallizer as shown in Figure 2529.
Figure 25: Swenson-Walker continuous cooling crystallizer
The cost for this equipment was estimated by using a combination of the CAPCOST equations for a
horizontal vessel, and a screw conveyer belt. They were then adjusted slightly to accommodate the
smaller scale.
12.5 Rinses
The patents had little details given on the rinses for each main process step, often just giving the solvent
used. To fill in the gaps, when the solvent was not specified, the reaction solvent was used. The rinses
were always cooled to five degrees Celsius in order to reduce the product dissolving as much as possible.
The rinse flow rate was generalized to be 0.5 kg/hr for all sections; this flow could be easily adjusted to
whatever would be necessary. The equipment for rinses was assumed to only require pipes and valves.
The rinse would flow past the crystals to clean them – this does not need to occur in any specific
29
Picture credit: Separation Process Principles; Seader, Henley and Roper
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Team 13: Linezolid
equipment. Due to uncertainty on how much pipe this would require, the normal amount of pipe used per
equipment piece was doubled (see pipe section).
12.6 Dryers
Dryers follow the rinse step; their goal was to eliminate any remaining solvent from the crystals. The
dryers consisted of a conveyor system to move the crystals through, a heat source to evaporate the
solvent, and possibly an air stream to help with the evaporation process. Possible equipment was
researched; it was determined that a belt dryer would be the best fit for this process. Most belt dryers are
too large for this process so pricing one out was difficult; however, some small stainless steel dryers were
found and priced at $7,000. This was the price used moving forward.
12.7 Storage Tanks
Since a flow process was being designed, few storage tanks were used. They were placed where a crystal
product was being mixed in with its new solvent for the next stage of the process. This happened in three
locations. The tanks were chosen to be fairly small in order to keep their space time reasonable. Five
gallon stainless steel storage vessels were found with a price of $100 each30.
12.8 Separation Tanks
The separation tanks have the purpose of allowing the organic and aqueous phases time to separate so that
the phase no longer required can be discarded. The organic phase would separate to the top, and the
aqueous phase to the bottom as the organic solvents are all less dense than water. The phase equilibrium
line would be in the middle of the tank, allowing two pipes to be connected near the top and the bottom to
pull off the respective half of the mixture. The tanks used for this would be the same as the storage tanks
listed above.
12.9 Heat Exchangers
Heat exchangers control the temperature of the reactants and products, heating or cooling them so they
are at an appropriate temperature for the reaction. Heat exchange area was calculated using the energy
amounts given from UniSim, along with some assumptions on overall heat transfer coefficients31 (See
Table 9).
30
Rapids Wholesale Equipment 5 gallon stainless steel storage tank
31
"Typical Overall Heat Transfer Coefficients (U - Values)." Engineering Page. N.p., n.d. Web. 10 Feb. 2016.
<http://www.engineeringpage.com/technology/thermal/transfer.html >.
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Table 9. Heat transfer coefficients used for calculating heat exchange area
Conditions
Steam evaporating organics
Steam evaporating water
Brine cooling organics
Water heating organics
Water condensing organics
Overall Heat Transfer
Coefficient U (W/m^2*K)
950
2500
550
800
850
The areas calculated were all less than a meter squared, making a normal heat exchanger not practical.
Instead, controlled temperature baths were used to keep water at a constant temperature within a vessel.
Pipes containing the fluid to heat/cool were run through the water tank. The length of pipe required was
determined by the minimum heat exchange area calculated. This process operated at five different
temperatures, meaning five control baths and water tanks were needed. After researching this equipment,
the average price found and was $4,500.
12.10 Pumps
Pumps are essential for moving the materials around the process. The one occurring issue found when
searching for the correct pumps to use was the scale. Generally for flow rates this low, pumping is done
by using rollers on plastic tubing to push the fluid forward. Since this process can’t use plastic tubing and
is instead using stainless steel pipes, an inline pump was required. The pump had to be consistent at very
low operating conditions. This requirement for pump operation made it so a piston pump was the only
logical choice for controlling flow. Three stainless steel pumps were found that had different maximum
flow rates32: 1.9 L/hr for $850, 3.0 L/hr for $990, and 11.4 L/hr for $1,800.
12.11 Agitators
Agitators were necessary for mixing in the storage tanks between each major section. Well mixed feeds
were required for consistent reactions and consistent products. In the long term, it would be best to
modify the storage tank to have a built in agitator or find a small storage tank that includes one. For this
point in the design, portable agitators were priced. They were stainless steel – with a shaft and propeller
that would be inserted into the tank at the height which leads to the best mixing. These mixers have 1Hp
motors and can be easily mounted33. Each agitator was priced at $2,500.
32
33
Promag Enviro Water and Waste Water Treatment Supply: Helwig Piston Pump
Fusion Express PDS-U-1
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Team 13: Linezolid
12.12 Pipes
Pipes used were ½” schedule 10 stainless steel pipes. Schedule 10 was chosen as it was cheaper, and there
were no points in this process where pressure or temperature got extremely high. The amount of pipe used
in the design is as follows: each piece of equipment that required piping has one foot of pipe between it
and the next piece of equipment; if an equipment bypass was required, two feet of pipe were allowed for
that; if a vapor escape system was required during startup and shutdown, then an additional ten feet of
pipe was allowed34.
12.13 Valves
This process used two main valve types, ball and control manifolds. It was assumed that each equipment
piece had a ball valve before and after, each bypass pipeline had two, and each vapor escape line had one.
A stainless steel ball valve for ½” pipe was $2035 and the control manifold was $34036. There were four
control manifolds, one to keep control of each main solvent flow rate.
34
Midwest Steel Supply
Flows.com stainless steel ball valves – 21 series ½ inch
36
PA double air pilot valve with manifold block 3 pos/4 way ½ inch
35
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Team 13: Linezolid
13. Hazardous Operations
This sections outlines the hazards, management, storage, and awareness of the chemicals included in the
process to make Linezolid. Hazard and Safety awareness is vital for any chemical process operation.
13.1 Waste Management
Table 10. Known disposal methods for chemicals in process
Compound
Acetic Acid
Acetone
Ammonia (aq. 28 wt%)
(S)-(+)-Epichlorohydrin
Ethyl Acetate
Hexane
Hydrogen Chloride
Disposal
Burn in a chemical incinerator equipped with an
afterburner and scrubber but exert extra care in
igniting as this material is highly flammable.
Burn in a chemical incinerator equipped with an
afterburner and scrubber but exert extra care in
igniting as this material is highly flammable.
Neutralization: Put into large vessel
containing water. Neutralize with hydrochloric
acid. Recommendable methods: Landfill, chemical
treatment. Not recommendable method: Thermal
destruction. Peer-review: Small amounts only:
Landfill, great dilution before discharge to sewer.
Large amounts of ammonia in landfill leachate may
make disposal of leachate difficult.
Epichlorohydrin is a waste chemical stream
constituent which may be subjected to ultimate
disposal by controlled incineration. Incineration,
preferably after mixing with another combustible
fuel. Care must be exercised to assure complete
combustion to prevent the formation of phosgene.
An acid scrubber is necessary to remove the halo
acids produced.
Incineration: Burn waste material in an approved
waste disposal incinerator.
Spray into the furnace. Incineration will become
easier by mixing with a more flammable solvent.
Recommendable methods: Incineration, open
burning, use as a boiler fuel, & evaporation. Not
recommendable method: Landfill. Peer review:
Care. Highly flammable. Evaporate only small amt.
Neutralization: Neutralize with limestone (CaCO3),
soda ash (Na2CO3), slaked lime (Ca(OH)2), or
sodium bicarbonate. Flushing to sewer with high
dilution depends on allowable neutral salt
concentration in effluent water. Consider use of
waste acid to neutralize alkaline wastes.
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Hydrogen Fluoride
Methanol
Methyl tert-butyl ether
Methylene chloride
Morpholine
Sodium Hydroxide
Neutralize with agricultural lime (CaO), crushed
limestone (CaCO3), or sodium
bicarbonate (NaHCO3). Add soda ash (NaCO3).
Adjust pH to neutral (pH=7). Reaction with excess
lime followed by lagooning and either recovery or
landfill disposal of the separated calcium fluoride.
... Alternatively, hydrogen can be recovered and
recycled in many cases.
Waste methanol must never be discharged directly
into sewers or surface waters. Large quantities of
waste methanol can either be disposed of at licensed
waste solvent disposal company or reclaimed by
filtration and distillation. It can also be incinerated.
Burn in a chemical incinerator equipped with an
afterburner and scrubber but exert extra care in
igniting as this material is highly flammable.
Observe all federal, state, and local environmental
regulations. Contact a licensed professional waste
disposal service to dispose of this material.
Contaminated packaging: Dispose of as unused
product.
Incineration, preferably after mixing with another
combustible fuel; care must be exercised to assure
complete combustion to prevent the formation
of phosgene; an acid scrubber is necessary to
remove the halo acids produced. Recommendable
method: Incineration.
Incineration is acceptable and the preferred method
of disposal; however, nitrogen oxide emission
controls may be required to meet environmental
regulations. Morpholine is also broken down by
activated sludge and this is a possible method of
disposal under controlled conditions.
Put into large vessel containing water. Neutralize
with HCL /hydrochloric acid/. Discharge into the
sewer with sufficient water. Recommendable
methods: Neutralization & discharge to sewer. Peer
review: Dilute greatly (< pH 9) before discharge.
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Team 13: Linezolid
13.2 Storage
Table 11. Known storage methods for chemicals in process
Compound
Acetone
Ammonia (aq. 28 wt%)
Benzenemethanol
Benzyl chloroformate
4-Chlorobenzaldehyde
3,4-Difluoronitrobenzene
(S)-(+)-Epichlorohydrin
Ethyl Acetate
Storage
Keep container tightly closed in a dry and wellventilated place. Containers which are opened
must be carefully resealed and kept upright to
prevent leakage.
Keep cool in strong glass, plastic, or rubber
stoppered bottles not completely filled.
Benzyl alcohol is stored in stainless steel tanks.
Because benzyl alcohol oxidizes readily, it is
advisable to cover the surface of the liquid
with nitrogen. Store in places that are cool. Provide
adequate ventilation. Locate the storage area away
from areas of fire hazard. Highly flammable
materials must be kept apart from powerful
oxidizing agents, materials susceptible to
spontaneous heating, explosives.
Separated from food and feedstuffs. Dry. Well
closed.37
Wash thoroughly after handling. Wash hands
before eating. Remove contaminated clothing and
wash before reuse. Use only in a well ventilated
area. Avoid contact with skin and eyes. Keep
container tightly closed. Avoid ingestion and
inhalation. Avoid contact with air and sunlight.
Keep from contact with moist air and steam.38
Keep away from heat, sparks, and flame. Store in a
tightly closed container. Store in a cool, dry, wellventilated area away from incompatible
substances.39
Epichlorohydrin should be stored in tightly
closed, labeled containers in fire-proof, cool, dry
rooms. Apply ventilation across the
floor. Epichlorohydrin attacks steel in the
presence of moisture. The compound should be
stored away from strong acids and
bases, zinc, aluminium, metal chlorides, alcoholcontaining material isoproplyamine,
trichloroethylene, and oxidizing agents.
Keep tightly closed in cool place.
37
PubChem. US National Library of Medicine, n.d. Web. 2016. <https://pubchem.ncbi.nlm.nih.gov/>.
"PCAD(104-88-1)."
PubChem.
ChemicalBook,
n.d.
Web.5
<http://www.chemicalbook.com/ProductMSDSDetailCB2316334_EN.htm>.
39
"3,4-Difluoronitrobenzene(369-34-6)."
PubChem.
ChemicalBook,
n.d.
Web.
<http://www.chemicalbook.com/ProductMSDSDetailCB7303128_EN.htm>.
38
May
5
May
2016.
2016.
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Team 13: Linezolid
Hexane
Hydrogen
Hydrogen Chloride
Iso-octane
Lithium t-butoxide
Methanol
Drums should be stored in a well-ventilated area in
fire-resistant containers. Metal containers should
be electrically-grounded, when liquid is being
transferred.
Store in a cool, dry, well-ventilated location.
Outside or detached storage is preferred. Isolate
from oxygen, halogens, other oxidizing materials.
Separated from combustible substances, reducing
agents, strong oxidants, strong bases and metals.
Keep in a well-ventilated room. Cool. Dry.
Fireproof. Separated from strong oxidants. Cool.
Keep in a well-ventilated room.
Handle under dry protective gas. Keep containers
tightly sealed. Store in cool, dry place in tightly
closed
containers.
Ensure
good
ventilation/exhaustion at the workplace. This
product is moisture sensitive. Protect from
humidity and keep away from water.40
Store in tightly closed containers in a cool, well
ventilated area away from heat.
Methyl tert-butyl ether
Store in tightly closed containers in a cool, well
ventilated area away from strong oxidizers, strong
acids. Where possible, automatically pump liquid
from drums or other storage containers to process
containers. Drums must be equipped with selfclosing valves, pressure vacuum bungs, and flame
arresters. Use only non-sparking tools and
equipment, especially when opening and closing
containers of this chemical. Wherever this
chemical is used, handled, manufactured, or stored,
use explosion-proof electrical equipment and
fittings.
Methylene chloride
Keep container tightly closed in a dry and wellventilated place. Containers which are opened
must be carefully resealed and kept upright to
prevent leakage. Heat sensitive. Store under inert
gas. To minimize the decomposition of
dichloromethane, storage containers should be
galvanized or lined with a phenolic coating.
Morpholine
Separate from oxidizing materials and acids. Store
in a cool, dry, well ventilated location. Outside or
detached storage is preferred. Inside storage should
be in a standard flammable liquids storage
warehouse, room, or cabinet.
40
Alfa Aesar GmbH & Co. KG. Safety Data Sheet: Lithium Tert Butoxide. Alfa Aesar GmbH & Co. KG. Karlsuhe, Germnay: Alfa
Aesar GmbH & Co. KG, 2013. Print.
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Nitrogen
Keep container tightly closed in a dry and wellventilated place. Containers which are opened
must be carefully resealed and kept upright to
prevent leakage.
Sodium Bicarbonate
Sodium bicarbonate tablets and effervescent
tablets should be stored in tightly closed containers
at a temperature less than 40 deg C, preferably
between
15-30
deg
C.
Sodium
bicarbonate injection should be stored at a
temperature less than 40 deg C, preferably between
15-30 deg C; freezing should be avoided.
Separated from acids.
Sodium Hydroxide
Store in a cool, dry, well-ventilated location.
Separate from organic and oxidizing materials,
acids, metal powders. Immediately remove and
properly dispose of any spilled material.
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13.3 Chemical Dangers
Table 12. Known dangers of chemicals in process
Compound
Acetic Acid
Acetone
Ammonia (aq. 28 wt%)
Benzenemethanol
Benzyl chloroformate
4-Chlorobenzaldehyde
GHS Identification
• Flammable liquid and vapor
• Harmful in contact with skin
• Causes severe skin burns and
eye damage
• Causes damage to organs
• Harmful to aquatic life
• Highly flammable liquid and
vapor
• May be fatal if swallowed
and enters airways
• Causes eye irritation
• May cause respiratory
irritation
• Suspected of damaging
fertility or the unborn child
• Causes damage to organs
through prolonged or
repeated exposure
• May be corrosive to metals
• Harmful if swallowed
• Causes severe skin burns and
eye damage
• May cause damage to organs
• Causes damage to organs
through prolonged or
repeated exposure
• Very toxic to aquatic life
with long lasting effects
• Harmful
if
swallowed,
Harmful in contact with skin
• Causes serious eye irritation
• Toxic if inhaled
Chemical Dangers
The substance is a weak acid. Reacts
violently with strong oxidants. This
generates fire and explosion hazard. Reacts
violently with strong bases, strong acids
and many other compounds. Attacks some
forms of plastic, rubber and coatings.
• Causes severe skin burns and
eye damage
• Very toxic to aquatic life
with long lasting effects
Decomposes on heating. This
produces phosgene. Decomposes on
contact with water. This produces toxic
and corrosive fumes including hydrogen
chloride. Attacks many metals in the
presence of water or moist air.
This chemical is sensitive to exposure to air.
Contact with strong oxidants such as acetic
acid, nitric acid and hydrogen
peroxide generates explosive peroxides.
Reacts with chloroform and bromoform
under basic conditions. This generates fire
and explosion hazard. Attacks plastics.
Reacts with many heavy metals and heavy
metal salts. This produces explosive
compounds. Attacks many metals. This
produces flammable/explosive gas. The
solution in water is a strong base. It reacts
violently with acids.
Reacts with strong oxidants. Attacks some
forms of plastic. On combustion, forms
toxic gases including carbon monoxide.
• Harmful if swallowed
• Causes skin irritation
Insoluble in water.
• Causes eye irritation
• May cause damage to organs
• Toxic to aquatic life with
long lasting effects
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•
•
•
•
•
(S)-(+)-Epichlorohydrin
•
•
•
•
•
Ethyl Acetate
•
•
•
•
•
Hexane
•
•
•
•
•
•
•
•
Hydrogen
Hydrogen Chloride
Flammable liquid and vapor
Toxic if swallowed
Toxic in contact with skin
Causes severe skin burns and
eye damage
May cause an allergic skin
reaction
Fatal if inhaled
Suspected of genetic defects
May cause cancer, Suspected
of damaging fertility or the
unborn child
Causes damage to organs,
Harmful to aquatic life
Highly flammable liquid and
vapor
Causes eye irritation
Harmful if inhaled
May cause respiratory
irritation
Highly flammable liquid and
vapor
May be fatal if swallowed
and enters airways
Causes skin irritation
Causes serious eye irritation
May cause drowsiness or
dizziness
Suspected of damaging
fertility or the unborn child
Causes damage to organs
through prolonged or
repeated exposure
Toxic to aquatic life
Extremely flammable gas
Contains refrigerated gas;
may cause cryogenic burns
or injury
• Contains gas under pressure;
may explode if heated, toxic
if swallowed
• Causes severe skin burns and
eye damage
• Fatal if inhaled
• Toxic if inhaled
The substance polymerizes due to heating
or under the influence of strong acids and
bases. On combustion, forms toxic and
corrosive fumes of hydrogen chloride
and chlorine. Reacts violently with strong
oxidants. Reacts violently
with aluminium, zinc, alcohols, phenols,
amines (especially aniline) and organic
acids. This generates fire and explosion
hazard. Attacks steel in the presence
of water.
Reacts with strong oxidants. This generates
fire and explosion hazard. Reacts violently
with strong bases and strong acids. Attacks
rubber and some forms of plastic.
Reacts with strong oxidants. This generates
fire and explosion hazard. Attacks some
plastics, rubber and coatings.
Heating may cause violent combustion or
explosion. Reacts violently with halogens,
oxidizing materials and greases. This
generates fire and explosion hazard. Metal
catalysts, such as platinum and nickel,
greatly enhance these reactions.
The solution in water is a strong acid. It
reacts violently with bases and is corrosive.
Reacts violently with oxidants. This
produces toxic gas (chlorine - see ICSC
0126). Attacks many metals in the
presence of water. This produces
flammable/explosive gas.
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Hydrogen Fluoride
Iso-octane
Methanol
Methyl tert-butyl ether
• May cause allergy or asthma
symptoms or breathing
difficulties if inhaled
• Causes damage to organs
• Causes damage to organs
through prolonged or
repeated exposure
• Very toxic to aquatic life
• Fatal if swallowed
• Fatal in contact with skin
• Causes severe skin burns and
eye damage
• Fatal if inhaled
• Highly Flammable liquid
and vapor
• May be fatal if swallowed
and enters airways
• Causes skin irritation
• May cause drowsiness or
dizziness
• Very toxic to aquatic life
with long lasting effects
• Highly flammable liquid and
vapor
• Harmful if swallowed,
Causes serious eye irritation
• May damage fertility or the
unborn child
• Causes damage to organs
through prolonged or
repeated exposure
• Highly flammable liquid and
vapor
• May be harmful if
swallowed
• May be fatal if swallowed
and enters airways
• Causes skin irritation
• Causes eye irritation
• May cause respiratory
irritation
• Suspected of causing cancer
The substance is a strong acid. It reacts
violently with bases and is corrosive. Reacts
violently with many compounds. This
generates fire and explosion hazard. Attacks
metals, glass, some forms of plastic, rubber
and coatings.
Heating may cause violent combustion or
explosion. Reacts with strong oxidants.
Reacts violently with oxidants. This
generates fire and explosion hazard.
Reacts violently with strong oxidants. This
generates fire hazard. Decomposes on
contact with acids.
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Methylene chloride
Morpholine
Nitrogen
• Harmful if swallowed
• Causes skin irritation
• Causes serious eye irritation
• Suspected of causing cancer
• Causes damage to organs
through prolonged or
repeated exposure
• Harmful to aquatic life
Decomposes on heating or on burning and
on contact with hot surfaces. This produces
toxic and corrosive fumes
including hydrogen chloride, phosgene
and carbon monoxide. Reacts violently
with strong oxidants, strong bases and
metals such as aluminium powder
and magnesium powder. This generates
fire and explosion hazard. Attacks some
forms of plastic, rubber and coatings.
• Flammable liquid and vapor
• Harmful if swallowed
• Toxic in contact with skin
• Causes severe skin burns and
eye damage
• Causes serious eye irritation
• Toxic if inhaled
• Suspected of causing genetic
defects
• Causes damage to organs
through prolonged or
repeated exposure
• Harmful to aquatic life with
long lasting effects
• Contains gas under pressure;
may explode if heated
Decomposes on burning. This produces
toxic fumes of nitrogen oxides and carbon
monoxide. The substance is a medium
strong base. Reacts with strong oxidants.
This generates fire hazard. Attacks plastics,
rubber and coatings. Unstable if stored
in copper or zinc containers.
Palladium on activated
carbon, 0.5%
Explosive reaction with hydrogen and
hydrogen peroxide.
Sodium Bicarbonate
The solution in water is a weak base. Reacts
with acids.
Sodium Hydroxide
• Causes severe skin burns and
eye damage
• Causes serious eye damage
• Causes damage to organs
• Harmful to aquatic life
The solution in water is a strong base. It
reacts violently with acid and is corrosive
to metals such as aluminium, tin, lead
and zinc. This produces a
combustible/explosive gas. Reacts with
ammonium salts. This produces ammonia.
This generates fire hazard. Contact with
moisture and water generates heat.
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14. Cost Analysis
14.1 Cost Goal
The goal of the design was to determine if the flow process’ operating cost could compete with the
current known batch cost of $800 per kilogram. In order to do this comparison, an operating cost needed
to be calculated. The costs estimated for this process were equipment, energy, material, FDA approval,
waste disposal, and labor costs. These estimates were made assuming a 30 year plant life and a
depreciation percentage of ten percent.
14.2 Equipment Costs
To see the method for how each individual equipment piece was priced, see the equipment section.
After the purchase cost of each individual piece of equipment was determined, a Lang Factor of 3.63 was
used to convert the purchase cost to an overall capital cost. This capital cost included factors like
installing and transporting the equipment. Table 13 shows the capital cost of each piece of equipment.
When using the CAPCOST equations, the values given from Analysis, Synthesis, and Design of Chemical
Processes were current prices for a Chemical Engineering Plant Cost Index (CEPCI) of 397 (year 2001).
Looking at the values over the past decades, an estimate CEPCI was made for 2016; its value is 588. This
translates roughly to an inflation price increase of 48.1%. This adjustment was made when applicable. All
prices shown within this report are for the CEPCI of 588.
14.3 Energy Costs
A yearly energy cost was estimated by pricing out how much it would cost to supply the appropriate type
of energy to each piece of equipment. Typically this is one of the following: electricity, cooling water, or
steam. Due to the scale and sensitivity of this process, steam was not a suitable source for heat. Heat was
supplied either directly by electricity, or by temperature controlled water – which is heated by electricity.
To simplify the pricing, it was assumed that all the pumps, heaters, and mixers would use electricity as its
energy source; electricity is valued at $0.06 per kWh. Pumps were assumed to be 80% efficient, while all
water plus electric heaters and heat exchangers were assumed to be 90% efficient. Table 13 shows all
equipment, capital costs, energy demand, and energy cost.
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Table 13. Equipment Price information
Equipment Name
Capital Cost
Energy Demand (kW)
Energy Cost ($/year)
Evaporator 1
$ 16,335
0.594
$ 232
Evaporator 2
$ 16,335
0.499
$ 195
Evaporator 3
$ 16,335
4.649
$ 1,813
Evaporator 4
$ 16,335
0.119
$ 46
Heat Bath 1
$ 16,369
0.073
$ 32
Heat Bath 2
$ 16,340
0.020
$9
Heat Bath 3
$ 16,344
0.257
$ 111
Heat Bath 4
$ 16,356
0.094
$ 41
Heat Bath 5
$ 16,442
0.092
$ 40
P-101
$ 3,085
0.105 ∗ 10/
$ 0.04
P-102
$ 3,085
P-104
$ 3,085
P-108
$ 6,534
P-115
$ 6,534
P-111
$ 6,534
P-113
$ 3,085
P-117
$ 3,085
P-105
$ 6,534
P-114
$ 6,534
P-116
$ 3,085
P-119
$ 3,085
P-107
$ 6,534
P-109
$ 13,068
P-110
$ 13,068
P-112
$ 13,068
P-100
$ 3,085
P-106
$ 3,593
0.130 ∗ 10/
$ 0.05
Auger 1
$ 58,340
0.828
$ 323
Auger 2
$ 58,340
0.828
$ 323
Auger 3
$ 58,340
0.828
$ 323
0.012 ∗ 10/
0.053 ∗ 10/
9.000 ∗ 10/
0.314 ∗ 10/
283 ∗ 10/
0.027 ∗ 10/
0.032 ∗ 10/
4.313 ∗ 10/
0.161 ∗ 10/
0.003 ∗ 10/
1.843 ∗ 10/
0.360 ∗ 10/
0.625 ∗ 10/
0.625 ∗ 10/
0.755 ∗ 10/
1.803 ∗ 10/
$ 0.01
$ 0.02
$ 3.51
$ 0.12
$ 110.7
$ 0.01
$ 0.01
$ 1.68
$ 0.06
$ 0.01
$ 0.72
$ 0.14
$ 0.24
$ 0.24
$ 0.29
$ 0.70
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Auger 4
$ 58,340
0.828
$ 323
Crystallizer 1
$ 17,275
0.178
$ 70
Crystallizer 2
$ 82,830
0.124
$ 48
Crystallizer 3
$ 33,132
0.493
$ 192
Crystallizer 4
$ 12,535
0.081
$ 32
Tank Mixer 1
$ 9,075
0.932
$ 364
Tank Mixer 2
$ 9,075
0.932
$ 364
Tank Mixer 3
$ 9,075
0.932
$ 364
Tank Mixer 4
$ 9,075
0.932
$ 364
Storage Tank 1
$ 363
--
--
Storage Tank 2
$ 363
--
--
Storage Tank 3
$ 363
--
--
Settling Tank 1
$ 363
--
--
Settling Tank 2
$ 363
--
--
Settling Tank 3
$ 363
--
--
Settling Tank 4
$ 363
--
--
Settling Tank 5
$ 363
--
--
Dryer 1
$ 25,410
0.064
$ 25
Dryer 2
$ 25,410
0.143
$ 56
Dryer 3
$ 25,410
0.041
$ 16
Dryer 4
$ 25,410
0.045
$ 18
Reactor A1
$ 9,587
-0.051
$ 0.38
Reactor A2
$ 90,148
-0.211
$ 1.58
Reactor Carbam1
$ 35,598
-0.059
$ 0.44
Reactor Carbam2
$ 194,760
-0.347
$ 2.59
Reactor Carbam3
$ 47,455
-0.201
$ 1.50
Reactor1-B2
$ 101,525
0.174
$ 51.49
Reactor1-C2
$ 77,338
-0.092
$ 0.69
Reactor1-C3
$ 65,556
-0.290
$ 2.16
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Team 13: Linezolid
Table 14. Pipe and valve price information
Equipment Type
Length/Number (feet)
Purchase Cost
Sch 10 SS ½” pipe
539
$ 5,489
SS ball valve
226
$ 16,407
4
$ 4,937
Control Manifold
14.4 Material Costs
Research was done on each feed material in order to find an accurate price per kilogram. These prices
were then multiplied by the feed rate to get a cost per hour and then per year of operation. Table 15 shows
the reactant feeds and costs. Table 16 shows the solvent feeds and costs as well as the amount of money
being saved by solvent recovery. The solvent recovery was assumed to be 95%. Rinse streams were not
included in solvent recovery.
Table 15. Material prices
Material
Cost per kilogram
Feed rate (kg/hr)
Yearly Cost
Ammonia
$ 36.6
0.308
$ 73,261
chlorobenzaldehyde
$ 168
0.444
$ 485,287
$2
0.295
$ 3,839
224-Mpentane
$ 1.8
0.578
$ 6,757
Acetic Acid
$ 15.1
3.656
$ 358,824
HCl
$ 8.52
3.084
$ 170,808
Water
$ 0.001
13.429
$ 87
Sodium Hydroxide
$ 7.17
0.198
$ 9,202
Acetic Anhydride
$ 22.06
0.485
$ 69,599
Morpholine
$ 16.13
0.406
$ 42,610
$ 130
0.353
$ 298,651
$ 0.001
0.019
$ 0.12
Benzylchloroformate
$ 17
0.448
$ 49,532
n-hexane
$ 0.1
0.287
$ 187
Lithium t-butoxide
$ 45
0.401
$ 117,401
$ 20,000
14 kg per year
$ 280,000
Epichlorohydrn
Difluoronitrobenzene
Hydrogen
Pd-C catalyst
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Table 16. Solvent costs and recovery
Solvent
Feed Rate
Recovery Rate
Cost per kg
Yearly Cost Post Recovery
MTBE
2.404
1.809
$ 35.33
$ 136,693
Methanol
6.026
5.44
$ 17.19
$ 65,514
Methylene Chloride
21.24
19.70
$ 7.90
$ 78,924
Ethyl Acetate
14.88
13.82
$ 1.10
$ 7,558
Acetone
5.222
4.961
$ 8.39
$ 14,240
14.5 Other Costs
Some other costs taken into consideration were refrigeration, waste disposal, and the energy cost of the
solvent recovery. Refrigeration costs were calculated by using a monetary value per gigajoule of energy
presented in Analysis, Synthesis, and Design of Chemical Processes. The value is $7.89 per GJ. The total
number of joules per year used for cooling was calculated from UniSim values with an efficiency of 80%.
In total there were 31.46 GJ of energy for cooling which costs $250 per year.
The textbook also had a value for hazardous waste disposal. It was assumed that all waste from this
process is hazardous. The mass flow rates for all waste streams were totaled up to get the mass of waste
generated per year (after solvent recovery). Every year, 16.39 tons of waste would be generated; the book
gives a disposal cost of $1,000 per ton. The waste disposal cost would be $16,388 per year.
For calculating the energy cost for solvent recovery, a distillation column was setup in UniSim to distill a
section of our solvent. It was assumed that the column was already paid for; only the energy costs were
considered. Steam was used in the reboiler at a cost of $14.05 per GJ and cooling water in the condenser
at $0.35 per GJ. The energy values from UniSim were used to calculate an energy cost per kg of solvent
purified (purifying to a purity of 99.9%). The cost came out to $0.015 per kg of solvent; the yearly energy
cost for the solvent purification for this process was $4,569 per year.
14.6 Total Production Cost
Table 17 and Figure 26 summarize all of the values used in estimating the production cost for this
process. For this level of design, this cost is accurate to +/- 40%.
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Table 17. Cost summary for producing 4300 kg of Linezolid per year
Cost Type
Money Amount
Total Capital
Percentage of Total
$ 1,423,000
5.4 %
FDA process approval
$ 500,000
1.9 %
Purchase annuity
$ 204,000
--
Annual Energy
$ 11,000
0.38 %
Annual Material
$ 2,547,000
90.46 %
Annual Waste Disposal
$ 16,000
0.58 %
Annual Labor
$ 37,500
1.33 %
Production cost per kg
$ 653.57
--
Yearly Process Cost Breakdown: $2,815,500 Total
0.58%
1.33%
5.40%
1.90%
0.38%
Total capital
FDA approval
Energy
Materials
Waste
Labor
90.46%
Figure 26: Percentage breakdown for producing 4300 kg of Linezolid per year
14.7 Implications
Batch processing is generally simpler than flow processing to design; due to this, it was assumed that
flow will take roughly six months longer to design and implement. During this six month time, the
company would not be producing or selling any drug. Analysis was done to see how this opportunity cost
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Team 13: Linezolid
affected the profitability of the design presented here. With an average Linezolid price of $56 per 600 mg
pill, two thousand kilograms (six months’ worth of production) could be sold for $186.3 million. The
difference in production cost between the flow and batch process designs was a savings of $600,000 per
year if using flow. Assuming these numbers are accurate, it would take just over 320 years for the flow
process to pay off the six months of no operation.
Recall that the life of the plant presented here is only thirty years. Another analysis was done to determine
what price Linezolid would have to be to break even in 30 years; the operation savings equals the six
months lost in operation time. This resulted in a price of $5.79 per pill. It is hard to determine at this point
if the price of Linezolid will ever get this low. It has dropped by over half in less than a year (initial
research showed prices of $120 per pill41).
41
Price found in September 2015. Drugs.com
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15. Sensitivity Analysis
For the sensitivity analysis, three variables were observed to have a high impact on how the process
would perform. The first variable was the percent conversion of each of the reactions. It was desired to
have a 95% conversion for a reaction, but this was not always attainable. A higher percent conversion
resulted in a decreased overall production cost. The percent conversion for each reactor influences the
overall conversion of the entire process. As reactor conversion increase, reactor sizes and price also
increases. However, Figure 27 below shows that the overall production cost per kg of linezolid decreases
with an increased average reactor conversion. This is because majority of the production cost is incurred
in the raw materials needed for the reactions. With a higher conversion, less raw materials are consumed
and thus the production cost decreases.
Production Cost per kg Linezolid
Cost as a Function of Reactor Conversion
$740
$720
$700
$680
$660
$640
$620
$600
0.95
0.96
0.97
0.98
0.99
1
Average Reactor Conversion
Figure 27. Summary of the analysis on the effect of reactor conversion on overall production cost
Another variable of interest was the yield of the separation processes. This parameter was very strict as
purity is a big concern for pharmaceutical products. A purity standard of around 98% was established for
all of the recrystallization separation processes. Although this standard was something that would be
upheld to the utmost ability of the plant, an analysis was completed on how the yields affect the overall
production cost of Linezolid. The results of this analysis can be seen in Table 18 and Figure 28
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Table 18. Summary of the analysis on the effect of crystallizer yields on the overall production cost
setup #
control
1
2
3
4
worst
case
Crystallizer
1 yield
99.70%
95.00%
Crystallizer
2 yield
99.90%
Crystallizer
3 yield
94.00%
Crystallizer
4 yield
98.00%
95.00%
kg per hr
Linezolid
0.663
0.6629
0.631
0.6338
0.6428
production
cost
$ 641.03
$ 641.13
$ 676.62
$ 673.37
$ 663.08
% change
-0.017%
5.553%
5.045%
3.441%
95.00%
0.5836
$ 736.53
14.898%
95.00%
90.00%
95.00%
95.00%
90.00%
Production Cost per Kilogram
Cost Changes with Crystallization Yield Variance
$850
$800
$750
$700
$650
$600
99.7%95%
99.9%95%
94% 90%
98% 95%
control all
Crystallizer 1
Crystallizer 2
Crystallizer 3
Crystallizer 4
All Together
Batch
Figure 28: Production cost variance due to decreasing crystallization yield
The last variable of interest was the percent recovery of the solvents that were used. A large majority of
the chemicals being used for the process was solvents. With the concept of this process being an
expansion to a currently operating pharmaceutical plant it was assumed that there would be an on-site
solvent recovery system that could be used. An analysis was done on the effect of the achievable percent
solvent recovery on the overall production cost for Linezolid. As expected, with a lower percent recovery
of solvents the production cost would be driven higher because of the cost of the solvents. See Figure 29
for a summary of these results.
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Team 13: Linezolid
Production Cost per kg Linezolid
Cost as a Function of Solvent Recovery
$680.00
$670.00
$660.00
$650.00
$640.00
$630.00
$620.00
$610.00
88%
90%
92%
94%
96%
98%
100%
Percent Solvent Recovered
Figure 29. Summary of the analysis of the effect of percent solvent recovery on the overall production cost
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Team 13: Linezolid
16. Conclusion
Ignoring money altogether, this flow design provides better product quality and is more efficient with
energy and materials. The main reason why this process operates more cost effectively than the batch is
the higher yields of the reactors and separations, leading to less materials used. The ethics of these
benefits must be weighed against the differences in profit in order to determine which process is better.
Based on the current design and cost analysis, the team does not recommend further research into flow
processing for producing Linezolid for a company that is not currently producing Linezolid, unless the
price of the drug drops substantially. At its current state, the money saved by the lower production cost is
not enough when compared to the money lost by not producing during the six months of extra design
time. However, if the price continues to drop, the flow process gains more value.
This project has lead into some key insights into the pharmaceutical industry. For instance, as the scale
for the production of a pharmaceutical increases, a continuous flow process has a higher chance of
becoming more profitable. The savings in operation costs would be become more substantial as the
amount of product produced increases. Also, the drugs more highly demanded tend to have lower prices.
This effect results in operational cost differences having a larger impact on profitability, because the loss
in revenue due to extra development time is decreased.
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17. Acknowledgements
Team 13 would like to thank and acknowledge the following people and their contributions to the project:
Professor Jeremy VanAntwerp: for his guidance and advice throughout the entire project.
Professor Michael Barbachyn: for the idea behind the project and providing technical expertise on
the chemistry.
Professor Wayne Wentzheimer: for his expertise on reactor design.
Mark Boekeloo: Team 13’s industrial mentor, for his expertise in the pharmaceutical industry.
Mike Dokter: for giving Team 13 a tour of the Pfizer plant in Kalamazoo.
The CEAC board: for reviewing the project as it approached completion.
Karis Kim: for helping with website troubleshooting.
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Team 13: Linezolid
18. References
[1] "ZYVOX - Linezolid Injection, Solution, Tablet, Film Coated, Suspension." Labeling.Pfizer. Pfizer, 1
July 2015. Web. 10 Oct. 2015.
[2] Zyvox Prices, Coupons and Patient Assistance Programs. Drugs.com, 2015. Web. 24 April 2016.
[3] Boekeloo, Mark. Personal interview. 10 Nov. 2015.
[4] Ermer, Gayle E., and Steven H. VanderLeest. "Using Design Norms to Teach Engineering Ethics."
American Society of Engineering Education. Calvin College, 2002. Google Scholar. Web. 13 Nov. 2015.
[5] Stefan, Koenig, ed. Scalable Green Chemistry. Singapore: Pan Stanford Publishing Pte. Ltd., 2013.
159. Print.
[6] Barbachyn, M and Karen Joy Shaw. The oxazolidinones: past, present, and future. 2011.
http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2011.06330.x/epdf PDF
[7] ChemSpider. Royal Society of Chemistry. 2015. http://www.chemspider.com/ChemicalStructure.66579.html
[8] Medscape. WebMD LLC. 2015. http://www.medscape.com/viewarticle/812840_9. September 16,
2015
[9] antimicrobe. E-sun technologies. 2014. http://www.antimicrobe.org/d13.asp#r5 September 16, 2015
[10] Barbachyn, M and Karen Joy Shaw. The oxazolidinones: past, present, and future. 2011.
http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2011.06330.x/epdf PDF
[11] "ZYVOX - Linezolid Injection, Solution, Tablet, Film Coated, Suspension." Labeling.Pfizer. Pfizer,
1 July 2015. Web. 10 Oct. 2015.
[12] Bone Marrow Suppression. Wikipedia. 2015.
https://en.wikipedia.org/wiki/Bone_marrow_suppression November 13, 2015
[13] Hypoglycemia. American Diabetes Association. 2015. http://www.diabetes.org/living-withdiabetes/treatment-and-care/blood-glucose-control/hypoglycemia-lowblood.html?referrer=https://www.google.com/ November 13, 2015
[14] Pharmacia & UpJohn Company, 'Process To Prepare Oxazolidinones'. Patent. US5837870. 17
Nov.1998 Print.
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Team 13: Linezolid
[15] Reeder, Michael. Linezolid: Process Chemistry Development of a Second Generation Process.
Pfizer. Print
[16] Stefan, Koenig, ed. Scalable Green Chemistry. Singapore: Pan Stanford Publishing Pte. Ltd., 2013.
157-66. Print.
[17] Imbordino, Rick Joseph, Williams Roland Perrault, and Michael Robert Reeder. Process for
Preparing Linezolid. Pfizer Products Inc., assignee. Patent WO 2007/116284 A1. 18 Oct. 2007. Print
[18] http://www.drugs.com/price-guide/zyvox
[19] Fogler, H. Scott. Elements of Chemical Reaction Engineering. Fourth ed. Upper Saddle River, NJ:
Prentice Hall, 2006. P 143-200. Print.
[20] Geankoplis, Chrisitie J. Transport Processes and Separation Process Principles. Fourth ed. Upper
Saddle River, NJ: Prentice Hall, 2003. Print. Table 4.9-2.
[21] "SYLTHERM XLT Heat Transfer Fluid: Product Technical Data." Heat Transfer Fluids. Dow
Chemical, Feb. 1998. Web. 10 May 2016. <http://www.dow.com/heattrans>.
[22] patent 116284, page 6 line 39
[23] Patent 116284, page 7, line 2
[24] Patent 068121, page 14, line 3
[25] Patent 068121, page 14, line 14
[26] Patent 116284, page 10, line 9
[27] Patent 116284, page 11, line 7
[28] Turton, Richard, Richard C. Bailie, Wallace B. Whiting, Joseph A. Shaeiwitz, and Debangsu
Bhattacharyya. Analysis, Synthesis, and Design of Chemical Processes. fourth ed. Ann Arbor: Edwards
Brothers, 2012. 988-1016. Print.
[29] Picture credit: Separation Process Principles; Seader, Henley and Roper
[30] Rapids Wholesale Equipment 5 gallon stainless steel storage tank
[31] "Typical Overall Heat Transfer Coefficients (U - Values)." Engineering Page. N.p., n.d. Web. 10
Feb. 2016. <http://www.engineeringpage.com/technology/thermal/transfer.html >.
[32] Promag Enviro Water and Waste Water Treatment Supply: Helwig Piston Pum
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Team 13: Linezolid
[33] Fusion Express PDS-U-1
[34] Midwest Steel Supply
[35] Flows.com stainless steel ball valves – 21 series ½ inch
[36] PA double air pilot valve with manifold block 3 pos/4 way ½ inch
[37] PubChem. US National Library of Medicine, n.d. Web. 2016. <https://pubchem.ncbi.nlm.nih.gov/>.
[38] "PCAD(104-88-1)." PubChem. ChemicalBook, n.d. Web.5 May 2016.
<http://www.chemicalbook.com/ProductMSDSDetailCB2316334_EN.htm>.
[39] "3,4-Difluoronitrobenzene(369-34-6)." PubChem. ChemicalBook, n.d. Web. 5 May 2016.
<http://www.chemicalbook.com/ProductMSDSDetailCB7303128_EN.htm>.
[40] Alfa Aesar GmbH & Co. KG. Safety Data Sheet: Lithium Tert Butoxide. Alfa Aesar GmbH & Co.
KG. Karlsuhe, Germnay: Alfa Aesar GmbH & Co. KG, 2013. Print.
[41] Price found in September 2015. Drugs.com
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Appendix A: International Chemical Safety Cards
Acetic Acid
Glacial acetic acid
Ethanoic acid
Ethylic acid
Methanecarboxylic acid
C2H4O2 / CH3COOH
Molecular mass: 60.1
ICSC # 0363
TYPES OF
ACUTE HAZARDS/
HAZARD/
SYMPTOMS
EXPOSURE
Flammable.
FIRE
CAS # 64-19-7
RTECS # AF1225000
UN # 2789 (>80%)
EC # 607-002-00-6
July 10, 1997 Validated
PREVENTION
FIRST AID/
FIRE FIGHTING
NO open flames, NO sparks, Powder, alcohol-resistant
and NO smoking.
foam, water spray, carbon
dioxide.
Above 39°C explosive
Above 39°C use a closed
In case of fire: keep drums,
vapour/air mixtures may be system, ventilation, and
etc., cool by spraying with
EXPLOSION
formed.
explosion-proof electrical
water.
equipment.
AVOID ALL CONTACT!
EXPOSURE
Sore throat. Cough. Burning Ventilation, local exhaust, or Fresh air, rest. Half-upright
sensation. Headache.
breathing protection.
position. Refer for medical
Dizziness. Shortness of
attention.
•INHALATION
breath. Laboured breathing.
Symptoms may be delayed
(see Notes).
Pain. Redness. Blisters. Skin Protective gloves. Protective Remove contaminated
burns.
clothing.
clothes. Rinse and then wash
skin with water and soap.
•SKIN
Rinse skin with plenty of
water or shower. Refer for
medical attention.
Redness. Pain. Severe deep Face shield or eye protection First rinse with plenty of
burns. Loss of vision.
in combination with
water for several minutes
breathing protection.
(remove contact lenses if
•EYES
easily possible), then take to
a doctor.
Abdominal pain. Burning
Do not eat, drink, or smoke Rinse mouth. Do NOT
sensation. Diarrhoea. Shock during work.
induce vomiting. Give plenty
•INGESTION
or collapse. Sore throat.
of water to drink. Refer for
Vomiting.
medical attention.
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Collect leaking liquid in sealable Fireproof. Separated from food
Do not transport with food and
containers. Cautiously neutralize and feedstuffs . See Chemical
feedstuffs.
spilled liquid with sodium
Dangers. Keep in a wellNote: B
carbonate only under the
ventilated room.
C symbol
responsibility of an expert. Wash
R: 10-35
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away remainder with plenty of
water. Personal protection:
chemical protection suit including
self-contained breathing
apparatus.
I
M
P
O
R
T
A
N
T
D
A
T
A
PHYSICAL
PROPERTIES
S: 1/2-23-26-45
UN Hazard Class: 8
UN Subsidiary Risks: 3
UN Packing Group: II
PHYSICAL STATE;
APPEARANCE:
COLOURLESS LIQUID , WITH
PUNGENT ODOUR.
ROUTES OF EXPOSURE:
The substance can be absorbed into the
body by inhalation of its vapour and by
ingestion.
PHYSICAL DANGERS:
INHALATION RISK:
A harmful contamination of the air can be
reached rather quickly on evaporation of
this substance at 20°C.
CHEMICAL DANGERS:
The substance is a weak acid. Reacts
violently with oxidants and bases . EFFECTS OF SHORT-TERM
Attacks many metals forming
EXPOSURE:
flammable/explosive gas (hydrogen The substance and the vapour is corrosive
- see ICSC 0001). Attacks some
to the eyes, the skin and the respiratory
forms of plastic, rubber and
tract. Corrosive on ingestion. Inhalation of
coatings.
the vapor may cause lung oedema (see
Notes). The effects may be delayed.
OCCUPATIONAL EXPOSURE Medical observation is indicated.
LIMITS:
TLV: 10 ppm as TWA, 15 ppm as EFFECTS OF LONG-TERM OR
STEL; (ACGIH 2004).
REPEATED EXPOSURE:
MAK: IIb (not established but data Repeated or prolonged contact with skin
is available); (DFG 2004).
may cause dermatitis. The substance may
OSHA PEL: TWA 10 ppm (25
have effects on the gastrointestinal tract ,
mg/m3)
resulting in digestive disorders including
NIOSH REL: TWA 10 ppm (25
pyrosis and constipation.
mg/m3) ST 15 ppm (37 mg/m3)
NIOSH IDLH: 50 ppm See: 64197
Boiling point: 118°C
Melting point: 16.7°C
Relative density (water = 1): 1.05
Solubility in water:
miscible
Vapour pressure, kPa at 20°C: 1.5
Relative vapour density (air = 1): 2.1
Relative density of the vapour/airmixture at 20°C (air = 1): 1.02
Flash point: 39°C c.c.
Auto-ignition temperature: 427°C
Explosive limits, vol% in air: 5.4-16
Octanol/water partition coefficient as
log Pow: -0.31
ENVIRONMENTAL The substance is harmful to aquatic organisms.
DATA
79
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Team 13: Linezolid
NOTES
The symptoms of lung oedema often do not become manifest until a few hours have passed and they are
aggravated by physical effort. Rest and medical observation is therefore essential. Immediate
administration of an appropriate inhalation therapy by a doctor or a person authorized by him/her, should
be considered. Other UN numbers: UN 2790 acetic acid solution (10-80% acetic acid); UN hazard class
8. Card has been partly updated in October 2005. See sections Occupational Exposure Limits,
Emergency Response.
Transport Emergency Card: TEC (R)-80GCF1-II
NFPA Code: H2; F2; R0; 42
42
"Acetic Acid." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health, 22 July
2015. Web. 22 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0363.html>.
80
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Team 13: Linezolid
Acetone
2-Propanone
Dimethyl ketone
Methyl ketone
C3H6O / CH3COCH3
Molecular mass: 58.1
ICSC # 0087
CAS # 67-64-1
RTECS # AL3150000
UN # 1090
EC # 606-001-00-8
April 22, 1994 Validated
Fi, review at IHE: 10/09/89
TYPES OF
HAZARD/
EXPOSURE
PREVENTION
ACUTE HAZARDS/
SYMPTOMS
Highly flammable.
FIRE
Vapour/air mixtures are
explosive.
EXPLOSION
Sore throat. Cough.
Confusion. Headache.
•INHALATION
Dizziness. Drowsiness.
Unconsciousness.
Dry skin.
•SKIN
FIRST AID/
FIRE FIGHTING
NO open flames, NO sparks, Powder, alcohol-resistant
and NO smoking.
foam, water in large
amounts, carbon dioxide.
Closed system, ventilation, In case of fire: keep drums,
explosion-proof electrical
etc., cool by spraying with
equipment and lighting. Do water.
NOT use compressed air for
filling, discharging, or
handling.
Ventilation, local exhaust, or Fresh air, rest. Refer for
breathing protection.
medical attention.
Remove contaminated
clothes. Rinse skin with
plenty of water or shower.
Redness. Pain. Blurred
Safety spectacles or face
First rinse with plenty of
vision. Possible corneal
shield . Contact lenses
water for several minutes
damage.
should not be worn.
(remove contact lenses if
•EYES
easily possible), then take to
a doctor.
Nausea. Vomiting. (Further Do not eat, drink, or smoke Rinse mouth. Refer for
•INGESTION
see Inhalation).
during work.
medical attention.
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Personal protection: selfFireproof. Separated from strong
contained breathing apparatus.
oxidants. Store in an area without F symbol
Ventilation. Collect leaking liquid drain or sewer access.
Xi symbol
in sealable containers. Absorb
R: 11-36-66-67
remaining liquid in sand or inert
S: 2-9-16-26
absorbent and remove to safe
UN Hazard Class: 3
place. Do NOT wash away into
UN Packing Group: II
sewer. Then wash away with
plenty of water.
I
M
Protective gloves.
PHYSICAL STATE;
APPEARANCE:
COLOURLESS LIQUID , WITH
CHARACTERISTIC ODOUR.
ROUTES OF EXPOSURE:
The substance can be absorbed into
the body by inhalation and through the
skin.
81
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Team 13: Linezolid
P
O
R
T
A
N
T
D
A
T
A
PHYSICAL DANGERS:
The vapour is heavier than air and
may travel along the ground; distant
ignition possible.
CHEMICAL DANGERS:
The substance can form explosive
peroxides on contact with strong
oxidants such as acetic acid, nitric
acid, hydrogen peroxide. Reacts with
chloroform and bromoform under
basic conditions, causing fire and
explosion hazard. Attacks plastic.
INHALATION RISK:
A harmful contamination of the air
can be reached rather quickly on
evaporation of this substance at 20°C;
on spraying or dispersing, however,
much faster.
EFFECTS OF SHORT-TERM
EXPOSURE:
The vapour irritates the eyes and the
respiratory tract. The substance may
cause effects on the central nervous
system , liver , kidneys and
gastrointestinal tract .
OCCUPATIONAL EXPOSURE
EFFECTS OF LONG-TERM OR
LIMITS:
TLV: 500 ppm as TWA, 750 ppm as REPEATED EXPOSURE:
STEL; A4 (not classifiable as a human Repeated or prolonged contact with
carcinogen); BEI issued; (ACGIH
skin may cause dermatitis. The
2004).
substance may have effects on the
MAK: 500 ppm 1200 mg/m3
blood and bone marrow .
Peak limitation category: I(2);
Pregnancy risk group: D;
(DFG 2006).
OSHA PEL†: TWA 1000 ppm (2400
mg/m3)
NIOSH REL: TWA 250 ppm (590
mg/m3)
NIOSH IDLH: 2500 ppm 10%LEL
See: 67641
Boiling point: 56°C
Melting point: -95°C
Relative density (water = 1): 0.8
Solubility in water:
PHYSICAL
PROPERTIES miscible
Vapour pressure, kPa at 20°C: 24
Relative vapour density (air = 1): 2.0
Relative density of the vapour/air-mixture
at 20°C (air = 1): 1.2
Flash point: -18°C c.c.
Auto-ignition temperature: 465°C
Explosive limits, vol% in air: 2.2-13
Octanol/water partition coefficient as log
Pow: -0.24
NOTES
Use of alcoholic beverages enhances the harmful effect. 43
43
"Acetone." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health, 22 July
2015. Web. 22 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0087.html>.
82
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Team 13: Linezolid
Ammonium Hydroxide (10%-30% solution)
Aqua ammonia
Ammonium hydrate
NH4OH
Molecular mass: 35.1
ICSC # 0215
TYPES OF
ACUTE HAZARDS/
HAZARD/
SYMPTOMS
EXPOSURE
Not combustible.
FIRE
See Notes.
EXPLOSION
EXPOSURE
CAS # 1336-21-6
RTECS # BQ9625000
UN # 2672
EC # 007-001-01-2
March 17, 1995 Validated
PREVENTION
FIRST AID/
FIRE FIGHTING
In case of fire in the
surroundings: use
appropriate extinguishing
media.
In case of fire: keep drums,
etc., cool by spraying with
water.
STRICT HYGIENE!
IN ALL CASES CONSULT
A DOCTOR!
Ventilation, local exhaust, or Fresh air, rest. Artificial
breathing protection. Keep respiration if indicated.
containers properly closed. Refer for medical attention.
Burning sensation. Cough.
Laboured breathing.
•INHALATION
Shortness of breath. Sore
throat.
Corrosive. Redness. Serious Protective gloves. Protective Remove contaminated
skin burns. Pain. Blisters.
clothing.
clothes. Rinse skin with
•SKIN
plenty of water or shower.
Refer for medical attention.
Corrosive. Redness. Pain.
Face shield or eye protection First rinse with plenty of
Blurred vision. Severe deep in combination with
water for several minutes
burns.
breathing protection.
(remove contact lenses if
•EYES
easily possible), then take to
a doctor.
Corrosive. Abdominal
Do not eat, drink, or smoke Rinse mouth. Do NOT
cramps. Abdominal pain.
during work.
induce vomiting. Give
•INGESTION
Sore throat. Vomiting.
plenty of water to drink.
(Further see Inhalation).
Refer for medical attention.
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Evacuate danger area! Consult an Separated from food and
Unbreakable packaging; put
expert in case of a large spillage! feedstuffs . See Chemical
breakable packaging into closed
Ventilation. Cautiously neutralize Dangers. Cool. Well closed. Keep unbreakable container.
spilled liquid with a dilute acid, in a well-ventilated room (further Note: B
such as dilute sulfuric acid. Wash see Notes).
C symbol
away remainder with plenty of
N symbol
water. Do NOT let this chemical
R: 34-50
enter the environment. Personal
S: 1/2-26-36/37/39-45-61
protection: complete protective
UN Hazard Class: 8
clothing including self-contained
UN Packing Group: III
breathing apparatus.
83
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Team 13: Linezolid
I
M
P
O
R
T
A
N
T
D
A
T
A
PHYSICAL
PROPERTIES
ROUTES OF EXPOSURE:
PHYSICAL STATE;
The substance can be absorbed into
APPEARANCE:
VERY VOLATILE, COLOURLESS the body by inhalation of its vapour
SOLUTION OF AMMONIA IN
or aerosol and by ingestion.
WATER , WITH PUNGENT
ODOUR.
INHALATION RISK:
A harmful contamination of the air
can be reached very quickly on
PHYSICAL DANGERS:
evaporation of this substance at
20°C.
CHEMICAL DANGERS:
Reacts with many heavy metals and EFFECTS OF SHORT-TERM
their salts forming explosive
EXPOSURE:
compounds. Attacks many metals
The substance is corrosive to the
eyes, the skin and the respiratory
forming flammable/explosive gas
(hydrogen - see ICSC 0001). The
tract. Corrosive on ingestion as well.
solution in water is a strong base, it Inhalation of high concentrations of
vapour may cause laryngeal oedema,
reacts violently with acids.
inflamation of the respiratory tract,
OCCUPATIONAL EXPOSURE and pneumonia. The effects may be
delayed.
LIMITS:
TLV: (as NH3) 25 ppm as TWA; 40
ppm as STEL; (ACGIH 2004).
EFFECTS OF LONG-TERM OR
MAK: 20 ppm, 14 mg/m3;
REPEATED EXPOSURE:
Lungs may be affected by repeated
Peak limitation category: I(2);
or prolonged exposure to the vapour
Pregnancy risk group: C;
or aerosol.
(DFG 2004).
Boiling point: (25%) 38°C
Melting point: (25%) -58°C
Relative density (water = 1): (25%) 0.9
Solubility in water:
miscible
Vapour pressure, kPa at 20°C: (25%)
48
Relative vapour density (air = 1): 0.61.2
ENVIRONMENTAL The substance is very toxic to aquatic organisms.
DATA
NOTES
Ammonia vapour is flammable and explosive under certain conditions. Be aware that ammonia gas can
evolve from ammonia solution. Depending on the degree of exposure, periodic medical examination is
suggested. Do NOT completely fill bottles with the substance; strong solutions may develop pressure.
Release caps with care. Other UN numbers are: UN 1005 Ammonia, anhydrous liquefied or ammonia
solutions, relative density of less than 0.880 at 15°C in water, with more than 50% ammonia; UN 2073
Ammonia, 35-50%. Also consult ICSC 0414 Ammonia. Card has been partly updated in October 2004.
See sections Occupational Exposure Limits, EU classification, Emergency Response.
Transport Emergency Card: TEC (R)-80S2672
NFPA Code: H3; F1; R0 44
44
"AMMONIUM HYDROXIDE (10%-35% solution)." Centers for Disease Control and Prevention. The National Institute for
Occupational Safety and Health, 22 July 2015. Web. 24 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0215.html>.
84
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Team 13: Linezolid
Benzyl Alcohol
Benzenemethanol
Phenyl carbinol
alpha-Hydroxytoluene
Benzoyl alcohol
Phenyl methanol
C7H8O / C6H5CH2OH
Molecular mass: 108.1
ICSC # 0833
TYPES OF
ACUTE HAZARDS/
HAZARD/
SYMPTOMS
EXPOSURE
Combustible.
FIRE
CAS # 100-51-6
RTECS # DN3150000
EC # 603-057-00-5
April 13, 2000 Validated
PREVENTION
FIRST AID/
FIRE FIGHTING
NO open flames.
Powder, AFFF, foam,
carbon dioxide.
Cough. Dizziness.
Ventilation.
Fresh air, rest. Refer for
•INHALATION
Headache.
medical attention.
Redness.
Protective gloves.
Remove contaminated
clothes. First rinse with
plenty of water, then remove
•SKIN
contaminated clothes and
rinse again.
Redness.
Safety spectacles.
First rinse with plenty of
water for several minutes
(remove contact lenses if
•EYES
easily possible), then take to
a doctor.
Abdominal pain. Diarrhoea. Do not eat, drink, or smoke Rinse mouth. Refer for
during work.
medical attention.
•INGESTION Drowsiness. Nausea.
Vomiting.
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Collect leaking liquid in sealable Separated from strong oxidants.
Xn symbol
containers. Absorb remaining
liquid in sand or inert absorbent
R: 20/22
and remove to safe place. Personal
S: 2-26
protection: filter respirator for
organic gases and vapours.
85
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Team 13: Linezolid
I
M
P
O
R
T
A
N
T
D
A
T
A
PHYSICAL
PROPERTIES
ROUTES OF EXPOSURE:
PHYSICAL STATE;
The substance can be absorbed into the body
APPEARANCE:
COLOURLESS LIQUID , WITH by inhalation of its vapour and by ingestion.
CHARACTERISTIC ODOUR.
INHALATION RISK:
No indication can be given about the rate in
PHYSICAL DANGERS:
which a harmful concentration in the air is
reached on evaporation of this substance at
20°C.
CHEMICAL DANGERS:
Reacts with strong oxidants.
Attacks some forms of plastic. On EFFECTS OF SHORT-TERM
combustion, forms toxic gases
EXPOSURE:
The aerosol irritates the eyes and the skin.
including carbon monoxide.
The substance may cause effects on the
OCCUPATIONAL EXPOSURE nervous system .
LIMITS:
TLV not established.
EFFECTS OF LONG-TERM OR
MAK: IIb (not established but data REPEATED EXPOSURE:
is available); (DFG 2004).
Repeated or prolonged contact may cause
skin sensitization.
Boiling point: 205°C
Melting point: -15°C
Relative density (water = 1): 1.04
Solubility in water, g/100 ml: 4
Vapour pressure, Pa at 20°C: 13.2
Relative vapour density (air = 1): 3.7
Relative density of the vapour/airmixture at 20°C (air = 1): 1.0
Flash point:
93°C c.c.
Auto-ignition temperature: 436°C
Explosive limits, vol% in air: 1.3-13
Octanol/water partition coefficient as
log Pow: 1.1
45
ENVIRONMENTAL The substance is toxic to aquatic organisms.
DATA
45
"Benzyl Alcohol." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health, 22
July 2015. Web. 22 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0833.html>.
86
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Team 13: Linezolid
Benzyl Chloroformate
Benzylcarbonyl chloride
Carbobenzoxy chloride
Formic acid, chlorobenzyl ester
C8H7ClO2
Molecular mass: 170.6
ICSC # 0990
TYPES OF
ACUTE HAZARDS/
HAZARD/
SYMPTOMS
EXPOSURE
Combustible. Gives off
irritating or toxic fumes (or
FIRE
gases) in a fire.
EXPOSURE
Cough. Shortness of breath.
Sore throat. Laboured
•INHALATION
breathing.
CAS # 501-53-1
RTECS # LQ5860000
UN # 1739
EC # 607-064-00-4
April 21, 2004 Validated
PREVENTION
FIRST AID/
FIRE FIGHTING
NO open flames. NO contact Dry powder, foam, carbon
with water.
dioxide .
AVOID ALL CONTACT!
Ventilation, local exhaust, or Fresh air, rest. Half-upright
breathing protection.
position. Artificial
respiration may be needed.
Refer for medical attention.
Skin burns.
Protective gloves. Protective Remove contaminated
clothing.
clothes. Rinse skin with
•SKIN
plenty of water or shower.
Causes watering of the eyes. Face shield, or eye
First rinse with plenty of
Severe deep burns.
protection in combination water for several minutes
with breathing protection. (remove contact lenses if
•EYES
easily possible), then take to
a doctor.
Burning sensation.
Do not eat, drink, or smoke Do NOT induce vomiting.
Abdominal pain. Shock or during work.
Give plenty of water to
•INGESTION
collapse.
drink. Refer for medical
attention.
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Collect leaking liquid in sealable Separated from food and
Do not transport with food and
containers. Carefully collect
feedstuffs . Dry. Well closed.
feedstuffs.
remainder, then remove to safe
Marine pollutant.
place. Personal protection:
C symbol
complete protective clothing
N symbol
including self-contained breathing
R: 34-50/53
apparatus.
S: 1/2-26-45-60-61
UN Hazard Class: 8
UN Packing Group: I
I
P
PHYSICAL STATE;
APPEARANCE:
OILY COLOURLESS TO
YELLOW LIQUID , WITH
PUNGENT ODOUR.
O
PHYSICAL DANGERS:
M
ROUTES OF EXPOSURE:
The substance can be absorbed into
the body by inhalation and by
ingestion.
INHALATION RISK:
A harmful concentration of airborne
particles can be reached quickly on
87
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Team 13: Linezolid
R
T
A
N
T
D
A
spraying.
CHEMICAL DANGERS:
The substance decomposes on
heating producing phosgene , or on
contact with water producing toxic
and corrosive fumes including
hydrogen chloride . Attacks many
metals in the presence of water or
moist air.
OCCUPATIONAL EXPOSURE
LIMITS:
TLV not established.
MAK not established.
EFFECTS OF SHORT-TERM
EXPOSURE:
Lachrymation. The substance is
corrosive to the eyes, the skin and
the respiratory tract . Corrosive on
ingestion. Inhalation of the aerosol
may cause lung oedema (see Notes).
The effects may be delayed. Medical
observation is indicated.
EFFECTS OF LONG-TERM OR
REPEATED EXPOSURE:
T
A
PHYSICAL
PROPERTIES
Boiling point (decomposes): above
100°C
Melting point: 0°C
Relative density (water = 1): 1.20
Solubility in water: reaction
Vapour pressure, kPa at 85-87°C: 0.009
Relative vapour density (air = 1): 1
Flash point: 80.0°C c.c.
NOTES
The symptoms of lung oedema often do not become manifest until a few hours have passed and they are
aggravated by physical effort. Rest and medical observation is therefore essential. Immediate
administration of an appropriate inhalation therapy by a doctor or a person authorized by him/her, should
be considered.
Transport Emergency Card: TEC (R)-80GC9-I 46
46
"Benzyl Chloroformate." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health,
22 July 2015. Web. 22 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0990.html>.
88
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Team 13: Linezolid
Epichlorohydrin
1-Chloro-2,3-epoxypropane
gamma-Chloropropylene oxide
2-(Chloromethyl)oxirane
C3H5ClO
Molecular mass: 92.5
ICSC # 0043
TYPES OF
HAZARD/
EXPOSURE
FIRE
EXPLOSION
ACUTE HAZARDS/
SYMPTOMS
Flammable. Gives off
irritating or toxic fumes (or
gases) in a fire.
Above 31°C explosive
vapour/air mixtures may be
formed.
CAS # 106-89-8
RTECS # TX4900000
UN # 2023
EC # 603-026-00-6
November 24, 2003 Validated
PREVENTION
FIRST AID/
FIRE FIGHTING
NO open flames, NO sparks, Powder, water spray, foam,
and NO smoking.
carbon dioxide.
Above 31°C use a closed
system, ventilation, and
explosion-proof electrical
equipment.
AVOID ALL CONTACT!
In case of fire: keep drums,
etc., cool by spraying with
water.
IN ALL CASES CONSULT
A DOCTOR!
Burning sensation. Cough. Ventilation, local exhaust, or Fresh air, rest. Half-upright
Sore throat. Headache.
breathing protection.
position. Artificial
Laboured breathing. Nausea.
respiration may be needed.
Refer for medical attention.
•INHALATION Shortness of breath.
Vomiting. Tremor.
Symptoms may be delayed
(see Notes).
MAY BE ABSORBED!
Protective gloves. Protective Remove contaminated
Redness. Serious skin burns. clothing.
clothes. Rinse skin with
•SKIN
Burning sensation. Pain.
plenty of water or shower.
Blisters.
Refer for medical attention.
First rinse with plenty of
Pain. Redness. Permanent Face shield, or eye
loss of vision. Severe deep protection in combination water for several minutes
burns.
with breathing protection. (remove contact lenses if
•EYES
easily possible), then take to
a doctor.
Abdominal cramps. Burning Do not eat, drink, or smoke Rinse mouth. Do NOT
sensation in the throat and during work. Wash hands
induce vomiting. Give
chest. Diarrhoea. Headache. before eating.
plenty of water to drink.
•INGESTION
Nausea. Sore throat.
Rest. Refer for medical
Vomiting. Shock or
attention.
collapse.
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Evacuate danger area! Consult an Fireproof. Separated from strong Unbreakable packaging; put
expert! Collect leaking liquid in oxidants, acids, bases , aluminium breakable packaging into closed
EXPOSURE
89
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Team 13: Linezolid
sealable containers. Absorb
remaining liquid in sand or inert
absorbent and remove to safe
place. Do NOT let this chemical
enter the environment. Chemical
protection suit including selfcontained breathing apparatus.
, zinc , amines , food and
feedstuffs . Well closed.
PHYSICAL STATE;
APPEARANCE:
COLOURLESS LIQUID , WITH
CHARACTERISTIC ODOUR.
ROUTES OF EXPOSURE:
The substance can be absorbed into
the body by inhalation, through the
skin and by ingestion.
PHYSICAL DANGERS:
INHALATION RISK:
A harmful contamination of the air
can be reached very quickly on
evaporation of this substance at
20°C.
I
M
P
O
R
T
A
N
T
D
A
T
A
unbreakable container. Do not
transport with food and
feedstuffs.
Note: E
T symbol
R: 45-10-23/24/25-34-43
S: 53-45
UN Hazard Class: 6.1
UN Subsidiary Risks: 3
UN Packing Group: II
CHEMICAL DANGERS:
The substance will polymerize due
to heating or under the influence of
strong acid(s) , base(s) . On
combustion, forms toxic and
corrosive fumes,hydrogen chloride
(see ICSC0163)andchlorine fumes
(see ICSC0126). Reacts violently
with strong oxidants. Reacts
violently with aluminium , zinc ,
alcohols , phenols, amines
(especially aniline), and organic
acids causing fire and explosion
hazard. Attacks steel in the presence
of water.
EFFECTS OF SHORT-TERM
EXPOSURE:
The substance is corrosive to the
eyes, the skin and the respiratory
tract. Corrosive on ingestion.
Inhalation of the vapour may cause
lung oedema (see Notes). Inhalation
of the vapour may cause asthma-like
reactions. The substance may cause
effects on the central nervous system
, kidneys and liver , resulting in
convulsions , kidney impairment ,
liver impairment . Exposure at high
OCCUPATIONAL EXPOSURE levels may result in death. The
effects may be delayed. Medical
LIMITS:
TLV: 0.5 ppm as TWA; (skin); A3; observation is indicated.
(ACGIH 2003).
MAK: H; Sh;
EFFECTS OF LONG-TERM OR
Carcinogen category: 2; Germ cell REPEATED EXPOSURE:
Repeated or prolonged contact may
mutagen group: 3B;
cause skin sensitization. The
(DFG 2003).
substance may have effects on the
OSHA PEL†: TWA 5 ppm (19
3
mg/m ) skin
kidneys , liver and lungs , resulting
NIOSH REL: Ca See Appendix A in impaired functions . This
NIOSH IDLH: Ca 75 ppm
substance is probably carcinogenic
See: 106898
to humans. Animal tests show that
this substance possibly causes
toxicity to human reproduction or
development.
90
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PHYSICAL
PROPERTIES
Team 13: Linezolid
Boiling point: 116°C
Melting point: (see Notes) -48°C
Relative density (water = 1): 1.2
Solubility in water, g/100 ml: 6
Vapour pressure, kPa at 20°C: 1.6
Relative vapour density (air = 1): 3.2
Relative density of the vapour/airmixture at 20°C (air = 1): 1.05
Flash point: 31°C c.c.
Auto-ignition temperature: 385°C
Explosive limits, vol% in air: 3.8-21
Octanol/water partition coefficient as
log Pow: 0.26
ENVIRONMENTAL The substance is harmful to aquatic organisms.
DATA
NOTES
Other melting points: -25.6 °C and -57°C. Depending on the degree of exposure, periodic medical
examination is indicated. The symptoms of lung oedema often do not become manifest until a few hours
have passed and they are aggravated by physical effort. Rest and medical observation are therefore
essential. Immediate administration of an appropriate spray, by a doctor or a person authorized by
him/her, should be considered. The odour warning when the exposure limit value is exceeded is
insufficient. Do NOT take working clothes home.
Transport Emergency Card: TEC (R)-61S2023
NFPA Code: H3; F3; R2; 47
47
"Epichlorohydrin." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health, 22
July 2015. Web. 22 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0043.html>.
91
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Team 13: Linezolid
Ethyl Acetate
Acetic acid, ethyl ester
Acetic ether
C4H8O2 / CH3COOC2H5
Molecular mass: 88.1
ICSC # 0367
CAS # 141-78-6
RTECS # AH5425000
UN # 1173
EC # 607-022-00-5
September 10, 1997 Validated
TYPES OF
HAZARD/
EXPOSURE
PREVENTION
ACUTE HAZARDS/
SYMPTOMS
Highly flammable.
FIRE
EXPLOSION
Vapour/air mixtures are
explosive.
EXPOSURE
Cough. Dizziness.
Drowsiness. Headache.
•INHALATION Nausea. Sore throat.
Unconsciousness.
Weakness.
Dry skin.
FIRST AID/
FIRE FIGHTING
NO open flames, NO sparks, AFFF, alcohol-resistant
and NO smoking.
foam, powder, carbon
dioxide.
Closed system, ventilation, In case of fire: keep drums,
explosion-proof electrical
etc., cool by spraying with
equipment and lighting. Use water.
non-sparking handtools.
PREVENT GENERATION
OF MISTS!
Ventilation, local exhaust, or Fresh air, rest. Artificial
breathing protection.
respiration may be needed.
Refer for medical attention.
Protective gloves. Protective Remove contaminated
clothing.
clothes. Rinse skin with
•SKIN
plenty of water or shower.
Refer for medical attention.
Redness. Pain.
Safety goggles, or eye
First rinse with plenty of
protection in combination water for several minutes
with breathing protection. (remove contact lenses if
•EYES
easily possible), then take to
a doctor.
Do not eat, drink, or smoke Rinse mouth. Give plenty of
•INGESTION
during work.
water to drink.
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Fireproof. Separated from strong
Evacuate danger area! Collect
leaking and spilled liquid in
oxidants. Cool. Well closed.
F symbol
sealable containers as far as
Xi symbol
possible. Absorb remaining liquid
R: 11-36-66-67
in sand or inert absorbent and
S: 2-16-26-33
remove to safe place. Do NOT
UN Hazard Class: 3
wash away into sewer. Personal
UN Packing Group: II
protection: complete protective
clothing including self-contained
breathing apparatus.
92
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Team 13: Linezolid
PHYSICAL STATE;
APPEARANCE:
COLOURLESS LIQUID , WITH
CHARACTERISTIC ODOUR.
I
M
P
O
R
T
A
N
T
D
A
T
A
PHYSICAL
PROPERTIES
ROUTES OF EXPOSURE:
The substance can be absorbed into
the body by inhalation of its vapour.
INHALATION RISK:
A harmful contamination of the air
PHYSICAL DANGERS:
The vapour is heavier than air and can be reached rather quickly on
may travel along the ground; distant evaporation of this substance at
20°C.
ignition possible.
CHEMICAL DANGERS:
Heating may cause violent
combustion or explosion. The
substance decomposes under the
influence of UV light , acids , bases .
Reacts with strong oxidants , bases
or acids . Attacks aluminium and
plastics.
EFFECTS OF SHORT-TERM
EXPOSURE:
The substance is irritating to the eyes
and the respiratory tract . The
substance may cause effects on the
central nervous system. Exposure far
above the OEL may result in death.
EFFECTS OF LONG-TERM OR
OCCUPATIONAL EXPOSURE REPEATED EXPOSURE:
The liquid defats the skin.
LIMITS:
TLV: 400 ppm as TWA; (ACGIH
2004).
MAK: 400 ppm, 1500 mg/m3;
Peak limitation category: I(2);
Pregnancy risk group: C;
(DFG 2004).
OSHA PEL: TWA 400 ppm (1400
mg/m3)
NIOSH REL: TWA 400 ppm (1400
mg/m3)
NIOSH IDLH: 2000 ppm 10%LEL
See: 141786
Boiling point: 77°C
Melting point: -84°C
Relative density (water = 1): 0.9
Solubility in water:
very good
Vapour pressure, kPa at 20°C: 10
Relative vapour density (air = 1): 3.0
Flash point: -4°C c.c.
Auto-ignition temperature: 427°C
Explosive limits, vol% in air: 2.2-11.5
Octanol/water partition coefficient as
log Pow: 0.73
NOTES
Use of alcoholic beverages enhances the harmful effect. Acetidin, Vinegar naphtha are trade names. Card
has been partly updated in October 2004. See sections Occupational Exposure Limits, EU classification,
Emergency Response.
Transport Emergency Card: TEC (R)-30S1173
NFPA Code: H1; F3; R0; 48
48
"Ethyl Acetate." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health, 22 July
2015. Web. 22 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0367.html>.
93
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Team 13: Linezolid
n-Hexane
Hexyl hydride
C6H14
Molecular mass: 86.2
ICSC # 0279
TYPES OF
HAZARD/
EXPOSURE
ACUTE HAZARDS/
SYMPTOMS
CAS # 110-54-3
RTECS # MN9275000
UN # 1208
EC # 601-037-00-0
April 13, 2000 Validated
PREVENTION
FIRST AID/
FIRE FIGHTING
NO open flames, NO sparks, Powder, AFFF, foam,
and NO smoking.
carbon dioxide.
Vapour/air mixtures are
Closed system, ventilation, In case of fire: keep drums,
explosive.
explosion-proof electrical
etc., cool by spraying with
equipment and lighting. Do water.
NOT use compressed air for
EXPLOSION
filling, discharging, or
handling. Use non-sparking
handtools.
Dizziness. Drowsiness.
Ventilation, local exhaust, or Fresh air, rest. Refer for
Dullness. Headache. Nausea. breathing protection.
medical attention.
•INHALATION
Weakness.
Unconsciousness.
Dry skin. Redness. Pain.
Protective gloves.
Remove contaminated
clothes. Rinse and then wash
•SKIN
skin with water and soap.
Refer for medical attention.
Redness. Pain.
Safety goggles , face shield First rinse with plenty of
or eye protection in
water for several minutes
combination with breathing (remove contact lenses if
•EYES
protection.
easily possible), then take to
a doctor.
Abdominal pain. (Further
Do not eat, drink, or smoke Rinse mouth. Do NOT
during work.
induce vomiting. Rest. Refer
•INGESTION see Inhalation).
for medical attention.
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Consult an expert! Remove all
Fireproof. Separated from strong
ignition sources. Collect leaking oxidants. Well closed.
F symbol
and spilled liquid in sealable
Xn symbol
containers as far as possible.
N symbol
Absorb remaining liquid in sand
R: 11-38-48/20-62-65-67-51/53
or inert absorbent and remove to
S: 2-9-16-29-33-36/37-61-62
safe place. Do NOT wash away
UN Hazard Class: 3
into sewer. Do NOT let this
UN Packing Group: II
chemical enter the environment.
Personal protection: filter
FIRE
Highly flammable.
94
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Team 13: Linezolid
respirator for organic gases and
vapours.
I
M
P
O
R
T
A
N
T
D
A
T
A
PHYSICAL
PROPERTIES
ENVIRONMENTAL
DATA
PHYSICAL STATE; APPEARANCE: ROUTES OF EXPOSURE:
VOLATILE COLOURLESS LIQUID , The substance can be absorbed into the
WITH CHARACTERISTIC ODOUR.
body by inhalation of its vapour and by
ingestion.
PHYSICAL DANGERS:
The vapour is heavier than air and may INHALATION RISK:
travel along the ground; distant ignition A harmful contamination of the air can be
possible.
reached rather quickly on evaporation of
this substance at 20°C.
CHEMICAL DANGERS:
Reacts with strong oxidants causing fire EFFECTS OF SHORT-TERM
and explosion hazard. Attacks some
EXPOSURE:
plastics, rubber and coatings.
The substance irritates the skin. Swallowing
the liquid may cause aspiration into the
lungs with the risk of chemical
OCCUPATIONAL EXPOSURE
pneumonitis. Exposure at high levels could
LIMITS:
OSHA PEL†: TWA 500 ppm (1800
cause lowering of consciousness.
mg/m3)
NIOSH REL: TWA 50 ppm (180 mg/m3) EFFECTS OF LONG-TERM OR
NIOSH IDLH: 1100 ppm 10%LEL
REPEATED EXPOSURE:
See: 110543
Repeated or prolonged contact with skin
may cause dermatitis. The substance may
TLV: 50 ppm, 176 mg/m3 as TWA;
have effects on the central nervous system
(skin); BEI issued; (ACGIH 2004).
EU OEL: 72 mg/m3 20 ppm as TWA (EU and especially peripheral nervous system ,
resulting in polyneuropathy. Animal tests
2006).
show that this substance possibly causes
MAK:
toxic effects upon human reproduction.
Pregnancy risk group: C;
(DFG 2004).
Boiling point: 69°C
Melting point: -95°C
Relative density (water = 1): 0.7
Solubility in water, g/100 ml at 20°C:
0.0013
Vapour pressure, kPa at 20°C: 17
Relative vapour density (air = 1): 3.0
Relative density of the vapour/airmixture at 20°C (air = 1): 1.3
Flash point: -22°C c.c.
Auto-ignition temperature: 225°C
Explosive limits, vol% in air: 1.1-7.5
Octanol/water partition coefficient as log
Pow: 3.9
The substance is toxic to aquatic organisms.
NOTES
Depending on the degree of exposure, periodic medical examination is suggested. Card has been partly updated
in October 2004. See sections Occupational Exposure Limits, EU classification, Emergency Response. Card has
been partly updated in October 2006. See sections Occupational Exposure Limits.
95
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Transport Emergency Card: TEC (R)-30S1208
NFPA Code: H 1; F 3; R 0; 49
Hydrogen
H2
Molecular mass: 2.0
(cylinder)
ICSC # 0001
TYPES OF
HAZARD/
EXPOSURE
ACUTE HAZARDS/
SYMPTOMS
CAS # 1333-74-0
RTECS # MW8900000
UN # 1049
EC # 001-001-00-9
June 03, 2002 Validated
PREVENTION
FIRST AID/
FIRE FIGHTING
Extremely flammable. Many NO open flames, NO sparks, Shut off supply; if not
reactions may cause fire or and NO smoking.
possible and no risk to
explosion.
surroundings, let the fire
FIRE
burn itself out; in other cases
extinguish with water spray,
powder, carbon dioxide.
Gas/air mixtures are
Closed system, ventilation, In case of fire: keep cylinder
explosive.
explosion-proof electrical
cool by spraying with water.
equipment and lighting. Use Combat fire from a sheltered
EXPLOSION
non-sparking handtools. Do position.
not handle cylinders with
oily hands.
Suffocation.
Closed system and
Fresh air, rest. Artificial
ventilation.
respiration may be needed.
•INHALATION
Refer for medical attention.
Serious frostbite.
Cold-insulating gloves.
Refer for medical attention.
•SKIN
Safety spectacles.
•EYES
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Remove all ignition sources.
Fireproof. Cool.
Evacuate danger area! Consult an
F+ symbol
expert! Ventilation. Remove
R: 12
vapour with fine water spray.
S: 2-9-16-33
UN Hazard Class: 2.1
49
"n-Hexane." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health, 22 July
2015. Web. 23 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0279.html>.
96
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Team 13: Linezolid
I
M
PHYSICAL STATE;
APPEARANCE:
ODOURLESS , COLOURLESS
COMPRESSED GAS
P
O
R
T
A
N
T
D
A
PHYSICAL DANGERS:
The gas mixes well with air,
explosive mixtures are easily
formed. The gas is lighter than air.
CHEMICAL DANGERS:
Heating may cause violent
combustion or explosion. Reacts
violently with air, oxygen , halogens
and strong oxidants causing fire and
explosion hazard. Metal catalysts,
such as platinum and nickel, greatly
enhance these reactions.
ROUTES OF EXPOSURE:
The substance can be absorbed into
the body by inhalation.
INHALATION RISK:
On loss of containment, a harmful
concentration of this gas in the air
will be reached very quickly.
EFFECTS OF SHORT-TERM
EXPOSURE:
Simple asphyxiant. See Notes.
EFFECTS OF LONG-TERM OR
REPEATED EXPOSURE:
OCCUPATIONAL EXPOSURE
LIMITS:
TLV: Simple asphyxiant (ACGIH
2002).
T
A
PHYSICAL
PROPERTIES
Boiling point: -253°C
Relative vapour density (air = 1): 0.07
Flash point:
flammable gas
Auto-ignition temperature: 500-571°C
Explosive limits, vol% in air: 4-76
NOTES
High concentrations in the air cause a deficiency of oxygen with the risk of unconsciousness or death.
Check oxygen content before entering area. No odour warning if toxic concentrations are present.
Measure hydrogen concentrations with suitable gas detector (a normal flammable gas detector is not
suited for the purpose).
Transport Emergency Card: TEC (R)-20S1049
NFPA Code: H0; F4; R0; 50
50
"Hydrogen." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health, 22 July
2015. Web. 23 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0001.html>.
97
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Team 13: Linezolid
Hydrogen Chloride
Anhydrous hydrogen chloride
Hydrochloric acid, anhydrous
HCl
Molecular mass: 36.5
(cylinder)
ICSC # 0163
TYPES OF
HAZARD/
EXPOSURE
ACUTE HAZARDS/
SYMPTOMS
CAS # 7647-01-0
RTECS # MW4025000
UN # 1050
EC # 017-002-00-2
October 04, 2000 Validated
PREVENTION
FIRST AID/
FIRE FIGHTING
Not combustible.
In case of fire in the
surroundings: use
FIRE
appropriate extinguishing
media.
In case of fire: keep cylinder
EXPLOSION
cool by spraying with water.
AVOID ALL CONTACT! IN ALL CASES CONSULT
EXPOSURE
A DOCTOR!
Corrosive. Burning
Ventilation, local exhaust, or Fresh air, rest. Half-upright
position. Artificial
sensation. Cough. Laboured breathing protection.
breathing. Shortness of
respiration may be needed.
•INHALATION
Refer for medical attention.
breath. Sore throat.
Symptoms may be delayed
(see Notes).
ON CONTACT WITH
Cold-insulating gloves.
First rinse with plenty of
LIQUID: FROSTBITE.
Protective clothing.
water, then remove
Corrosive. Serious skin
contaminated clothes and
•SKIN
burns. Pain.
rinse again. Refer for
medical attention.
Corrosive. Pain. Blurred
Safety goggles or eye
First rinse with plenty of
vision. Severe deep burns. protection in combination water for several minutes
with breathing protection. (remove contact lenses if
•EYES
easily possible), then take to
a doctor.
•INGESTION
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Evacuate danger area! Consult an Separated from combustible and
expert! Ventilation. Remove gas reducing substances, strong
T symbol
with fine water spray. Personal
oxidants, strong bases, metals .
C symbol
protection: complete protective
Keep in a well-ventilated room. R: 23-35
clothing including self-contained Cool. Dry.
S: 1/2-9-26-36/37/39-45
breathing apparatus.
UN Hazard Class: 2.3
UN Subsidiary Risks: 8
98
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Team 13: Linezolid
I
M
P
O
R
T
A
N
T
D
A
T
A
PHYSICAL STATE; APPEARANCE:
COLOURLESS COMPRESSED
LIQUEFIED GAS , WITH PUNGENT
ODOUR.
PHYSICAL DANGERS:
The gas is heavier than air.
CHEMICAL DANGERS:
The solution in water is a strong acid, it
reacts violently with bases and is corrosive.
Reacts violently with oxidants forming
toxic gas (chlorine - see ICSC 0126).
Attacks many metals in the presence of
water forming flammable/explosive gas
(hydrogen - see ICSC0001).
OCCUPATIONAL EXPOSURE
LIMITS:
TLV: 2 ppm; (Ceiling value); A4 (not
classifiable as a human carcinogen);
(ACGIH 2004).
MAK: 2 ppm, 3.0 mg/m3;
Peak limitation category: I(2); Pregnancy
risk group: C;
(DFG 2004).
OSHA PEL: C 5 ppm (7 mg/m3)
NIOSH REL: C 5 ppm (7 mg/m3)
NIOSH IDLH: 50 ppm See: 7647010
Boiling point: -85°C
PHYSICAL
Melting point: -114°C
PROPERTIES
Density: 1.00045 g/l (gas)
ROUTES OF EXPOSURE:
The substance can be absorbed into the
body by inhalation.
INHALATION RISK:
A harmful concentration of this gas in the
air will be reached very quickly on loss of
containment.
EFFECTS OF SHORT-TERM
EXPOSURE:
Rapid evaporation of the liquid may cause
frostbite. The substance is corrosive to the
eyes, the skin and the respiratory tract.
Inhalation of high concentrations of the gas
may cause pneumonitis and lung oedema,
resulting in reactive airways dysfunction
syndrome (RADS) (see Notes). The effects
may be delayed. Medical observation is
indicated.
EFFECTS OF LONG-TERM OR
REPEATED EXPOSURE:
The substance may have effects on the
lungs , resulting in chronic bronchitis. The
substance may have effects on the teeth,
resulting in erosion.
Solubility in water, g/100 ml at 30°C: 67
Relative vapour density (air = 1): 1.3
Octanol/water partition coefficient as log
Pow: 0.25
NOTES
The applying occupational exposure limit value should not be exceeded during any part of the working
exposure. The symptoms of lung oedema often do not become manifest until a few hours have passed
and they are aggravated by physical effort. Rest and medical observation are therefore essential.
Immediate administration of an appropriate inhalation therapy by a doctor or a person authorized by
him/her, should be considered. Do NOT spray water on leaking cylinder (to prevent corrosion of
cylinder). Turn leaking cylinder with the leak up to prevent escape of gas in liquid state. Other UN
numbers: 2186 (refridgerated liquid) hazard class: 2.3; subsidiary hazard: 8; 1789 (hydrochloric acid)
hazard class: 8, pack group II or III. Aqueous solutions may contain up to 38% hydrogen chloride. Card
has been partly updated in April 2005. See sections Occupational Exposure Limits, Emergency
Response.
Transport Emergency Card: TEC (R)-20S1050
NFPA Code: H 3; F 0; R 1; 51
51
"Hydrogen Chloride." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health,
22 July 2015. Web. 23 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0163.html>.
99
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Team 13: Linezolid
Hydrogen Fluoride
Hydrofluoric acid, anhydrous
HF
Molecular mass: 20.0
(cylinder)
ICSC # 0283
TYPES OF
HAZARD/
EXPOSURE
ACUTE HAZARDS/
SYMPTOMS
CAS # 7664-39-3
RTECS # MW7875000
UN # 1052
EC # 009-002-00-6
December 04, 2000 Validated
PREVENTION
FIRST AID/
FIRE FIGHTING
Not combustible. Many
reactions may cause fire or
explosion.
In case of fire in the
surroundings: use
FIRE
appropriate extinguishing
media.
In case of fire: keep cylinder
cool by spraying with water
but NO direct contact with
EXPLOSION
water. Combat fire from a
sheltered position.
AVOID ALL CONTACT! IN ALL CASES CONSULT
EXPOSURE
A DOCTOR!
Burning sensation. Cough. Ventilation, local exhaust, or Fresh air, rest. Half-upright
Dizziness. Headache.
breathing protection.
position. Refer for medical
Laboured breathing. Nausea.
attention.
•INHALATION
Shortness of breath. Sore
throat. Vomiting. Symptoms
may be delayed (see Notes).
MAY BE ABSORBED!
Protective gloves. Protective Remove contaminated
Redness. Pain. Serious skin clothing.
clothes. Rinse skin with
•SKIN
burns. Blisters. (See
plenty of water or shower.
Inhalation).
Refer for medical attention.
Redness. Pain. Severe deep Face shield or eye protection First rinse with plenty of
burns.
in combination with
water for several minutes
breathing protection.
(remove contact lenses if
•EYES
easily possible), then take to
a doctor.
Do not eat, drink, or smoke Rinse mouth. Do NOT
Abdominal pain. Burning
sensation. Diarrhoea.
during work. Wash hands
induce vomiting. Refer for
•INGESTION
Nausea. Vomiting.
before eating.
medical attention.
Weakness. Collapse.
100
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SPILLAGE DISPOSAL
STORAGE
Evacuate danger area! Consult an Fireproof. Separated from food
expert! Ventilation. Remove
and feedstuffs . See Chemical
vapour with fine water spray. Gas- Dangers. Cool. Keep in a welltight chemical protection suit
ventilated room.
including self-contained breathing
apparatus.
I
M
P
O
R
T
A
N
T
D
A
T
A
PHYSICAL STATE;
APPEARANCE:
COLOURLESS GAS OR
COLOURLESS FUMING LIQUID ,
WITH PUNGENT ODOUR.
PHYSICAL DANGERS:
CHEMICAL DANGERS:
The substance is a strong acid, it
reacts violently with bases and is
corrosive. Reacts violently with
many compounds causing fire and
explosion hazard. Attacks metal,
glass, some forms of plastic, rubber
and coatings.
PACKAGING & LABELLING
Do not transport with food and
feedstuffs.
T+ symbol
C symbol
R: 26/27/28-35
S: 1/2-7/9-26-36/37/39-45
UN Hazard Class: 8
UN Subsidiary Risks: 6.1
UN Packing Group: I
ROUTES OF EXPOSURE:
The substance can be absorbed into the body by
inhalation, through the skin and by ingestion.
INHALATION RISK:
A harmful concentration of this gas in the air will
be reached very quickly on loss of containment.
EFFECTS OF SHORT-TERM EXPOSURE:
The substance is corrosive to the eyes, the skin
and the respiratory tract. Inhalation of this gas or
vapour may cause lung oedema (see Notes). The
substance may cause hypocalcemia. Exposure
above the OEL may result in death. The effects
may be delayed. Medical observation is
indicated.
EFFECTS OF LONG-TERM OR
OCCUPATIONAL EXPOSURE REPEATED EXPOSURE:
The substance may cause fluorosis.
LIMITS:
OSHA PEL†: TWA 3 ppm
NIOSH REL: TWA 3 ppm (2.5
mg/m3) C 6 ppm (5 mg/m3) 15minute
NIOSH IDLH: 30 ppm
See: 7664393
TLV: (as F) 0.5 ppm as TWA, 2 ppm
(Ceiling value); BEI issued; (ACGIH
2005).
MAK: 1 ppm, 0.83 mg/m3;
Peak limitation category: I(2);
Pregnancy risk group: C;
MAK: BAT 7 mg/g creatinine; (DFG
2005).
101
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Boiling point: 20°C
Melting point: -83°C
Relative density (water = 1): 1.0 as liquid
PHYSICAL
PROPERTIES at 4°C
Solubility in water:
very good
Team 13: Linezolid
Vapour pressure, kPa at 25°C: 122
Relative vapour density (air = 1): 0.7
NOTES
The occupational exposure limit value should not be exceeded during any part of the working exposure.
The symptoms of lung oedema often do not become manifest until a few hours have passed and they are
aggravated by physical effort. Rest and medical observation are therefore essential. Immediate
administration of an appropriate inhalation therapy by a doctor or a person authorized by him/her, should
be considered. Turn leaking cylinder with the leak up to prevent escape of gas in liquid state. Depending
on the degree of exposure, periodic medical examination is suggested. UN number for hydrogen fluoride
in aqueous solution: 1790, hazard class 8, subsidiary hazard 6.1, pack group I (>60%). Card has been
partly updated in April 2005. See sections Occupational Exposure Limits, Emergency Response.
Transport Emergency Card: TEC (R)-80S1052 or 80GCT1-I
NFPA Code: H 3; F 0; R 2; 52
52
"Hydrogen Fluoride." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health,
22 July 2015. Web. 23 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0283.html>.
102
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Team 13: Linezolid
2,2,4-Trimethylpetane
Isooctane
Isobutyltrimethylmethane
CH3C(CH3)2CH2CH(CH3)2 / C8H18
Molecular mass: 114.3
ICSC # 0496
TYPES OF
ACUTE HAZARDS/
HAZARD/
SYMPTOMS
EXPOSURE
Highly flammable.
FIRE
CAS # 540-84-1
RTECS # SA3320000
UN # 1262
EC # 601-009-00-8
October 19, 1999 Validated
PREVENTION
FIRST AID/
FIRE FIGHTING
NO open flames, NO sparks, Powder, AFFF, foam,
and NO smoking.
carbon dioxide.
Vapour/air mixtures are
Closed system, ventilation, In case of fire: keep drums,
explosive.
explosion-proof electrical
etc., cool by spraying with
equipment and lighting.
water. Combat fire from a
Prevent build-up of
sheltered position.
EXPLOSION
electrostatic charges (e.g., by
grounding). Do NOT use
compressed air for filling,
discharging, or handling.
Confusion. Dizziness.
Ventilation, local exhaust, or Fresh air, rest. Artificial
breathing protection.
respiration may be needed.
•INHALATION Headache. Nausea.
Vomiting.
Refer for medical attention.
Dry skin. Redness. Pain.
Protective gloves.
Remove contaminated
clothes. Rinse and then wash
•SKIN
skin with water and soap.
Redness.
Safety goggles.
First rinse with plenty of
water for several minutes
(remove contact lenses if
•EYES
easily possible), then take to
a doctor.
(Further see Inhalation).
Do not eat, drink, or smoke Rinse mouth. Do NOT
during work.
induce vomiting. Refer for
•INGESTION
medical attention.
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Evacuate danger area! Remove all Fireproof. Separated from strong
ignition sources. Collect leaking oxidants. Cool. Keep in a wellNote: C
and spilled liquid in sealable
ventilated room.
F symbol
containers as far as possible.
Xn symbol
Absorb remaining liquid in sand
N symbol
or inert absorbent and remove to
R: 11-38-50/53-65-67
safe place. Personal protection:
S: 2-9-16-29-33-60-61-62
self-contained breathing
UN Hazard Class: 3
apparatus.
UN Packing Group: II
103
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Team 13: Linezolid
I
M
P
O
R
T
A
N
T
D
A
T
PHYSICAL STATE;
APPEARANCE:
COLOURLESS LIQUID , WITH
CHARACTERISTIC ODOUR.
ROUTES OF EXPOSURE:
The substance can be absorbed into the body by
inhalation and by ingestion.
INHALATION RISK:
No indication can be given about the rate in which
PHYSICAL DANGERS:
The vapour is heavier than air and a harmful concentration in the air is reached on
may travel along the ground; distant evaporation of this substance at 20°C.
ignition possible. As a result of flow,
agitation, etc., electrostatic charges EFFECTS OF SHORT-TERM EXPOSURE:
can be generated.
The substance irritates the eyes, the skin and the
respiratory tract. The substance may cause effects
on the kidneys , liver and nervous system . If this
CHEMICAL DANGERS:
Heating may cause violent
liquid is swallowed, aspiration into the lungs may
combustion or explosion. Reacts
result in chemical pneumonitis.
with strong oxidants.
EFFECTS OF LONG-TERM OR REPEATED
OCCUPATIONAL EXPOSURE EXPOSURE:
The liquid defats the skin.
LIMITS:
TLV: 300 ppm as TWA; (ACGIH
2004).
MAK:
Carcinogen category: 3A;
(DFG 2004).
A
Boiling point: 99°C
Melting point: -107°C
PHYSICAL
Relative density (water = 1): 0.69
PROPERTIES
Solubility in water:
none
Vapour pressure, kPa at 20°C: 5.1
Relative vapour density (air = 1): 3.9
Flash point:
4.5°C o.c.
Auto-ignition temperature: 417°C
Explosive limits, vol% in air: 1.1-6.0
NOTES
Card has been partly updated in October 2005. See sections Occupational Exposure Limits, Emergency
Response.
Transport Emergency Card: TEC (R)-30S1262 or 30GF1-I+II
NFPA Code: H 0; F 3; R 0; 53
53
" 2,2,4-TRIMETHYLPENTANE." Centers for Disease Control and Prevention. The National Institute for Occupational Safety
and Health, 22 July 2015. Web. 23 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0496.html>.
104
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Team 13: Linezolid
Methanol
Methyl alcohol
Carbinol
Wood alcohol
CH4O / CH3OH
Molecular mass: 32.0
ICSC # 0057
TYPES OF
ACUTE HAZARDS/
HAZARD/
SYMPTOMS
EXPOSURE
Highly flammable. See
Notes.
FIRE
CAS # 67-56-1
RTECS # PC1400000
UN # 1230
EC # 603-001-00-X
November 04, 2000 Validated
PREVENTION
FIRST AID/
FIRE FIGHTING
NO open flames, NO sparks, and NO Powder, alcohol-resistant foam,
smoking. NO contact with oxidants. water in large amounts, carbon
dioxide.
Vapour/air mixtures are Closed system, ventilation, explosion- In case of fire: keep drums,
explosive.
proof electrical equipment and
etc., cool by spraying with
lighting. Do NOT use compressed air water.
EXPLOSION
for filling, discharging, or handling.
Use non-sparking handtools.
AVOID EXPOSURE OF
ADOLESCENTS AND
EXPOSURE
CHILDREN!
Cough. Dizziness.
Ventilation. Local exhaust or
Fresh air, rest. Refer for
Headache. Nausea.
breathing protection.
medical attention.
•INHALATION
Weakness. Visual
disturbance.
MAY BE ABSORBED! Protective gloves. Protective
Remove contaminated clothes.
Dry skin. Redness.
clothing.
Rinse skin with plenty of water
•SKIN
or shower. Refer for medical
attention.
Redness. Pain.
Safety goggles or eye protection in First rinse with plenty of water
combination with breathing
for several minutes (remove
protection.
contact lenses if easily
•EYES
possible), then take to a
doctor.
Abdominal pain.
Do not eat, drink, or smoke during
Induce vomiting (ONLY IN
Shortness of breath.
work. Wash hands before eating.
CONSCIOUS PERSONS!).
Vomiting. Convulsions.
Refer for medical attention.
•INGESTION
Unconsciousness.
(Further see Inhalation).
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Evacuate danger area! Ventilation.
Fireproof. Separated from Do not transport with food and feedstuffs.
Collect leaking liquid in sealable
strong oxidants, food and F symbol
containers. Wash away remainder
feedstuffs . Cool.
T symbol
with plenty of water. Remove vapour
R: 11-23/24/25-39/23/24/25
with fine water spray. Chemical
S: 1/2-7-16-36/37-45
protection suit including selfUN Hazard Class: 3
contained breathing apparatus.
UN Subsidiary Risks: 6.1
UN Packing Group: II
105
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Team 13: Linezolid
I
M
P
O
R
T
A
N
T
D
A
T
A
PHYSICAL STATE;
APPEARANCE:
COLOURLESS LIQUID , WITH
CHARACTERISTIC ODOUR.
ROUTES OF EXPOSURE:
The substance can be absorbed into the
body by inhalation and through the
skin and by ingestion.
PHYSICAL DANGERS:
The vapour mixes well with air,
explosive mixtures are easily formed.
INHALATION RISK:
A harmful contamination of the air can
be reached rather quickly on
evaporation of this substance at 20°C.
CHEMICAL DANGERS:
Reacts violently with oxidants causing
fire and explosion hazard.
OCCUPATIONAL EXPOSURE
LIMITS:
TLV: 200 ppm as TWA, 250 ppm as
STEL; (skin); BEI issued; (ACGIH
2004).
MAK:
Pregnancy risk group: C
(DFG 2004).
EU OEL: 260 mg/m3 200 ppm as TWA
(skin) (EU 2006).
OSHA PEL†: TWA 200 ppm (260
mg/m3)
NIOSH REL: TWA 200 ppm (260
mg/m3) ST 250 ppm (325 mg/m3) skin
NIOSH IDLH: 6000 ppm See: 67561
Boiling point: 65°C
Melting point: -98°C
Relative density (water = 1): 0.79
Solubility in water:
PHYSICAL
PROPERTIES miscible
Vapour pressure, kPa at 20°C: 12.3
EFFECTS OF SHORT-TERM
EXPOSURE:
The substance is irritating to the eyes ,
the skin and the respiratory tract . The
substance may cause effects on the
central nervous system , resulting in
loss of consciousness.
EFFECTS OF LONG-TERM OR
REPEATED EXPOSURE:
Repeated or prolonged contact with
skin may cause dermatitis. The
substance may have effects on the
central nervous system , resulting in
persistent or recurring headaches and
impaired vision.
Relative vapour density (air = 1): 1.1
Relative density of the vapour/air-mixture
at 20°C (air = 1): 1.01
Flash point: 12°C c.c.
Auto-ignition temperature: 464°C
Explosive limits, vol% in air: 5.5-44
Octanol/water partition coefficient as log
Pow: -0.82/-0.66
NOTES
Burns with nonluminous bluish flame. Depending on the degree of exposure, periodic medical
examination is suggested. Card has been partly updated in October 2006: see section Occupational
Exposure Limits.
Transport Emergency Card: TEC (R)-30S1230
NFPA Code: H 1; F 3; R 0; 54
54
"Methanol." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health, 22 July
2015. Web. 23 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0057.html>.
106
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Team 13: Linezolid
Methyl tert-butyl ether
tert-Butyl methyl ether
MTBE
Methyl-1,1-dimethylethyl ether
2-Methoxy-2-methyl propane
(CH3)3COCH3 / C5H12O
Molecular mass: 88.2
ICSC # 1164
TYPES OF
ACUTE HAZARDS/
HAZARD/
SYMPTOMS
EXPOSURE
Highly flammable.
FIRE
CAS # 1634-04-4
RTECS # KN5250000
UN # 2398
EC # 603-181-00-X
November 04, 2000 Validated
PREVENTION
FIRST AID/
FIRE FIGHTING
NO open flames, NO sparks, Powder, AFFF, foam,
and NO smoking. NO
carbon dioxide.
contact with oxidants.
Vapour/air mixtures are
Closed system, ventilation, In case of fire: keep drums,
explosive.
explosion-proof electrical
etc., cool by spraying with
equipment and lighting. Do water.
EXPLOSION
NOT use compressed air for
filling, discharging, or
handling.
Drowsiness. Dizziness.
Ventilation, local exhaust, or Fresh air, rest. Artificial
breathing protection.
respiration may be needed.
•INHALATION Headache. Weakness.
Refer for medical attention.
Unconsciousness.
Dry skin. Redness.
Protective gloves.
Remove contaminated
clothes. Rinse and then wash
•SKIN
skin with water and soap.
Redness.
Safety goggles or face
First rinse with plenty of
shield.
water for several minutes
(remove contact lenses if
•EYES
easily possible), then take to
a doctor.
Abdominal pain. Nausea.
Do not eat, drink, or smoke Rinse mouth. Give a slurry
during work.
of activated charcoal in
Vomiting. (Further see
water to drink. Do NOT
•INGESTION Inhalation).
induce vomiting. Refer for
medical attention.
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Remove all ignition sources.
Fireproof. Separated from strong
Collect leaking and spilled liquid oxidants, strong acids.
F symbol
in sealable containers as far as
Xi symbol
possible. Absorb remaining liquid
R: 11-38
in sand or inert absorbent and
S: 2-9-16-24
remove to safe place. Do NOT
UN Hazard Class: 3
wash away into sewer. Personal
UN Packing Group: II
protection: filter respirator for
organic gases and vapours.
107
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Team 13: Linezolid
I
M
PHYSICAL STATE;
APPEARANCE:
COLOURLESS LIQUID , WITH
CHARACTERISTIC ODOUR.
ROUTES OF EXPOSURE:
The substance can be absorbed into
the body by inhalation and by
ingestion.
PHYSICAL DANGERS:
The vapour is heavier than air and
may travel along the ground; distant
ignition possible.
INHALATION RISK:
A harmful contamination of the air
can be reached rather quickly on
evaporation of this substance at
20°C.
P
O
R
T
A
N
T
D
A
T
CHEMICAL DANGERS:
Reacts violently with strong oxidants EFFECTS OF SHORT-TERM
causing fire hazard. The substance EXPOSURE:
decomposes on contact with acids. The substance is irritating to the
skin. If this liquid is swallowed,
OCCUPATIONAL EXPOSURE aspiration into the lungs may result
in chemical pneumonitis. Exposure
LIMITS:
TLV: 50 ppm as TWA; A3; (ACGIH far above the OEL could cause
2004).
lowering of consciousness.
MAK: 50 ppm, 180 mg/m3;
Peak limitation category: I(1.5);
EFFECTS OF LONG-TERM OR
Carcinogen category: 3B; Pregnancy REPEATED EXPOSURE:
risk group: C;
(DFG 2004).
A
PHYSICAL
PROPERTIES
Boiling point: 55°C
Melting point: -109°C
Relative density (water = 1): 0.7
Solubility in water, g/100 ml at 20°C:
4.2
Vapour pressure, kPa at 20°C: 27
Relative vapour density (air = 1): 3.0
Relative density of the vapour/airmixture at 20°C (air = 1): 1.5
Flash point:
-28°C c.c.
Auto-ignition temperature: 375°C
Explosive limits, vol% in air: 1.6-15.1
Octanol/water partition coefficient as
log Pow: 1.06
ENVIRONMENTAL It is strongly advised not to let the chemical enter into the
environment because it persists in the environment.
DATA
NOTES
Much less likely to form peroxides than other ethers. Card has been partly updated in October 2004. See
sections Occupational Exposure Limits, EU classification, Emergency Response.
Transport Emergency Card: TEC (R)-30GF1-I+II 55
55
"Methyl tert-butyl ether." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health,
22 July 2015. Web. 23 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng1164.html>.
108
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Team 13: Linezolid
Methylene Chloride
dichloromethane
DCM
CH2Cl2
Molecular mass: 84.9
ICSC # 0058
TYPES OF
HAZARD/
EXPOSURE
ACUTE HAZARDS/
SYMPTOMS
CAS # 75-09-2
RTECS # PA8050000
UN # 1593
EC # 602-004-00-3
December 04, 2000 Validated
PREVENTION
FIRST AID/
FIRE FIGHTING
Combustible under specific
In case of fire in the
conditions. Gives off
surroundings: use
FIRE
irritating or toxic fumes (or
appropriate extinguishing
media.
gases) in a fire.
In case of fire: keep drums,
Risk of fire and explosion Prevent build-up of
electrostatic charges (e.g., by etc., cool by spraying with
EXPLOSION (see Chemical Dangers).
grounding).
water.
PREVENT GENERATION
OF MISTS! STRICT
EXPOSURE
HYGIENE!
Dizziness. Drowsiness.
Ventilation, local exhaust, or Fresh air, rest. Artificial
Headache. Nausea.
breathing protection.
respiration may be needed.
•INHALATION
Weakness.
Refer for medical attention.
Unconsciousness. Death.
Dry skin. Redness. Burning Protective gloves. Protective Remove contaminated
sensation.
clothing.
clothes. Rinse and then wash
•SKIN
skin with water and soap.
Redness. Pain. Severe deep Safety goggles , face shield First rinse with plenty of
burns.
or eye protection in
water for several minutes
combination with breathing (remove contact lenses if
•EYES
protection.
easily possible), then take to
a doctor.
Abdominal pain. (Further
Do not eat, drink, or smoke Rinse mouth. Do NOT
see Inhalation).
during work. Wash hands
induce vomiting. Give
•INGESTION
before eating.
plenty of water to drink.
Rest.
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Personal protection: filter
Separated from metals ( see
Do not transport with food and
respirator for organic gases and
Chemical Dangers ), food and
feedstuffs.
vapours. Do NOT let this
feedstuffs . Cool. Ventilation
Xn symbol
chemical enter the environment. along the floor.
R: 40
Ventilation. Collect leaking and
S: (2-)23-24/25-36/37
spilled liquid in sealable
UN Hazard Class: 6.1
containers as far as possible.
UN Packing Group: III
Absorb remaining liquid in sand
109
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Team 13: Linezolid
or inert absorbent and remove to
safe place.
PHYSICAL STATE;
APPEARANCE:
COLOURLESS LIQUID , WITH
CHARACTERISTIC ODOUR.
I
M
P
O
R
T
A
N
T
D
A
T
A
ROUTES OF EXPOSURE:
The substance can be absorbed into
the body by inhalation and by
ingestion.
INHALATION RISK:
PHYSICAL DANGERS:
The vapour is heavier than air. As a A harmful contamination of the air
can be reached very quickly on
result of flow, agitation, etc.,
evaporation of this substance at
electrostatic charges can be
20°C.
generated.
CHEMICAL DANGERS:
EFFECTS OF SHORT-TERM
On contact with hot surfaces or
EXPOSURE:
flames this substance decomposes The substance is irritating to the
forming toxic and corrosive fumes. eyes , the skin and the respiratory
Reacts violently with metals such tract . Exposure could cause
lowering of consciousness.
as aluminium powder and
magnesium powder, strong bases Exposure could cause the formation
of methaemoglobin.
and strong oxidants causing fire
and explosion hazard. Attacks some
forms of plastic rubber and
EFFECTS OF LONG-TERM OR
coatings.
REPEATED EXPOSURE:
Repeated or prolonged contact with
OCCUPATIONAL EXPOSURE skin may cause dermatitis. The
substance may have effects on the
LIMITS:
TLV: 50 ppm as TWA; A3
central nervous system and liver .
(confirmed animal carcinogen with This substance is possibly
unknown relevance to humans);
carcinogenic to humans.
BEI issued; (ACGIH 2004).
MAK:
Carcinogen category: 3A;
(DFG 2004).
OSHA PEL: 1910.1052 TWA 25
ppm ST 125 ppm
NIOSH REL: Ca See Appendix A
NIOSH IDLH: Ca 2300 ppm
See: 75092
110
5/11/16
PHYSICAL
PROPERTIES
Team 13: Linezolid
Boiling point: 40°C
Melting point: -95.1°C
Relative density (water = 1): 1.3
Solubility in water, g/100 ml at 20°C:
1.3
Vapour pressure, kPa at 20°C: 47.4
Relative vapour density (air = 1): 2.9
Relative density of the vapour/airmixture at 20°C (air = 1): 1.9
Auto-ignition temperature: 556°C
Explosive limits, vol% in air: 12-25
Octanol/water partition coefficient as
log Pow: 1.25
ENVIRONMENTAL This substance may be hazardous in the environment; special
attention should be given to ground water contamination.
DATA
NOTES
Addition of small amounts of a flammable substance or an increase in the oxygen content of the air
strongly enhances combustibility. Depending on the degree of exposure, periodic medical examination is
suggested. The odour warning when the exposure limit value is exceeded is insufficient. Do NOT use in
the vicinity of a fire or a hot surface, or during welding. R30 is a trade name. Card has been partly
updated in April 2005. See section Occupational Exposure Limits.
Transport Emergency Card: TEC (R)-61S1593
NFPA Code: H2; F1; R0; 56
56
"Dichloromethane." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health, 22
July 2015. Web. 23 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0058.html>.
111
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Team 13: Linezolid
Morpholine
Tetrahydro-1,4-oxazine
Diethylene oximide
C4H9NO
Molecular mass: 87.1
ICSC # 0302
CAS # 110-91-8
RTECS # QD6475000
UN # 2054
EC # 613-028-00-9
November 04, 2000 Validated
TYPES OF
HAZARD/
EXPOSURE
PREVENTION
ACUTE HAZARDS/
SYMPTOMS
FIRST AID/
FIRE FIGHTING
Flammable. Gives off
irritating or toxic fumes (or
gases) in a fire.
Above 35°C explosive
vapour/air mixtures may be
formed.
NO open flames, NO sparks, Powder, alcohol-resistant
and NO smoking.
foam, water spray, carbon
dioxide.
Above 35°C use a closed
In case of fire: keep drums,
system, ventilation, and
etc., cool by spraying with
EXPLOSION
explosion-proof electrical
water.
equipment.
PREVENT GENERATION IN ALL CASES CONSULT
OF MISTS! AVOID ALL A DOCTOR!
EXPOSURE
CONTACT!
Burning sensation. Cough. Ventilation, local exhaust, or Fresh air, rest. Half-upright
Laboured breathing.
breathing protection.
position. Artificial
respiration if indicated.
•INHALATION Shortness of breath.
Symptoms may be delayed
Refer for medical attention.
(see Notes).
See Notes.
MAY BE ABSORBED!
Protective gloves. Protective Remove contaminated
Redness. Pain. Skin burns. clothing.
clothes. Rinse skin with
•SKIN
Blisters.
plenty of water or shower.
Refer for medical attention.
Redness. Pain. Blurred
Face shield or eye protection First rinse with plenty of
vision. Severe deep burns. in combination with
water for several minutes
breathing protection.
(remove contact lenses if
•EYES
easily possible), then take to
a doctor.
Abdominal pain. Burning
Do not eat, drink, or smoke Rinse mouth. Give one or
sensation. Cough. Diarrhoea. during work.
two glasses of water to
drink. Do NOT induce
•INGESTION Nausea. Shock or collapse.
Vomiting.
vomiting. Refer for medical
attention.
FIRE
112
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SPILLAGE DISPOSAL
STORAGE
Collect leaking and spilled liquid Fireproof. Separated from strong
in sealable containers as far as
oxidants, acids. Dry.
possible. Absorb remaining liquid
in sand or inert absorbent and
remove to safe place. (Extra
personal protection: complete
protective clothing including selfcontained breathing apparatus).
PHYSICAL STATE;
APPEARANCE:
COLOURLESS HYGROSCOPIC
LIQUID , WITH
CHARACTERISTIC ODOUR.
I
M
P
O
R
T
A
N
T
D
A
T
A
PHYSICAL DANGERS:
PACKAGING & LABELLING
C symbol
R: 10-20/21/22-34
S: (1/2-)23-36-45
UN Hazard Class: 8
UN Subsidiary Risks: 3
UN Packing Group: I
ROUTES OF EXPOSURE:
The substance can be absorbed into
the body by inhalation, through the
skin and by ingestion.
INHALATION RISK:
A harmful contamination of the air
can be reached rather quickly on
evaporation of this substance at
20°C.
CHEMICAL DANGERS:
The substance decomposes on
burning producing toxic fumes
EFFECTS OF SHORT-TERM
including nitrogen oxides and carbon EXPOSURE:
monoxide . The substance is a
The substance is corrosive to the
medium strong base. Reacts with
eyes, the skin and the respiratory
strong oxidants causing fire hazard. tract. Corrosive on ingestion.
Attacks plastics, rubber and coatings. Inhalation of vapour of the substance
Unstable if stored in copper or zinc may cause lung oedema (see Notes).
containers.
EFFECTS OF LONG-TERM OR
OCCUPATIONAL EXPOSURE REPEATED EXPOSURE:
The substance may have effects on
LIMITS:
TLV (as TWA): 20 ppm; mg/m3 (A4 the liver and kidneys .
skin) (ACGIH 1999).
EU OEL: 10 ppm, 36 mg/m3 as
TWA; 20 ppm, 72 mg/m3 as STEL
(EU 2006).
MAK:
Pregnancy risk group: D
(DFG 2006).
OSHA PEL†: TWA 20 ppm (70
mg/m3) skin
NIOSH REL: TWA 20 ppm (70
mg/m3) ST 30 ppm (105 mg/m3)
skin
NIOSH IDLH: 1400 ppm 10%LEL
See: 110918
113
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PHYSICAL
PROPERTIES
Team 13: Linezolid
Boiling point: 129°C
Melting point: -5°C
Relative density (water = 1): 1.0
Solubility in water:
miscible
Vapour pressure, kPa at 20°C: 1.06
Relative vapour density (air = 1): 3.00
Relative density of the vapour/airmixture at 20°C (air = 1): 1.01
Flash point:
35°C c.c.
Auto-ignition temperature: 310°C
Explosive limits, vol% in air: 1.4-11.2
Octanol/water partition coefficient as
log Pow: -0.86
NOTES
Depending on the degree of exposure, periodic medical examination is indicated. The symptoms of lung
oedema often do not become manifest until a few hours have passed and they are aggravated by physical
effort. Rest and medical observation are therefore essential. Immediate administration of an appropriate
inhalation therapy (e.g. spray), by a doctor or a person authorized by him/her, should be considered. Card
has been partly updated in October 2006. See sections Occupational Exposure Limits, Ingestion First
Aid.
Transport Emergency Card: TEC (R)-697
NFPA Code: H 2; F 3; R 0; 57
57
"Morpholine." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health, 22 July
2015. Web. 24 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0302.html>.
114
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Team 13: Linezolid
Nitrogen (Compressed Gas)
N2
Molecular mass: 28.01
ICSC # 1198
TYPES OF
HAZARD/
EXPOSURE
CAS # 7727-37-9
RTECS # QW9700000
UN # 1066
March 22, 1999 Validated
ACUTE HAZARDS/
SYMPTOMS
FIRST AID/
FIRE FIGHTING
PREVENTION
Not combustible. Heating
will cause rise in pressure
with risk of bursting.
FIRE
EXPLOSION
Unconsciousness.
Ventilation.
•INHALATION Weakness. Suffocation. See
Notes.
SPILLAGE DISPOSAL
STORAGE
Ventilation. Personal protection: Fireproof if in building. Cool.
self-contained breathing
Keep in a well-ventilated room.
apparatus.
I
M
P
O
R
T
A
N
T
D
A
T
A
PHYSICAL
PROPERTIES
PHYSICAL STATE;
APPEARANCE:
ODOURLESS, COLOURLESS
COMPRESSED GAS
PHYSICAL DANGERS:
Gas mixes readily with air.
CHEMICAL DANGERS:
In case of fire in the
surroundings: use
appropriate extinguishing
media.
In case of fire: keep cylinder
cool by spraying with water.
Fresh air, rest. Artificial
respiration may be needed.
Refer for medical attention.
PACKAGING & LABELLING
UN Hazard Class: 2.2
ROUTES OF EXPOSURE:
The substance can be absorbed into
the body by inhalation.
INHALATION RISK:
On loss of containment this gas can
cause suffocation by lowering the
oxygen content of the air in
confined areas. See Notes.
EFFECTS OF SHORT-TERM
OCCUPATIONAL EXPOSURE EXPOSURE:
LIMITS:
TLV: Simple asphyxiant; (ACGIH
2004).
EFFECTS OF LONG-TERM
OR REPEATED EXPOSURE:
Boiling point: -196°C
Melting point: -210°C
Solubility in water: poor
Relative vapour density (air = 1): 0.97
NOTES
High concentrations in the air cause a deficiency of oxygen with the risk of unconsciousness or death.
Check oxygen content before entering area. Card has been partly updated in April 2005. See sections
Emergency Response, Occupational Exposure Limits.
Transport Emergency Card: TEC (R)-20G1A 58
58
115
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Team 13: Linezolid
Sodium Bicarbonate
Carbonic acid monosodium salt
Baking soda
Bicarbonate of soda
Sodium hydrogen carbonate
Sodium acid carbonate
NaHCO3
Molecular mass: 84.0
ICSC # 1044
TYPES OF
HAZARD/
EXPOSURE
ACUTE HAZARDS/
SYMPTOMS
CAS # 144-55-8
RTECS # VZ0950000
April 21, 2004 Validated
PREVENTION
Not combustible.
FIRE
Redness.
Safety spectacles.
•EYES
SPILLAGE DISPOSAL
STORAGE
Sweep spilled substance into
Separated from acids.
containers; if appropriate, moisten
first to prevent dusting. Wash
away remainder with plenty of
water.
FIRST AID/
FIRE FIGHTING
In case of fire in the
surroundings: use
appropriate extinguishing
media.
First rinse with plenty of
water for several minutes
(remove contact lenses if
easily possible), then take to
a doctor.
PACKAGING & LABELLING
116
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Team 13: Linezolid
I
M
PHYSICAL STATE;
APPEARANCE:
WHITE SOLID IN VARIOUS
FORMS.
P
PHYSICAL DANGERS:
O
R
T
A
N
CHEMICAL DANGERS:
The solution in water is a weak base.
Reacts with acids .
OCCUPATIONAL EXPOSURE
LIMITS:
TLV not established.
MAK not established.
T
ROUTES OF EXPOSURE:
The substance can be absorbed into the
body by ingestion.
INHALATION RISK:
Evaporation at 20°C is negligible; a
nuisance-causing concentration of
airborne particles can, however, be
reached quickly when dispersed,
especially, if powdered.
EFFECTS OF SHORT-TERM
EXPOSURE:
The substance is mildly irritating to the
eyes .
EFFECTS OF LONG-TERM OR
REPEATED EXPOSURE:
D
A
T
A
PHYSICAL
PROPERTIES
Melting point (decomposes): 50°C
Density: 2.1
g/cm3
Solubility in water, g/100 ml at 20°C:
8.7 59
Sodium Hydroxide
59
"Sodium Bicarbonate." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health,
22 July 2015. Web. 24 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng1044.html>.
117
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Caustic soda
Sodium hydrate
Soda lye
NaOH
Molecular mass: 40.0
ICSC # 0360
TYPES OF
ACUTE HAZARDS/
HAZARD/
SYMPTOMS
EXPOSURE
Not combustible. Contact
with moisture or water may
generate sufficient heat to
FIRE
ignite combustible
substances.
EXPOSURE
Corrosive. Burning
sensation. Sore throat.
Cough. Laboured breathing.
•INHALATION
Shortness of breath.
Symptoms may be delayed
(see Notes).
Corrosive. Redness. Pain.
Serious skin burns. Blisters.
•SKIN
Team 13: Linezolid
CAS # 1310-73-2
RTECS # WB4900000
UN # 1823
EC # 011-002-00-6
February 10, 2000 Validated
PREVENTION
FIRST AID/
FIRE FIGHTING
In case of fire in the
surroundings: use
appropriate extinguishing
media.
AVOID ALL CONTACT!
Local exhaust or breathing
protection.
IN ALL CASES CONSULT
A DOCTOR!
Fresh air, rest. Half-upright
position. Artificial
respiration may be needed.
Refer for medical attention.
Protective gloves. Protective Remove contaminated
clothing.
clothes. Rinse skin with
plenty of water or shower.
Refer for medical attention.
Corrosive. Redness. Pain. Face shield or eye protection First rinse with plenty of
Blurred vision. Severe deep in combination with
water for several minutes
burns.
breathing protection if
(remove contact lenses if
•EYES
powder.
easily possible), then take to
a doctor.
Corrosive. Burning
Do not eat, drink, or smoke Rinse mouth. Do NOT
sensation. Abdominal pain. during work.
induce vomiting. Give
•INGESTION
Shock or collapse.
plenty of water to drink.
Refer for medical attention.
SPILLAGE DISPOSAL
STORAGE
PACKAGING & LABELLING
Sweep spilled substance into
Separated from strong acids,
Unbreakable packaging; put
suitable containers. Wash away
metals , food and feedstuffs . Dry. breakable packaging into closed
remainder with plenty of water.
Well closed. Store in an area
unbreakable container. Do not
Personal protection: complete
having corrosion resistant
transport with food and
protective clothing including self- concrete floor.
feedstuffs.
contained breathing apparatus.
C symbol
R: 35
S: 1/2-26-37/39-45
UN Hazard Class: 8
UN Packing Group: II
118
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Team 13: Linezolid
I
M
P
O
R
T
A
N
T
D
A
T
A
PHYSICAL
PROPERTIES
ROUTES OF EXPOSURE:
PHYSICAL STATE;
The substance can be absorbed into the
APPEARANCE:
WHITE , DELIQUESCENT SOLID IN body by inhalation of its aerosol and by
ingestion.
VARIOUS FORMS , WITH NO
ODOUR.
INHALATION RISK:
Evaporation at 20°C is negligible; a
CHEMICAL DANGERS:
The substance is a strong base, it reacts harmful concentration of airborne
violently with acid and is corrosive in particles can, however, be reached
quickly.
moist air to metals like zinc,
aluminium, tin and lead forming a
combustible/explosive gas (hydrogen - EFFECTS OF SHORT-TERM
see ICSC 0001). Reacts with
EXPOSURE:
ammonium salts to produce ammonia , Corrosive. The substance is very
corrosive to the eyes, the skin and the
causing fire hazard. Attacks some
forms of plastics, rubber or coatings.
respiratory tract. Corrosive on
ingestion. Inhalation of an aerosol of
Rapidly absorbs carbon dioxide and
water from air. Contact with moisture the substance may cause lung oedema
(see Notes).
or water may generate heat (see
Notes).
EFFECTS OF LONG-TERM OR
REPEATED EXPOSURE:
OCCUPATIONAL EXPOSURE
Repeated or prolonged contact with
LIMITS:
TLV: 2 mg/m3 (Ceiling value) (ACGIH skin may cause dermatitis.
2004).
MAK: IIb (not established but data is
available) (DFG 2004).
OSHA PEL†: TWA 2 mg/m3
NIOSH REL: C 2 mg/m3
NIOSH IDLH: 10
mg/m3 See: 1310732
Boiling point: 1390°C
Melting point: 318°C
Density: 2.1 g/cm3
Solubility in water, g/100 ml at 20°C:
109
ENVIRONMENTAL This substance may be hazardous to the environment; special
attention should be given to water organisms.
DATA
NOTES
The occupational exposure limit value should not be exceeded during any part of the working exposure.
The symptoms of lung oedema often do not become manifest until a few hours have passed and they are
aggravated by physical effort. Rest and medical observation are therefore essential. NEVER pour water
into this substance; when dissolving or diluting always add it slowly to the water. Other UN number:
UN1824 Sodium hydroxide solution, Hazard class 8. Card has been partly updated in October 2005. See
sections Occupational Exposure Limits, Emergency Response.
Transport Emergency Card: TEC (R)-80GC6-II+III
NFPA Code: H 3; F 0; R 1;60
60
"Sodium Hydroxide." Centers for Disease Control and Prevention. The National Institute for Occupational Safety and Health,
22 July 2015. Web. 24 Apr. 2016. <http://www.cdc.gov/niosh/ipcsneng/neng0360.html>.
119
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Team 13: Linezolid
Appendix B: UniSim Process Flow Diagram
Figure 30:PFD first section in making Linezolid
120
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Team 13: Linezolid
Figure 31: PFD section for creating carbamic acid
121
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Team 13: Linezolid
Figure 32: PFD second section for Linezolid production
122
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Team 13: Linezolid
Figure 33: PFD third section for Linezolid production
123
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Team 13: Linezolid
Stream Tables
Table 19: Stream tables for UniSim simulations
Name
Reaction 1b
feed
Reaction 1a outlet
Rct1_solvent_
waste
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
40.0
202.6
0.0
2.2
Aqueous
Waste
0.0
40.0
202.6
0.0
2.5
Carbam1 Product
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
1.0
59.3
202.6
0.1
3.2
Ammonium
hydroxide feed
0.0
59.3
202.6
0.1
5.2
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.3
25.0
101.3
0.0
0.3
EthylAcetate_4
0.2
25.0
202.6
0.0
0.3
difluoronitrobenzene
0.0
25.0
101.3
0.0
0.4
Morphlene
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
25.0
101.3
0.0
1.9
Benzyl
chlorformate
0.0
25.0
101.3
0.0
0.4
reactor 1-B2 outlet
0.0
25.0
101.3
0.0
0.4
EthylAcetate_1
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
0.0
25.0
101.3
0.0
0.4
0.0
41.0
202.6
0.1
12.2
0.0
25.0
202.6
0.1
9.1
14
Reaction 1
concentrated
0.8
100.0
202.6
0.0
1.0
4
0.4
100.0
202.6
0.0
1.4
31
0.0
30.0
202.6
0.1
5.2
4chlorobenzald
ehyde
0.0
30.0
202.6
0.0
0.6
9
0.0
40.0
202.6
0.0
0.3
hydrogen
(ammonium formate)
1.0
30.0
202.6
0.0
0.0
HCl
1.0
25.0
202.6
0.0
0.2
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Name
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
Team 13: Linezolid
reactor 1C2-1 prod
Methylene
Chloride_2
0.0
0.0
25.0
25.0
202.6
202.6
0.4
0.1
7.4
9.2
17
Epichlorohydrin2
Acetic
Anhydride_1
13
0.0
25.0
202.6
0.0
0.5
IsoOctane
0.0
25.0
202.6
0.5
16.7
20
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
25.0
101.3
0.0
1.8
seed recycle
0.0
25.1
206.1
0.0
0.3
seed crystals
0.0
25.0
101.3
0.0
0.8
dryer vapors
0.0
25.1
202.6
0.0
0.8
step 1 crystals
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
5.0
202.6
0.0
0.1
24
0.0
5.0
202.6
0.0
0.1
0.0
60.0
202.6
0.0
0.0
Water_3
0.0
60.0
202.6
0.0
0.7
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
25.0
202.6
0.3
10.3
Hexane
Waste
0.0
4.9
202.6
0.0
0.4
44
0.0
4.9
202.6
0.0
0.7
more waste
0.0
60.0
202.6
0.0
0.0
47
0.0
60.0
202.6
0.0
0.7
Methanol_2
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
0.0
31.9
202.6
0.3
19.6
0.5
70.0
202.6
0.3
16.8
0.0
70.0
202.6
0.1
4.2
0.0
25.0
202.6
0.0
1.4
33
0.0
53.3
202.6
0.3
10.3
40
0.0
25.0
202.6
0.2
3.1
38
35
0.0
3.0
202.6
0.0
0.8
41
125
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Name
Team 13: Linezolid
51
52
Methanol_3
45
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
3.0
202.6
0.0
0.0
organic phase
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
25.0
202.6
0.1
9.6
EthylAcetate_3
0.0
25.0
202.6
0.4
7.4
58
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
25.0
202.6
0.0
0.7
1.0
30.0
20.3
0.0
1.4
0.0
30.0
20.3
0.0
0.8
pumpt outlet
0.0
30.1
202.6
0.0
0.8
MTBE_2
0.0
0.0
3.0
3.0
202.6
202.6
0.0
0.0
0.0
0.0
71.0
Methanol_4
0.2
40.8
202.6
0.0
0.3
84.0
0.0
25.0
101.3
0.0
0.5
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
Vapour Fraction
66
0.0
0.0
69.6
25.0
202.6
202.6
0.1
0.0
4.3
0.3
aqu phase EthylAcetate_2
67
0.0
3.5
202.6
0.0
0.5
87
0.0
5.0
202.6
0.0
0.3
HCL_Carbam1
1.0
0.0
25.0
202.6
0.0
0.6
91
0.0
25.0
202.6
0.1
5.4
6
0.7
0.0
3.0
202.6
0.0
0.2
the good stuff
0.0
25.0
202.6
0.0
0.3
59
0.0
25.0
202.6
0.4
7.8
61
NaOH
0.0
5.0
202.6
0.0
0.5
92
0.0
25.0
101.3
0.0
0.1
93
0.0
25.0
202.6
0.1
5.4
30
0.0
0.0
41.0
202.6
0.1
6.1
88
0.0
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Team 13: Linezolid
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
25.0
101.3
0.1
2.9
Carbamic feed
0.0
5.0
202.6
0.3
10.3
Aqueous Waste
2
7.6
101.3
0.1
5.7
1
0.0
85.0
202.6
0.0
2.6
Carbam2
Prod
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.1
29.6
200.8
0.0
0.9
Epichlorlohydrin
0.0
29.7
200.8
0.1
4.9
MTBE_1
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
25.0
101.3
0.0
0.3
Acetone_1
0.0
25.0
101.3
0.0
1.4
Water_2
0.0
25.1
202.6
0.0
1.8
water waste
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
25.0
101.3
0.1
5.2
Water_1
0.0
25.0
202.6
0.2
3.5
5
0.0
3.0
202.6
0.5
12.5
reactor 1-C2-1
outlet
0.0
3.0
202.6
0.0
0.8
ETa wash waste
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
0.0
25.0
202.6
0.4
6.8
0.0
26.1
202.6
0.5
16.1
0.0
25.0
202.6
0.5
17.0
0.0
25.0
202.6
0.0
0.3
Name
Sodium
Hydroxide_1
30.0
200.8
0.1
5.9
0.0
85.0
202.6
0.0
2.6
Carbam3 Raw
25.0
202.6
0.0
0.8
MethyleneChloride_1
0.0
25.0
202.6
0.1
10.8
8
0.0
8.5
10.1
0.3
10.3
0.0
25.0
202.6
0.0
2.2
3
18
Reactor 1-C3
Outlet
19
final waste
0.0
25.0
101.3
0.0
2.6
Crystals
Linezolid
127
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Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
Team 13: Linezolid
0.0
25.0
202.6
0.0
0.1
26
0.0
90.5
202.6
0.0
2.3
2
0.0
29.5
202.6
0.1
6.1
36
0.0
25.0
202.6
0.5
17.2
more waste
solvent
1.0
50.0
20.3
0.0
0.0
crystal cake
0.0
5.0
202.6
0.0
1.5
29
0.0
5.0
202.6
0.0
0.8
evapSolvent
0.0
25.1
202.6
0.0
2.6
37
0.2
20.0
10.1
0.0
3.8
hexane
0.0
3.0
202.6
0.0
0.0
AceticAcid_1
0.0
25.0
101.3
0.0
0.3
Methanol_1
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
23
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
29.5
202.6
0.1
6.1
recrystalizer3waste
0.0
25.0
101.3
0.1
3.7
46
0.0
25.0
202.6
0.1
3.7
49
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
0.0
3.0
202.6
0.1
3.3
0.0
3.0
202.6
0.0
0.9
0.0
3.0
202.6
0.0
0.9
0.0
3.0
202.6
0.0
0.0
0.0
50.0
20.3
0.0
0.7
28
0.0
5.0
202.6
0.0
0.7
32
0.0
20.0
10.1
0.0
1.1
39
0.0
25.1
202.6
0.0
0.3
42
0.0
25.1
202.6
0.1
3.7
50
0.0
3.0
202.6
0.0
0.0
128
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Name
Team 13: Linezolid
53
Nitrogen_1
54
55
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
3.0
202.6
0.0
1.0
organic
stuff
1.0
10.0
202.6
0.0
0.1
Methylene
Chloride_3
0.6
50.0
202.6
0.0
0.3
aq waste 2
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
25.0
202.6
0.1
9.4
62
0.0
25.0
202.6
0.0
0.8
63
0.0
25.0
202.6
0.4
7.1
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
29.0
202.6
0.0
0.8
68
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
0.0
5.0
202.6
0.0
0.8
89.0
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
0.0
5.0
202.6
0.0
0.5
64
60
0.0
25.0
202.6
0.0
1.5
65
0.0
0.0
3.0
3.0
202.6
202.6
0.0
0.0
0.1
0.7
MTBE
MethyleneChloride_4
rinse
waste
0.0
0.0
5.0
25.0
202.6
202.6
0.0
0.0
0.5
0.5
90.0
85
0.0
25.1
202.6
0.0
0.5
0.0
50.0
202.6
0.0
0.8
0.0
25.1
202.6
0.1
5.2
0.0
3.0
202.6
0.0
0.7
70
0.0
3.5
202.6
0.0
0.7
86
0.0
5.0
202.6
0.0
0.3
129
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Name
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Name
Vapour Fraction
Temperature (°C)
Pressure (kPa)
Molar Flow (kmol/h)
Mass Flow (kg/hr)
Team 13: Linezolid
94
95
0.0
29.7
202.6
0.1
6.1
7
0.0
41.0
202.6
0.1
12.2
0.0
41.0
202.6
0.1
6.1
NaOH ph
0.0
25.0
202.6
0.0
0.1
27
0.8
30.1
202.6
0.1
5.7
Ethy Acetate
0.0
25.0
101.3
0.0
2.8
130