chem21 solvent selection guide - igcw 2019 · 2018-03-26 · chem21 solvent selection guide denis...
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| 1Green Solvents
CHEM21 Solvent SelectionGuide
Denis PRAT, Process Safety & Environment Chemistry & Biochemistry
Sanofi Chimie, Gentilly (France)
4th Industrial Green Chemistry World Conference, Mumbai,
05 December 2015
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AGENDA
● The CHEM21 project
● What is a green solvent
● Survey of published solvent guides
● Elaboration of CHEM21 solvent guide
● Greenness of bio-derived solvents
Green Solvents | 3
THE IMI-CHEM21 PROJECT
● IMI-CHEM21 project:
● Created in 2012
● Six pharmaceutical companies from the European Foundation of
Pharmaceutical Industries and Associations (EFPIA)
● Ten Universities
● Five small to medium companies
● Funded by the EFPIA & European Community
● Develops sustainable biological and chemical methodologies
● Supports research projects
• Catalytic chemistry
• Enzymatic chemistry
• Synthetic biology
● Provides training packages
• Education of the future chemists
• Elaboration of a solvent guide including bio-derived solvents
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IMPACT OF SOLVENTS IN THE PROCESS GREENNESS
● 1 kg of API necessitates more than 100 kg of material
● Solvents and water represent >80% of these
● Reduce the impact by reduction of solvent & water amount
● Use the “greenest” solvents
C. Jimenez-Gonzalez et al, OPRD, 2011, 15, 912.
56%
32%
7% 5%
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WHAT IS A GREEN SOLVENT?
● Criteria for a green solvent
● From renewable feedstock
● Low carbon footprint
● Biodegradable
● Not soluble in water
● No VOCs (BP not too low)
● Easy to recycle: BP not too high
● Criteria for a safe solvent
● Stability
● Low flammability (high FP)
● Moderate toxicity
P. G. Jessop, Green Chem,
2011, 13, 1391.
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SOLVENT SELECTION GUIDES
● The definition of a green solvent is not straightforward
● Some criteria are contradictory
● There is no universal metrics set to compare the greenness criteria
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SOLVENT SELECTION GUIDES
● The definition of a green solvent is not straightforward
● Some criteria are contradictory
● There is no universal metrics set to compare the greenness criteria
● Some companies/ institutions have edited solvent selection guides in
order to help chemists in their choice
● These guides reflect their policy and culture
● Local constraints
● Accidents
● Habits
● These guides are different
● Structure
● Weighing of SH&E criteria
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PFIZER’S SOLVENT GUIDE
Green Chem, 2008, 10, 31
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GSK SOLVENT GUIDE
Green Chem, 2011, 13, 854
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GCI-PR GUIDE
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SANOFI’S SOLVENTS GUIDE
● One chapter per solvent family
● Alcohols, ketones, esters, ethers, hydrocarbons, halogenated, aprotic polar,
bifunctional, miscellaneous.
● In these chapters, one paragraph per solvent
● Several levels of lecture
OPRD, 2013, 17, 1517
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SOLVENT GUIDES COMPARISON
● Pfizer: 3 levels of ranking
● Preferred, Usable, Undesirable
● Sanofi: 4 levels of ranking
● Recommended, Subst. advisable, Subst. requested, Banned
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SOLVENT GUIDES COMPARISON
● Pfizer: 3 levels of ranking
● Preferred, Usable, Undesirable
● Sanofi: 4 levels of ranking
● Recommended, Subst. advisable, Subst. requested, Banned
● Astra Zeneca: no clear ranking
● 2 Safety criteria, 1 health, 7 environment
● Criteria scored from 1 (best) to 10 (worse)
● GCI-PR: similar, but simpler
● 1 safety criterion, 1 health, 3 environment
● Criteria scored from 1 (best) to 10 (worse)
● GSK: similar
● Plus legislation flags and EHS flags
● But scored from 10 (best) to 1 (worse)!
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SOLVENT GUIDES COMPARISON
● What is the level of convergence of
these guides?
● Survey based on 51 solvents
● Some manipulation was needed to
establish a solvent ranking from AZ,
GSK and GCI-PR guides
● Limit the number of criteria
• One of each: Health, Safety,
Environment
• Select the most stringent one in
each category
● Ex: GCI-PR guide
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SOLVENT GUIDES COMPARISON
● transformation of AZ, GSK and GCI-PR
guides
● Sum of H, S, E scores
● Arithmetical mean of this sum
● 3 groups of similar sizes centred on
this mean
● 3-color code
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SOLVENT GUIDES OVERVIEW
● Compare the colours
● If large majority, easy conclusion
● Other cases: to be confirmed (TBC)
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COMPARISON OF THE DIFFERENT GUIDES
● Aligned with regulations
● 67% convergence
● The divergences reflect the different weighing of criteria
D. Prat, J. Hayler, A. Wells, Green Chem., 2014, 16, 4546
Ranking Solvents
Recommended Water, EtOH, iPrOH, nBuOH, AcOEt, AcOiPr, AcOnBu, PhOMe, sulfolane
Recommended or Problematic ?
MeOH, tBuOH, BnOH, ethylene glycol, acetone, MEK, MIBK, cyclohexanone, AcOMe, AcOH, Ac2O
Problematic Me-THF, heptane, Me-cyclohexane, toluene, xylene, chlorobenzene, acetonitrile, DMPU, DMSO
Problematic or Hazardous ?
THF, MTBE, cyclohexane, DCM, formic acid, pyridine
Hazardous iPr2O, dioxane, DME, pentane, hexane, DMF, DMA, NMP, TEA, methoxyethanol
Highly hazardous Et2O, Benzene, CCl4, chloroform, DCE, nitromethane
Green Solvents | 18
CHEM21 SOLVENT GUIDE
● CHEM21 solvent guide is based on this analysis
● A simple ranking methodology was needed
● Based on HSE criteria
● To rank the intermediate solvents
● To rank newer/ bio-derived solvents
Ranking Solvents
Recommended Water, EtOH, iPrOH, nBuOH, AcOEt, AcOiPr, AcOnBu, PhOMe, sulfolane
Recommended or Problematic ?
MeOH, tBuOH, BnOH, ethylene glycol, acetone, MEK, MIBK, cyclohexanone, AcOMe, AcOH, Ac2O
Problematic Me-THF, heptane, Me-cyclohexane, toluene, xylene, chlorobenzene, acetonitrile, DMPU, DMSO
Problematic or Hazardous ?
THF, MTBE, cyclohexane, DCM, formic acid, pyridine
Hazardous iPr2O, dioxane, DME, pentane, hexane, DMF, DMA, NMP, TEA, methoxyethanol
Highly hazardous Et2O, benzene, CCl4, chloroform, DCE, nitromethane
● Ranking methodology
1) Collect physical data and GHS statements from the Safety Data Sheets
Family Solvent BP
(°C)
FP
(°C)
AIT
(°C)
Worst
H3xx
H4xx
Water Water 100 na na none none
Alcohols EtOH 78 13 423 H319 none
i-PrOH 82 12 456 H319 none
n-BuOH 118 29 367 H318 none
Esters Ethyl acetate 77 -4 484 H319 none
i-PrOAc 89 2 460 H319 none
n-BuOAc 126 22 421 H336 none
Ethers Diethyl ether 34 -45 160 H302 none
Diisopropyl ether 69 -28 405 H336 none
Me-THF 80 -11 270 H318 none
1,4-Dioxane 101 12 180 H351 none
Anisole 154 52 475 none none
DME 85 -6 200 H360 none
Hydrocarbons Pentane 36 -40 285 H304 H411
Hexane 69 -22 225 H361 H411
Heptane 98 -4 215 H304 H410
Me-Cyclohexane 101 -4 258 H304 H411
Benzene 80 -11 562 H350 none
Toluene 111 4 480 H351 none
Xylenes 140 27 480 H312 none
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CHEM21 SOLVENT GUIDE
● Ranking methodology
2) The safety score is calculated from the FP, the AIT, the resistivity, etc
Family Solvent FP
(°C)
AIT
(°C)
Safety
score
Water Water na na 1
Alcohols EtOH 13 423 4
i-PrOH 12 456 4
n-BuOH 29 367 3
Esters Ethyl acetate -4 484 5
i-PrOAc 2 460 4
n-BuOAc 22 421 4
Ethers Diethyl ether -45 160 10
Diisopropyl ether -28 405 9
Me-THF -11 270 6
1,4-Dioxane 12 180 7
Anisole 52 475 4
DME -6 200 7
Hydrocarbons Pentane -40 285 8
Hexane -22 225 8
Heptane -4 215 6
Me-Cyclohexane -4 258 6
Benzene -11 562 6
Toluene 4 480 5
Xylenes 27 480 4
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Basic
Safety
score
1 3 4 5 7
Flash Point
(°C)
> 60 23 to 60 22 to 0 -1 to -20 < -20
GHS - H226 H225 or H224
1 is added to the safety score for each of the following properties:
- AIT < 200°C
- Resistivity > 108 W.m
- Ability to form peroxides (EUH019)
CHEM21 SOLVENT GUIDE
● Ranking methodology
3) The health score derives from the most stringent H3xx GHS statement
+ 1 if BP < 85°C
Family Solvent BP
(°C)
Worst
H3xx
Health
score
Water Water 100 none 1
Alcohols EtOH 78 H319 3
i-PrOH 82 H319 3
n-BuOH 118 H318 4
Esters Ethyl acetate 77 H319 3
i-PrOAc 89 H319 2
n-BuOAc 126 H336 2
Ethers Diethyl ether 34 H302 3
Diisopropyl ether 69 H336 3
Me-THF 80 H318 5
1,4-Dioxane 101 H351 6
Anisole 154 none 1
DME 85 H360 9
Hydrocarbons Pentane 36 H304 3
Hexane 69 H361 7
Heptane 98 H304 2
Me-Cyclohexane 101 H304 2
Benzene 80 H350 10
Toluene 111 H351 6
Xylenes 140 H312 2
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Health score 2 4 6 7 9
CMR H341 H351
H361
(cat. 2)
H340 H350
H360
(cat. 1)
STOT H371 H373 H334 H370 H372
Acute toxicity
H302 H312
H332 H336
H301 H311
H331
H300 H310
H330
Irritation
H315 H317
H319 H335
H318
(eyes)
H314 (skin)
CHEM21 SOLVENT GUIDE
● Ranking methodology
4) The Environment score depends on the BP and on the H4xx statement
Family Solvent BP
(°C)
H4xx Env.
score
Water Water 100 none 1
Alcohols EtOH 78 none 3
i-PrOH 82 none 3
n-BuOH 118 none 3
Esters Ethyl acetate 77 none 3
i-PrOAc 89 none 3
n-BuOAc 126 none 3
Ethers Diethyl ether 34 none 7
Diisopropyl ether 69 none 5
Me-THF 80 none 3
1,4-Dioxane 101 none 3
Anisole 154 none 5
DME 85 none 3
Hydrocarbons Pentane 36 H411 7
Hexane 69 H411 7
Heptane 98 H410 7
Me-Cyclohexane 101 H411 7
Benzene 80 none 3
Toluene 111 none 3
Xylenes 140 none 5
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Environment
score
3 5 7
BP (°C) 70-139 50-69
140-200
<50
>200
GHS No H4xx after full
REACh registration
H412 H413 H400 H410 H411
Other No, or partial REACh
registration
Water: score= 1
H420 (ozone layer hazard): score = 10
CHEM21 SOLVENT GUIDE
● Ranking methodology
5) The ranking by default is given by the combination of HS&E scores
Family Solvent Safety
score
Health
score
Env.
score
Ranking by
default
Water Water 1 1 1 Recommended
Alcohols EtOH 4 3 3 Recommended
i-PrOH 4 3 3 Recommended
n-BuOH 3 4 3 Recommended
Esters Ethyl acetate 5 3 3 Recommended
i-PrOAc 4 2 3 Recommended
n-BuOAc 4 2 3 Recommended
Ethers Diethyl ether 10 3 7 Hazardous
Diisopropyl ether 9 3 5 Hazardous
Me-THF 6 5 3 Problematic
1,4-Dioxane 7 6 3 Problematic
Anisole 4 1 5 Problematic
DME 7 9 3 Hazardous
Hydrocarbons Pentane 8 3 7 Hazardous
Hexane 8 7 7 Hazardous
Heptane 6 2 7 Problematic
Me-Cyclohexane 6 2 7 Problematic
Benzene 6 10 3 Hazardous
Toluene 5 6 3 Problematic
Xylenes 4 2 5 Problematic
Combination of
SH&E scores
Solvent ranking by
default
One score > 8
(red)
Hazardous
Two scores > 7
(red)
Hazardous
One score = 7
(red)
Problematic
4 < Two scores < 6
(yellow)
Problematic
Other Recommended
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CHEM21 SOLVENT GUIDE
● The ranking thus obtained is consistent with the ranking based on the
survey of classical solvents (81% agreement)
Family Solvent BP
(°C)
FP
(°C)
Worst
H3xx
H4xx Safety
score
Health
score
Env.
score
Ranking by
default
Ranking from
the survey
Water Water 100 na none none 1 1 1 Recommended Recommended
Alcohols EtOH 78 13 H319 none 4 3 3 Recommended Recommended
i-PrOH 82 12 H319 none 4 3 3 Recommended Recommended
n-BuOH 118 29 H318 none 3 4 3 Recommended Recommended
Esters Ethyl acetate 77 -4 H319 none 5 3 3 Recommended Recommended
i-PrOAc 89 2 H319 none 4 2 3 Recommended Recommended
n-BuOAc 126 22 H336 none 4 2 3 Recommended Recommended
Ethers Diethyl ether 34 -45 H302 none 10 3 7 Hazardous HH
Diisopropyl ether 69 -28 H336 none 9 3 5 Hazardous Hazardous
Me-THF 80 -11 H318 none 6 5 3 Problematic Problematic
1,4-Dioxane 101 12 H351 none 7 6 3 Problematic Hazardous
Anisole 154 52 none none 4 1 5 Problematic Recommended
DME 85 -6 H360 none 7 9 3 Hazardous Hazardous
Hydrocarbons Pentane 36 -40 H304 H411 8 3 7 Hazardous Hazardous
Hexane 69 -22 H361 H411 8 7 7 Hazardous Hazardous
Heptane 98 -4 H304 H410 6 2 7 Problematic Problematic
Me-Cyclohexane 101 -4 H304 H411 6 2 7 Problematic Problematic
Benzene 80 -11 H350 none 6 10 3 Hazardous HH
Toluene 111 4 H351 none 5 6 3 Problematic Problematic
Xylenes 140 27 H312 none 4 2 5 Problematic Problematic
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CHEM21 SOLVENT GUIDE
● As the model is valid, it can be used to assign a preliminary greenness
assessment of any solvent
● Intermediate solvents
● Bio-derived solvents
Ranking Solvents
Recommended or Problematic ?
MeOH, tBuOH, BnOH, ethylene glycol, acetone, MEK, MIBK, cyclohexanone, AcOMe, AcOH, Ac2O
Problematic or Hazardous ?
THF, MTBE, cyclohexane, DCM, formic acid, pyridine
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CHEM21 SOLVENT GUIDE
● Ranking of intermediate solvents
● A debate is needed (chemists + occupational hygienists)
Family Solvent Safety
score
Health
score
Env. score Ranking by default
Alcohols MeOH 4 7 5 Problematic
t-BuOH 4 3 3 Recommended
Benzyl alcohol 1 2 7 Problematic
Ethylene glycol 1 2 5 Recommended
Ketones Acetone 5 3 5 Problematic
MEK 5 3 3 Recommended
MIBK 4 2 3 Recommended
Cyclohexanone 3 2 5 Recommended
Esters Methyl acetate 5 3 5 Problematic
Ethers MTBE 8 3 5 Hazardous
THF 6 7 5 Problematic
Hydrocarbons Cyclohexane 6 3 7 Problematic
Halogenated DCM 1 7 7 Hazardous
Amines Pyridine 4 2 3 Recommended
Acids Formic acid 3 7 3 Problematic
Acetic acid 3 7 3 Problematic
Ac2O 3 7 3 Problematic
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CHEM21 SOLVENT GUIDE
● Ranking of intermediate solvents
● A debate is needed (chemists + occupational hygienists)
Family Solvent Safety
score
Health
score
Env. score Ranking by default Ranking after
discussion
Alcohols MeOH 4 7 5 Problematic Recommended
t-BuOH 4 3 3 Recommended Recommended
Benzyl alcohol 1 2 7 Problematic Problematic
Ethylene glycol 1 2 5 Recommended Recommended
Ketones Acetone 5 3 5 Problematic Recommended
MEK 5 3 3 Recommended Recommended
MIBK 4 2 3 Recommended Recommended
Cyclohexanone 3 2 5 Recommended Problematic
Esters Methyl acetate 5 3 5 Problematic Problematic
Ethers MTBE 8 3 5 Hazardous Hazardous
THF 6 7 5 Problematic Problematic
Hydrocarbons Cyclohexane 6 3 7 Problematic Problematic
Halogenated DCM 1 7 7 Hazardous Hazardous
Amines Pyridine 4 2 3 Recommended Hazardous
Acids Formic acid 3 7 3 Problematic Problematic
Acetic acid 3 7 3 Problematic Problematic
Ac2O 3 7 3 Problematic Problematic
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CHEM21 SOLVENT GUIDE
● Ranking of bio-derived solvents
Family Solvent BP (°C) FP (°C) Worst
H3xx
H4xx Safety
score#
Health
score
Env.
score
Ranking by
default
Alcohols i-Butanol 107 28 H318 none 3 4 3 Recommended
i-Amyl alcohol 131 43 H315 none 3 2 3 Recommended
1, 3-Propane diol 214 >100 none none 1 1 7 Problematic
Glycerol 290 177 none none 1 1 7 Problematic
Esters i-Butyl acetate 115 22 H336 none 4 2 3 Recommended
i-Amyl acetate 142 25 none none 3 1 5 Recommended
Glycol diacetate 186 82 none none 1 1 5 Recommended
g-Valerolactone 207 100 n.a. n.a. 1 5 7 Problematic
Diethyl succinate 218 91 n.a. n.a. 1 5 7 Problematic
Hydrocarbons D-Limonene 175 49 H304 H400 4 2 7 Problematic
Turpentine 166 38 H302 H411 4 2 7 Problematic
p-Cymene 177 27 n.a. n.a. 4 5 5 Problematic
Aprotic polar Dimethyl carbonate 90 16 none none 4 1 3 Recommended
Ethylene carbonate 248 143 H302 none 1 2 7 Problematic
Propylene carbonate 242 132 H319 none 1 2 7 Problematic
Cyrene 203 61 H319 n.a. 1 2 7 Problematic
Miscellaneous Ethyl lactate 155 47 H318 none 3 4 5 Problematic
Lactic acid 230 113 H318 none 1 4 7 Problematic
TH-Furfuryl alcohol 178 75 H360 none 1 9 5 Hazardous
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CHEM21 SOLVENT GUIDE
● Gives a preliminary desirability of any solvents for fine chemistry scale-
up purposes
● Classical solvents
● Bio-derived solvents
● Newer solvents (little data)
● The methodology is not perfect
● The health criterion should be based on OEL
● It only gives a preliminary assessment, a discussion is needed in each
institution to challenge the ranking
● The environment criterion should include the CO2 synthesis impact
D. Prat, A. Wells, J. Hayler, H. Sneddon, C. R. McElroy, S. Abou-
Shehada, P. J. Dunn, Green Chem., advance article
Green Solvents | 29
CHEM21 SOLVENT GUIDE
Green Solvents | 30
CONCLUSIONS
● There is no universal solvent guide but:
● Guides tend to homogenize, inspired by each others
● Regulations are the same for everyone, and restrain the solvent choice
Green Solvents | 31
CONCLUSIONS
● Solvents guide have been elaborated for
pharma of fine chemical industries
● This does not favor bio-sourced solvents
(high BP)
● The field of green chemistry is wider
● Solvents guide are needed for other
applications
● There is no universal solvent guide but:
● Guides tend to homogenize, inspired by each others
● Regulations are the same for everyone, and restrain the solvent choice
Green Solvents | 32
CONCLUSIONS
● Solvents guide have been elaborated for
pharma of fine chemical industries
● This does not favor bio-sourced solvents
(high BP)
● The field of green chemistry is wider
● Solvents guide are needed for other
applications
● The methodology of CHEM21 guide can
be adapted to these applications
• Different weighing of criteria
Combination of
SH&E scores
Solvent ranking by
default
One score > 8 (red) Hazardous
Two scores > 7
(red)
Hazardous
One score = 7 (red) Problematic
4 < Two scores < 6
(yellow)
Problematic
Other Recommended
● There is no universal solvent guide but:
● Guides tend to homogenize, inspired by each others
● Regulations are the same for everyone, and restrain the solvent choice
Green Solvents | 33
Main contributors:
CHEM21: A. Wells (Charwood Consulting), J. Hayler (GSK), C.R. McElroy (York), P. J. Dunn (Pfizer), H. Sneddon (GSK), S. Abou-Shehada (York).
The research for this work has received funding from the Innovative Medicines Initiative joint undertaking project CHEM21 grant agreement n°115360, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution.
The conclusions reached in this presentation are the collective opinion of the authors who contribute to the CHEM21 consortium and do not reflect, at this time, official policy of any individual company or institution.
CHEM21- Who We Are
● EFPIA● GSK (coordinator), Sanofi (co-coordinator), Orion, J & J, Bayer, Pfizer
● Universities● University of Manchester (Managing Entity)
● Austrian Center of Industrial Biotechnology
● University of Stuttgart (Institute for Technical Biochemistry)
● University of Leeds
● University of Antwerp
● University of Durham
● Leibniz Institute for Catalysis (LIKAT)
● University of York
● Small and medium companies● Charnwood Technical Consulting
● Evolva Biotec
● Reaxa Ltd.
● CatSci Ltc.
● VU Amsterdam
Green Solvents | 34