CHEM21 Solvent Selection
Guide
Denis PRAT, Process Safety & Environment Chemistry & Biochemistry
Sanofi Chimie, Gentilly (France)
4th Industrial Green Chemistry World Conference, Mumbai,
05 December 2015
Green Solvents
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1
AGENDA
●
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●
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The CHEM21 project
What is a green solvent
Survey of published solvent guides
Elaboration of CHEM21 solvent guide
Greenness of bio-derived solvents
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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
7%
5%
56%
32%
C. Jimenez-Gonzalez et al, OPRD, 2011, 15, 912.
Green Solvents
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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
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The definition of a green solvent is not straightforward
Some criteria are contradictory
There is no universal metrics set to compare the greenness criteria
Green Solvents
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SOLVENT SELECTION GUIDES
●
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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
Green Solvents
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GSK SOLVENT GUIDE
Green Chem, 2011, 13, 854
Green Solvents
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GCI-PR GUIDE
Green Solvents
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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
Ranking
Solvents
Recommended
Recommended or
Problematic ?
Problematic
Problematic or
Hazardous ?
Hazardous
Highly hazardous
●
●
●
Water, EtOH, iPrOH, nBuOH, AcOEt, AcOiPr, AcOnBu, PhOMe, sulfolane
MeOH, tBuOH, BnOH, ethylene glycol, acetone, MEK, MIBK, cyclohexanone, AcOMe,
AcOH, Ac2O
Me-THF, heptane, Me-cyclohexane, toluene, xylene, chlorobenzene, acetonitrile,
DMPU, DMSO
THF, MTBE, cyclohexane, DCM, formic acid, pyridine
iPr2O, dioxane, DME, pentane, hexane, DMF, DMA, NMP, TEA, methoxyethanol
Et2O, Benzene, CCl4, chloroform, DCE, nitromethane
Aligned with regulations
67% convergence
The divergences reflect the different weighing of criteria
D. Prat, J. Hayler, A. Wells, Green Chem., 2014, 16, 4546
Green Solvents
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CHEM21 SOLVENT GUIDE
Ranking
Recommended
Recommended or
Problematic ?
Problematic
Problematic or
Hazardous ?
Hazardous
Highly hazardous
●
●
Solvents
Water, EtOH, iPrOH, nBuOH, AcOEt, AcOiPr, AcOnBu, PhOMe, sulfolane
MeOH, tBuOH, BnOH, ethylene glycol, acetone, MEK, MIBK, cyclohexanone, AcOMe,
AcOH, Ac2O
Me-THF, heptane, Me-cyclohexane, toluene, xylene, chlorobenzene, acetonitrile,
DMPU, DMSO
THF, MTBE, cyclohexane, DCM, formic acid, pyridine
iPr2O, dioxane, DME, pentane, hexane, DMF, DMA, NMP, TEA, methoxyethanol
Et2O, benzene, CCl4, chloroform, DCE, nitromethane
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
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CHEM21 SOLVENT GUIDE
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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
Alcohols
Water
EtOH
i-PrOH
n-BuOH
Ethyl acetate
i-PrOAc
n-BuOAc
Diethyl ether
Diisopropyl ether
Me-THF
1,4-Dioxane
Anisole
DME
Pentane
Hexane
Heptane
Me-Cyclohexane
Benzene
Toluene
Xylenes
100
78
82
118
77
89
126
34
69
80
101
154
85
36
69
98
101
80
111
140
na
13
12
29
-4
2
22
-45
-28
-11
12
52
-6
-40
-22
-4
-4
-11
4
27
na
423
456
367
484
460
421
160
405
270
180
475
200
285
225
215
258
562
480
480
none
H319
H319
H318
H319
H319
H336
H302
H336
H318
H351
none
H360
H304
H361
H304
H304
H350
H351
H312
none
none
none
none
none
none
none
none
none
none
none
none
none
H411
H411
H410
H411
none
none
none
Esters
Ethers
Hydrocarbons
Green Solvents
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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
Alcohols
Water
EtOH
i-PrOH
n-BuOH
Ethyl acetate
i-PrOAc
n-BuOAc
Diethyl ether
Diisopropyl ether
Me-THF
1,4-Dioxane
Anisole
DME
Pentane
Hexane
Heptane
Me-Cyclohexane
Benzene
Toluene
Xylenes
na
13
12
29
-4
2
22
-45
-28
-11
12
52
-6
-40
-22
-4
-4
-11
4
27
na
423
456
367
484
460
421
160
405
270
180
475
200
285
225
215
258
562
480
480
1
4
4
3
5
4
4
10
9
6
7
4
7
8
8
6
6
6
5
4
Esters
Ethers
Hydrocarbons
Basic
Safety
score
Flash Point
(°C)
GHS
1
3
4
5
7
> 60
23 to 60
22 to 0
-1 to -20
< -20
-
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)
Green Solvents
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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
Health score
Water
Alcohols
Water
EtOH
i-PrOH
n-BuOH
Ethyl acetate
i-PrOAc
n-BuOAc
Diethyl ether
Diisopropyl ether
Me-THF
1,4-Dioxane
Anisole
DME
Pentane
Hexane
Heptane
Me-Cyclohexane
Benzene
Toluene
Xylenes
100
78
82
118
77
89
126
34
69
80
101
154
85
36
69
98
101
80
111
140
none
H319
H319
H318
H319
H319
H336
H302
H336
H318
H351
none
H360
H304
H361
H304
H304
H350
H351
H312
1
3
3
4
3
2
2
3
3
5
6
1
9
3
7
2
2
10
6
2
CMR
Esters
Ethers
Hydrocarbons
2
4
6
7
H341 H351
H361
(cat. 2)
STOT
H371 H373
Acute toxicity
H302 H312
H332 H336
Irritation
H315 H317
H319 H335
H334
H340 H350
H360
(cat. 1)
H370 H372
H301 H311
H331
H318
(eyes)
9
H300 H310
H330
H314 (skin)
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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
Alcohols
Water
EtOH
i-PrOH
n-BuOH
Ethyl acetate
i-PrOAc
n-BuOAc
Diethyl ether
Diisopropyl ether
Me-THF
1,4-Dioxane
Anisole
DME
Pentane
Hexane
Heptane
Me-Cyclohexane
Benzene
Toluene
Xylenes
100
78
82
118
77
89
126
34
69
80
101
154
85
36
69
98
101
80
111
140
none
none
none
none
none
none
none
none
none
none
none
none
none
H411
H411
H410
H411
none
none
none
1
3
3
3
3
3
3
7
5
3
3
5
3
7
7
7
7
3
3
5
Esters
Ethers
Hydrocarbons
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
Green Solvents
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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
Alcohols
Water
EtOH
i-PrOH
n-BuOH
Ethyl acetate
i-PrOAc
n-BuOAc
Diethyl ether
Diisopropyl ether
Me-THF
1,4-Dioxane
Anisole
DME
Pentane
Hexane
Heptane
Me-Cyclohexane
Benzene
Toluene
Xylenes
1
4
4
3
5
4
4
10
9
6
7
4
7
8
8
6
6
6
5
4
1
3
3
4
3
2
2
3
3
5
6
1
9
3
7
2
2
10
6
2
1
3
3
3
3
3
3
7
5
3
3
5
3
7
7
7
7
3
3
5
Recommended
Recommended
Recommended
Recommended
Recommended
Recommended
Recommended
Hazardous
Hazardous
Problematic
Problematic
Problematic
Hazardous
Hazardous
Hazardous
Problematic
Problematic
Hazardous
Problematic
Problematic
Esters
Ethers
Hydrocarbons
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
Green Solvents
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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
Alcohols
Water
EtOH
i-PrOH
n-BuOH
Ethyl acetate
i-PrOAc
n-BuOAc
Diethyl ether
Diisopropyl ether
Me-THF
1,4-Dioxane
Anisole
DME
Pentane
Hexane
Heptane
Me-Cyclohexane
Benzene
Toluene
Xylenes
100
78
82
118
77
89
126
34
69
80
101
154
85
36
69
98
101
80
111
140
na
13
12
29
-4
2
22
-45
-28
-11
12
52
-6
-40
-22
-4
-4
-11
4
27
none
H319
H319
H318
H319
H319
H336
H302
H336
H318
H351
none
H360
H304
H361
H304
H304
H350
H351
H312
none
none
none
none
none
none
none
none
none
none
none
none
none
H411
H411
H410
H411
none
none
none
1
4
4
3
5
4
4
10
9
6
7
4
7
8
8
6
6
6
5
4
1
3
3
4
3
2
2
3
3
5
6
1
9
3
7
2
2
10
6
2
1
3
3
3
3
3
3
7
5
3
3
5
3
7
7
7
7
3
3
5
Recommended
Recommended
Recommended
Recommended
Recommended
Recommended
Recommended
Hazardous
Hazardous
Problematic
Problematic
Problematic
Hazardous
Hazardous
Hazardous
Problematic
Problematic
Hazardous
Problematic
Problematic
Recommended
Recommended
Recommended
Recommended
Recommended
Recommended
Recommended
HH
Hazardous
Problematic
Hazardous
Recommended
Hazardous
Hazardous
Hazardous
Problematic
Problematic
HH
Problematic
Problematic
Esters
Ethers
Hydrocarbons
Green Solvents
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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
Green Solvents
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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
t-BuOH
Benzyl alcohol
Ethylene glycol
Acetone
MEK
MIBK
Cyclohexanone
Methyl acetate
MTBE
THF
Cyclohexane
DCM
Pyridine
Formic acid
Acetic acid
Ac2O
4
4
1
1
5
5
4
3
5
8
6
6
1
4
3
3
3
7
3
2
2
3
3
2
2
3
3
7
3
7
2
7
7
7
5
3
7
5
5
3
3
5
5
5
5
7
7
3
3
3
3
Problematic
Recommended
Problematic
Recommended
Problematic
Recommended
Recommended
Recommended
Problematic
Hazardous
Problematic
Problematic
Hazardous
Recommended
Problematic
Problematic
Problematic
Ketones
Esters
Ethers
Hydrocarbons
Halogenated
Amines
Acids
Green Solvents
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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
t-BuOH
Benzyl alcohol
Ethylene glycol
Acetone
MEK
MIBK
Cyclohexanone
Methyl acetate
MTBE
THF
Cyclohexane
DCM
Pyridine
Formic acid
Acetic acid
Ac2O
4
4
1
1
5
5
4
3
5
8
6
6
1
4
3
3
3
7
3
2
2
3
3
2
2
3
3
7
3
7
2
7
7
7
5
3
7
5
5
3
3
5
5
5
5
7
7
3
3
3
3
Problematic
Recommended
Problematic
Recommended
Problematic
Recommended
Recommended
Recommended
Problematic
Hazardous
Problematic
Problematic
Hazardous
Recommended
Problematic
Problematic
Problematic
Recommended
Recommended
Problematic
Recommended
Recommended
Recommended
Recommended
Problematic
Problematic
Hazardous
Problematic
Problematic
Hazardous
Hazardous
Problematic
Problematic
Problematic
Ketones
Esters
Ethers
Hydrocarbons
Halogenated
Amines
Acids
Green Solvents
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27
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
i-Amyl alcohol
1, 3-Propane diol
Glycerol
i-Butyl acetate
i-Amyl acetate
Glycol diacetate
g-Valerolactone
Diethyl succinate
D-Limonene
Turpentine
p-Cymene
Dimethyl carbonate
Ethylene carbonate
Propylene carbonate
Cyrene
Ethyl lactate
Lactic acid
TH-Furfuryl alcohol
107
131
214
290
115
142
186
207
218
175
166
177
90
248
242
203
155
230
178
28
43
>100
177
22
25
82
100
91
49
38
27
16
143
132
61
47
113
75
H318
H315
none
none
H336
none
none
n.a.
n.a.
H304
H302
n.a.
none
H302
H319
H319
H318
H318
H360
none
none
none
none
none
none
none
n.a.
n.a.
H400
H411
n.a.
none
none
none
n.a.
none
none
none
3
3
1
1
4
3
1
1
1
4
4
4
4
1
1
1
3
1
1
4
2
1
1
2
1
1
5
5
2
2
5
1
2
2
2
4
4
9
3
3
7
7
3
5
5
7
7
7
7
5
3
7
7
7
5
7
5
Recommended
Recommended
Problematic
Problematic
Recommended
Recommended
Recommended
Problematic
Problematic
Problematic
Problematic
Problematic
Recommended
Problematic
Problematic
Problematic
Problematic
Problematic
Hazardous
Esters
Hydrocarbons
Aprotic polar
Miscellaneous
Green Solvents
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28
CHEM21 SOLVENT GUIDE
●
●
Gives a preliminary desirability of any solvents for fine chemistry scaleup 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. AbouShehada, P. J. Dunn, Green Chem., advance article
Green Solvents
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29
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
|
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
●
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
Green Solvents
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31
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
●
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
Green Solvents
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32
Main contributors:
CHEM21: A. Wells (Charwood Consulting), J. Hayler (GSK), C.R.
McElroy (York), P. J. Dunn (Pfizer), H. Sneddon (GSK), S. AbouShehada (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 (FP7/20072013) 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.
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CHEM21- Who We Are
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EFPIA
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Universities
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● GSK (coordinator), Sanofi (co-coordinator), Orion, J & J, Bayer, Pfizer
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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
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Charnwood Technical Consulting
Evolva Biotec
Reaxa Ltd.
CatSci Ltc.
VU Amsterdam
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