Selection of Green Solvents

Denis PRAT, Process Safety & Environment Chemistry & Biochemistry

Sanofi Chimie, Gentilly (France)

4th Industrial Green Chemistry World Conference, Mumbai,

05 December 2015

Green Solvents | 1
AGENDA

Sanofi Social Responsibility

What is a green solvent
Published solvent selection guides
Including Sanofis !!
The CHEM21 European project
Comparison of solvent guides
Elaboration of CHEM21 solvent guide
How to rank bio-derived solvents?

Green Solvents | 2
SANOFI CORPORATE SOCIAL
RESPONSIBILITY: 4 PILLARS

Access to Healthcare
PATIENT Patient Safety
Innovation for the Patient

Ethics in R&D
ETHICS Business Ethics
Human Rights

Health & Safety

PEOPLE Diversity
Workforce Development

CO2 reduction
PLANET Water
Green chemistry

Green Solvents | 3
 SANOFIS INDUSTRIAL PRODUCTION OF
SEMISYNTHETIC ARTEMISININ IN YEAST
S. cerevisiae
Synthetic Biology
Mevalonate pathway Hydroxyase
Mevalonate pathway Synthase
(BOTTOM) Unit
(TOP)
Artemisinic
Acetyl- atoB HMGS tHMGRMevalonate ADS Amorphadiene CPR p450 Acid
MK PMK MPD idi ispA FPP
CoA H
H
O
CH3 OH
HO 2C OPP
H3C SCoA OH H
HO
H
J. D. Keasling et al., Nature, 2006, 440, 940-943 O

Green Chemistry Photo oxidation Purification

Cyclisation
H H
H Rduction H
O Drivatisation
H H
O O
HOO
H H H H
O HO RO HO

O
O O O

Artemisinin J. Turconi et al., OPRD, 2014, 18, 417 Artemisinic Acid

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IMPACT OF SOLVENTS IN THE
PROCESS GREENNESS
1 kg of API necessitates more than 100 kg of material
PMI
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.

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SOLVENTS IMPACT IN THE PROCESS
GREENNESS
Whatever the metrics considered, the yield (process efficiency) has a
direct impact on the synthesis greenness
But solvents are most often the main contributors

PMI CO2 Impact

Cumulated
Energy Demand
Life Cycle
Assessment
Global Warming
Potential

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WHAT IS A GREEN SOLVENT?

Criteria for a green solvent

From renewable feedstock
Low energy demand
Biodegradable
Not soluble in water
No VOCs (BP not too low)
Easy to recycle: BP not too high
Criteria for a safe solvent P. G. Jessop, Green Chem,
Stability 2011, 13, 1391.
Low flammability (high FP)
Moderate toxicity

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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
Occupational health
Safety (Flash point, resistivity, peroxides,)
Environment
Industrial & regulation issues
These guides reflect their policy and culture
Local constraints
Accidents
Habits

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PFIZERS SOLVENT GUIDE

Green Chem, 2008, 10, 31

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GSK SOLVENT GUIDE

Green Chem, 2011, 13, 854 Green Solvents | 11

GCI-PR GUIDE

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GENESIS OF SANOFIS SOLVENT GUIDE

We did not have a common vision of the preferred solvents

Sanofi-Synthelabo-Hoechst-Marion-Roussel-Rhone-Poulenc-Rorer
Research vs Production
Working group created in 2009
Reshaping of former HSE guide
Integration of industrial constraints
Integration of GHS/ CLP
Constraints:
Increasing difficulties to change the solvents during development
Purposes:
To educate chemists to SH&E, regulatory & industrial issues.
To promote renewable solvents
To give clear recommendations, but with supporting data
To make proposals for substitution of undesirable solvents (e. g. CMR)
To offer useful data and advice

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STRUCTURE OF SANOFIS SOLVENTS
GUIDE
One chapter per solvent family
Alcohols, ketones, esters, ethers, hydrocarbons, halogenated, aprotic polar,
bifunctional, miscellaneous.
In these chapters, one paragraph per solvent

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SANOFIS SOLVENTS GUIDE

First level of lecture

Overview per family of solvents, with clear recommendations
Which is the most advisable aprotic polar solvent?

OPRD, 2013, 17, 1517 Green Solvents | 15

SANOFIS SOLVENTS GUIDE

Second level of lecture

One ID card for each solvent
Third level
One paragraph per solvent

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SANOFIS SOLVENTS GUIDE

Four levels of ranking

OPRD, 2013, 17, 1517 Green Solvents | 17

THE IMI-CHEM21 PROJECT

IMI-CHEM21 project:
Created in 2012
4-year project
Six pharmaceutical companies from the European Foundation of
Pharmaceutical Industries and Associations (EFPIA)
Ten Universities
Five small to medium companies
Funded by EFPIA and the European Union
Develops sustainable biological and chemical methodologies
Supports research projects
Catalytic chemistry
Enzymatic chemistry
Synthetic biology
Provides training packages
Education of the future chemists

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THE IMI-CHEM21 PROJECT

Benchmark and gap analysis (WP1)

Portfolio review: the most used reactions in Pharmaceutical Industry
Catalysts to be replaced (critical elements)
Chemicals of concern & regulatory issues
Survey of solvent selection guides

Education and Training Package (WP5)

Green metrics
Renewable resources
York University
New transformations
CHEM21 solvent selection guide
Including bio-derived solvents

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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 SURVEY

Based on qualitative rankings (51 solvents)

If large majority, easy conclusion
Other cases: to be confirmed (TBC)

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COMPARISON OF THE DIFFERENT
GUIDES
Ranking Solvents
Recommended Water, EtOH, iPrOH, nBuOH, AcOEt, AcOiPr, AcOnBu, PhOMe, sulfolane

Recommended or MeOH, tBuOH, BnOH, ethylene glycol, acetone, MEK, MIBK, cyclohexanone, AcOMe,
Problematic ? AcOH, Ac2O
Problematic Me-THF, heptane, Me-cyclohexane, toluene, xylene, chlorobenzene, acetonitrile,
DMPU, DMSO
Problematic or THF, MTBE, cyclohexane, DCM, formic acid, pyridine
Hazardous ?
Hazardous iPr2O, dioxane, DME, pentane, hexane, DMF, DMA, NMP, TEA, methoxyethanol

Highly hazardous 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

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CHEM21 SOLVENT GUIDE

Ranking Solvents
Recommended Water, EtOH, iPrOH, nBuOH, AcOEt, AcOiPr, AcOnBu, PhOMe, sulfolane

Recommended or MeOH, tBuOH, BnOH, ethylene glycol, acetone, MEK, MIBK, cyclohexanone, AcOMe,
Problematic ? AcOH, Ac2O
Problematic Me-THF, heptane, Me-cyclohexane, toluene, xylene, chlorobenzene, acetonitrile,
DMPU, DMSO
Problematic or THF, MTBE, cyclohexane, DCM, formic acid, pyridine
Hazardous ?
Hazardous iPr2O, dioxane, DME, pentane, hexane, DMF, DMA, NMP, TEA, methoxyethanol

Highly hazardous Et2O, benzene, CCl4, chloroform, DCE, nitromethane

CHEM21 solvent guide based on this survey

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

Ranking methodology
1) Collect physical data and GHS statements from the Safety Data Sheets

Family Solvent BP FP AIT Worst H4xx

(C) (C) (C) H3xx
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 AIT Safety
(C) (C) score
Water Water na na 1
Alcohols EtOH 13 423 4
i-PrOH 12 456 4 Basic 1 3 4 5 7
n-BuOH 29 367 3 Safety
Esters Ethyl acetate -4 484 5 score
Flash Point > 60 23 to 60 22 to 0 -1 to -20 < -20
i-PrOAc 2 460 4
(C)
n-BuOAc 22 421 4
GHS - H226 H225 or H224
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 1 is added to the safety score for each of the following properties:
DME -6 200 7 - AIT < 200C
Hydrocarbons Pentane -40 285 8 - Resistivity > 108 W.m
Hexane -22 225 8 - Ability to form peroxides (EUH019)
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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 CHEM21 SOLVENT GUIDE

Ranking methodology
3) The health score derives from the most stringent H3xx statement
+ 1 if BP < 85C
Family Solvent BP Worst Health Health score 2 4 6 7 9
(C) H3xx score
Water Water 100 none 1 CMR H341 H351 H340 H350
Alcohols EtOH 78 H319 3 H361 H360
i-PrOH 82 H319 3 (cat. 2) (cat. 1)
n-BuOH 118 H318 4
Esters Ethyl acetate 77 H319 3 STOT H371 H373 H334 H370 H372
i-PrOAc 89 H319 2
n-BuOAc 126 H336 2
Ethers Diethyl ether 34 H302 3
Diisopropyl ether 69 H336 3 H302 H312 H301 H311 H300 H310
Me-THF 80 H318 5 Acute toxicity H332 H336 H331 H330
1,4-Dioxane 101 H351 6
Anisole 154 none 1
DME 85 H360 9
Hydrocarbons Pentane 36 H304 3 H315 H317 H318 H314 (skin)
Hexane 69 H361 7 Irritation H319 H335 (eyes)
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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CHEM21 SOLVENT GUIDE

Ranking methodology
4) The Environment score depends on the BP and on the H4xx statement
Family Solvent BP H4xx Env.
(C) score
Water Water 100 none 1
Alcohols EtOH 78 none 3
i-PrOH 82 none 3 Environment 3 5 7
n-BuOH 118 none 3 score
Esters Ethyl acetate 77 none 3 BP (C) 70-139 50-69 <50
i-PrOAc 89 none 3 140-200 >200
n-BuOAc 126 none 3 GHS No H4xx after full H412 H413 H400 H410 H411
Ethers Diethyl ether 34 none 7 REACh registration
Diisopropyl ether 69 none 5
Me-THF 80 none 3
1,4-Dioxane 101 none 3
Anisole 154 none 5
Other No, or partial REACh
DME 85 none 3
registration
Hydrocarbons Pentane 36 H411 7
Hexane 69 H411 7
Heptane 98 H410 7 Water: score= 1
Me-Cyclohexane 101 H411 7 H420 (ozone layer hazard): score = 10
Benzene 80 none 3
Toluene 111 none 3
Xylenes 140 none 5

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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 Health Env. Ranking by

score score score default
Water Water 1 1 1 Recommended
Alcohols EtOH 4 3 3 Recommended Combination of Solvent ranking by
i-PrOH 4 3 3 Recommended
SH&E scores default
n-BuOH 3 4 3 Recommended
Esters Ethyl acetate 5 3 3 Recommended One score > 8 Hazardous
i-PrOAc 4 2 3 Recommended
(red)
n-BuOAc 4 2 3 Recommended
Ethers Diethyl ether 10 3 7 Hazardous Two scores > 7 Hazardous
Diisopropyl ether 9 3 5 Hazardous
(red)
Me-THF 6 5 3 Problematic
1,4-Dioxane 7 6 3 Problematic One score = 7 Problematic
Anisole 4 1 5 Problematic
DME 7 9 3 Hazardous
(red)
Hydrocarbons Pentane 8 3 7 Hazardous 4 < Two scores < 6 Problematic
Hexane 8 7 7 Hazardous
Heptane 6 2 7 Problematic
(yellow)
Me-Cyclohexane 6 2 7 Problematic
Other Recommended
Benzene 6 10 3 Hazardous
Toluene 5 6 3 Problematic
Xylenes 4 2 5 Problematic

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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 FP Worst H4xx Safety Health Env. Ranking by Ranking from
(C) (C) H3xx score score score default 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
Newer solvents
Ranking Solvents
Recommended MeOH, tBuOH, BnOH, ethylene glycol,
or Problematic acetone, MEK, MIBK, cyclohexanone,
? AcOMe, AcOH, Ac2O
Problematic or THF, MTBE, cyclohexane, DCM, formic
Hazardous ? acid, pyridine

Green Solvents | 33
CHEM21 SOLVENT GUIDE

Ranking of intermediate solvents

A debate is needed (chemists + occupational hygienists)
Family Solvent Safety Health Env. score Ranking by default
score score
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 Health Env. score Ranking by default Ranking after
score score 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 H4xx Safety Health Env. Ranking by
H3xx score# score score 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

Ranking of ethers

Solvent BP (C) FP (C) Worst H4xx Safety Health Env. Ranking by

H3xx score# score score default

MTBE 55 -28 H315 none 8 3 5 Hazardous

ETBE 72 -19 H336 none 7 3 3 Problematic
CPME 106 -1 H302 H412 7 2 5 Problematic
TAME 86 -7 H302 none 6 2 3 Recommended
THF 66 -14 H351 none 6 7 5 Problematic
Me-THF 80 -11 H318 none 6 5 3 Problematic

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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
Is the fruit of a successful collaboration between (inter alia) Sanofi, GSK,
Pfizer, Orion, J&J, and the University of York.
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

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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
CHEM21 solvent guide is very useful for a preliminary ranking
Especially when little data are available
But a discussion between experts will always be necessary to give a final
ranking
Companies guide, like Sanofis, will continue to exist and evolve
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

Green Solvents | 39
 Main contributors:
Sanofi: O. Pardigon, H. Flemming, S. Letestu, V. Ducandas, P.
Isnard, E. Guntrum, T. Senac, S. Ruisseau, P. Cruciani and P.
Hosek.

CHEM21: A. Wells (Charnwood Consulting), J. Hayler & H.

Sneddon (GSK) , C.R. McElroy & S. Abou-Shehada (York), P. J.
Dunn (Pfizer).

The research for this work has received funding from the Innovative Medicines Initiative joint
undertaking project CHEM21 grant agreement n115360, resources of which are composed of
financial contribution from the European Unions 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.

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HEMI-SYNTHESIS OF ARTEMISININE

Green Solvents | 41
HEMI-SYNTHESIS OF ARTEMISININE

Green Solvents | 42
 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 | 43