green and sustainable chemistry by design · time: idea to product (average) 11-15 years . 9 years...

Green and Sustainable Chemistry by Design

Green Chemistry Summer School

ACS Green Chemistry Institute®

24 July 2013

ACS GREEN CHEMISTRY INSTITUTE®

2


Part 1

The Big Picture


How long will things last? Should I worry?

Outline

A few green chemistry challenges Something has to change

Some thoughts about design How you think about the problem is key


THE BIG DRIVERS How do you view the world?

• Plenty of resources vs. finite and diminishing resources?

• Room for lots more people vs. too many people?

• The environment will take care of itself vs. the

environment is stressed?

Sustainability Risks are Real


5

How Long Will Things Last?

ACS GREEN CHEMISTRY INSTITUTE® ACS GREEN CHEMISTRY INSTITUTE®

6

http://www.newscientist.com/data/images/archive/2605/26051202.jpg


7

Supply of Key Elements is not

Sustainable


We are Criticality Dependent on Some

Materials


PGM

supply of many “technology metals” is price-inelastic:

• Increased demand can only be met by primary production if

demand for major metal rises accordingly

• Short term demand surges lead to price peaks (see Ir, Ru, In)

• Effective recycling important for supply security

Metal families – most precious and special

metals are coupled to major metals production

Source: Ch. Hagelueken

(Umicore)


Zinc – Dwindling Supply of a Useful Metal

• 23rd most abundant element in the

Earth’s crust

• Makes up an average of 65 grams for

every ton of the Earth’s crust

• Commercially exploitable reserves

exceed 100 million tons

• Chemically used in a variety of

chemistries and as a catalyst in the

form of zinc oxide

• One of the most common uses (50%)

of zinc is in galvanizing steel for

corrosion resistance

• Estimated 5-50 years Zinc left if

consumption continues at current

rate


Tin Has Many Important Uses

Uses:

• Coatings for metals as component in corrosion inhibition, protective oxide layer that prevents further oxidation

• Historically used in formulations of marine anti-foulants

• Used in a number of catalyst systems

• Component in solder for electronics

Abundance

• Global production of tin is more than 140 tonnes per year – Reserves are approximately 4 million tonnes.

– An estimated 130 tonnes of tin concentrates are produced each year.

• If current consumption continues, 5-50 years of Tin are left


Tin has Negative Social and

Environmental Impacts

• One third of all tin mined in the world comes from

the Indonesian island of Bangka

• Mining in Bangka has become dangerous

– Low income workers and cheap tools safety measures

have been ignored

– Lethal cave-ins have risen as tin ore pits become deeper

• Most of the human health and environmental

impacts come through exposure to organo-tin

compounds.

– Very significant toxicity to multiple environmental

organisms


Uses of indium

Thin films: transparent and conductive coatings of indium tin oxide (ITO) for

- liquid crystal displays (50% of In use!)

- flat panel displays

- touch screens

- photovoltaic cells

- smart windows

Example By-product Element: Indium

Demand is rising sharply

Recycling challenge: Very small quantities per unit, but many units


Rhodium is Not Abundant

• Found mainly in South Africa (60%) and Russia. Also found in

the state of Montana, U.S.A.

• The annual world production of rhodium is around 16 tonnes a

year with an estimated reserve of 3 tonnes

• It is one of the rarest elements in the Earth’s crust as it accounts

for only 0.0002 parts per million

• If this element is used at the rate it is consumed now, only 5-50

years of rhodium are left

• 82.7% of Rhodium used as a catalytic converter for cars and

used extensively in many catalytic reactions

• Finish for jewelry, mirrors, and search lights as it is highly

reflective; manufacture of nitric acid; hydrogenation of organic

compounds; alloying agent for hardening and improving the

corrosion resistance of platinum and palladium


The Socio-Economic Cost Of Mining

Pt Group Metals Is High

“South African platinum miners must

return to work Monday, despite 34

strikers killed by police” ASSOCIATED PRESS AND REUTERS | Aug 19, 2012 11:51 AM

ET

“The world's second-largest platinum miner,

Johannesburg-listed Impala Platinum

Holdings Ltd., fired more than 17,000 striking

workers in February, sending the price to a

year-to-date high over $1,600 an ounce. The

12-month high is around $1,900 an ounce.” By 24/7 Wall St.

Posted 8:33AM 08/17/12

http://news.nationalpost.com/author/associatedpressnp/





http://news.nationalpost.com/author/reutersnp/

http://news.nationalpost.com/author/reutersnp/

http://www.dailyfinance.com/writers/24-7-wall-st/


Cheap Phosphorus Won’t be Available

Forever Endangered Species: Should Cheap Phosphorus

Be First On an Elemental 'Red List?'

ScienceDaily (Oct. 13, 2011) — Should the periodic

table bear a warning label in the 21st century or be

revised with a lesson about elemental supply and

demand? http://www.sciencedaily.com/releases/2011/10/111014104948.htm

James Elser,

Elena Bennett.

Phosphorus cycle:

A broken

biogeochemical

cycle.

Nature, 2011;

478 (7367): 29

DOI:10.1038/478029a

http://phosphorusfutures.net/

http://www.sciencedaily.com/releases/2011/10/111014104948.htm

http://dx.doi.org/10.1038/478029a

http://phosphorusfutures.net/


Reasons Chemists Use the Chemical

Building Blocks They Use

Because they:

– Ensure thermodynamically and kinetically favored

reactions

– Result in the highest yields

– React in predictable ways

– Are “easily” obtained (lowest cost)

– Generally don’t require sophisticated reactors or

technology in the laboratory

17

But….


…These Chemical Building Blocks

Have Sustainability Risks

• Feedstocks

• Process efficiencies

• Missing Data

• High-hazard materials

• High risk process chemistries

• Inappropriate engineering or process

controls

• Human and environmental exposures

• Legislation/regulations


19

A Few Green Chemistry

Challenges


Current Batch Chemical Process

Development is Complicated

• Large portfolios

• Significant route modifications or

complete substitution

• Incremental optimisation of chemical

processes

• Focus on yield, quality, CoG and

number of steps


Chemists Use Ancient Chemistries

A random selection of 100 chemistries in a review of named reactions:

54% before World War 1

74% before World War 2

91% before 1975

9% during the 1980’s

Grignard, François

Auguste

Born: Cherbourg, 1871

Died: Lyon, 1935

Williamson,

Alexander William

Born: London, 1824

Died: Hindhead, 1904

Wurtz, Charles Adolphe

Born: Wolfisheim, 1817

Died: Paris, 1884


Top 10 Chemistries Used 2004 - 2005 N-acylation

11%

N-alkylations

8%

recrystallisation

8%

salt formation/salt swap

6%

hydrolysis (base)

6%

S-alkylation

6%Chlorinations

6%

hydrogenation

4%

O-alkylation

3%

OH activation/functional

group change

3%

others

39%


Chemical Technology Hasn’t Changed Much Batch reactor

Distillations

Crystallisation

E.g., Dutch gin was

imported before the

English industry for

distilled spirits took over

in the 18th century

Salt crystallisation during

bronze age

“The difficulty lies, not in the new ideas, but in

escaping the old ones, which ramify, for those brought

up as most of us have been, into every corner of our

minds.”

-John Maynard Keynes

Bronze age


Two Major Focal Points of Most Green

Chemistry Efforts

1. Elimination of the use of toxics (hazardous

substances in general)

– Examples of how governments use policy to drive this:

Green Chemistry initiative in California, EU REACH

legislation, TSCA reauthorization, TRI, etc.

2. Elimination/reduction of waste

– Examples of how governments use policy to drive this:

EU Producer Responsibility, RCRA, etc.

– Voluntary initiatives: Energy Star, Green Energy

Leaders, etc.

24


25

The Enlightened Design of

Chemicals and Chemical

Processes are Key

Objectives of Green

Chemistry


Thinking About Design

“Design is a signal of

intention” “Cradle to Cradle”

William McDonough

2002


Principles of Green Chemistry and

Engineering – Simplified*

Maximize resource efficiency

Eliminate and minimize hazards

and pollution

Design systems holistically and use

life cycle thinking

*See: Green Chemistry and Engineering: A Practical Design Approach. Jimenez-Gonzalez C, Constable DJC. John Wiley and Sons. 2011, p 35- 37. http://www.amazon.com/Green-Chemistry-Engineering-Practical-Approach/dp/0470170875


NSF Sustainable Chemistry

Workshop Conclusions – Jan, 2012

• Systems-level thinking is required

• More fundamental research should be use inspired

• Green is not synonymous with sustainable

• Efficiency is necessary but not sufficient due to the

rebound effect (Jevon’s paradox)

• Sustainability research and education is multi-

disciplinary and collaborative

28


Sustainability Needs to be Designed

into Products and Processes

• If we want to make the biggest impacts to products,

services and costs, we have to start from the ground

up.

• If we want to build sustainability into the design of

products and services we have to think differently

about the what and how of R&D.

• Increasing demands and decreasing budgets are likely

to mean greater reliance on easily accessible

company-wide tools that provide early assessments

and highlight sustainability issues.


Sustainable process

design early when

costs are lower

Attrition

Commercial

Focus on

Speed to

Market

Finding the Right Balance is Challenging


Summary

• The ready supply of key raw materials that are converted into chemically interesting and commercially useful chemicals is dwindling

• Supply of these materials will be accompanied by rapidly increasing economic, social and environmental cost

• In many cases, recycling of key chemicals is not done and is not trivial

• Ready alternatives to these substances are not commercially available

• There is a general lack of awareness for any looming problems

32


Part 2

Thinking about Molecular

Design Drivers, Rules,

Possibilities


Presuppositions

• Historically, designing a new chemical entity for a

particular function has not routinely incorporated

environmental, health, safety or sustainability as

design criteria

• A response in an organism, toxic or otherwise,

and chemical activity/product functionality, are

generally a result of specific molecular structural

features / physicochemical properties

• Accurately predicting potential linkages between

inherent chemical features and less hazardous

product attributes can be the basis for developing

preferred products


Magnitude of the Challenge is Large

• 500-1000 (or more) new chemical entities

developed/yr

− Across a range of industries and chemical classes

− To achieve a wide range of functions

• Aspirations:

− Build green chemistry into the fabric of new

chemical product design

− Safer molecular structures are one approach, but

other approaches include innovative formulations

and wisely selecting targets to achieve

functionality


What we Want

• Functional and Safer Products:

– Performance equal to or better than existing materials

– Non-VOCs, not HAP’s, and not TRI listed chemicals

– Not Ozone Depleting Agents

– Not containing toxic elements such as heavy metals

– Not classified as carcinogens, mutagens or reproductive toxins (CMR)

– Not persistent, bioaccumulative, toxic (PBTs) or Persistent Organic Pollutants (POP)

– Cost effective


Examples of Molecules We Don’t Want:

Persistent Organic Pollutants (POPs) Aldrin Chlordane

Heptachlor Hexachlorobenzene Endrin Mirex

Dieldrin DDT

Chlorinated

Dioxins

Chlorinated

Dibenzofurans PCBs Toxaphene


The Hard Work of Predicting Effects

Highly toxic Moderately toxic

How knowable &

predictable are the

molecular features

controlling safety?

“Toward molecular design for hazard reduction—fundamental relationships between chemical properties and

toxicity” Anastas et al. Trahedron, 2010, 1031, and Chem. Rev. 2010, 110, 5845.


New Chemical Development

Characteristic Bioactive Chemicals Other Chemicals

Regulatory Oversight Pharmaceuticals

(FFDCA in US)

Crop protection

(FIFRA in US)

“Industrial”

(TSCA in US)

Time: Idea to Product

(average)

11-15 years 9 years Less, but 2 yrs would

be very fast

Cost: Idea to Product

(average)

$1.3 billion $256 million ? (less, but so are

margins)

Success rate Millions screened in

Discovery to yield 1

product

139,000 in Discovery to

yield 1 product

? In R&D (but ~ half of

PMNs are

commercialized)

Importance of patent

period

+++++ +++ +

Sterochemistry “fixed”

early

YES Pragmatic yes No

EHS Test Data during

development

Extensive (preclinical /

clinical)

~ 120 Health, safety, and

environmental tests

No (US) (Yes

in EU with REACH)

Slide source: Williams, SETAC conference 2011

Pharmaceuticals

Challenges in the R&D Process(18)

Preclinical Pharmacology

Preclinical Safety

Millions of

Compounds Screened

Idea Drug 11 - 15 Years

1 - 2

Products

Discovery Phase I Phase II Phase III

0 15 5 10

Clinical Pharmacology & Safety

High Risk Process, 11-15 years, $1.3 billion

• Large number of compounds are screened

• Drug substance structure becomes “fixed” relatively early (need to get it right early)

• Increasing investment with R&D progression

• Substantial attrition

• Defined period of patent protection - speed to market is important

Slide source: B. Cue


Crop Protection Products – R&D

• Many parallels to pharmaceuticals

– Discovery through registration is methodical, demanding,

lengthy, costly

– Approximately 120 pre-registration safety (human and

environmental) studies

• Expectation: environmentally preferred structural

changes need to be identified and incorporated

early

Based on RT Williams, SETAC presentation, November 2011


TSCA (“Industrial”) Chemicals

• Few parallels in R&D to FFDCA/FIFRA regulated chemicals

• Greater flexibility – can modify design to achieve environmentally

preferred attributes up to PMN submission (90 days prior to commercial

manufacture)

• R&D appears to be more forgiving to enable development of greener

molecules and greener substitutes

− No repeat testing costs (as in Pharma or Ag) if chemical modifications are

made to remove hazardous attributes

− Less likely to have significant delays to market

− Less pressure to get environmentally preferred decision right early on

Questions to think about: (1) Does this mean computational and other tools that

inform design chemists can be less precise, but still be effective, for TSCA (industrial)

chemicals than for bioactives? (2) If testing is required prior to registration, does that

discourage the further refinement of structure to achieve greener characteristics?

Based on: RT Williams, SETAC presentation, November 2011


Why We Need New Initiatives to Guide

Preferred Molecular Design to Reduce

Chemical Toxicity • Traditional tiered toxicity testing is slow, expensive, animal

intensive, tests one chemical at a time, and typically does not

elucidate mechanisms of action or adverse outcome pathways

• QSARs/SARs or other modeling approaches typically have a

limited application (structures within the training set)

• Needs: Molecular design tools that:

– Build the scientific foundation

– Can evaluate groups of compounds (structurally similar or diverse)

– Handle the 100’s to 1,000’s of new chemicals produced per year

– Provide a level of confidence commensurate with the magnitude

of the decision being considered


Importance of Knowing the Biochemical

Basis (Mechanism) of Chemical Toxicity

43

• Often empowers chemist to infer structural

modifications that may help to reduce toxicity.

• The mechanisms of toxicity of many commercial

chemicals are either:

− known;

− suspected; or

− often discernable from a comprehensive review

and analysis of metabolism, toxicity and other

studies found in the literature.

Slide courtesy of Dr. Steve DeVito, US EPA


Some Approaches to Designing Chemicals

of Reduced Hazard

• Determine if there any known hazardous effects associated

with the chemical class to which the substance belongs

• Pay attention to key molecular properties (e.g., polarity, vapor

pressure, melting point, molecular weight, solubility, etc.)

• Design molecules to have low bioavailability;

• Attempt to predict how this substance would be metabolized

– are metabolism data available?

– what are the known or likely products of metabolism?

• Avoid structural features (toxicophores) known to bestow

toxicity;

– If such features must be present for technical performance reasons, it

may be possible to make other molecular modifications that mitigate

toxicity without affecting performance

44


45

Binding Matters

Oxidation is one of the first ways that biology interacts with chemicals.


Some Approaches to Designing Chemicals

of Reduced Hazard • Look for potential isosteric substitution of functional groups

or features responsible for observed toxicity.

• Consider the structural and biochemical bases of chemical-

induced toxicity;

– Determine if any toxicity-related (e.g., mechanistic) studies been

conducted on the substance or analogous substances

– Attempt to learn the mechanism of toxicity or identify plausible

possibilities that help you to infer structural modifications

– Know your chemicals, evaluate toxicity and linkages to

structure/features

• Develop predictive relationships from your data

• If it seems likely that your substance will be toxic and the

toxicity cannot be reduced through structural modification,

consider using a less toxic, structurally unrelated substance

that has comparable commercial usefulness.

46


Mechanism Matters


48 J. Warner and N. Anastas, J. Chem Health & Safety, 2005, 12(2), 9.


Environmental Fate

Key Chemical Properties: Quick Model: PBT-Profiler, EPA

Melting Point http://www.pbtprofiler.net/

Vapor Pressure, P

Partition Coefficients

octanol-water, KOW

octanol-air, KOA

air-water, KAW

Organic carbon-water, KOC

Water solubility, CsatW

Henry’s Law constant, H

49

http://www.pbtprofiler.net/


Using statistical methods to identify

molecular property and toxicity correlations

Voutchkova, et. al. Green Chem, 2011, DOI: 10.1039/c1gc15651a 50


Molecular Structure considerations: toxicophores

DiVito, “Toxicological considerations for Chemists” 1996, ACS Symposium Designing Safer Chemicals

React with natural

nucleophiles

Electrophile

Non-Electrophile

Metabolism/oxidation

Non-toxic adduct React with

Biological

substrate Excretion

Toxicity


Avoid Toxicophores: Structural Features

Known to Bestow Toxicity

Examples of electrophilic toxicophores found in molecules:

52 Slide courtesy of Dr. Steve DeVito, US EPA


Structural Features Known to Bestow

Toxicity Examples of other toxicophores found in molecules:

53 Slide courtesy of Dr. Steve DeVito, US EPA


54

Examples of

Isosteres


Isosteres are molecules with similar molecular

and electronic characteristics. They often have

similar physical properties, possess nearly equal

or similar molecular shape and volume, have

approximately the same distribution of electrons,

and exhibit similar chemical properties.


55

Examples of Isosteres



56

Isosteric Substitution in Drug Design



57

Isosteric Substitution in Design of Safer

Pesticides



58

Isosteric Substitution in Design of

Safer Pesticides


RfD = Reference Dose = an estimate of a daily exposure to the

human population that is likely to be without an appreciable risk of

deleterious effects during a lifetime


59

Isosteric Substitution in Design of

Commercial Chemicals



A successful oral drug must:

be stable to manufacturing and storage

conditions

dissolve

survive a range of pHs

be stable in the presence of intestinal

bacteria

cross membranes

survive liver metabolism

avoid active transport to bile

avoid excretion by kidneys

partition into target site (organ)

avoid partitioning to potentially sensitive

places (e.g. brain, foetus)

have an approvable Benefit:Risk profile

Drug Design Hurdles in Addition to Receptor Binding

liver

Bile

duct

kidneys

bladder

Body


Molecular Property

considerations

Not too polar

Not too big

Not too hydrophobic


But these Guidelines are not Perfect - Molecules

Failing Lipinski’s “Rule of 5”

Atorvastatin

Liothyronine

Ethopropazine

Olmesartan

Doxycycline

Bexarotene

Acarbose

MW

MW

MW / HA

log P log P

(5.088)

HA / HD MW / HA


Polymer Design Rules

• Promote Degradation

– Hydrophilicty

– Hydrolysable linkages such as amide, esters, urea, and

urethane groups.

– Biological feedstocks

– Include chromophores

• Hinder Degradation

– Branching

– Highly substituted polymers

– Halogens

R Jayasekara, I Harding, I Bowater, and G Lonergan J. Polymer. Environ. 2005, 231


Common Biodegradable Polymers

Starches

Esters

Polyalcohols

PHB/V PLA PCL


Starches: Balance between functions

• Derivitization at the -OH is needed to increase ease of processing,

function and compatibility.

– Acetylation reaction using an active chloride or anhydride in a

pyridine solvent

– Green Alternative: acetylation of starch in 3% aqueous sodium

hydroxide and at pH 8

• Best plasticity occurs with ~1.5 substitutions/monomer

• Increasing substitution, decreases biodegrability.


Esters: The polymer du jour

• PHB & PLA are fermentation products.

• Degradation in sea water: PCL > PHB > PLA

• Polyesters can be depolymerized to give monomer.

• Polyesters disrupt the recycling of polyethylene

Esters PHB/V PLA PCL


Closing the Loop

• Incineration-Combustion Pathway

– One hundred tons of town refuse is equal to 30 tons of

coal in fuel value

– Problems with halogenated compounds

• Recycling- Engineering new cycles

– About 27% of PET bottles (US) are currently recycled

– At present the cost of recovery limits recycling activities.

– EU targets to recover 50–65% and recycle 25–45% of

all packaging waste

• Creating products using “Design-for-X” principles


Definitions

1. Degradation: Breakdown of chemicals, through physical, chemical or biological pathways

2. Biodegradation: Breakdown of chemicals by living organisms

3. Readily Biodegradable: At least 60-70% of the material must be broken down within ten days

4. Mineralization: Complete conversion of chemical substances into their simplest naturally occurring fragments (Usually CO2 and H2O)

5. Recalcitrance: Resistant to biological action


Pathways for chemical degradation

Pathways:

• Abiotic

– Combustion

– Photolysis

– Hydrorolysis

• Biotic

– Aerobic

– Anaerobic

Factors:

• Environmental Compartment

• Absorption Cross-section


Design for Degradation

Help Degradation:

• Esters

• Oxygen (except ethers)

• Unsubstituted Linear alkyl chains

Hinder Degradation:

• halogens, especially chlorine and fluorine and especially if there are more than three in a small molecule (iodine and (probably) bromine contribute to a lesser extent);

• chain branching if extensive (quaternary C is especially problematic);

• Nitrogen: tertiary amine, nitro, nitroso, azo, and arylamino groups;

• polycyclic residues (such as in polycyclic aromatic hydrocarbons), especially with more than three fused rings;

• heterocyclic residues, for example, imidazole;

• aliphatic ether bonds (except in ethoxylates)

“All rules of thumb are half-

truths… some are useful.”

Boethling, et al. Chem. Rev. 2007,

2207.


Biodegradability vs. Hazard reduction:

Design trade-offs


Existing Chemical Hazard Assessment Tools

1. Structure:Activity (SAR) rules of

thumb – Example: Presence halogens (Cl/F),

especially > 3 in a molecule, reduces aerobic

biodegradation

2. QSAR/computational methods

3. Short term assays/surrogate tests

4. Traditional in vivo tiered testing

batteries

Increasing:

• Cost

• Time

• Reliability*


Estimation methods and rules of thumb

− Example: Pharmaceutical industry - structural

alerts and computational (in silico) techniques are

relatively advanced tools that guide drug design

o Predictability not 100% accurate, see: “Raising Red Flags

On Drug Design,” C&ENews, January 9, 2012. Volume

90, Number 2, p. 34

CleanGredients

University of Minnesota

Biocatalysis/Biodegradation database.

Shows detailed pathways with enzymes identified.

Existing Tools


Predicting Toxicity to Environmental

Species through QSAR

• US EPA distributes a computer program called Ecological

Structure Activity Relationships (ECOSAR)

(http://www.epa.gov/oppt/newchems/tools/21ecosar. htm)

– Estimates the aquatic toxicity of planned or untested chemicals

for nonspecific (narcosis-type) mechanisms of toxicity

– Contains regression equations for certain types chemicals that

are believed to be toxic to aquatic organisms via specific (non-

narcotic) mechanisms

– Contains hundreds of regression equations for many chemical

classes

• EPA’s EPI Suite - Screening suite of physical/chemical

property and environmental fate estimation programs

74


The amount of data available in the public domain that

can be used to guide design is substantial

Database example: ACToR (Aggregated Computational

Toxicology Resource)

Collection of databases developed by the US EPA

National Center for Computational Toxicology

More than 200 sources of publicly available data

searchable

Data includes structure, physicochemical properties,

and in-vivo toxicology

February 2011, ~ 547,000 chemicals (unique CAS

numbers) in ACToR

Toxicity Information Databases


Reasons for Optimism

• A comprehensive (across chemical classes)

molecular design strategy for less hazardous

chemicals is at a nascent stage, but:

– Progress in toxicology and molecular science over

the past 20 years has increased our understanding

of mechanisms, modes of action, and adverse

outcome pathways

– New knowledge and database advances have

enabled predictive models of increasing

sophistication that link chemical features (functional

group topology, electronic density, molecular

volume, etc.) to effects


Key Learning Points

• Design of preferred chemicals with less hazard holds great promise

• Incorporating safety into the design thought process is vital

• Existing safety design tools are valuable, but scientific innovation is needed to improve the toolbox for designers

• There are trade-offs, so understanding the specific product application and pathways to make the best decisions is critical


Example: Dielectric Coolants (and pump oil…)

Replacing:


Example: Soap


Which Biocide would you pick?

81


Part 3

Using Metrics to Promote

Better Process Design


Metrics are Essential Ask the right questions

Outline

Develop a Process Start early, measure at key stages

Find the Right Metrics There is no single metric to assess

“greenness”

Process

Energy Solvent Recovery

Energy

Net Mass Excluding

Water

Total CO2

Total Water

Mass Efficiency

Stoichiometry

Atom

Economy

Carbon Efficiency

Yiel

d

Reaction Mass

Efficiency


Green Chemistry and

Metrics

“All he’s done is call it Green” The person who sat behind me, GRC Green

Chemistry Meeting, Oxford, 1999, as related by John Hayler, GSK

WELCOME TO

Pine View, Colorado

Established 1872

Population 732

Elevation 5755

TOTAL 8359*

*Audited by

3iDataCen (Formerly,

the Center for

irrelevant, immaterial

and inconvenient

Data)

“If you don’t keep score,

you’re only practicing”

Jan Leshley, former CEO SB & GSK


Key Message

Ask the right questions!

Avoid “the perfect uselessness of

knowing the answer to the wrong

question” The Left Hand of Darkness

Ursula K. LeGuin

1969


85

FIND THE RIGHT

METRICS

• Make objective comparisons

• Benchmark progress

• Drive change

• Demonstrate improvement

• Increase transparency


Key Metrics are Essential

• Reaction Mass Efficiency (RME)

• No. of stages and no. of

chemistry steps

• Total no. of solvents and solvents

per stage

• Mass Intensity and Mass

Productivity (Efficiency)

• Materials of Concern

• Process life cycle environmental

impact:

Focus on

optimising

use of a few

key materials

Can we change

the chemistry?

Recycle/reuse 80 –

90 % of the mass!

Telescope, maximise

convergency, pay

attention to order of

side chain coupling

Starting

Materials matter!


Increasing yields will not be a major driver

of Green Chemistry in Batch Operations

• Stage yields average 86%

• 6-stage process overall yield = 30 - 40%

• Average 16 kg total/kg of intermediate.

• A 100% yield for 6-stage process will still

only result in an overall Mass Productivity

of about 1%.


Reaction Mass Efficiency (RME)

RME = efficiency of conversion of

reactants into product. It includes:

– Yield

– Atom Economy

– Stoichiometry of the reactants


Reaction Mass Efficiency

yield B/A) ratiomolar x B of (m.w. A of m.w.

Cproduct of m.w. RME

100 X B of mass A of mass

Cproduct of mass RME

For a generic reaction:

A + B C

or more simply:


Solvent Use is Significant

• In 2008, 10 solvents

represented approximately

80% of all solvents used in

GSK

• Solvent use is the largest

contributor to:

• Primary manufacturing process

mass intensity

• Primary manufacturing life

cycle environmental impacts

(e.g., ~80% mass, ~75%

energy)

Water 32% Solvents 56%

Reactants 7%

Other 5%

Composition by mass of types of

material used to manufacture an API American Chemical Society Green Chemistry Institute

Pharmaceutical Roundtable Benchmarking 2006 & 2008


Calculating the Average Number of

Solvents per Stage is Easy

processainstagesofnumberprocessainsolventsofnumberNS

__________

Number of solvents = 5

Number of stages = 3

NS = 5/3 = 1.7

Material Weight (kg/Kg

API) Stage

tetramethylethylenediamine 1.9 3

ACETONE 18 4

ALUMINUM-CHLORIDE 1.6 1

DICHLORO METHANE 32.3 1, 3

DIMETHYL FORMAMIDE (DMF) 0 1

Compound A 1.3 1

Compound B 1 3

Compound C 0 4

HYDROCHLORIC ACID 0.3

IMS 25.1 1, 3

IODINE 1.1 3

N-METHYL-2-PYRROLIDONE 0.4 3

SODIUM SULFITE 1.4 3

THIONYL-CHLORIDE 0.8 1

TITANIUM-TETRACHLORIDE 0.8 3

WATER 24.2 3, 4

PHENETOLE 1 1


• A solvent score may be generated from aspects such as:

– Environmental impact –fate and effects.

– Environmental waste –recycle, incineration, VOC’s, and biotreatment.

– Health –acute and chronic effects and exposure potential.

– and Safety –explosivity, flammability and operational hazards.

• Calculate the geometric mean of the different EHS aspects, multiply by the mass of each solvent, normalise by the molecular weight of the target molecule. A final score for a process or route may be derived by benchmarking the result against a group of benchmark processes.

Solvent Score Definition and Calculation


But wait a minute, what happened to

Waste (E-factor)?

kg waste = kg input - kg API

kg API kg API kg API

Efactor = MI – 1

So who cares about what side of the

equation we focus on???


• Example of MP calculation:

– Benzyl alcohol (1wt) is reacted with p-toluenesulfonyl

chloride (2.0wt) in toluene (46.3wt) and triethylamine

(1.4wt) to give the sulfonate ester isolated with 90%

yield (2.2wt of product).

Mass Productivity Calculation Example

)(________)(__

KgprocessainusedmaterialinputofmasstotalKgAPIofmassMP

%3.4)(4.13.460.21

)(2.2

wt

wtMP


Cumulative Mass of Waste for a Major API

Cumulative Mass going to waste after solvent

and resolving agent recovery

Mass productivity 0.6%

0.0

20.0

40.0

60.0

80.0

100.0

120.0

140.0

160.0

180.0

200.0

1 2 3 4 5 6

Stages

Cu

mu

lati

ve

Ma

ss

kg

/kg

Other

Solvents

Reactants


Mass Productivity

• Mass productivity is governed by:

– process efficiency (process intensity, dilution,

extraction, put-and-take, crystallisation etc)

– chemistry efficiency (yield, RME, AE)

– complexity of the active pharmaceutical and

intermediate(s)

– complexity of the key starting material. For

example, mass productivity will appear to

improve or be better than average if a complex

or advanced intermediate is purchased rather

than manufactured.


Mass Productivity • Mass productivity is a leading metric that correlates

well with total process energy use

• Water is excluded - although data are available and

water usage will affect capacity/throughput

• The data excludes secondary manufacturing

efficiency (which for most solid dosage forms is

90+%) and associated inefficiencies

• Packaging is excluded

• The mass productivity of a given process will

generally improve as a product moves towards

transfer to manufacture during routine process

development activities.


Mass Productivity Example with no

Solvent Recovery

13 96 kg total

materials /kg

API

+ + + + +

Solvent Other

This corresponds to a mass productivity of approximately 1%

3


Mass Productivities for One

Manufacturing site

Product Without Solvent

Recovery (%)

With Solvent

Recovery (%)

Process Stages

Compound 1 0.4 NA 5, linear

Compound 2 1.3 NA 5, convergent

Compound 3 1.4 1.9 3, linear


Compound 5 1.2 NA 4, linear


Compound 7 0.6 0.9 7, linear


Mass productivity Example with Solvent

Recovery

If there is an average 75% recovery of solvents

and a 100% overall yield, mass productivity would

approximately double. For example:

4

42 kg total

materials /kg

API

+ + + + +

Solvent Other

This corresponds to a mass productivity of approximately 2%

3


Selected GC Metrics for Development

Compounds

RME =

mass

of

reactan

ts /kg

Yield

%

Mass

productivit

y excl

water%

Mass

Intensit

y

e-

factor

FLASC

score

Solvent

score

P

h

a

s

e

w

h

e

n

a

s

s

e

s

s

e

d

25 50 1.5 66.7 65.7 3.8 3.6

F

i

l

e

a

n

d

l

a

u

n

c

h

51 4.1 24.4 23.4 4 3.7

P

h

a

s

e

I

I

I

27 68 2.3 42.9 41.9 4.1 3.8

P

O

C

t

o

C

o

m

m

i

t

t

o

p

h

a

s

e

I

I

I

14 1.6 64.5 63.5 2.9 2.8

P

O

C

t

o

C

o

m

m

i

t

t

o

p

h

a

s

e

I

I

I

14 53 0.5 184.7 183.7 2.8 1.7

P

O

C

t

o

C

o

m

m

i

t

t

o

p

h

a

s

e

I

I

I

8 28 0.7 137.1 136.1 2.4 2.3

P

O

C

t

o

C

o

m

m

i

t

t

o

p

h

a

s

e

I

I

I

6 19 0.5 208.3 207.3 2.1 1.9

P

O

C

t

o

C

o

m

m

i

t

t

o

p

h

a

s

e

I

I

I

4 10 0.2 451.1 450.1 1.0 1.0

P

O

C

t

o

C

o

m

m

i

t

t

o

p

h

a

s

e

I

I

I

19 48 1.5 69.0 68.0 3.9 3.4

F

T

I

H

t

o

P

O

C

21 56 1.2 82.0 81.0 3.8 3.1

F

T

I

H

t

o

P

O

C

24 29 1.3 76.7 75.7 3.6 3.4

F

T

I

H

t

o

P

O

C

34 55 1.4 72.5 71.5 3.4 3.2

F

T

I

H

t

o

P

O

C

23 28 1.8 54.3 53.3 3.3 4.2

F

T

I

H

t

o

P

O

C

26 51 1.0 101.2 100.2 3.3 2.6

F

T

I

H

t

o

P

O

C

24 51 0.7 134.3 133.3 3.2 2.5

F

T

I

H

t

o

P

O

C

8 48 1.6 62.5 61.5 3.1 3.2

F

T

I

H

t

o

P

O

C

18 45 0.8 131.6 130.6 2.8 2.4

F

T

I

H

t

o

P

O

C

22 44 0.8 133.3 132.3 2.5 2.6

F

T

I

H

t

o

P

O

C

8 27 0.5 217.4 216.4 2 1.8

F

T

I

H

t

o

P

O

C

RME =

mass of

reactants

/kg

Yield %

Mass

productivity

excl water%

Mass

Intensitye-factor

FLASC

score

Solvent

score

25 50 1.5 66.7 65.7 3.8 3.6

51 4.1 24.4 23.4 4 3.7

27 68 2.3 42.9 41.9 4.1 3.8

14 1.6 64.5 63.5 2.9 2.8

14 53 0.5 184.7 183.7 2.8 1.7

8 28 0.7 137.1 136.1 2.4 2.3

6 19 0.5 208.3 207.3 2.1 1.9

4 10 0.2 451.1 450.1 1.0 1.0

19 48 1.5 69.0 68.0 3.9 3.4

21 56 1.2 82.0 81.0 3.8 3.1

24 29 1.3 76.7 75.7 3.6 3.4

34 55 1.4 72.5 71.5 3.4 3.2

23 28 1.8 54.3 53.3 3.3 4.2

26 51 1.0 101.2 100.2 3.3 2.6

24 51 0.7 134.3 133.3 3.2 2.5

8 48 1.6 62.5 61.5 3.1 3.2

18 45 0.8 131.6 130.6 2.8 2.4

22 44 0.8 133.3 132.3 2.5 2.6

8 27 0.5 217.4 216.4 2 1.8

FTIH to POC

FTIH to POC

FTIH to POC

FTIH to POC

FTIH to POC

FTIH to POC

FTIH to POC

FTIH to POC

POC to Commit to phase III

FTIH to POC

FTIH to POC

FTIH to POC

POC to Commit to

POC to Commit to

POC to Commit to

POC to Commit to

Phase when

assessed

File and launch

Phase III

POC to Commit to


Example of GSK R&D Mass

Productivity Improvements

Mass productivity

(% ) Route

Solvent

Recovery

Included

7.6 B4 - MCC with epimerisation Yes

4.9 B4 - MCC with epimerisation

No

2.2 B4 - MCC

1.6

B3 - currently proposed

manufacture

1 B2

0.4 B1


Cost Comparison for Four GSK Drugs

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

90.00

100.00

% o

f T

ota

l D

rug

Co

st

Dru

g 1

Dru

g 2

Dru

g 3

Dru

g 4

Cost Model

Comparison of Total Costs for Four DrugsMinimum Cost for Minimum

Process Stoichiometry + Standard

Yield, Reactant Stoichiometry and

Solvent

Minimum Cost at 100% Atom

Economy + Standard Yield, Solvent

and Process Stoichiometry

Minimum Cost at 100% Yield +

Standard Solvent and Process

Stoichiometry

Minimum Cost at 100% Solvent

Recovery and Standard Yield and

Process Stoichiometry

Minimum Cost at 100% Atom

Economy, Process Stoichiometry

and Solvent Recovery

Minimum Cost at 100% Yield,

Solvent Recovery and Standard


Minimum Cost at 100% Yield,

Solvent Recovery and Reactant and



Allocation of Costs

2%16%

82%

Process Chemical £/kg Solvent £/kg Reactant Chemical Total £/kg

Mass Productivity = 0.6%

Principle Cost Breakdown for

Commercial Product


Principle Cost Breakdown for Commercial

Product

53%

13%

17%

7%2%

8%

Total Process Chemical Cost Total Solvent Cost

Total Reactant Chemical Cost Total, Environmental Cost

Utilities Labour


What does it take to achieve MP > 1?* • RME > 25% for MP > 1%

• RME 15 – 25% yields a 40% probability of MP > 1%

• Having < 4 stages increases probability for a MP > 1%

stages

% probability of MP

>1%

2 85

3 75

4 50

5 50

>6 15

*Based on about 40 mature R&D processes


Materials of Concern

• Chemicals for which there is evidence of probable serious effects to humans or the environment

– carcinogens, mutagens or reproductive hazards (CMR’s),

– toxic and bioaccumulate or persist in the environment (PBT’s),

– very persistent or very bioaccumulative in the environment (vPvB),

– ozone depleting chemicals (ODC’s),

– endocrine disruptors (ED’s)

– those known to cause asthma (asthmagens)

• Materials of Concern should be identified early to develop strategies to eliminate or substitute.


Resource Extraction

Raw Material Manufacture

Intermediate Products

Final Product

Final Consumer Use

Ultimate Ecological

Fate

Store

R&D: Process Development Material Selection Hazard & Risk assessment

Sales and Marketing

Distribution

Raw material and energy consumption

Emissions to air, water and land


So what do chemists need?

• The chemists’ “3 R’s Sustainability

Toolkit” :

– Renewables

• Reactants

• Reagents

– Reactions

– Reaction Spaces


So what do Chemical Engineers need?

• The Chemical Engineer’s “3S’s

Sustainability Toolkit“:

– Separations

– Set-up (flexibility in batch, semi-

continuous and continuous)

– Scale (flexible, characterized

scalability from lab to plant)


So why is this a long-term proposition?

• Some traditional sticking points:

– In ground capital

– Economics / Financial analysis

– Alternative technologies and different expertise may be needed

– Current business climate

– Bigger SD / CSR issues dominate Sr. Executive agendas

– Educational system

– Resistance to change (not invented here) and risk aversion

– Maintaining status quo


Metrics are Essential

• Assessment must be multivariate

• Influence chemists and engineers during

development

• Green Chemistry Metrics:

– help Project Teams

– should include a life cycle assessment

– should be collected for every compound

– by themselves do not tell the whole story

– should be drivers for innovation


Conclusions

• The obstacles are large, but not insurmountable

• Industry and Acedemia need to collaborate to

develop the “3 R & S Sustainability Toolkits”

• The economics favor the transition even if Sr.

Executives don’t know it yet

• To proactively promote sustainable chemical

technologies those pushing the program may

need a different set of skills than in the past, e.g.,

chemical synthesis, LCI/A, etc.

• Leadership is required

• Extraordinary people skills


Acknowledgements:

Alan D. Curzons

Conchita Jimenez-Gonzalez

Richard K. Henderson

GSK Sustainable Processing Team

Virginia L. Cunningham,

David N. Mortimer

114


Questions?

David J. C. Constable

[email protected]

green and sustainable chemistry by design · time: idea to product (average) 11-15 years . 9 years...

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