Greener PharmaceuticalsThrough Synthesis Optimisation

James Clark and Louise SummertonGreen Chemistry Centre of Excellence

Chemistry DepartmentUniversity of York

What is Green Chemistry?• Green chemistry is the design of chemical products and

processes that reduce or eliminate the use and generation of hazardous substances

• Discovery and application of new chemistry/technology leading to prevention/reduction of environmental, health and safety impacts at source

• It can be considered as a set of reductions:

Materials

Energy

Cost

Non-renewables

Risk & Hazard

Waste

ReducingReducing

What is Green Chemistry?Sustainable Development and Business

A way of expressing SDin a business context is in terms of the triplebottom line

– economic– society– environment

SD

ECONOMIC

SOCIALENVIRONMENTAL

Raw Materials

Chemical Manufacturing

Product use/fate

Environmentalimpact (e.g. degradability)becoming part of approval

process ?

Increasing pressurefrom end users

/retailers

New legislation(e.g. REACH)

IncreasingPublic/NGO

concerns

Increasing costsfor storing hazardous

substances

Stricter Legislation

Increasing Energy Costs

IncreasedCosts of

HazardousWaste

Disposal

Increasingpetrochemical

prices

Supply problemsdue to diminishing

resources and marketdistortions

Pressures on the chemical industry across the lifecycle

Green Pharmaceutical ManufacturingRaw Materials

Intermediates

Active compounds

Drug formulation

Use/end-of-life

Increasing costs & uncertainty of supply of traditional feedstocks

Chemistry used by suppliers and transport adds to environmental

footprint of final product

Low efficiency processes (ca.1%) and hazardous

auxiliaries

Loss of actives and resource intensive waste

treatment

Poor understanding of interactions

Cleaning of equipment

Energy consumption

Packaging

Efficiency in use (egrecovery of active) & fate

of wastes

Candidate drug selectionInfluenced by Green Chemistry issues?

Clean S

ynthesis

E FactorE = Total Waste (kg)

Product (kg)

- system boundaries? process only? include water?

- can be sub-divided into organic waste, aqueous waste

- useful simple estimate of waste and resource efficiency – the smaller the better!

E factors by sector

Sector Product tunnage Efactor

Oil refining 106 – 108 <0-1

Bulk chemicals 104 – 106 1-5

Fine chemicals 102 – 104 5-50+

Pharmaceuticals 10 – 103 25-100+

Green Metrics Chemistryfor some Common Organic

ReactionsReaction Yield Atom Environmental MassType Economy Impact Factor of

assuming 100% yield Waste/Mole

Nitration 96% 0.93 0.21 ~ 600

Amidation 92% 0.69 4.53 ~ 104

Reduction 100% 0.94 0.06 ~ 0.2

Methylation 91% 0.63 0.55 ~ 30

Bromination 31% 0.71 0.41 ~ 1

Catalysis

Adsorption & Separation

Alternative reactors

Environmental footprinting & Life Cycle Assessment

Renewable Feedstocks

Alternative Solvents

Telescoped Reactions

Green Chemical Technologies Hot SpotsAlternative Solvents

(and solvent avoidance)

Adsorption & Separation

Greener Reagents / Heterogeneous & Bio-Catalysis

Alternative Reactors

Telescoped Reactions

Maximum use of Local Renewable Energy

Resources

Solvents / VOCs

Cleaning

Hazardous Processes

Energy

Primary Synthesis

Waste

Multi-step reactions and Work-ups

External Exploitation of Skills / Resources

Green Chemical Technologies Hot Spots

Environmental Footprinting & Green Chemistry Review

Renewable Resources

Biodegradable Plastics

Green Chemistry Courses, CPD, On-line Learning,

Placements etc

Closing-up Manufacturing Supply Chain / Use of Local

Resources

Increasing Costs of Feedstocks / Sustainable

Resources

Understanding Sources of / Measuring Waste /

Impacts

Packaging

Staff Awareness / Staff Training

Location of Manufacturing / Primary

–Secondary distances

Eco-efficient Solvents

Existing organic solvents

Bio-solvent Supercriticalfluids

Water solvent Ionic liquids

Renewable+ non-toxic Environmentally

benign and safe

Easily separable and safe

Zero Volatility

Greener Alternatives

Evaluation of Alternative Solvents

11Sustainable biodegradable but VOCs (2)

Mixed but prices falling (2)

Generally good (2)

May be distilled (2)

Wide range available (3)

Bio-resource solvents

12Sustainable Safe after purification (2)

Not expensive (3)

Non-toxic and safe (3)

Purification requires energy (2)

Dissolves small amounts of many (2)

Water

8Resource demanding; persistant (1)

Very expensive (1)

Problematic (1)

Forms biphases; can be reused (3)

Non-polar solutes only (2)

Fluoroussolvents

8Synthesis wasteful; end-of-life? (2)

Expensive but some less so (1)

Some toxic and flammable (1)

Easy for volatiles; difficult otherwise (1)

Solvents available to suit all (3)

Ionic Liquids

11Sustainable and no end-of-life issues (3)

Energy costs high (2)

Non-toxic; high pressure reactors (2)

Excellent (3)

Poor solvent for many (1)

Sc CO2

Arbitrary score

Env impactacross life-cycle

CostHealth and safety

Separation/ reuse

Key properties

Solvent type

Decaffeination of Coffee

Chemical Hydrogenation

Process

Extraction of Wheatstraw

Waxes

Supercritical Carbon Dioxide

Established New ProcessThomas Swan

New Extraction

TechnologyBotanix

Solvents from RenewablesBiomass

IsosorbideIsosorbide esters

Roquette

Dextrose --> lactic acidGlucose + H2

sorbitol

Glucose succinic acid

Levulinic acid

Fermentation

Succinateesters

Lactate esters Ashland

Methyl-THF

Green Chemical Transformations

CatalysisLeading green chemical technology

Homogeneous catalysis(eg PTC-Membranes)

Heterogeneous(eg Zeolites / mesoporous solids)

Biocatalysis(eg immobilised enzymes)

New, simple direct route to amides

O

OH NH2

O

NH

High surface

area solid catalyst

Simple, readily available solid catalyst only

Non-toxic solid

Works with a wide range of substrates

Easily recoverable and re-useable catalyst

Much improved green chemistry metrics

e.g.

R-COOH R-COOCH2-CH3EtOH

R-OH

HAc

R-OAc

Starbon®R

CH2Cl

R

AACCYYLLAATTIIOONNSS

ESTERIFICATIONSESTERIFICATIONS

AALLKKYYLLAATTIIOONNSSRCO2H RCONH2

AMIDATIONS

Catalytic applications for Starbon acids

Used in liquid phase organic catalytic reactions

Surfactant Micelle

Silica Precursor

Self-assembly

Removal of Template

Addition of enzyme

Reaction with substrate

Enzymes as Immobilized Catalysts Novozyme

Process Intensification

Methods

Multifunctional Reactors

Alternative energy sources

Other methods

Hybrid separators

Equipment

Reaction Non-reaction

e.g. spinning disc reactors, microreactors

e.g. compact heat exchanges e.g. reactive distillation,

membrane reactors

e.g. membrane adsorption

e.g. microwaves

Fluorination with elemental fluorine

Conditions: Cu or Ni channels. Syringe pump. Liquid-gas “cylindrical flow”Very good conversion compared to batch synthesis (15%)

Major advantages:

i) Small quantity of fluorine in reaction zone

ii) Good temperature control (extremely exothermic)

iii) Simple scale-up

O O

FCl

OEt

OO

OEt

Cl

62%

10% F2 in N2

90%

Some easily accessible Platform Molecules

CO2HHO2C

OH

CO2H

OCO2H

CO2HHO2C O CHOOH

CHOMeO

succinic acid lactic acid levulinic acid

adipic acidClean

Synthesis

Methods

A very wide range of useful products

SA as a Platform Molecules• Can be produced from fermentation of sugars using E. coli and

Actinobacillus succinogenes.• Up to 110 g l-1 concentrations have been achieved.

Raw MaterialsPre-manufacturing

Manufacturing & Production

Product Use and fate

Standardised methods of measuring ‘greenness’ across the whole lifecycle

Replacing hazardous materials

Reducing energy and

waste

Environmentally compatiblepackaging

PPs designed to have reduced environmental

impact at end-of-life

Ecopharmacostewardship approaches & opportunities to develop new generation of green and sustainable pharmaceutical products

Engaging key stakeholders across the lifecycle

Renewable-derivedstarting

materials

Increased awareness of benefits to

pharmaceutical industry

Safer solvents

Green Production

technologies

Catalysis

Classification & labelling schemes

Drug-take back

schemes

Education of prescribers &

users

Better understanding and control of

chemical process of suppliers

Timescale for Green and Sustainable

GREEN

&

SUSTAINABLE

Footprinting and Green Chemistry Review

Training

Alternative Solvents

Greener Reagents Hetero / Bio-Catalysis

Adsorption / Separation

Biodegradable Packaging

Telescoped Reactions

Alternative Reactors

Biofeedstocks

Location, Local Energy

Immediate

Immediate

Immediate - Medium

Immediate – Medium

Immediate – Medium

Medium

Medium

Medium – Long

Medium – Long

Long

Education and Training:e-learning and CPD in Sustainable

Technology and Policy

For technical and non-technical audience from the chemical and related industry, government, NGOs, retail and manufacturing companies

Available online or blended with workshops

Delivered in collaboration with academic (York + WUN) and other experts

Industry surveys in collaboration with Envirowise (UK) and Shanghai Chemical Industry Association (China)

1st & 2nd July 2008The Kings Manor, York, UK

5th Green Chemistry & the Consumer symposium

Plus pre-symposium Masterclass & evening event

Speakers from retail, industry, academia, NGO and others

Raw Materials

Research & Development

Primary Manufacturing

Secondary Manufacturing

Use /End

of Life

Clean SynthesisResearch

“Benign-by-Design” Research

EU project ‘KNAPPE’

Green Chemistry Training Environmental Footprinting

Greener Pharmaceuticals

Research

Industry

Networking

Education

Worldwide Universities Networkwww.wun.ac.uk/research/greenchem/index.html

Green Chemistry

Networkwww.chemsoc.org/gcn

MSc in Green Chemistry and Sustainable Industrial Technology

www.york.ac.uk/res/gcg/MRes/home

Green Chemistry & the Consumerwww.chemsoc.org/networks/gcn.htm#consumer

Greener Industrywww.greener-industry.org

Centre of Excellence

for Industrywww.greenchemistry.net

www.greenchemistry.net