Greener Pharmaceuticals - DBU › media › 130508051120a525.pdf · Conditions: Cu or Ni channels....
Transcript of Greener Pharmaceuticals - DBU › media › 130508051120a525.pdf · Conditions: Cu or Ni channels....
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