Incorporating Green Chemistry Concepts into New...
Transcript of Incorporating Green Chemistry Concepts into New...
Incorporating Green Chemistry Concepts into
New Product R&D
Incorporating Green Incorporating Green Chemistry Concepts into Chemistry Concepts into
New Product R&DNew Product R&D
Mark E. Thompson, DirectorDuPont Haskell Global Centers for Health and Environmental Sciences
20 September 2011
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~11%
~12%
~11%
~5%
~61%
DuPont R&D Investment
85% of R&D spend was on Innovation addressing Megatrends*
Chemistry
Engineering
Materials Science
Nanotechnology
Industrial Biotech
Ag Biotech
FEEDING THE WORLD*
DECREASING DEPENDENCE ON FOSSIL FUELS *
PROTECTING PEOPLE & THE ENVIROMENT *
CHEMICALS AND MATERIALS
ELECTRONICS
$1.7 Billion in 2010
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• 2010 Revenue from products launched between 2007-2010 was > $9.5B (USD)
• 1,786 New products introduced• 2,034 U.S. patent applications filed• Global expansion in R&D
• New labs in Meyrin, Switzerland, and Wilmington, Delaware, for photovoltaics
• New research facilities in the Ukraine, the Philippines, and the U.S. foragriculture
2010 Innovation at DuPont
• Expanding in Paulinia, Brazil, for next generation biofuels and advanced protective materials
• Expanding in Hyderabad, India, for advanced protective materials,automotive lightweighting, bio-based materials, and agriculture
• Expanding in Shanghai, China, for photovoltaics, bio-based materials, andautomotive applications
DuPont Knowledge CenterHyderabad, India
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DuPont Integrated Science
• Innovation occurs at the nexus of disciplines and markets
• DuPont is uniquely positioned for innovation in industrial biotechnology
• Haskell Global Centers for Health & Environmental Sciences areas of focus:
• Human toxicology• Ecotoxicology• Environmental sciences• Risk assessment and
modeling
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CompetenciesGeneral and Inhalation Toxicology Anatomic and Clinical PathologyNeurobehavioral ToxicologyImmunotoxicity / SensitizationDevelopmental Repro and EndocrineBiochemistry and MetabolismGenetic & Molecular ToxicologyIn vitro methods and alternativesAcute and chronic EcotoxicologyBioaccumulation studiesEnvironmental FateEnvironmental exposure modelingIn Silico profilingMicrobiology / Molecular BiologyRisk Assessment
Original Haskell Lab 1935
Advancing Science for 75 Years
DuPont Haskell Global Centers for Health and Environmental Sciences
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Green
Chemistry
Green
Engineering
Sustainability
Green Chemistry incorporates 12 principles1 aimed at designing materials that minimize impact on health and environment, and that also maximize efficiency and renewable resources
Implementing Green Chemistry and Green Engineering principles2 provides progress toward a more sustainable society
Implementing Green Chemistry principles is a knowledge-intensive effort that requires increasingly sophisticated tools and methods to better understand the molecules we make and use
DuPont is working hard to develop those tools and methods
1 Anastas, P.T.; Warner, J.C. Green Chemistry: Theory and Practice. Oxford University Press: New York, 1998, p. 30.
2 Anastas, P.T.; Zimmerman, J.B. Env. Sci. and Tech. 2003, 37, 5, 94A-101A.
Green Chemistry at DuPont
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• Computational scientist sits down at computer
• Enters physicochemical and other specifications for desired properties:
• Performance / efficacy• Mammalian toxicity• Ecotox• Environmental fate• Formulation / packaging / delivery• Manufacturing / cost
The ‘Holy Grail’ of New Chemical Product R&D
• Computer generates the optimal chemical structure
• A commercially feasible synthesis route with no, or only “green”solvents, 100% yields, and zero waste is highly desirable
• Chemist synthesizes the target, which is tested to confirm properties
• Register, scale up, and launch the product!
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• Computational / in silico• Data mining • Data visualization• SAR / QSAR
• Synthetic chemistry• Small scale, high throughput,
parallel synthesis, “Click chemistry”• Catalysis• Analytical• Process development
• Performance / efficacy testing• HTS• Miniaturization• Imaging• Bioinformatics
Research Tools Continue to Advance3
• Mammalian toxicity and ecotox
• Chemical characterization• Computational tox• Tiered screening using in
vitro assays• Targeted in vivo testing• Surrogate species (e.g.,
Daphnia)• “Omics” technologies
• Environmental fate• Physicochemical properties –
predicted, measured• Modeling• Persistence and
bioaccumulation assessment
3 Voutchkova, A.M.; Osimitz, T.G.; Anastas, P.T. Toward a Comprehensive Molecular Design Framework for Reduced Hazard. Chem. Rev., 2010, 110, 5845-5882.
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Tox and Risk Assessment in the 21st Century4
Shift paradigm for toxicity testing• Elucidate human toxicity pathways• Chemical characterization: Computational modeling, in silico profiling• Cell-based, high throughput in vitro assays• Targeted in vivo testing• Dose-response and extrapolation modeling
Risk Assessment• Population-based and human exposure data considered at each step• Risk context: what data are required for decision-making
Potential Benefits Better tools for exposure and hazard will allow for more robust risk
assessment on a greater number of chemicalsMore information earlier in R&D will lead to better decisions Accelerated commercialization timelines, reduced animal testing
4 National Research Council. Toxicity Testing in the 21st Century: A Visionand a Strategy. Washington, D.C.: National Academy Press, 2007.
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Knowledge Feedback Loops Are Critical in Early R&D
Molecular Designand Synthesis
Performance /Efficacy
Mammalian Toxicity
and Ecotox
EnvironmentalFate
Business Case
Lab-based assays: rapid turnaround inexpensive small sample requirements appropriate throughput validated
O
SO2
NH
O
NH
N
N CH3
CH3
OMeCl
SO2
NH
O
NH
N N
N
CH3
OMe
Metsulfuron-methyl:“OUST” Non-selective
Herbicide
Chlorsulfuron:“GLEAN” Wheat
Herbicide
• Discovered in the late 1970s• Mode of Action: Inhibition of branched chain amino acid
biosynthesis• Site of Action: Acetohydroxyacid synthase (AHAS) – found
only in plants • Highly favorable environmental profile
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Sulfonylurea HerbicidesSulfonylurea Herbicides
MidMid--80s Challenge: Design and synthesize sulfonylureas that 80s Challenge: Design and synthesize sulfonylureas that degrade rapidly in the environment to avoid rotational crop injudegrade rapidly in the environment to avoid rotational crop injuryry
• Formed a special, multidisciplinary task team• Developed a lab-based soil degradation assay
Designed to mimic worst-case scenario: Soil type, temperature, pH, sterile and non-sterile conditions
Easy to run, inexpensive, low sample requirements
Measured % parent molecule remaining after two weeks
Rapid data feedback to synthetic chemists and biologists
Five classes of degradation: A (fastest), B, C, D, E (slowest)
• Proved to have very good predictive capability in the real world – especially at the extremes
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Sulfonylurea HerbicidesSulfonylurea Herbicides
Two degradation mechanisms: Functional group modification Two degradation mechanisms: Functional group modification and skeletal rearrangementand skeletal rearrangement
EXAMPLE 1. Certain functional groups undergo changes that greatEXAMPLE 1. Certain functional groups undergo changes that greatly reduce bioavailabilityly reduce bioavailability
EXAMPLE 2. Molecular skeleton degrades to give nonEXAMPLE 2. Molecular skeleton degrades to give non--herbicidal compounds herbicidal compounds
SO2
NH
O
NH
CO2CH3
N
N
OMe
OMeHO2CSO2
NH
O
NH
CO2CH3
N
N
OMe
OMeNC
N SO2
NH
O
NH
CF3
CO2CH3
N
N
OMe
OMeNCF3
CO2CH3
NCONHSO2H
N N
OMeMeO
Conjugation or bindingreduces
bioavailability
1. Hydrolysis
2. Microbialdegradation
NCF3
CO2CH3
NH
N N
OMeMeO
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Sulfonylurea HerbicidesSulfonylurea Herbicides
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Disciplined Project Management is Key
Ideation Concept Evaluation
CandidateOptimization
PrototypeTesting
CustomerQualification Launch
• Disciplined, but flexible “Stage Gate” process with well defined advancement criteria
• Front End Loading: Generate as much knowledge as early as possible while options are still open
• ‘Fail Fast / Succeed Early’• Two-phases of R&D5
1. Early quickly eliminate poor candidates and absorb risk2. Late increase probability of launch
• Backup candidate: Equal performance, chemically distinct, different MoA, different toxicity and environmental profiles, equivalent economics
Investment: $ $$ $$$ $$$ $$$ $$
5 Bonabeau, E.; Bodick, R. A More Rational Approach to New Product Development. Harvard Business Review, March 2008, 96-102.
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Treatment Larvae (#)Untreated 28RynaxypyrTM 0
Insect Pressure per Plant (N=20)
Untreated Check
Rynaxypyr®
10 g/Ha
Control of Plutella xylostella on CabbageRio Grande, Texas, USA (2002)
P. xylostella(Diamondback Moth)
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Registered on more than 100 crops in >70 countries
• Superior crop protection• Novel mode of action: Ryanodine
receptor agonist• Low environmental impact• Wide range of crop applications
Rynaxypyr®: Enthusiastic Grower Acceptance
All products designated with a ® or TM are trademarks or registered trademarks of DuPont.
“Coragen® can replace several of the pesticides we currently use. It will give us extended control of pests, which will be cost-effective and help the health of our crops.”
Sara Hornsby, Agricultural Crop Consulting, Inc., Florida
Codling moth damageTreated with Rynaxypyr®
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What is the Ryanodine Receptor (RyR)?
Regulation of muscle contraction
Four identical monomers form a tetramer with channel
Large protein: 5000 amino acid residues; cDNA ~15 kb; multipleaccessory proteins
No synthetic RyR agents previously known with insecticidal properties
Rynaxypyr® SoA/MoA discovered very early in the program• Excellent tool for combating insect resistance
• Led to a smoother registration process globally
• Bolstered confidence in highly favorable mammalian tox profile
Ca2+
FKBPFKBP
Triad
inJunctin
lumen
cytosol
CAM CAM
RyanodineRyanodineReceptor ComplexReceptor Complex
CSQ
RyR RyR
Ryanodine
O
O
O
O
O
O
O
O
O
N
Chiral
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Nanoscale Science &
Engineering
Optical Films
Printable Electronics
BarrierMaterials
ElectronicsPackaging
Photovoltaics
Structural Composites
Nanomaterials• The NanoRisk Framework (2007)
• Environmental Defense and DuPont partnership• Process for identifying, managing, and reducing
potential environmental safety and health risks of engineered nanomaterials across all stages of a product’s lifecycle
• Guidance on key questions an organization should consider in developing applications of nanomaterials, and on the information needed to make sound risk evaluations and risk-management decisions
• ISO/TR 13121:2011 – Nanomaterial Risk Evaluation (May 2011)• Many similarities to NanoRisk Framework, but more compact• Aims to help decision makers follow sound risk-management strategies
- Methods to update assumptions as new information becomes available throughout a product’s lifecycle
- Methods of organizing information and communicating decisions with key stakeholders- Offers tiered tox testing approaches in silico, validated in vitro and in vivo methods
where applicable based on exposure routes
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Purpose: Support selection of more sustainable chemicals during development of new applications, new formulations, and new products
Screening-level web-based tool that:
• Enhances sustainability thinking in the R&D process
• Is aligned with research phases
• Asks the right questions at the right time and provides resources to answer them
• Generates information for discussion at milestone business reviews
• Encourages interaction with business, product stewards, exposure experts, and hazard experts
PRO3 - Promoting Proactive Product Stewardship
Potential for ConcernIndicated by Color: Red: High / Very High; Orange: Moderate; Green: Low
orIndicated by Wedge Length: 1 = Low; 2 = Moderate; 3 = High; 4 = Very High
DuPont METIS Chemical Screening Visualization Tool 21
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Product Selection by InspectionHigher level choices require expert consultation
Potential for High level of concernPotential for Moderate level of concernPotential for Low level of concern
Key
1 2 3
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Alternatives Assessment FrameworkA formalized approach to making informed decisions about chemical selection
Set Baseline Conditions
Decide Among Alternatives
Compare Baseline and Alternatives
Identify Feasible Alternatives Based on Functionality
PerformanceManufacturabilityHuman Health ProfileEnvironmental ProfileSafetyEconomic FeasibilityMarket Impact / Green Labeling OpportunitiesScreening Life Cycle Assessment
(energy/water/emissions)Exposure Potential throughout Product TrailSocial Considerations / Stakeholder Buy-In
• A “one-size-fits all”approach is unworkable given the diversity of products and processes
• Has been used within DuPont to capture information on refrigerant replacement, to document a REACH-related alternatives assessment, and for various voluntary solvent replacement projects
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What do we need for better green chemical design in R&D?
• Continued improvement of research tools with better predictive capabilities for performance / efficacy, mammalian toxicity, ecotox, and e-fate
• Implementation of ‘21st Century’ approaches to hazard identification and risk assessment
• Multidisciplinary, well-integrated teams• A “fail fast / succeed early” approach• Highly-effective knowledge feedback loops
Tiered testing strategy Computational tox / modeling / in silico profiling Lab-based in vitro assays coupled with targeted in vivo testing
- rapid turnaround- inexpensive - small sample requirements - high (appropriate) throughput - validated