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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Understanding Adverse Outcome Pathways

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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

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