Green Chemistry Principles

How Green was my How Green was my Process ?:Process ?:

Case Studies of the Role of Case Studies of the Role of Process Chemistry in Drug Process Chemistry in Drug

DevelopmentDevelopmentSteven A. Weissman (Ph.D. ’87)Steven A. Weissman (Ph.D. ’87)

Tufts UniversityTufts University29March 200429March 2004

““Industrial Strength Chemistry”Industrial Strength Chemistry”

OverviewOverview

1.1. What is Process Research ?What is Process Research ?

2.2. 12 Principles of 12 Principles of Green ChemistryGreen Chemistry

3.3. Case Studies-Merck Process Case Studies-Merck Process ResearchResearch

4.4. Lesson Learned: “Unlocking the Lesson Learned: “Unlocking the Potential of Process Innovation” Potential of Process Innovation”

5.5. Q & AQ & A

Net Cost: $802 Million

Invested Over 15 Years Net Cost: $802 Million

Invested Over 15 Years

5,000–10,000Screened

250Enter Preclinical

Testing

5Enter

Clinical Testing

Compound Success Rates by Stage

Phase II100–300 Patient Volunteers Used to Look for Efficacy and Side Effects

Phase II100–300 Patient Volunteers Used to Look for Efficacy and Side EffectsPhase III

1,000–5,000 Patient Volunteers Used to Monitor

Adverse Reactions to Long-Term Use

Phase III1,000–5,000 Patient

Volunteers Used to Monitor Adverse Reactions to

Long-Term Use FDA Review ApprovalFDA Review Approval

Additional Post-Marketing Testing

Phase I 20–80 Healthy Volunteers Used to Determine Safety

and Dosage

Phase I 20–80 Healthy Volunteers Used to Determine Safety

and Dosage

Preclinical TestingLaboratory and Animal Testing

Discovery(2–10 Years)

YearsYears

New Product Development – New Product Development – A Risky and Expensive PropositionA Risky and Expensive Proposition

Source: Tufts Center for the Study of Drug DevelopmentSource: Tufts Center for the Study of Drug Development

Approved by the FDA

What is Process Research ?What is Process Research ?MissionMission: :

To design elegant, practical, efficient, environmentally benign To design elegant, practical, efficient, environmentally benign

and economically viable chemical syntheses for Merck drug and economically viable chemical syntheses for Merck drug

substances (“active pharmaceutical ingredient” (API))substances (“active pharmaceutical ingredient” (API)) Pre-Clinical:Pre-Clinical: 50 g - 5 kg: Safety Assessment, 50 g - 5 kg: Safety Assessment,

formulation, metabolismformulation, metabolism

ClinicalClinical: 50-500 kg: Ph I-III human trials, long-term : 50-500 kg: Ph I-III human trials, long-term safetysafety

Post ClinicalPost Clinical: transfer process technology to : transfer process technology to Manufacturing (1000 kg - metric ton quantities/yr; Manufacturing (1000 kg - metric ton quantities/yr; depending on dose)depending on dose)

Advent of Process ResearchAdvent of Process Research

MSc Degree- Univ. LiverpoolMSc Degree- Univ. Liverpool

Dedicated ACS Journal (Dedicated ACS Journal (Org Process R&D)Org Process R&D)

Dedicated Conferences (ACS, Gordon)Dedicated Conferences (ACS, Gordon)

Books/CoursesBooks/Courses

C&E NewsC&E News cover stories cover stories

Wall Street JournalWall Street Journal cover story cover story

What is Process Research ?What is Process Research ?

““The ideal chemical process is that The ideal chemical process is that which a one-armed operator can which a one-armed operator can perform by pouring the reactants perform by pouring the reactants

into a bath tub and collecting pure into a bath tub and collecting pure product from the drain hole”product from the drain hole”

Sir John Conforth Sir John Conforth

(1975 Nobel Prize: Chemistry)(1975 Nobel Prize: Chemistry)

An amalgam of:An amalgam of:

1.1. Modern synthetic organic methodologyModern synthetic organic methodology2.2. Physicochemical propertiesPhysicochemical properties

• Salt selection: based on stability, suitabilitySalt selection: based on stability, suitability• Solid State Properties: Solvent dependantSolid State Properties: Solvent dependant

Crystal Morphology: internal shape-affects solubility, Crystal Morphology: internal shape-affects solubility, stabilitystability

Crystal Habit: external shape-affects flowability, Crystal Habit: external shape-affects flowability, mixability mixability

Particle Size: can affect bioavailabilityParticle Size: can affect bioavailability

3.3. Purification/Isolation technologiesPurification/Isolation technologies

4.4. Chemical Engineering principles: Chemical Engineering principles: mixing, heat transfer, vessel mixing, heat transfer, vessel configurationconfiguration

5.5. Practical Process Aspects:Practical Process Aspects:• SafetySafety• QualityQuality• CostCost• ReproducibilityReproducibility• RuggednessRuggedness

Process Research: CustomersProcess Research: Customers

MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

responsible for developing In-processassay and critical evaluation of

drug substance and intermediates

MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

responsible for toxicity studies: (carcinogen, teratogen, gene toxicity)

MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

responsible for formulatingdrug substance (API) into

drug product

MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

Oversee process transfer intoPilot plants

MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

Conducts clinical trials (Ph I-III) and evaluates data

MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

Discovers new chemical entities (NCE’s) and

prepares intitial quantities

Other CustomersOther Customers

PatentPatent: : drafting, inventorship, litigationdrafting, inventorship, litigation

OutsourcingOutsourcing:: work with vendors on tech work with vendors on tech

transfer; setting specs; qualifyingtransfer; setting specs; qualifying

RegulatoryRegulatory: : drafting of NDA; process drafting of NDA; process

range findingrange finding

Manufacturing:Manufacturing: transfer of processtransfer of process

‘‘know-how’; oversee start-upknow-how’; oversee start-up

12 Principles of Green Chemistry12 Principles of Green Chemistry

Developed in 1997 by:Developed in 1997 by:

Paul Anastas- EPAPaul Anastas- EPA

Prof John Warner- UMass-BostonProf John Warner- UMass-Boston

Presidential Green Chemistry Presidential Green Chemistry Challenge Challenge

1.1. PreventionPrevention: It is better to prevent : It is better to prevent waste than to treat/clean up after waste than to treat/clean up after its created.its created.

2. 2. Atom EconomyAtom Economy: : synthetic methods synthetic methods should be designed to incorporate all the should be designed to incorporate all the atoms used in the process into the final atoms used in the process into the final product product

% atom economy =% atom economy =

100 x 100 x MW of all atoms utilizedMW of all atoms utilized

MW of all reagents/reactants usedMW of all reagents/reactants used

Example of 100% efficiency: Rearrangements, Diels-Example of 100% efficiency: Rearrangements, Diels-AlderAlder

Atom Economy:ExampleAtom Economy:Example

Atom Economy = (MW of atoms utilized/MW of all reactants) X 100 = (137/275) X 100 = 50%

3. 3. Minimize Hazardous Conditions:Minimize Hazardous Conditions:

Design process to avoid using Design process to avoid using reagents that pose safety threat reagents that pose safety threat

12. 12. Safer Chemistry-Accident Safer Chemistry-Accident Prevention:Prevention:

Design processes that minimize Design processes that minimize hazards to environment and human hazards to environment and human healthhealth

4. 4. Design Safer Products: Design Safer Products:

Products should be designed to effect Products should be designed to effect their desired function while their desired function while minimizing toxicityminimizing toxicity

Example: Use of single enantiomer drug vs Example: Use of single enantiomer drug vs racemateracemate

5. 5. Use Safer Solvents/AuxiliariesUse Safer Solvents/Auxiliaries

Use of innocuous solvents should be Use of innocuous solvents should be considered (e.g. water, supercritical considered (e.g. water, supercritical COCO22))

Avoid use of unnecessary substancesAvoid use of unnecessary substances

(e.g. drying agents, column (e.g. drying agents, column chromatography)chromatography)

6. 6. Design for Energy Efficiency:Design for Energy Efficiency:

Energy requirements for a process Energy requirements for a process should be recognized for should be recognized for environmental and economic impactenvironmental and economic impact

ExamplesExamples: avoid extreme cryogenics (-78 : avoid extreme cryogenics (-78 ooC)C)

Avoid prolonged reaction timesAvoid prolonged reaction times

7. 7. Use of Renewable Raw Materials:Use of Renewable Raw Materials:

Use a renewable source rather that Use a renewable source rather that depleting whenever technically and depleting whenever technically and

economically feasible.economically feasible.

example: plant-derived RM; microbial example: plant-derived RM; microbial reactionsreactions

8. 8. Minimize DerivatizationMinimize Derivatization::

Avoid the use of protecting groups Avoid the use of protecting groups when possible as it add steps, requires when possible as it add steps, requires extra reagents and generates more extra reagents and generates more waste.waste.

9. 9. Catalysis:Catalysis:

Use of catalytic reagents is far Use of catalytic reagents is far superior than stoichiometric amountssuperior than stoichiometric amounts

Example: using air as a source of oxygen for Example: using air as a source of oxygen for oxidation reactionoxidation reaction

10. 10. Design for Degradation:Design for Degradation:

Ideally, process products and by-Ideally, process products and by-products should breakdown into products should breakdown into innocuous materials and/or do not innocuous materials and/or do not persist in the environmentpersist in the environment

11.11.Real Time Analysis:Real Time Analysis: Analytical methods designed for Analytical methods designed for

‘real-time’‘real-time’ In-process monitoring/control of a In-process monitoring/control of a

reactionreaction

Example: Example: Reactor-IRReactor-IR (in-situ probe for (in-situ probe for monitoring reactions)monitoring reactions)

Process EconomicsProcess Economics- Minimize - Minimize inventory cost of API via:inventory cost of API via:

Low cost RMLow cost RM Productive/Efficient ReactionsProductive/Efficient Reactions

• High YieldHigh Yield• Highly concentratedHighly concentrated• Few StepsFew Steps• Short time cyclesShort time cycles• Few VesselsFew Vessels

Case Studies from MerckCase Studies from Merck

Remoxipride-----schizophreniaRemoxipride-----schizophrenia Crixivan-----AIDSCrixivan-----AIDS Emend-----Depression, EmesisEmend-----Depression, Emesis L778,123----CancerL778,123----Cancer

Case Study 1: Remoxipride

Remoxipride

Selective Dopamine-2 Antagonist

Indication: Anti-psychotic (Depression/Schizophrenia)

Clinical Trials: halted in 1993 due to anemia side-effects

Original Bromination

OH Br2 dioxane

84% yield

93% purity

Drawbacks: Use of toxic oxidant (bromine)

Use of suspect carcinogen (dioxane)

Product requires additional purification

Improved Bromination

94% yield

98% purity

water/NaOH

Br(0.55 equiv)

Green Chemistry Principles: Safer Solvents

Less Hazardous Chemical Synthesis

Other ExamplesOMe

90% yield

90 % yield

86% yield

91 % yield

98 % yield

Literature: 4 steps-17% yield

Auerbach, Weissman Tet Letters 1993, 931

Useful Methodology

Alkaloid Chelerythrine

Harayama et al Synthesis 2001, 444

J. Fuchs, R. Funk Org. Letters 2001, 3923

Alkaloid Lennoxamine

Case Study 2: Crixivan®

HIV Protease Inhibitor-AIDS therapyFDA Approval - March 1996

Fastest FDA Approval Ever (42 Days)Daily Dosage: 2400 mg

NNH OH

t-BuHN O

N . H2SO4N

t-BuHN O

N . H2SO4

Retrosynthetic Analysis of Crixivan-I

Aminoindanol Amide

Glycidyl Fragment

Piperazine

Crixivan

" "(-)

NNH OH

OH N O

Retrosynthetic Analysis of Crixivan-II

NNH OH

t-BuHN O

Crixivan

* Five Asymmetric Centers (Arrows)

3-Picolyl Chloride

t-BuHN O

H2N OH

Piperazine FragmentEpoxide Fragment

Allyl Bromide

(-)-cis-Aminoindanol

Synthesis of Pyrazine Carboxamide

CONHt-Bu

Original Route

N C(O)Cl

(COCl)2 t-BuNH2

95% yield

Drawbacks:1. Use of costly Oxalyl Chloride2. CO and CO2 by-products3. Lengthy time cycle due to exothermic amination reaction4. Need for 3 equiv of volatile t-butylamine5. Filtration/Disposal of voluminous amine hydrochloride salt

Improved Route to Pyrazine Carboxamide

CN CONHt-Bu

t-BuOH, H2SO4

Ritter Reaction

Aq AcOH

5 oC/2 h

Green Chemistry Principles: - Prevention- Safer Solvents- Less Hazardous Chemical Synthesis- Energy Efficiency

Atom Economy Comparison

CO2H N

C5H4N2O2Mol. Wt.: 124.10

C5H3N3Mol. Wt.: 105.10

C9H13N3OMol. Wt.: 179.22

(COCl)2 [127]

2 t-butylNH2 [ 73]

H2SO4 [98]

t-BuOH [74]

H2O [18]

A: 179/[124+127+73+73] = 45 %

B: 179/[105 + 98 +74 +18] = 61%

Chiral Piperazine via Resolution/Racemization

Green Chemistry Principles: Prevention (Recycle R-isomer)Prevention (Recovery of PGA)Atom EconomyRenewable Feedstock (PGA)Catalysis

CONHt-Bu

Pd (OH)2

95% NH

CONHt-Bu

2 L-PGA

86% ee- in ML's

CONHt-Bu

2 L-PGA

98 % ee-crystalline salt

95%aq NaOH

CONHt-Bu

99% ee 80% yield

NNH OH

t-BuHN O

Crixivan

3-Picolyl Chloride

t-BuHN O

H2N OH

Allyl Bromide

Original Route to cis-Amino Indanol

OCH3CN,H2O2, MeOH CH3CN, CH3SO3H

88% yield 57% yield

racemic cis amino indanol47% yield from indene

1. tartaric acid/MeOH resolution 40% yield 2. NaOH - Salt Break 92% yield

(-) cis amino indanol 100% ee300 kg (15-17% overall yield)

Drawbacks: Low YieldNo Recycle of (+)-isomer

Asymmetric Route to CAINH2

0.7 % S,S-MnII(salen)Cl/aq NaOCl

Tartaric Acid;

(-) CAI

50 % Overall

Catalytic Oxidant:

Oleum, CH3CN;

78 % @ 87 % ee

> 99 % ee

Tetrahedron Lett. 1995, 36, 3993.

Green Chemistry Principles: Prevention (Reduced Waste)Catalysis

NNH OH

t-BuHN O

Crixivan

3-Picolyl Chloride

t-BuHN O

H2N OH

Allyl Bromide

Synthesis of Acetonide

88% yield

aq. KHCO3/IpAc

2-methoxypropene;

Amide Enolate Precursor Prepared in High Yield in One Pot Process

Glycidyl Introduction with (S)-Glycidyl Tosylate

-25°C

72% yield96% de%

Epoxide

* (S)-Glycidyl Tosylate: High Cost ($150/kg)

* Two Asymmetric Centers Introduced in a Single Step in High Diastereoselectivity

* Dimer By-Product Also Produced

Tetrahedron Lett. 1994, 35, 673-676.

Glycidyl Introduction with Allylation/Epoxidation

ON S RO

Diastereoselectivity = 97:3

-35°C

EpoxidizeR

Epoxide Synthesis

87 % (three steps)82% from cis-Aminoindanol

NCS/NaI

aq NaHCO3

Epoxidation----Instantaneous reaction: Performed in continuous stirred tank reactor (CSTR) on Manufacturing scale

End Game: Coupling

t-BuHN OO

t-BuHN O

Penultimate94% for 2 steps

1) MeOH, reflux;

2) HCl (g)

End Game: Alkylation

Ot-BuHN

t-BuHN O

N OHNH

2) H2SO4/ethanol . H2SO4

Penultimate Indinavir Sulfate

Crixivan: Summary

• Overall nine step yield from CAI to sulfate salt is > 60%

• Efficient assembly of optically pure fragments to produce Crixivan®

• Chiral synthesis of cis-aminoindanol via novel Ritter reaction• Diastereoselective syn epoxidation of 2-benzyl-4-enamide

intermediate via the iodohydrin• Novel asymmetric hydrogenation of differentially protected

tetrahydropiperazine• 17,000 gallons of solvent passed through the process train

daily at its peak !

Case Study #3: L778,123

L778,123

ras-Farnesyl transferase Inhibitor (Cancer)

Imidazole Piperazinone

Maligres et al J. Heterocyclic Chem. 2003, 229

L778,123

Med Chem Route: Imidazole

1. Tr-Cl

2. Ac2O

1. ArCH2Br

2. MeOH

LiOH/aq THF

SO3-pyr

66% 80%

Drawbacks: (1) costly starting material; (2) double protection/deprotection

Marckwald Route to Imidazole

SCN OH

Delapine/Marckwald Route

NH2-H3PO4

EtOH/80 oC

aq MeCN

60-70 oC

CN82% yield

Delapine/Marckwald Route

NH2-H3PO4

EtOH/80 oC

aq MeCN

60-70 oC

CN82% yield

conc HNO3

Fe (III)

Raney Ni

Dethionation: Green Approach

NH2-H3PO4

EtOH/80 oC

aq MeCN

60-70 oC

CN82% yield

H2O2aq AcOH

35-40 oC

Green Principles: Prevention/Degradation

L778,123

Med Chem Route: Piperazinone

O NH2-HCl

+160 oC

NH2-HCl

NHBocCl

Et3N/DCM

22% yieldSiO2 purification

HCl (g)

-78 oCN

Piperazinone:New Route

Weissman et. al. Tetrahedron Lett. 1998, 7459

aq KHCO3

5 oC60 oC/2 h

DIADR3PEtOAc1 h/RT

Green Chem Principles: Energy Efficient, Safer Solvent,

Reduced Derivitization, Prevention (SiO2 waste)

L778,123: Summary

L778,123

DIEA/MeCN

2 steps4 steps

Case Study #4: Synthesis of Emend

Emend®

Neurokinin-1 Receptor Antagonist

(Agonist is Substance-P)

• emesis (CINV)- FDA approved 2003• depression- Phase III trials -discontinued• asthma• arthritis• migraine• pain

Potential Indications:

synthesis/biology: Hale et. al. JMC 1998, 4607

Disconnection

Diastereoselective Reduction

+ Me-epimer

1) H2, Pd/Al2O3 acetone

2) pTSA

88% isolated yield (d.e. > 99%)

Med Chem Route to Vinyl EtherCHO

+1) NaCN 2) HCl

3) KHCO3

89% isolated yield

e.e. > 98%

IpAc(-)-BCSA

1) L-selectride

CF3F3C

C(O)Cl

Drawbacks: (1) use of toxic NaCN; (2) costly resolving agent;(3) Lack of racemization/recycle

Petasis Methylenation

92% isolated yield

toluene

Cp2TiMe2

(Cp2TiMe)2O

Cp2TiCl2

2.5 eq.

Drawbacks: Titanocene reagent is very expensive and potentially hazardous------recycling imperative-- HUGE capital investment

Vinyl Ether via Hofmann Elimination ?

Ar-FBn

(F3C)2-Ar

CF3F3C

Synthesis of Aminodiol

CF3F3C

Sharpless AD

CF3F3C

80% yield

92% ee: (S)-isomer 99% ee upgrade

1.Ms-Cl/lutidine

2. ethanolamineCF3F3C

Morpholine Synthesis

Ar-FBn

(F3C)2-Ar

CF3F3C

Morpholine via Novel Condensation ?

CF3F3C

B(OH)2

CF3F3C

86% yield

Petasis et. al. JACS 1997, 119, 445.

Synthesis of Bicyclic Acetal

(F3C)2-Ar

EtOAc/77 oC N

(F3C)2-Ar

98% yield

(F3C)2-Ar

HCl (g)

(F3C)2-Ar

1. aq base/EtOAc

2. TBP/DIAD/THF

86% yield

Regioselective ‘Hofmann’ Elimination

BnAr-F

(F3C)2 Ar

aq EtOH

1 equiv NaOH

5 h/40-75 oC

90% yield

99% ee

(F3C)2-Ar

BnIacetone

89% yield

more acidic proton

(F3C)2 Ar

Summary

CF3F3CCF3F3C

(F3C)2-Ar

7 steps overall

Green Chemistry Principles:Prevention (no Ti waste)Less Hazardous Chemical Synthesis (CN, DMT)Catalysis (Sharpless, Hydrog)Atom Economy More Economic (avoid BCSA)

Pye et. al. Chem Eur J. 2002, 8, 1372

Unlocking the Potential of Unlocking the Potential of Process InnovationProcess Innovation

Industry ChallengesIndustry Challenges Increased Regulatory controls (FDA, Increased Regulatory controls (FDA,

EPA)EPA) Downward Pricing PressureDownward Pricing Pressure Greater Competition in treatment Greater Competition in treatment

optionsoptions More complex moleculesMore complex molecules Corporate consolidationCorporate consolidation Dwindling # of diseases to conquerDwindling # of diseases to conquer

Lessons LearnedLessons Learned

Process Development as a Process Development as a Competitive Weapon/Leveraging Competitive Weapon/Leveraging

CapabilitiesCapabilities

““The power of process development lies The power of process development lies in how it helps companies achieve in how it helps companies achieve accelerated time to market, rapid accelerated time to market, rapid

production ramp-up and a stronger production ramp-up and a stronger proprietary position”proprietary position”

Lessons LearnedLessons Learned

““A firm that can develop A firm that can develop sophisticated process sophisticated process

technologies more rapidly and technologies more rapidly and with fewer development with fewer development

resources has strategic options resources has strategic options that less capable competitors that less capable competitors

lacklack””

Further ReadingFurther Reading Practical Process Research & Development; Practical Process Research & Development;

Neal AndersonNeal Anderson

The Merck Druggernaut: The Inside Story of a The Merck Druggernaut: The Inside Story of a Pharmaceutical GiantPharmaceutical Giant; ; Fran HawthorneFran Hawthorne

The Development Factory: Unlocking the Potential of The Development Factory: Unlocking the Potential of Process InnovationProcess Innovation; ; Gary P. Gary P. PisanoPisano

Principles of Process Research and Chemical Development Principles of Process Research and Chemical Development in the Pharmaceutical Industryin the Pharmaceutical Industry; ; Oljan RepicOljan Repic

Process Chemistry in the Pharmaceutical Industry; Process Chemistry in the Pharmaceutical Industry; Kumar Kumar GadamasettiGadamasetti

1,3-Asymmetric Induction

R1 = Me, BnR2 = H, Me

aq DMEOR2

trans selectivity 90-99%

Yoshida JACS 1984, 1079

pH Dependence of Outcome

I2 H2O-THF

High trans selectivity

pH < 7

pH Dependence of Outcome

I2 H2O-THF

High trans selectivity

pH < 7

pH > 7

Marckwald Mechanism

ArCH2NH2

ArCH2N

Green Chemistry Principles

Documents

Teaching Green Chemistry Principles to Undergraduate Students

SCH 3U- GREEN CHEMISTRY DEFINITION Green Chemistry is the utilisation of a set of principles that reduces or eliminates the use or generation of hazardous

M.Sc.-Applied Chemist… · Web viewTwelve principles of Green Chemistry with their explanations and examples; Designing a Green Synthesis using these principles; Prevention of

PRINCIPLES OF GREEN CHEMISTRY & ENGINEERING ... - Michigan · PRINCIPLES OF GREEN CHEMISTRY & ENGINEERING: APPLICATION OF THESE ... hazardous substances in the design, manufacture

From Environmental Toxicology to Green Chemistry · Principles of Green Chemistry. Technical Substitution in process Feedstocks, reagents, solvents Process control Catalysis (preferable

Green Chemistry: Principles and Practicedepa.fquim.unam.mx/amyd//archivero/GreenChemistryPrinciples_351… · The Twelve Principles of Green Chemistry are ‘‘design rules’’

The Twelve Principles of Green Chemistry*

The Twelve Principles of Green Chemistry. 12 Principles of Green Chemistry 1. Prevention. It is better to prevent waste than to treat or clean up waste

principles of green chemistry & engineering: application of these

Principal Scientist, Green Chemistry - Michigan · Green Chemistry is the utilization of a set of principles that reduces or eliminates the use or generation of hazardous substances

A Roadmap for Advancing Green Chemistry in ... - Washington › publications › documents › 1204009.pdf1 2012-2017 principles that reduces or eliminates the use or “Green Chemistry

Catalogue leaflet Perfumery Ingredients 2020 - Firmenich · 2020. 11. 15. · GREEN CHEMISTRY SCORE A ratio that covers most of the remaining Green Chemistry Principles in addition

New Tools to Improve Access to Green Chemistry and ...acscinf.org/docs/meetings/230nm/presentations/230nm75.pdf · to Green Chemistry and Engineering Resources ... • Based on principles

Teaching Green Chemistry Principles to Undergraduate Students · Vol. X, No. Y Rozov et al.: Teaching Green Chemistry Principles to Undergraduate Students 2 implementation of chemical

Using Green Chemistry Principles as a Framework to

Ecofriendly Synthetic Methodologies in Organic Chemistry · 2013. 11. 19. · 1.2 Principles of green chemistry 3 1.3 Synthetic strategy to achieve green chemistry processes 4 1.3.1

12 principles of Green chemistry

Design Principles for Sustainable & Green Chemistry ... ENGINEERING American Chemical Society Design Principles for Sustainable & Green Chemistry & Engineering THE ACS GREEN CHEMISTRY

2. Green Chemistry and Technology for Sustainable ...gcpcenvis.nic.in/Thesis/GREEN-CHEMISTRY-PDF-2-INTRODUCTION-2012.pdf · Green Chemistry-Green Engineering 2. Green Chemistry and

Principles of green chemistry