What is the Green Chemistry Commitment?
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Tools for Innovation in Chemistry from the ACS Green Chemistry Institute Pharmaceutical Roundtable Paul Richardson, Ph.D. Director of Analytical and Synthetic Technologies, Pfizer Co-Chair of the ACS GCI Pharmaceutical Roundtable
Transcript of What is the Green Chemistry Commitment?
Tools for Innovation in Chemistry
from the
ACS Green Chemistry Institute Pharmaceutical Roundtable
Paul Richardson, Ph.D.Director of Analytical and Synthetic Technologies, Pfizer
Co-Chair of the ACS GCI Pharmaceutical Roundtable
M a s s a c h u s e t t s - b a s e d
5 0 1 - c 3 n o n - p r o f i t
D e d i c a t e d t o g r e e n
c h e m i s t r y e d u c a t i o n
K - 1 2 & H i g h e r E d .
D e v e l o p c u r r i c u l u m
r e s o u r c e s c e n t e r e d
a r o u n d t h e p r i n c i p l e s
a n d p r a c t i c e s o f
g r e e n c h e m i s t r y
G r e e n C h e m i s t r y
C o m m i t m e n t
About Us
Natalie O’Neil, Ph.D.Program Manager
Higher Education
Beyond Benign
@natjoneil
Welcome to the Green Chemistry Commitment
Green Chemistry Education Webinar Series
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Natalie O’Neil, Ph.D.Program Manager
Higher Education
Beyond Benign
@natjoneil
Isamir Martinez, Ph.D. PMPManager of Scientific Alliances
&
Business Engagement
ACS Green Chemistry Institute
Join the conversation!
@beyondbenign
#greenchemistry
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What is the GCC?
The Green Chemistry Commitment (GCC) is a consortium
program that unites the green chemistry community around shared
goals and a common vision to:
o expand the community of green chemists
o grow departmental resources
o share best practices in green chemistry education
o affect systemic and lasting change in chemistry education
https://www.beyondbenign.org/he-green-chemistry-commitment/
Green Chemistry Swag
Tools for Innovation in Chemistry from
the ACS Green Chemistry Institute Pharmaceutical
Roundtable
Paul Richardson, Ph.D.Director of Analytical and Synthetic Technologies, Pfizer
Co-Chair of the ACS GCI Pharmaceutical Roundtable
ACS GCIPR “Tools for Innovation in Chemistry”
20th November 2019
American Chemical Society
Why Green Chemistry ?
• Provide the best efficiency for
a chemical process.
• New frontier of exploration
• Great opportunity for
innovation
• The achievement of superior
synthetic efficiency will
ultimately deliver a competitive
advantage.
US EPA & OPRD., 2006, 10, 315.
Twelve Principles of Green Chemistry
Green
Chemistry
Prevent Waste
Atom Economy
Less Hazardous Synthesis
Design Benign
Chemicals
Benign Solvents
Energy Efficiency
Renewable Feedstocks
Reduce Derivatives
Catalysis
Design to Degrade
Real Time Analysis
Benign Chemistry
P. T. Anastas and J. C. Warner,
“Green Chemistry : Theory and
Practice”, Oxford University
Press, 1998, p. 30
Principles encompass both
the process and the product
“…the utilization of a set of
principles that reduces or eliminates
the use or generation of hazardous
substances in the design,
manufacture and application of
chemical products.”
Where we stand today !!
“Green chemistry can
deliver for people, planet
and profit. Those who
embrace it will reap the
benefits in future. Those
who fail to evolve may
cease to be relevant”.
Nature, 2016, 534, 27
American Chemical Society
“To catalyze the implementation
of green chemistry and
engineering in the pharmaceutical
industry globally”
Inform and Influence the
Research Agenda
Define and Deliver Tools for
Innovation
Promote Education and
Training
Enable Global Collaboration
Strategic Priorities
Mission of the ACS-GCI PRACS GCI Pharma Roundtable
GCIPR created in 2005 with 3
members, now > 30 members
• Pharma and generics produce > 100
million kg of API per year
• Estimated 150 kg waste per kg API
(> 99.3%). > 15 billion kg of
waste/year
• Estimated cost of waste disposal ca.
$30 billion
Development/Evolution of Tools
American Chemical Society
Development
of Tools
American Chemical Society
Accessing the Tools !!
www.acsgcipr.org
American Chemical Society
Accessing the Tools !!
https://www.acsgcipr.org/tools-for-innovation-in-chemistry/• PMI Prediction Tool
• PMI-LCA Tool
• Biopharma PMI Tool
• Reagent Guides
• Solvent Tool and Guides
• Green Chemistry Innovation
Scorecard/Calculator
• MedChem Tips and Tricks
• Analytical Chemistry
Greenness Calculator
American Chemical Society
Tools We Will Discuss Today !!
Metrics (PMI) Solvents Reagents
Why Metrics ??
• We measure what we care about ↔ we care about what we measure
• Standardize measurement of chemical process greenness when
possible
• Proper choice of metrics is critical for ‘behavior of system
• Green metrics correlate to process economics !!!
American Chemical Society
Initial Metrics…….
Yield
• Pharma Average ~
86%/step.
• Does not capture all
materials used.
Atom Economy
• Mass Product/Mass
Reagents * 100.
• Science, 1991, 254,
1471.
E-Factor
• Total kg waste/kg
product.
• Green Chem., 2017,
19, 18
Green Chem., 2002, 4, 521
Chem. Ind., 1992, 903
American Chemical Society
“Metrics……But which one do
you use ?”
Metric Waste Yield Stoich. Solvents Water Optimal
Chemical Yield 100%
Atom Economy 100%
E-Factor 0
Mass Intensity 1
Process Mass Intensity (PMI) 1
Process Mass Efficiency (PME) 100%
Mass Productivity 100%
Reaction Mass Efficiency 100%
Effective Mass Yield 100%
Reaction Mass Intensity 1
Carbon Efficiency 100%
Solvent Intensity 0
Wastewater Intensity 0
Solvent Impact in Pharma Manufacturing
Source: 2008 ACS GCIPR
benchmarking exercise of 10
member companies
C. Jimenez-Gonzalez
et al, OPRD, 2011,
15, 912.
• Solvents & water contribute significant
waste to process mass intensity
• PMI = kg inputs / kg product
• If PMI = 100, 1 kg of API needs
100 kg of input materials
• Solvents and water represent
> 85% of total input and waste
• Clear need for process intensification
to reduce solvent waste
• Opportunity to minimize waste hazards (through
better choices)
American Chemical Society
Process Mass Intensity (PMI)
Metric
OPRD, 2011, 15, 912
Why Measure PMI ?
• Drive change towards more sustainable manufacturing processes
– Track environmental manufacturing footprint.
– Measurement of process efficiency.
• Quantify improvements throughout process development life-cycle
• To be more transparent; basis for objective comparison
– Increasing expectations from internal and external audiences to describe progress, demonstrate
improvement.
• Benchmark
– Allows a simple comparison to the on-going green efforts throughout the industry in the pursuit of
mass efficient pharmaceutical processes.
• Insight in sustainability of overall manufacturing process, from bulk chemicals to API, is
required
American Chemical Society
PMI Calculator Tool
PMI Excel Spreadsheet
– Spreadsheet with embedded
Calculations.
– Only need to fill in amounts of
reagents, solvents, and aqueous.
– Spreadsheet calculates step
and overall PMI for linear
sequences.
– Calculates overall PMI as well
as separate PMI for solvents,
water, and reagents.
PMI by Development Phase –Median Values
American Chemical Society
Sildenalfil Citrate
Initial Medicinal Chemistry 17675
Optimized Med Chem (through phase 3) 116
Commercial Route 60
Green Chem., 2004, 6, 43 ; Green Chem., 2015, 17, 3390
Convergent PMI Calculator
Goal to maintain simplicity and the calculations behind the original PMI
calculation tool whilst allowing convergent syntheses with a range of
complexities to be accommodated.
Convergent PMI Tool
• Up to 11 step linear sequence.
• Up to 3 branches for convergent
synthesis (11 steps per branch).
• Multiple branch points possible in a
single step.
• Up to 44 step linear sequence if
treating additional steps as branches.
PMI Prediction Tool - App
• Predicts a range of probable
process efficiencies of
proposed synthetic routes at
various phases of drug
development.
• Uses historical PMI (and yield)
data from pharma companies
and predictive analytics (Monte
Carlo simulations) to estimate
the probable PMI ranges.
• Assess and compare potential
route changes !!
• PMI and various reported
metrics provide assessment on
Greenness after synthesis.
• Goal : To provide a quantitative
method to predict potential
efficiency.
• Increased molecular complexity
leads to increased synthetic
complexity and consequently
the potential number of
approaches to access a target
molecule (how to evaluate ?).
PMI Prediction Tool App –Screenshots
[1] Define synthesis tree and stoichiometry. [2] Define reaction PMI and yield ranges based on
reaction subtypes. [3] Obtain predicted cPMI histogram. [4] Obtain step metrics for all steps.
PMI Predictor - Benchmarking
Nat. Sustainability, 2019, 2, 1034
15 examples
Accuracy of
the prediction
shown to be
dependent on
development
status of the
compound.
PMI Tracks With Environmental Impacts
Global Warming Potential Aqueous Mass Intensity
Tangible Value of Greener Processes
American Chemical Society
Importance of Solvent Selection
• Solvents are critical parameters in chemical processing.
– Promoting chemistry
– Control of reaction temperature
– Dissolving reactants
– Modifying solute properties
• pKa
• Redox potential
• H-Bonding
– Removing impurities/by-products (partitioning)
– Isolating products (crystallization)
Judicious solvent
selection for a
chemical reaction can
often be the
difference between a
straightforward
outcome and a host
of problems.
Solvent Guide Considerations
• Worker Safety – including carcinogenicity, mutagenicity, reprotoxicity, skin absorption/sensitization and toxicity.
• Process Safety – including flammability, potential for high emissions through high vapour pressure, static charge, potential for peroxide formation and odour issues.
• Environmental and Regulatory considerations – including ecotoxicity and ground water contamination, potential EHS regulatory restrictions, ozone depletion potential, photoreactive potential. Compliance with regulations and company guidelines.
American Chemical Society
Examples of Solvent Selection
Guides
AZ, GSK, Pfizer, ACS GCIPR, Sanofi
Green Chem., 2014, 16, 4546
American Chemical Society
Chem21 Solvent Selection Guide
• Select from 77 solvents, ranking based on :
– Health, Safety, Environment criteria
– physical data and GHS (Global Harmonized System)
– Recommended, Problematic or Hazardous rating
Solvent Selection Guides
• Guides offer assistance in identifying solvents
• Most support post-selection comparison between solvent options
• Objective selection decisions for comparison can sometimes be compromised in
such situations :
– What is in the lab solvent cupboard ?
– What did I use last time, or what does the literature say ?
– What other similar solvents are commercially available ?
• The choice of solvent is often restricted to simple consideration of the chemistry
– Polarity, incompatible functional groups, temperature window
“Solvent Selection Tool reverses this philosophy, and provides a proactive
approach to solvent selection”
• Selection variables based on:
– molecular & physical
properties
– EH&S criteria
– ICH guidelines
– Over 100 properties !!!
• 272 solvents in the dataset
• Properties refined through
PCA (5 PCs)
• Interactive, adjustable
visualization
Solvent Selection Tool for Pharma
OPRD, 2016, 20, 760
Each spot
represents a
discrete solvent
Filters
# of solvents
Optimization/Screening of Solvents
• Applying an appropriate set of filters
provides a shortlist of potential
solvents for initial evaluation in a
specific transformation.
• With an initial hit, it is reasonable to
expect that proximal solvents will
display some degree of similar
behavior.
Development of a Reagent Guide
Three Ideal Characteristics……
1) To provide a balanced assessment of chemical methods.
– Ability to work in good yield in a wide variety of “drug-like” molecules.
– Ability to be utilized for “scale-up” purposes.
– To be as “green as possible”. (worker safety, atom economy etc).
2) To provide easy access to the chemical literature.
3) To raise awareness of newer emerging “greener” methodologies.
American Chemical Society
Green Chem., 2008, 10, 31
American Chemical Society
Reagent Guides
Boc deprotection
Amide reduction
Bromination
Reductive amination
Metals removal
Buchwald-Hartwig
Iodination
Chlorination
Chiral Hydrogenation
Suzuki-Miyaura
In Progress
Biocatalysis
Fluorination
Amide bond formation
Borylation
Thioether Formation
Achiral Hydrogenation
Cyclopropanation
American Chemical Society
Alcohol Oxidation - Visual
Depiction of a Reagent’s Utility
Details include i)
mechanism, ii)
comments, iii)
references, iv)
scale-up examples,
and v) a “Green”
review.
American Chemical Society
Synthesis of Maraviroc
Org. Process Res.
Dev. 2008, 12, 1104
(Pfizer)
Green Review
i) Atom Efficiency
ii) Safety
iii) Toxicity/environmental
impact
iv) Cost, availability and
sustainable feedstocks
v) Sustainable
implications
Catalyzing the integration of green
chemistry and engineering in the
pharmaceutical industry since 2005.
Acknowledgements/Questions
Alina Borovika, Christiana Briddell, Amy Cannon,
Louis Diorazio, Isamir Martinez, Natalie O’Neil
Recording and supporting documents will be available:
https://www.beyondbenign.org/he-webinars/
Submit questions at any time during the webinar in the
Control/Chat box on the Control Panel
Natalie O’Neil, Ph.D.Program Manager
Higher Education
Beyond Benign
@natjoneil
Questions
Isamir Martinez, Ph.D. PMPManager of Scientific Alliances
&
Business Engagement
ACS Green Chemistry Institute
Join us for our next webinar in February!
Recordings, supporting documents and upcoming webinars (with registration links):
http://www.beyondbenign.org/he-webinars/
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