Institute of Medicine Round Table on Environmental Health Sciences , Research and Medicine Green Che

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Institute of Medicine Round Tableon
Environmental Health Sciences , Research and
MedicineGreen Chemistry in the Pharmaceutical
Industry Alternative Reaction Pathways

• Berkeley W. Cue, Jr., Ph.D.
• Green Chemistry Institute
• October 13, 2004

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Meeting the Economic, Environmental and Social
Needs of the Present Without Compromising the
Ability of Future Generations to Meet Their Own
Needs
Embracing Sustainable Development
Our Common Future, Brundtland Report, 1987
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PhRMA Companies Mission
The PhRMA represents the leading research-based
pharmaceutical and biotechnology companies in
the United States. PhRMA companies are devoted
to discovering and developing new medicines that
will enable patients to live longer, healthier
and more productive lives. In 2002 the
companies invested more than 32 billion in
discovering and developing new medicines,
marking the 32nd straight year the industry has
increased its investment in RD Source PhRMA
Website BUT- Pharma Industrys commitment to
improving health is not complete without a
commitment to a healthy environment.
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DJSI 2003 Pharma

• DJSI evaluates industry peer groups against five
  categories each for economic, environmental and
  social performance.
• First Tier
• Second Tier
• Third Tier

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The Challenge Regulatory Advance
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What is Green Chemistry?
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.
Source Paul T. Anastas and John C. Warner,
Green Chemistry Theory and Practice (New York,
NY Oxford University Press Inc., 1998). ISBN 0
19 850698 8
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12 Principles of Green Chemistry

• Prevention
• Atom Economy
• Less Hazardous Chemical Synthesis
• Design Safer Chemicals
• Safety Solvents Auxiliaries
• Design for Energy Efficiency

• Use Renewable Feedstocks
• Reduce Derivatives
• Catalysis
• Design for Degradation
• Real-Time Analysis for Pollution Prevention
• Inherently Safer Chemistry for Accident Prevention

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GSK Publication Cradle to GateLife Cycle Study

• For a typical API
• 80 waste is solvent
• 20 waste is chemical
• BWC Note Sometimes, solvents can be recovered
  and reused or burned as fuel additives to
  generate energy
• Gonzalez, Curzons, Constable and Cunningham,
• Int. J. LCA, 9 (2), 114 (2004)

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Commercial Sildenafil Process Solvent Usage
Source Dunn, et. al., Green Chemistry, 6,
43(2004).
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Solvent use comparison
Medicinal Chemistry Route
Process Chemistry Route
43 mL/g CP-809,101-42
1,180 mL/g CP-809,101-42
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US EPA Presidential Green Chemistry Award

• Promotes and recognizes green chemistry
• Five Categories
• Alternate synthetic pathways (focus area 1)
• Alternate reaction conditions (focus area 2)
• Design of safer chemicals (focus area 3)
• Small business (any focus area)
• Academic investigator
• Awarded since 1996 (41 recipients)

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Presidential Green Chemistry Challenge Award
The Presidential Green Chemistry Challenge
promotes pollution prevention through an EPA
Design for the Environment partnership with the
chemistry community. Through high level
recognition and support, the Challenge promotes
innovative developments in and uses of green
chemistry for pollution prevention
Source www.epa.gov/green chemistry
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Pharmaceutical Industry Winners

• 1999 Lilly Research Laboratories for
  Alternative Synthetic Pathways
• 2000 Roche Colorado Corp for Alternative
  Synthetic Pathways
• 2002 Pfizer, Inc for Alternative Synthetic
  Pathways
• 2004 BMS for Alternative Synthetic Pathways

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Lilly Research Labs LY300164 (talampanol)

• 1999 EPA Green Chemistry Award
• Non competitive AMPA antagonist for treating
  epilepsy and neuro degenerative diseases
• New process
• 7 steps with 3 product isolations
• Eliminated 34000 l and 300 kg chromium waste per
  100 kg API
• Yield increased from 16 to 55
• Bioreduction of a ketone to a chiral alcohol with
  Zygosaccaromyces rouxii in 96 yield with 99.9
  ee

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Source Provided by Vladuchick, Lilly
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Roche Colorado CorporationGanciclovir Process

• API in Cytovene
• 2000 US EPA Green Chemistry Award Recipient
• New Process Reduced
• Air emissions by 66
• Liquid/solid waste generation by 89
• Solvent usage by 94

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Pfizer, Inc, 2002 for Sertraline Process

• Eliminated
• Use of 140 metric tons/year of titanium
  tetrachloride
• Generation of 440 metric tons/year of solid
  titanium dioxide waste
• 150 metric tons/year of 35 HCl waste
• Need for 100 metric tons/year of 50 NaOH
• Some aqueous washes
• Dramatically reduced the number
  and volume of solvents used

Source GCI, Green Chemistry Proceedings, 2002
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Re-designed Sertraline Process

Source Taber, Colberg and Pfistere, OPRD, 2004
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Bristol Myers Squibb
Taxol
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Evolution of the Taxol (Paclitaxel) Process

• 1st Generation Extract from bark of Pacific yew
• 2nd Generation Semi-synthesis from 10- DAB
  TM
• 3rd Generation Phyton PCF Process

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API Manufacturing Cost Reductions Possible Using
Green Chemistry Principles

• We target a 25 reduction in manufacturing
  costs for processes developed using green
  chemistry principles
• 2003 Green Chemistry Congressional Education
  Initiative Forum

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Green Chemistry Performance Metrics
E-FactorRoger Sheldon, Chem Tech, 1994, 24, 38

• Table 1. Sectors of the chemical industry by
  quantity of byproduct per kg of product
• Industry Sector Product tonnage kg byproducts/
• kg of product
• __________________________________________________
  _________
• Oil refining 106 - 108 ca 0.1
• Bulk Chemicals 104 106
• Fine Chemicals 102 104 5-50
• Pharmaceuticals 101 103 25-100

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IMS 2003 Pharmaceutical Sales By Region
2003 Global pharma sales by region
Source IMS World Review 2004
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Opportunities

• Adopt a benign first time mind set. No
  exemptions for lab chemists.
• Move from a fossil fuel based to a biomass based
  synthesis paradigm
• Design manufacturing processes for APIs based on
  biomass-based raw materials
• Measure and publish E-factors for your API
  processes
• Commit to improvement goals
• More extensive use of benign solvents
• Water, supercritical CO2, ionic liquids and
  solvent-free
• Closer collaboration with academia, government
  and NGOs
• More industrial seminars, participation in
  workshops, recruiting and hiring green chemists
• Integrate Chemical synthesis and chemical
  engineering
• Semi continuous and continuous processing for
  typical pharma scale synthesis

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The significant problems we face today cannot be
solved at the same level of thinking we were at
when we created them - Albert Einstein
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In Summary

• Many companies in the pharmaceutical industry are
  using green chemistry principles to achieve waste
  prevention at commercial scale
• But as much as hundreds of millions to a billion
  kilos of waste per year could still be prevented
• Some examples of these concepts making their way
  into the development stage
• Applying green chemistry principles at the
  earliest synthesis stage remains an unrealized
  opportunity
• Emerging technologies that are not yet commonly
  used could substantially enable waste prevention