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Green Chemistry talk presented at Tufts University


  • 1. How Green was my Process ?: Case Studies of the Role of Process Chemistry in Drug Development Steven A. Weissman (Ph.D. 87) Tufts University 29March 2004 Industrial Strength Chemistry

2. Overview

  • What is Process Research ?
  • 12 Principles ofGreen Chemistry
  • Case Studies-Merck Process Research
  • Lesson Learned: Unlocking the Potential of Process Innovation
  • Q & A

3. Net Cost: $802 MillionInvested Over 15 Years5,00010,000 Screened 250 Enter Preclinical Testing 5 Enter Clinical Testing 1 Compound SuccessRates by Stage 16 14 12 10 8 6 4 2 0 Phase II 100300 Patient Volunteers Used to Look for Efficacyand Side Effects Phase III 1,0005,000 Patient Volunteers Used to Monitor Adverse Reactions to Long-Term Use FDA Review Approval Additional Post-Marketing Testing Phase I2080 Healthy Volunteers Used to Determine Safety and Dosage Preclinical Testing Laboratory and Animal Testing Discovery (210 Years) Years New Product Development A Risky and Expensive Proposition Source: Tufts Center for the Study of Drug Development Approved by the FDA 4. What is Process Research ?

  • Mission :
  • To design elegant, practical, efficient, environmentally benign and economically viable chemical syntheses for Merck drug substances (active pharmaceutical ingredient (API))
  • Pre-Clinical:50 g - 5 kg: Safety Assessment, formulation, metabolism
  • Clinical : 50-500 kg: Ph I-III human trials, long-term safety
  • Post Clinical : transfer process technology toManufacturing (1000 kg - metric ton quantities/yr; depending on dose)

5. Advent of Process Research

  • MSc Degree- Univ. Liverpool
  • Dedicated ACS Journal ( Org Process R&D)
  • Dedicated Conferences (ACS, Gordon)
  • Books/Courses
  • C&E Newscover stories
  • Wall Street Journalcover story

6. What is Process Research ?

  • The ideal chemical process is that which a one-armed operator can perform by pouring the reactants into a bath tub and collecting pure product from the drain hole
  • Sir John Conforth
  • (1975 Nobel Prize: Chemistry)

7. What is Process Research ?

  • An amalgam of:
  • Modern synthetic organic methodology
  • Physicochemical properties
    • Salt selection: based on stability, suitability
    • Solid State Properties: Solvent dependant
      • Crystal Morphology: internal shape-affects solubility, stability
      • Crystal Habit:external shape-affects flowability, mixability
      • Particle Size: can affect bioavailability
  • Purification/Isolation technologies

8. What is Process Research ?

  • Chemical Engineering principles: mixing, heat transfer, vessel configuration
  • Practical Process Aspects:
    • Safety
    • Quality
    • Cost
    • Reproducibility
    • Ruggedness

9. Process Research: Customers Med Chem ClinicalChem E R&D PharmR&D Safety Analytical Process 10. Process Research: Customers responsible for developing In-process assay and critical evaluation ofdrug substance and intermediates Med Chem ClinicalChem E R&D PharmR&D Safety Analytical Process 11. Process Research: Customers responsible for toxicity studies:(carcinogen, teratogen, gene toxicity ) Med Chem ClinicalChem E R&D PharmR&D Safety Analytical Process 12. Process Research: Customers responsible for formulating drug substance (API) into drug product Med Chem ClinicalChem E R&D PharmR&D Safety Analytical Process 13. Process Research: Customers Oversee process transfer into Pilot plants Med Chem ClinicalChem E R&D PharmR&D Safety Analytical Process 14. Process Research: Customers Conducts clinical trials(Ph I-III) and evaluates data Med Chem ClinicalChem E R&D PharmR&D Safety Analytical Process 15. Process Research: Customers Discovers new chemicalentities (NCEs) andprepares intitial quantities Med Chem ClinicalChem E R&D PharmR&D Safety Analytical Process 16. Other Customers

  • Patent :drafting, inventorship, litigation
  • Outsourcing : work with vendors on tech transfer; setting specs; qualifying
  • Regulatory :drafting of NDA; process range finding
  • Manufacturing: transfer of process
  • know-how; oversee start-up

17. 12 Principles of Green Chemistry

  • Developed in 1997 by:
  • Paul Anastas- EPA
  • Prof John Warner- UMass-Boston
  • Presidential Green Chemistry Challenge

18. 12 Principles of Green Chemistry

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

19. 12 Principles of Green Chemistry

  • 2.Atom Economy :synthetic methods should be designed to incorporate all the atoms used in the process into the final product
  • % atom economy =
  • 100 xMW of all atoms utilized
  • MW of all reagents/reactants used
  • Example of 100% efficiency: Rearrangements, Diels-Alder

20. Atom Economy:Example Atom Economy = (MW of atoms utilized/MW of all reactants) X 100=(137/275) X 100 = 50% 21. 12 Principles of Green Chemistry

  • 3.Minimize Hazardous Conditions:
  • Design process to avoid using reagents that pose safety threat
  • 12.Safer Chemistry-Accident Prevention:
  • Design processes that minimize hazards to environment and human health

22. 12 Principles of Green Chemistry

  • 4.Design Safer Products:
  • Products should be designed to effect their desired function while minimizing toxicity
  • Example: Use of single enantiomer drug vs racemate

23. 12 Principles of Green Chemistry

  • 5.Use Safer Solvents/Auxiliaries
  • Use of innocuous solvents should be considered (e.g. water, supercritical CO 2 )
  • Avoid use of unnecessary substances
  • (e.g. drying agents, column chromatography)

24. 12 Principles of Green Chemistry

  • 6.Design for Energy Efficiency:
  • Energy requirements for a process should be recognized for environmental and economic impact
  • Examples : avoid extreme cryogenics (-78o C)
  • Avoid prolonged reaction times

25. 12 Principles of Green Chemistry

  • 7.Use of Renewable Raw Materials:
  • Use a renewable source rather that depleting whenever technically and
  • economically feasible.
  • example: plant-derived RM; microbial reactions

26. 12 Principles of Green Chemistry

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

27. 12 Principles of Green Chemistry

  • 9.Catalysis:
  • Use of catalytic reagents is far superior than stoichiometric amounts
  • Example: using air as a source of oxygen for oxidation reaction

28. 12 Principles of Green Chemistry

  • 10.Design for Degradation:
  • Ideally, process products and by-products should breakdown into innocuous materials and/or do not persist in the environment

29. 12 Principles of Green Chemistry

  • 11. Real Time Analysis:
  • Analytical methods designed for real-time
  • In-process monitoring/control of a reaction
  • Example:Reactor-IR(in-situ probe for monitoring reactions)

30. 13 Principles of Green Chemistry

  • Process Economics -Minimize inventory cost of API via:
  • Low cost RM
  • Productive/Efficient Reactions
    • High Yield
    • Highly concentrated
    • Few Steps
    • Short time cycles
    • Few Vessels

31. Case Studies from Merck

  • Remoxipride-----schizophrenia
  • Crixivan-----AIDS
  • Emend-----Depression, Emesis
  • L778,123----Cancer

32. Case Study 1: Remoxipride Selective Dopamine-2 Antagonist Indication: Anti-psychotic (Depression/Schizophrenia) Clinical Trials: halted in 1993 due to anemia side-effects 33. Original Bromination 34. Improved Bromination 35. Other Examples Auerbach, WeissmanTet Letters 1993,931 36. Useful Methodology 37. Case Study 2: Crixivan HIV Protease Inhibitor-AIDS therapy FDAApproval - March 1996 Fastest FDA Approval Ever (42 Days) Daily Dosage: 2400 mg 38. Retrosynthetic Analysis of Crixivan-I 39. Retrosynthetic Analysis of Crixivan-II 40. Synthesis of Pyrazine Carboxamide Drawbacks: 1. Use of costly Oxalyl Chloride 2. CO and CO 2by-products 3. Lengthy time cycle due to exothermic amination reaction 4. Need for 3 equiv of volatilet


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