Selection of synthetic route for API

1. Selection of Synthetic
Route and ROS
Template
By
Veerabhadrarao Bobbili
Asst Manager- R&D

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4. Sr.No Topics
1 Introduction
2 Principles of Route selection
3 Impact of the good route selection on life
cycle of drug substance
4 Examples
5 Summary

6. S E L E C T
S SAFETY
E ENVIRONMENTAL
L LEGAL
E ECONOMICS
C CONTROL
T THROUGHPUT

7. SAFETY

8. Flixborough, UK, 1974 Allentown, PA, 1999
Pasadena, TX, 1989

9. SAFETY
Potential Safety Issues and Their
Significance
Prediction and Assessment of Safety
Issues
Prediction and Assessment of Safety
Issues
Designing a Safer New Route

10. SAFETY
Potential Safety Issues and Their Significance
8) Pyrophoric and highly flammable materials.
1) Thermal runaway
2) Gas evolution
3) Potentially explosive, shock sensitive materials
4) Highly corrosive materials
5) Acute toxicity
6) Chronic toxicity
7) Genotoxicity

11. SAFETY
Prediction and assessment for safety issues
 By reading Safety data sheets of the RM
 COSHH (Control of substances to hazardous to health )
 Understanding the nature of reaction and reaction
mechanism
 Study the heat of the reaction HR

12. SAFETY
Desk screening
Literature search
1) Bretherick's Handbook of Reactive Chemical Hazards
2) National fire protection Association’s manual of hazardous
chemicals.
Desktop calculations
1) Oxygen balance and CHETAH calculations
2) Molecules contain hazardous functional groups
Ref:- Frurip, D. J.; Freedman, E.; Hertel, G. R. International Symposium
on Runaway Reactions, Boston, 1989; CCPS/Institute of Chemical
Engineers: New York, 1989; p 39.
Prediction and assessment for safety issues

13. SAFETY
Prediction and assessment for safety issues
Thermal screening
 Used to primarily at the lab scale development
Instruments like DSC, Carius tube, TSU, RSD and DTA
these techniques used to examine the thermal stability of
the reactant and reaction mixture
Techniques such as Carius tube, TSU, RSD, and Radex have
the ability to measure the pressure as well as temperature
excursions

14. SAFETY
Options to manage the Safety issues
Early Stage review with CFT
Brainstorm with cross functional teams
Process safety
Reactive chemicals
Industrial Hygiene
Operations
EHS
Regulatory
Business technology team

15. SAFETY
Options to manage the Safety issues
Inherent safety design
• Recognized in 1970’s for chemical industry
– Trevor Kletz, “What You Don’t Have Can’t Leak”
• Inherent - “existing in something as a permanent and
inseparable element...”
– safety “built in”, not “added on”
• Eliminate or minimize hazards rather than control
hazards

16. SAFETY
Options to manage the Safety issues
Strategy Examples
Substitute Replace material with a less hazardous substance.
Minimize Use smaller quantities; eliminate unnecessary equipment;
reduce size of equipment or volumes processed.
Moderate Use less hazardous conditions, a less hazardous form of
material or facilities which minimize the impact of a
release.
Simplify Design facilities which eliminate unnecessary complexity
and make operating errors less likely.

17. SAFETY
Options to manage the Safety issues
Identify the critical reaction class and modify the
reaction intrinsically safe.
According to Stoessel Diagram
1.Class-A
2.Class-B
3.Class-C
4.Class-D
5.Class-E
References:
1)Hofelich, T. C.; Thomas, R. C. The Use/Misuse of the 100 °C Rule in the Interpretation of
Thermal Hazard Tests. International Symposium on Runaway Reactions, Boston, 1989;
CCPS/Institute of Chemical Engineers: New York, 1989; p 74.
(2) Stoessel, F.; Fierz, H.; Lerena, P.; Kille, G. Org. Process Res. DeV. 1997, 1 (6), 428

18. SAFETY
Options to manage the Safety issues
Stoessel Diagram
A B C D E

19. SAFETY
Example of Idoxifene
Iodine- Lithium halogen
exchange HR = -53kJ/mole
Carbon-Carbon bond
formation HR = -126kJ/mole

20. Environmental
Potential Environmental Issues and Their Significance
(1)ENVIRONMENTAL IMPACT
(a) Toxicity (human, plant, and animal)
(b) Ozone depletion
(c) Climate change
(2) SUSTAINABILITY
(a) Depletion of natural resources;
(b) High mass of materials used and waste generated
(c) Energy-inefficient processes

21. Environmental
Prediction and assessment of Environmental Issues
(1)Solvent usage
(2)) Atom economy
(3)Reaction mass efficiency (RME)
(4) Mass productivity
(5) Carbon efficiency
(6) Environmental factor
Reference:
a)Constable, D. J. C.; Curzons, A. D.; Cunningham, V. L. Green Chem. 2002, 4, 521
b) TY - BOOKAU - P. Dicks, AndrewAU - Hent, AndreiPY - 2015/09/01SP -17 EP -
44SN - 978-3-319-10499-7T1 - Atom Economy and Reaction Mass Efficiency.

22. Environmental

23. Environmental

24. Environmental

25. Environmental
Options to manage Environmental Issues
(1) Telescoping the stages together
(2)Avoid the need of isolating the toxic intermediate
(3) Develop process with High catalyst turn over and
remove the stoichiometric reagents
(4) Solvents use is responsible for the 60% of the over all
energy used in the process and accounts for the 50% of
the post treatment of Green house emission
Reference:
Fujita, K. Org. Lett. 2004, 6 (20), 3525

26. Environmental
Designing a greener Route
Avoiding the Use of a Mercury Reagent.
Reference:
Lee, S. A. J. Fluorine Chem. 2001, 109 (1), 55.

27. Legal
Potential Legal issues and their significance
Regulated substances
1) Use of controlled or banned substances
2) Using unacceptable quantities of COMAH
3) Transportation of certain hazardous materials
4) Use of materials with third party restrictions
Patent infringement
1) Direct infringement
2) In-direct infringement
3) Doctrine of Equivalence

28. LegalPrediction and assessment of Legal issues
Regulated substances
Ex:- Acetic anhydride, Phenyl
acetone, Methanol, Ethanol,
Ammonium chloride ..Etc
Pseudoephedrine

29. Legal
Prediction and assessment of Legal issues
Merck Index
Synthline
Orange Book
Becker’s Associate
Drug bank
Rx list
Physicians desk references
Pharmacopoeia
Martindale
EMEA
CDER
USPTO
Espacenet
Patents lens
FPO

30. Legal
Prediction and assessment of Legal issues
NCE expiry date
Possible modification on
base patent
Prior art ROS
Polymorph claims
Passible impurities claims
PSD/ surface area claims

31. LegalOptions to manage Legal issues

32. Potential economic issues
Failing to meet the CoG target
Unacceptable investment cost during
development
Licensing costs for third party IP
Economic Issues

33. Economic Issues

34. Economic Issues
Options to mange the economic issues
1.Product Volume
2.Asset costs and depreciation
3.Man power
4.Cost of raw materials and reagents
5. license cost
6.Supplier margin profit
7.Throughtput

35. Control Issues
Manufacture API according to FDA
published guidelines and in compliance
with ICH and equivalent guidelines in
EU and ROW
Control of API quality is achieved
through control of chemical and
physical parameters in the
process

36. Control Issues
Potential Control Issues
(1) Nonselective reactions (chemo-, regio-, and
stereo)
(2) The chemical stability and physical properties
of each intermediate and reagent
(3) The number and efficiency of potential
purification points in the route.

37. Control Issues
Options to manage Control Issues
 Detailed understanding of the reaction mechanism
and to screen alternative catalysts and conditions
 DoE
 PAT (Process analytical technology )
 QBD

38. “ Amount of material (in gm/kg/Ton) that can be
manufactured in unit time”

39. Throughput Issues
Potential Throughput Issues
1.Chemical Yield
2.The capacity, number & types of processing vessels
3.Cycle time
4. Number of Unit operations
5.Special equipment's like Chromatography
6.Use of protection & deprotection
7. Poor availability of Raw materials.

40. Throughput Issues
Options to manage Throughput Issues
1. Improve the chemical yield
2. Minimum amount reaction volume and work up
volume
3. Reduce the lengthy operations
4. Avoid heterogeneous reaction conditions
5. Don’t go for chromatography
6. Avoid protection and deprotection
7. KSM selection and vendor approval is crucial

42. Further reading
a) P. J. Dunn, The importance of Green Chemistry in Process Research and
Development, Chem. Soc. Rev., 2012, 41, 1452-1461.
b) R. B. Leng, M. V. M. Emonds, C. T. Hamilton and J. W. Ringer, Holistic Route
Selection, Org.Process Res. Dev., 2012, 16, 415-424.
c) R. Dach, J. J. Song, F. Roschangar, W. Samstag and C. H. Senanayake, The Eight
CriteriaDefining a Good Chemical Manufacturing Process, Org. Process Res.
Dev., 2012, 16, 1697-1706.
d) I. W. Davies and C. J. Welch, Looking Forward in Pharmaceutical Process
Chemistry, Science, 2009, 325, 701-704.
e) H. - J. Federsel, Chemical Process Research and Development in the 21st
Century: Challenges, Strategies, and Solutions from a Pharmaceutical Industry
Perspective, Acc. Chem. Res., 2009, 42, 671-680.
f) N. G. Anderson, Assessing the Benefits of Direct Isolation Processes, Org.
Process Res. Dev., 2004, 8, 260-265.
g) T. Y. Zhang, Process Chemistry: The Science, Business, Logic, and Logistics,
Chem. Rev., 2006, 106, 2583-2595.

43. Further reading
h) C. - K. Chen and A. K. Singh, A “Bottom-Up” Approach to Process
Development:Application of Physicochemical Properties of Reaction Products
toward the Development of Direct-Drop Processes, Org. Process Res. Dev.,
2001, 5, 508-513.
i) P. J. Dunn, Pharmaceutical Green Chemistry process changes - how long does
it take to obtain regulatory approval?, Green Chem., 2013, 15, 3099-3104.
J) D.E. Troy., “Drug Price Competition and Patent Term Restoration Act of 1984
(Hatch-Waxman Amendments)”, Before the Senate Committee on the Judiciary,
01-August, 2003).
k) http://www.osha.gov/
l) Pharmaceutical R&D, Costs, Risks and Rewards; Office of Technology
Assessment, Congress of the U.S.: 1993; Appendix G, p 302.
m) Federsel, H.-J.; Larsson, M. Asymmetric Catalysis on Industrial Scale;
Wiley: 2004; p 413.

44. Summary
 Route selection addressees the tough economics,
regulatory hurdles , have less time for development
 A variety of different process issues can prevent
scale up of a synthetic route. These issues grouped
in six category's S-Safety, E- Environment, L-legal, E-
Economics , C- Control, T- throughput.
 Discussed the potential issues and how predict and
circumvent those issues

46. Thank You,
Bhadra.