Deals with the different steps involved in Drug Developments and role of chemists to reduce the impurities is discussed here

1. Impurities In Drug Synthesis
Dr. S. Sreenivasa
Associate Professor and Chairman
Department of Studies and Research
in Organic Chemistry
Tumkur University

2. New Diseases
• AIDS, Alzheimer, Bacterial Infections
• Anthrax, Obesity, Viral Infections
Low Efficacy
• Dementia
• Cancer
Side Effects
• Antidepressants, Antipsychotics
• Antidiabetic, Anticancer
Downstream Health Costs
• Alzheimer’s
• Spinal Injury
Sustain Industrial Activity
• Pharmaceutical industry’s Contribution to overseas
earnings
Why are new drugs needed?

3. Reason for New Diseases

5. • In the past most drugs have been
discovered either by identifying the active
ingredient from traditional remedies or by
serendipitous discovery.
• But now we know diseases are controlled
at molecular and physiological level.
• Also shape of an molecule at atomic level
is well understood.
• Information of Human Genome

6. • Random Screening
• Synthesis of organic compounds
• Separation of mixture from isolated products
• In vivo & In vitro analysis
• Molecular Manipulation
• Lead Identification of new active compounds
“Hits” by screening natural materials
(plants, animals, fungi etc.) for desired
biological properties
• Lead Optimization - synthetic modification of
hits to obtain maximum potency and
selectivity with minimum toxicity
• Development large scale production and
formulation for clinical trials and Testing.
Drugs Discovery Methods

7. Aspirin
Salicin from willow bark reacts with water to produce
glucose and salicyl alcohol. In the body, salicyl alcohol
is oxidized to salicylic acid which is the active
substance that reduces fever (antipyretic), pain
(analgesic), and inflammation (anti-inflammatory
agent) in humans

8. Although salicylic acid reduces pain, fever, and
inflammation, it is far too corrosive to tissues in the
stomach to be taken internally by most people. In
1893 Felix Hofman, a chemist working for the
Bayer firm in Germany, converted salicyclic acid to
acetylsalicylic acid which can be better tolerated by
most people. Development: current sales are about
80 billion tablets per year in US alone.

9. Identify and validate target protein Understanding
target metabolism
Preparing 2D/3D structures mole files, PDB formats of
lead compounds
Synthesis of active drugs
Identify lead compounds from data base
Calculating Molecular Surface Critical Points and
Quadratic Shape Descriptors
Molecular Designing / Modeling
Molecular dynamics simulations
Dock Ligands To Receptor and Scoring successfully

10. Chemical Synthesis:
• Involve production of lead compound in suitable
quantity and quality to allow large scale animal
and eventual, extensive human clinical trials
• Optimization of chemical route for bulk industrial
production.
• Suitable drug formulation
• Drug discovery experts today are facing a serious
challenge because of the increased cost and
enormous amount of time taken to discover a new
drug, and also because of fierce competition
amongst different drug companies

11.  Approx. 10 to 17 years
 Approx. 1000 million dollars
TIME & COST OF NEW DRUG

13. Drug Discovery & Development
Identify disease
Isolate protein
involved in
disease (2-5 years)
Find a drug effective
against disease protein
(2-5 years)
Preclinical testing
(1-3 years)
Formulation
Human clinical trials
(2-10 years)
Scale-up
FDA approval
(2-3 years)

14. Administrative Support Analytical Chemistry Animal Health Anti-infective Disease Bacteriology
Behavioral Sciences Biochemistry Biology Biometrics Cardiology Cardiovascular Science Clinical Research
Communication Computer Science Cytogenetics Developmental Planning DNA Sequencing Diabetology
Document Preparation Dosage Form Development Drug Absorption Drug Degradation Drug Delivery
Electrical Engineering Electron Microscopy Electrophysiology Environmental Health & Safety Employee Resources
Endocrinology Enzymology Facilities Maintenance Fermentation Finance Formulation
Gastroenterology Graphic Design Histomorphology Intestinal Permeability Law Library Science Medical Services
Mechanical Engineering Medicinal Chemistry Molecular Biology Molecular Genetics Molecular Models
Natural Products Neurobiology Neurochemistry Neurology Neurophysiology Obesity
Oncology Organic Chemistry Pathology Peptide Chemistry Pharmacokinetics Pharmacology Photochemistry
Physical Chemistry Physiology Phytochemistry Planning Powder Flow Process Development
Project Management Protein Chemistry Psychiatry Public Relations Pulmonary Physiology
Radiochemistry Radiology Robotics Spectroscopy Statistics Sterile Manufacturing Tabletting Taxonomy
Technical Information Toxicology Transdermal Drug Delivery Veterinary Science Virology X-ray Spectroscopy
Over 100
Different
Disciplines
Working Together
Pharmaceutical R&D is
A Multi-Disciplinary Team

16. Impurity
• Impurity is Undesirable element or substance
commonly or naturally contained in something
that lowers the quality or value of the
material, but (depending on its amount) may
or may not make it unfit for its intended use.
Impurity in API
• Presence of impurity in trace quantity is
inevitable.
• Control and monitored.
• Effect may be teratogenic, mutagenic or
carcinogenic

17. By-products:
Because of incomplete reaction over reaction,
isomerization,,dimerization , rearrangement etc.
• Nanodralone deconoate
17OH and 4ene-3-oxo group leads to enol
ester impurity
• Enantiomer – Levefloxacin S & R

18. Inorganic Impurities:
• Heavy metals like As, Bi, Cd, Cr, Cu, Fe,
Pb, Hg, Ni, Na, Pt and Pd.
• Limit tests are available.
• Easily avoided by using demineralized
water and glass reactors
Residual Solvents
• Modify the property of certain API
compound.
• Effect physiochemical properties of the
bulk drug.
Crystallinity, dissolution, colour, odor etc.

19. Class 1 Solvents:
• Benzene (Carcinogen, 2 ppm)
• CCl4 (toxic 4 ppm)
• 1,1-dichloro ethane (toxic 8 ppm)
• 1,2-dichloroethane (toxic 5 ppm)
These solvents are not employed in bulk drug
manufacturing.
Class 2 Solvents
• Acetonitrile (410 ppm)
• Chlorobenzene (360 ppm)
• Chloroform (60 ppm)
• Cyclohexane (3880 ppm)
Usage is limited to pharmaceutical products only –
toxicity

20. Class 3 Solvents:
• Acetic acid, Anisole, Butanol, Methyl ether, Formic
acid, Pentanol.
• Less toxic
• long term effects are not known.
• No serious health hazards are reported.
Class 4 Solvents
• Dimethoxy propane, Methyl isopropyl ketone,
Isoocatne, Petroleum ether, trichloro acetic acid
• Adequate toxicology data are not avilable.
• Manufacturer has to justify the limit.

21. Impact of Impurities in API
• Can be toxic
• Can degrade the API
• Can alter the quality of the API
• Can render the API unusable.
Quantify
• All impurities needs to be identified and
quantified.
• Limit has to be defined for consumption.
• Proper validated method has to be used for
quantification.
• Genotoxic impurities has to be identified,
characterized and quantified.

22. Limits
• The limit of the impurities in the API will be specified
based on the daily usage.
• Normally it is Not More than 0.1% on the API quantity
• If they are genotoxic, it is Not More than 50 ppm or
based on the toxicity it also can even be less and can
be ppb levels.
• ICH guidelines will be used for specifying the limits.
• The limits vary from country to country
-US FDA for US, MHRA for Europe, TGA for Australia,
FDA for India etc.
• Each country will have its own guidelines
• ICH guidelines are commonly followed.

23. Removal by purification
For Solids
– Crystallization
– Precipitation
– Solvent wash
– Chromatographic Purification
For Liquids
– Distillation
– Can be simple or complicated including
fractional distillation, vacuum distillation, high
temperature distillation etc.

25. Synthesis of Diketones
Scheme 1
Disadvantage:
• Isolation of product and impurities was very
difficult.
• Strong base NaH quenching time is long and
extra care should be taken while doing.
Example: Ferrocene-containing β-Diketones
2,3-diketopiperazine oxytocin antagonist

26. Alternate Route of Synthesis:
Advantage:
• Impurities are minimized.
• Mild base and economical.
• Quenching of base during work up.
• Purification is easy.

27. Synthesis of Pyrazoline Derivatives
Scheme 2
Disadvantage:
• In this method at high temperatures stability of the
diketone is very less.
Example:
3-n- Nonylpyrazole -antimicrobial
Celecoxib- COX 2 inhibitor

28. Alternate Route of Synthesis:
Advantage:
• Impurities are minimized.
• Good yield obtained
• Low reaction Temperature.

29. Synthesis of N-BOC Piperazine
Scheme 3; Step 1
Disadvantage:
• Very less yield.
• Isolation of the product is difficult
• Both product and by product are having same Rf.
Eg: Amoxapine- Antideprasant,
Cetrazine-anti histamine

30. Alternate Route of Synthesis:
Advantage:
• Impurities are minimized.
• Good yield obtained.
• Mild base used and no extra care taken.
• Low reaction Temperature.

31. Synthesis of Cyanopiperazine Derivative
Scheme 3; Step 2
Disadvantage:
• Very less yield.
• Isolation of the product is difficult
• Both product and by product are having same Rf.
Example: m-cl phenyl piperazine-psychoactive
benzylpiperazine - stimulant

32. Alternate Route of Synthesis:
Advantage:
• Impurity was completely minimized.
• Excellent yield obtained.

33. Synthesis of Oxadiazole Derivatives
Scheme 3; Step 3
Disadvantage:
• Very less yield.
• Isolation of the product is difficult
Example: Furamizole -AB. Zibotentan –anti cancer

34. Alternate Route of Synthesis:
Scheme 3; Step 3
Advantage:
• Excellent yield.
• Isolation of the product is easy

35. Synthesis of Thiazole Drivatives
Scheme 4
Disadvantage:
• An impurity is largely formed.
• The BOC is unstable in acidic condition
Example: Aztreonam, Cefovecin, Cefpirome,-Antibiotic
Nitrosoprodenafil –Plumonory hypertension

36. Alternate Route of Synthesis:
Advantage:
• Impurities are minimized.
• Mild basic condition.
• Less hazardous.
• Purification is easy.

37. Synthesis of Pyrrole Derivatives
Scheme 5
Disadvantage:
• Because of strong base NaH used methyl chrotonate
is converted to sodium salt of Chrotonate leving
behind 1-((isocyanomethyl)sulfonyl)-4-methylbenzene
second starting material unreacted.
Example: Toceranib - tumor, Viminol, Semaxanib,-
analgesics and Amtolmetin guacil- antiinflamatory.

38. Alternate Route of Synthesis:
Advantage:
• Impurities are minimized.
• Organic base less hazards than inorganic base
• Reaction Fast.

39. Synthesis of Triazines Derivatives
Scheme 6
Disadvantage:
• Low yield.
• Isolation of the product is difficult
• Both product and by product are having same Rf.

40. Alternate Route of Synthesis:
Advantage:
• Impurities are minimized.
• Good yield obtained.
• Strong dehydrating agent .

41. Synthesis of Triazines Derivatives
Scheme 7
Disadvantage:
• Impurity observed.
• Isolation of the product is difficult

42. Alternate Route of Synthesis:
Advantage:
• Impurity was minimized.
• Good yield obtained.

43. Route of Synthesis (RoS)
Innovator Route of Synthesis
Mapi Route of Synthesis
HMDS Bis( trimethylsily) amine

44. Acknowledgement
Dr. K. S. Shridhara Bhat
Email: shridharabhat@yahoo.co.in
Dr. N. L. Shashidhara
Email: shashidhara@synuslab.com
Dr. N. R. Mohan
Email: nrmohana@gmail.com