The description, characterization and quantitation of identified and unidentified impurities present in the drug substances is known as impurity profile. IMPURITIES in pharmaceuticals are unwanted chemicals, that even in small amounts may influence the efficacy and safety of the pharmaceutical products.

1. BY
NADIKATLAANUSHA
M.Pharm

2. CONTENTS
1 Impurity profiling
2 Types of impurities
3 Isolation of impurities
4 Characterization of impurities
5 Sources of impurities
ANUSHA NADIKATLA

3. IMPURITY PROFILING
The description, characterization and quantitation of identified
and unidentified impurities present in the drug substances is
known as impurity profile.
IMPURITIES in pharmaceuticals are unwanted chemicals,
that even in small amounts may influence the efficacy and
safety of the pharmaceutical products.
ANUSHA NADIKATLA

4. TYPES OF IMPURITIES
● By products
● Degradation products
● Interaction products
● Intermediates
● Penultimate intermediate
● Related products
● Transformation products
ANUSHA NADIKATLA

5. ISOLATION OF IMPURITIES :
● liquid liquid chromatography
● Column chromatography
● Solid phase extraction methods
● Thin layer chromatography
● High performance liquid chromatography
● Supercritical fluid chromatography
CHARACTERIZATION OF IMPURITIES :
● LC MS / MS
● GC /MS
● FTICR - MS ANUSHA NADIKATLA

6. The different pharmacopoeias such as BP and USP are incorporating
limits to available levels of impurities present in APIs or
formulations.
International Conference On Harmonization (ICH) has published
guidelines on impurities in
 New drug substances
 Drug products
 residual solvents.
According to ICH guidelines on impurities in new drug products ,
identification of impurities below the 0.1% level is not considered to
be necessary.
In all cases, impurities should be qualified.
ANUSHA NADIKATLA

7. According To ICH Guidelines
MAXIMUM
DAILY DOSE
REPORTING
THRESHOLD
IDENTIFICAT
I-ON
THRESHOLD
QUALIFICATI
-ON
THRESHOLD
≤2 gm/day 0.05 %
0.1 %
(or)
1.0 mg/day
0.15 %
(or)
1.0 mg/day
˃2 gm/day 0.03 % 0.05 % 0.05 %
ANUSHA NADIKATLA

8. SOURCES OF IMPURITIES
IMPURITIES
ASSOSSIATED
IN WITH APIs
IMPURITIES
RELATED TO
FORMULATION
FORMATION
OF
IMPURITIES
ON AGING
• ORGANIC
•INORGANIC
•RESIDUAL
SOLVENTS
•METHOD
RELATED
•ENVIRONMENT
RELATED
•DOSAGE FORM
RELATED
•INGREDIENT
INTERACTION
•FUNCTIONAL
GROUP
DEGRADATION
ANUSHA NADIKATLA

9. IMPURITIES ASSOCIATED IN WITH APIs
ORGANIC IMPURITIES :
They may arise during the manufacturing process and/or storage of drug
substance.
They may be identified or unidentified, volatile or non-volatile , and
include the following :
● STARTING MATERIALS OR INTERMEDIATES
● BY – PRODUCTS
● DEGRADATION PRODUCTS
● REAGENTS, LIGANDS AND CATALYSTS
● ENANTIOMERIC IMPURITIES
ANUSHA NADIKATLA

10. • Although the end products are
always washed with solvents,
there are always chances of
having residual un reacted starting
materials
• Ex : p-aminophenol in
paracetamol
STARTING
MATERIALS
OR
INTERMEDIA
-TES
• Getting a single end product with
100% yield is very rare; there is
always a chance of having a by
product
• Ex : Diacetylated paracetamol in
paracetamol bulk
BY -
PRODUCTS
ANUSHA NADIKATLA

11. • Degradation products resulting from
storage or formulation to different
dosage forms or aging are common
impurities.
• Ex : In case of Penicillins and
Cephalosporins presence of ß – lactum
ring and an a-amino group in side chain
leads to degradation.
DEGRADATION
PRODUCTS
• These are less commonly found in
APIs.
• In some cases they may pose a
problem as impurities.
REAGENTS,
LIGANDS, AND
CATALYSTS
ANUSHA NADIKATLA

12. ENANTIOMERIC IMPURITIES :
Single enantiomeric form of chiral drug offer a better
pharmacological profile and an increased therapeutic index
with a more favourable adverse reaction profile.
However, the pharmacokinetic profile of Levofloxacin
(S- isomeric form)and Ofloxacin (R-isomeric form) are
comparable, suggesting lack of advantages of single isomer.
Marketed single isomer drugs include :
• Levofloxacin (S-ofloxacin)
• Levalbuterol (R-albuterol)
• Esomeprazole (S-omeprazole)
ANUSHA NADIKATLA

13. INORGANIC IMPURITIES
ANUSHA NADIKATLA

14. SOLVENT RESIDUES :
These are organic volatile chemicals used during the
manufacturing process or generated during the production.
Depending on possible risk to human health, residual solvents
are divided in to 3 classes.
Solvents such as benzene (Class 1, 2 ppm limit) & carbon
tetrachloride (Class 1, 4 ppm limit) are to be avoided.
Class 2 solvents : methylene chloride, methanol, pyridine,
toluene, acetonitrile.
Class 3 solvents : acetic acid, acetone, isopropyl alcohol,
butanol, ethanol, ethyl acetate have permitted daily exposure
of ≤ 50mg/day.
ANUSHA NADIKATLA

15. IMPURITIES RELATED TO FORMULATION
METHOD RELATED
A known impurity, 1-(2,6-dicloriphenyl)indolin-2-one is
formed in production of a parentral dosage form of diclofenac
sodium when sterilized b autoclave.
The formation of this impurity has been found to depend on
the initial pHof the formulation
The concentration of impurity in the resultant product in the
ampoule exceeds the limit of the raw material in the BP.
ANUSHA NADIKATLA

16. EXPOSURE
TO ADVERSE
TEMPERATU
RES
• Vitamins as drug
substances are very
heat-sensitive &
degradation frequency
leads to loss of potency
LIGHT –
ESPECIALL
Y UV LIGHT
• Ergometrine as well as
methyl ergometrine
injection is unstable
under topical conditions
such as heat and light
HUMIDITY
• For hygroscopic products,
like aspirin & ranitidine
humidity is considered
detrimental to both bulk
power and formulated
dosage forms
ENVIRONME-
NTAL
RELATED
ANUSHA NADIKATLA

17. ANUSHA NADIKATLA

18. FORMATION OF IMPURITIES ON AGING
MUTUAL INTERACTION AMONGEST INGREDIENTS
Degradation of vitamins such as folic acid, pantothenic acid,
cyanocobalamin , and thiamine do not give toxic impurities.
Because of mutual interaction, the presence of nicotinamide in a
formulation containing 4 vitamines (nicotinamide, pyridoxine, riboflavin,
& thiamine) causes degradation of thiamine to a sub-standard level with
in a 1-year shelf life of vitamin B-complex injections
ANUSHA NADIKATLA

19. FUNCTIONAL RELATED TYPICAL DEGRADATION
ESTER HYDROLYSIS :
Eg : Formation of salicylic acid impurity from aspirin,
benzocaine,
cefotaxime,
cocaine,
ethyl paraben, etc..
HYDROLYSIS :
Eg : benzylpenicillin,
barbitol,
chloramphenicol,
chlordiazepoxide,
lincomycin, and oxazepam, etc.. ANUSHA NADIKATLA

20. OXIDATIVE DEGRADATION :
Eg : Hydrocortisone,
adenazolam,
hydroxyl group directly bonded to an aromatic ring,
conjugated dienes,
heterocyclic aromatic rings,
aldehydes, etc..
PHOTOLYTIC CLEAVAGE :
In susceptible comounds, photochemical energy creates free
radicle intermediates, which can perpetuate chain reactions.
Most compounds will degrade as solutions when exposed to high
energy UV exposure.
Fluoroquinolones antibiotics are found to be susceptible to
photolytic cleavage.
ANUSHA NADIKATLA

21. In ciprofloxacin eye drops preparation (0.3%), sunlightinduces
photo cleavage reaction producing ethylenediamine along with
ciprofloxacin.
Eg : Ergometrine,
nifedipine,
nitroprusside,
riboflavin,
phenothiazines, etc..
DECARBOLYATION :
Some dissolved carboxylic acids, such as p-aminosalicylic acid,
lose carbon dioxide from the carboxyl group when heated.
Decarboxylation also occurred in the case of photoreaction of
rufloxacin.
ANUSHA NADIKATLA

22. ACCORDING TO ICH GUIDELINES REFERENCING SIM OR FORCED
DEGRADATION
GUIDELINE
REFERENC
E
TITLE
REF. TO SIM / FORCED
DEGRADATION
Q3A(R2) Impurities in New
Drug substances
Page 2:The registration application
should include documented evidence
that the analytical procedures have
been validated an are suitable for the
detection and quantification of
impurities
Q3B (R2) Impurities in New
Drug products
Page 2:The registration application
should include documented evidence
that the analytical procedures have
been validated an are suitable for the
detection and quantification of
degradation products

23. CRITICAL FACTORS REGARDING BULK DRUGS’
QUALITY
During crystallization
Washing the wet cake
Drying
Appropriate packaging
Use of protection method based on stability studies
Measures by pharmacopoeias.
ANUSHA NADIKATLA

24. REFRRENCES
 ICH, Draft Revised Guidance on Impurities in
New Drug Substances. Q3A (R). Federal
Register. 2ooo;65(140):45085-45090.
 ICH, Draft Revised Guidance on Impurities in
New Drug Products. Q3B (R). Federal Register.
2ooo;65(139):44791-44797.
 Ahuja S.Impurities Evaluation of
pharmaceuticals. New York:Marcel Dekker;1998.
 Gorog S. Identification and determination of
Impurities In Drugs. Amsterdam: Elsevier
Science Publishing company;2000.
ANUSHA NADIKATLA

25. ANUSHA NADIKATLA