Sources and Types of Impurities by Professor Beubenz

Useful for B Pharmacy Students

Subscribe to the YouTube Channel #Professor_Beubenz

https://www.youtube.com/channel/UC84jGf2iRN5VjwnQqi6qmXg?view_as=subscriber

1. SOURCES AND TYPES OF IMPURITIES BY # PROFESSOR _BEUBENZ

RSCP, BULDHANA Page 1

SOURCES AND TYPES OF IMPURITIES
Sant Gadge Baba Amravati University, Amravati
B PHARM I
st
YEAR


By:
Mr. S. L. KHAN
M PHARM (PhD),
ASSISTANT PROFESSOR,
PHARMACEUTICAL CHEMISTRY DEPARTMENT,
RAJARASHI SHAHU COLLEGE OF PHARMACY, BULDHANA
Subscribe to the YouTube Channel #PROFESSOR _BEUBENZ
https://www.youtube.com/channel/UC84jGf2iRN5VjwnQqi6qmXg?view_as=subscriber

2. SOURCES AND TYPES OF IMPURITIES BY # PROFESSOR _BEUBENZ

RSCP, BULDHANA Page 2

IMPURITY PROFILING
The description, characterization and quantitation of identified and unidentified impurities
present in the drug substances is known as impurity profile.
IMPURITIES
Impurities are substances that are present in small quantities in another substance and make it
dirty or of an unacceptable quality.
In pharmaceuticals there are unwanted chemicals that even in small amounts may influence the
efficacy and safety of the pharmaceutical products.
TYPES OF IMPURITIES
● By products
● Degradation products
● Interaction products
● Intermediates
● Penultimate intermediate
● Related products
● Transformation products
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

3. SOURCES AND TYPES OF IMPURITIES BY # PROFESSOR _BEUBENZ

RSCP, BULDHANA Page 3

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…


esidual 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.
SOURCES OF IMPURITIES IMPURITIES
A. ASSOSSIATED IN WITH APIs
a) Organic
b) Inorganic
c) Residual Solvents

B. IMPURITIES RELATED TO FORMULATION
a) Method Related
b) Environment Related
c) Dosage Form Related

C. FORMATION OF IMPURITIES ON AGING
a) Ingredient Interaction
b) Functional Group Degradation

4. SOURCES AND TYPES OF IMPURITIES BY # PROFESSOR _BEUBENZ

RSCP, BULDHANA Page 4

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:
1) Starting Materials or Intermediates
2) By – Products
3) Degradation Products
4) Reagents, Ligands and Catalysts
5) Enantiomeric Impurities

1) STARTING MATERIALS OR INTERMEDIATES
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
2) BY - PRODUCTS
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
3) DEGRADATION PRODUCTS
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 β– actum ring and an a-amino group in
side chain leads to degradation.

5. SOURCES AND TYPES OF IMPURITIES BY # PROFESSOR _BEUBENZ

RSCP, BULDHANA Page 5

4) REAGENTS, LIGANDS, AND CATALYSTS
These are less commonly found in APIs. In some cases they may pose a problem as impurities.
They may entrap into the crystals of final product.
5) ENANTIOMERIC IMPURITIES
Single enantiomeric form of chiral drug offers 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)

INORGANIC IMPURITIES
1) Reagents, Ligands & Catalysts
These create problems unless manufacturer does not take care of it.
2) Heavy Metals
The main sources of heavy metals are the water used in the processes and the reactors.
Remedy: Using demineralized water & glass lined reactor.
3) Other materials: Filler Aids, Charcoals…
Regular monitoring of fibers & black particles in bulk drugs is essential to avoid these
contaminations.

6. SOURCES AND TYPES OF IMPURITIES BY # PROFESSOR _BEUBENZ

RSCP, BULDHANA Page 6

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.
Class 1 Solvents:
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 etc…
Class 3 Solvents:
Acetic acid, acetone, isopropyl alcohol, butanol, ethanol, ethyl acetate have permitted daily
exposure of ≤ 50mg/day.
IMPURITIES RELATED TO FORMULATION
METHOD RELATED
A known impurity, 1-(2,6-diclorophenyl)indolin-2-one is formed in production of a parenteral
dosage form of Diclofinac Sodium when sterilized by autoclave. The formation of this impurity
has been found to depend on the initial pH of the formulation. Concentration of impurity in the
resultant product in the ampoule exceeds the limit of the raw material in the BP.
ENVIRONMENTAL RELATED
a) Exposure To Adverse Temperatures
Vitamins as drug substances are very heat-sensitive & degradation frequency leads to loss
of potency
b) Light – Especially Uv Light
Ergometrine as well as methyl ergometrine injection is unstable under topical conditions
such as heat and light.

7. SOURCES AND TYPES OF IMPURITIES BY # PROFESSOR _BEUBENZ

RSCP, BULDHANA Page 7

c) Humidity
For hygroscopic products, like aspirin & ranitidine humidity is considered detrimental to
both bulk powder and formulated dosage forms
DOSAGE FORM RELATED IMPURITIES
 Water contents
 Microbial Growth (bacteria, fungi & yeast)
 pH of solution / Suspension
 Compatibility of Anions & Cations
 Mutual interactions of ingredients
 Primary containers

FORMATION OF IMPURITIES ON AGING
MUTUAL INTERACTION AMONGEST INGREDIENTS
of vitamins such as folic acid, pantothenic acid, cyanocobalamin, and thiamine do
not give toxic impurities.
vitamines (nicotinamide, pyridoxine, riboflavin, & thiamine) causes degradation of thiamine to a
sub-standard level within a 1-year shelf life of vitamin B-complex injections.
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…

8. SOURCES AND TYPES OF IMPURITIES BY # PROFESSOR _BEUBENZ

RSCP, BULDHANA Page 8

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
elicit 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.
In ciprofloxacin eye drops preparation (0.3%), sunlight induces photo cleavage reaction
producing ethylenediamine along with ciprofloxacin.
Eg: Ergometrine, nifedipine, nitroprusside, riboflavin, phenothiazines, etc...
DECARBOXYLATION
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.
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