IMPURITIES-IN-PCEUTICAL-SUB-PIC-SEM-I.pdf

Impurities

1. Impurities in pharmaceutical
substances

2. Impure chemical compound-A compound said to be impure if it is
having foreign matter.

3. It is virtually impossible to have absolutely pure
chemical compounds and even
analytically pure chemical compounds contain minute
trace of impurities.
Impurities = a foreign unwanted matter present in a
compound which are differ from the actual molecular
formula.
Chemically a compound is impure if it contains
undesirable foreign matter i.e. impurities.
Thus chemical purity is freedom from foreign matter.

7. 1. Biproduct impurity:
In synthetic chemistry getting a single product with 100% yield is a very rare as
there is always a chance of some biproduct with desired end product.
E.g., In case of synthesis of paracetamol diacetylated paracetamol may be form as
biproduct.







2. Degradation product:
Impurity is also be form of degradation of end product during manufacturing of
bulk drug.
Degradation product resulting from storage or formulation to different dosage or
aging are common impurities in the medicines.
For examples- antibiotics, vitamins, injection etc.
3. Intermediate product:
This product are form within the reaction & sometimes this intermediate do not get
converted into end product & remains as impurity with end product.
Example- potassium iodide is prepared by the reaction of potassium hydroxide and
iodine.

8. 4. Reagent, ligand and catalyst-
These are the chemicals used to carry out various reaction, their impurities
are less commonly found in API.
5. Enantiomeric impurities: stereoisomers ( enantiomers and
diastereomers) are related products, similar to drug substance with
potential toxicological side effect or alter physiochemical property.
b) Inorganic impurity-
It involve reagent, ligand, catalyst, heavy metal or other residual metals,
inorganic salts, filter aids, charcoal etc.
Inorganic impurity may also obtain from the manufacturing processes
used for bulk drug, they are normally known and identified are as follows-
1. Reagent, ligand and catalyst- chances of having this impurity are rare.
Example- when calcium chloride is reacted with sodium carbonate it forms
the precipitation of calcium carbonate. If the precipitates are not properly
wash it may remains as an impurity. The pharmacopoeia prescribe the limit
of tolerance for soluble alkali and chloride as impurity.

9. 2. Heavy metals- The main sources of heavy metal are the water
used in the process and reactors.
3. Other material- (filter aids, charcoal)
C) Residual solvents- Residual solvents are organic volatile
chemicals during the manufacturing process or generated during the
production. It is very difficult to remove the solvents completely by
the work process. However some efforts should be taken to the
extend possible to meet safety data. residual solvent are classified
into three classes.
I) Class I solvents- solvents to be avoided.
II) Class II solvents- solvents to be limited.
III) Class III solvents- solvents to be low toxic potential.

10. There are various sources of impurity in pharmaceutical substances are as
follows-
1. Raw material
2. Method of manufacturing
i) Reaction vessels
ii) Reagent used
iii) Solvent used
iv) Intermediate
3. Manufacturing hazards
i) Particulate contamination
ii) Process error
iii) Packing error
iv) Cross contamination
v) Microbial contamination

Sources of impurities:

11. 4. Improper storage ( instability)
i) Temperature effect
ii) Reaction with container material
5. Atmospheric contamination
6. Deliberated adulteration

12. 1. Raw material-



The impurity is already present in raw material may pass onto the final
product through the manufacturing process, hence the final product may
found to be contaminated with these impurity.
e.g., 1. zinc sulphate is prepared by reacting either zinc oxide or zinc
metal with sulphuric acid it forms-





Zinc metal & zinc oxide contain aluminum, copper, ferric ( Fe),
magnesium( Mg), Nickel (Ni), Arsenic( As) as a impurity. This
impurity are lightly to be carried in the manufacturing process in
applicable amount of final product.

13. 2) Method of manufacturing

a) Reaction vessel:



The reaction vessels is employed in manufacturing process may be
metallic such as copper, iron, silver, aluminum, zinc and lead.
Some reagent employed in the manufacturing process may react with
metal to form corrosion and passing traces of metals impurity into the
solution that containing the final product.
Similarly glass vessels may give traces of alkali to the solvent.
e.g., strong acids leaches out alkali from borosilicate glass etc.
b) Reagent used
Calcium carbonate contain soluble alkali as impurity that arises from
sodium carbonate employed in the process.
Calcium carbonate is prepared by reaction of calcium chloride with
sodium carbonate, the product should contain soluble carbonate,
therefore the final product ( calcium carbonate) is contain small
amount of soluble alkali as impurity which can not be removed by
washing process.

14. c) Solvents used



Most of the pharmaceutical substances are prepared in solvents, small
amount of solvents employed in the preparation of inorganic
compounds and reaction intermediates.
Water is the cheapest solvent and can be a major source of impurity.
There are different types of waters. Generally used waters are-
1 Tap water- contain impurities of calcium, magnesium, sodium,
chloride, carbonate & sulphate in the form of ions in trace amount.
The use of water in large state can lead to contamination of final
product.
2) Softened water- if is almost free from divalent ions (Ca & Mg)
but contain more amount of sodium and chloride ions.
3) Demineralize water- it is prepared by ion exchange method &
free from sodium, calcium, magnesium, chloride, sulphate and
carbonate etc.
It may have pyrogen, bacteria and organic impurity.it is better than
tap water but in use of this water microbes & organic impurity may
contaminate the final product.

15. 4) Distilled water
It is free from organic & inorganic impurities and therefore it is
best solvent but quite expensive.
d) Intermediates: sometimes an intermediate substance
produce during the manufacturing process may contaminate the
final product.
e.g., potassium iodide is prepared by reaction of iodide with
potassium hydroxide.
3) Manufacturing hazards
There are various mfg hazards these are as follows-
1)Contamination from particulate matter
2)Error in the mfg process
3)Packaging error
4)Cross contaminations
5)Microbial contamination

16. 4) Improper storage
There are many chemical substances which may undergo changes
due to careless storage. The improper storage condition & their
defects are as follows-
1. Temperature effect
The rate at which the chemical decomposition & physical changes
occur in storage of product depends upon temperature.
The temperature storage requirements assign to the pharmaceutical
if order to protect the substances as per pharmacopoeia.
2. Reaction with container material
The possibility of reaction between the container material &
content constituents are not be ignored.
The cream & ointments are liable to react with metal surface.
For example- salicylic acid ointment must not be store & pack in
metal tube.

17. 5) Atmospheric contamination
Atmosphere may contain dust & some gases like carbon dioxide,
arsenic & hydrogen sulphide.
This may contaminate the final product during manufacturing
process.
Some substances which are susceptible to action by carbondioxide
with water during their preparation.
Example- NaOH readily absorb atmospheric carbondioxide when
exposed to the atmosphere.

6) Deliberate adulteration
Deliberate adulteration means a process of addition of impure, cheap,
useless & spurious substances to the genuine drug.