Define Impurities, 3 Types of Impurities, 13 Sources of Impurities - Raw martials, Reagents used, Methods used, Chemical process, Solvent, Atmospheric contamination, Intermediate process, Defect in manufacturing process, Manufacturing hazards, Impurities due to Storage condition, Impurities due to Crystal packing, Decomposition of product, Adulteration.

1. GRACE SHAJI CHITTILAPPILLY
ASSISTANT PROFESSOR
DEPT. OF PHARMACEUTICAL CHEMISTRY
KARPAGAM COLLEGE OF PHARMACY, COIMBATORE-32
12-01-2024
Dept. of P. Chemistry, KCP
1

2. Introduction
Types of Inorganic Impurities
Sources of Impurities
Effect of Impurities
Determination of Impurities
12-01-2024
Dept. of P. Chemistry, KCP 2

3.  Impurity: The impurities in pharmaceuticals are the unwanted chemicals that
remain with the active pharmaceutical ingredients(APIs), or develop during
formulation , or upon aging of both API and formulated APIs to medicines.
 The pharmaceutical preparation should be free from toxic and other impurities.
 Pharmacopoeias prescribe limits for harmful compounds present in the
substances.
12-01-2024
Dept. of P. Chemistry, KCP 3

4. TYPES OF INORGANIC IMPURITIES
1. Toxic Impurities: Impurities are very harmful and can cause death when taken once or in
short period of time.
Eg: Arsenic, Lead
2. Cumulative Impurities: This type of impurities shows their toxicity when it is taken over
a period of time.
Eg: Heavy metals
3. Harmless Impurities: This impurities may not cause harm to body but reduce the
therapeutic activity of active ingredient when it is present in large quantities.
Eg: Chlorides, Sulphates
12-01-2024
Dept. of P. Chemistry, KCP 4

5. SOURCES OF IMPURITES
o Raw materials
o Reagents used
o Method/Process used in the Manufacture
o Chemical processes used in Manufacture
o Atmospheric contamination
o Solvents
o Intermediate products
o Defect in manufacturing process
o Manufacturing hazards
o Impurities due to Storage condition
o Impurities due to Crystal Packing
o Decomposition of Products
o Accidental Substitution or Deliberate Adulteration
12-01-2024
Dept. of P. Chemistry, KCP 5

6. 1. Raw Materials
• Bismuth salts: Tin, lead, silver, copper, cobalt and gold metals occur along with bismuth in bismuth
ores.
• Rock salt contain small amount of calcium sulphate and magnesium chloride, so Sodium chloride
prepared from this source contain traces of calcium and magnesium compounds.
• Copper sulphate prepared by action of sulphuric acid on copper turnings. Copper turnings are known
to have iron and arsenic as impurities.
2. Reagents used
• Ammonium hydroxide as impurity in the preparation of Ammoniated mercury (prepared by adding
solution of Mercuric chloride to dilute ammonia solution). It can be removed by washing properly with
water.
+ H2SO4 CuSO4 + O
H2 + SO2
Cu
HgCl2 + 2NH4OH NH2HgCl + NH4Cl + 2H2O
soluble soluble soluble
Ammoniated
mercury(ppt)
12-01-2024
Dept. of P. Chemistry, KCP 6

7. • Soluble alkali as impurity in calcium carbonate which is made by reacting calcium chloride and
sodium carbonate.
• Potassium bromide contains traces of Barium, which is added in the manufacturing process to remove
excess of sulphate.
3. Method/Process used in the Manufacture
• Equipments used in the manufacturing process of drugs is constructed from glass, silica, earthenware,
wood, rubber, silver, copper, lead, iron, steel, aluminium, nickel, tin and different alloys, most of this
metallic substance react with some organic compounds and mineral acids and contaminate the final
products.
4. Chemical Process used in Manufacture
• Tap water used in various process contain chloride, calcium and magnesium as impurities, which are
generally found in the substance which is being manufactured.
12-01-2024
Dept. of P. Chemistry, KCP 7

8. 5. Atmospheric Contamination
• Atmosphere is contaminated with dust particles and some gases like Hydrogen sulphide, Sulphur
dioxide, and black smoke, these impurities may enter the final pharmaceutical product during
manufacture or purification.
• Eg: NaOH absorb atmospheric CO2, due to this reaction NaOH should not be kept open for a longer
time during its manufacture.
6. Solvents
• Water is a solvent easily available and cheap and is used in the manufacture of inorganic chemicals. This
can give rise to trace impurities such as sodium, calcium, magnesium, carbonate, chloride and sulphate
ions.
• These difficulties do not arise in the use of Purified water (Softened water, Demineralised and Distilled
water)
2NaOH + CO2 Na2CO3 + O
H2
12-01-2024
Dept. of P. Chemistry, KCP 8

9. 7. Intermediate Product
• Sodium bromide is prepared by reaction of sodium hydroxide and bromine in slight excess where
sodium bromate an intermediate product is reduced to sodium bromide by heating the residue with
charcoal.
• Sodium bromate become an impurity if it is not completely converted to the sodium bromide.
• Potassium iodide is prepared by reacting Iodine with Potassium hydroxide. The resulting solution is
first evaporated and then heated with charcoal.
• KIO3 which is the intermediate act as impurity if it is not completely converted into KI.
6NaOH + 3Br2 NaBrO3 + 5NaBr + 3H2O
NaBrO3 + 3C NaBr + 3CO
6KOH + 3I2 5KI + KIO3 + 3H2O
KIO3 + 3C KI + 3CO
12-01-2024
Dept. of P. Chemistry, KCP 9

10. 8. Defect in manufacturing process
• Manufacturing process defects are like imperfect mixing, incompleteness, non-adherence to proper
temperature, pressure, pH or reaction conditions which may give chemical compounds with impurities
in them.
• Eg: Zinc oxide may contain metallic zinc as impurity (due to less heat or air or both) when prepared by
heating metallic zinc to bright redness in a current of air. The vapour of zinc burns to form Zinc oxide
which is collected as a fine white powder.
9. Manufacturing hazards
a) Particulate contamination
b) Process errors
c) Cross contamination
d) Microbial contamination
e) Packing errors
12-01-2024
Dept. of P. Chemistry, KCP 10

11. a) Particulate contamination
 The presence of unwanted particulate matter can arise due to dirt, dust, glass, porcelain, plastic or
metallic fragments from sieves, granulating, tableting and filling machines or from product containers.
 Ware and tare of equipment or improperly cleaned equipment may also cause particulate
contamination.
 Clarity of solutions for injection is important.
b) Process error
 Gross errors: Due to incomplete solution of a solute in a liquid preparation must be detected readily by
the normal analytical control procedures.
 Minor errors: When manufacturing tolerance for the quantity of active ingredient in the product has
been wide.
12-01-2024
Dept. of P. Chemistry, KCP 11

12. c) Cross contamination
 Occur when 2 or more products are manufactured in same time.
 The handling of powders, granules, and tablets in large bulk creates air-borne dust, which leads to
cross contamination of the product.
 Use of face masks and special extraction equipment protect operators from harmful effects of drugs.
d) Microbial contamination
 Parenteral preparations and ophthalmic preparations require special care against microbial
contamination.
 Many liquid preparations and creams are liable to bacterial and fungal contamination from
atmosphere during manufacturing.
e) Packing errors
 Products of similar appearance such as tablets of same size, shape, colour packed in similar containers
– major source of danger.
 Improper labelling or destruction of stock of unused labels.
12-01-2024
Dept. of P. Chemistry, KCP 12

13. 10. Impurities due to Storage condition
• Leaching out effect: Alkalies stored in ordinary glass containers extract lead from it and is found as
impurity in the final product.
• Strong chemicals react with iron containers and extract Iron an impurity in final product.
• Plastic containers and closures have tendency to give undesirable additives, such as plasticizers,
particularly in the presence of non-aqueous solvents.
Inadequate Storage and their effects:
a) Filth: Stored products may become contaminated with dust, bodies of insects, animal and insect
excreta.
Stored
substance
Material of
storage vessel
Product formed
are found as
impurities in the
stored materials
12-01-2024
Dept. of P. Chemistry, KCP 13

14. b) Reaction with container materials: salicylic acid ointment must not be stored in metal tubes.
c) Chemical instability: Pharmaceutically important substances undergo chemical decomposition
when storage conditions are inadequate. This chemical decomposition is often catalyzed by light,
traces of acid or alkali, traces of metallic impurities, air oxidation, carbon dioxide and water vapours.
d) Changes in Physical Properties: There can be changes in crystal size and shape, sedimentation,
agglomeration and caking of the suspended particles during storage.
e) Temperature: The rate of chemical decomposition and physical changes of stored products depends
upon the temperature. The substances will have temperature storage requirements assigned to them in
order to protect them against undesirable decomposition.
• Eg: 1. Ferrous sulphate converted into insoluble ferric oxide by air and moisture.
2. Surgical solution of chlorinated soda rapidly deteriorates when exposed to light and heat.
3. Iodine reacts with rubber corks and some metals, therefore should be preserved in glass bottles
with glass stoppers.
12-01-2024
Dept. of P. Chemistry, KCP 14

15. 11. Impurities due to Crystal Packing
• In solids, reactions are very sensitive to crystal packing.
• Eg: Drugs like Cephalosphorin and tetracycline crystallization effect is very important. Polymorphic
transformations affect the properties of creams and if wrong polymorph is used, phase transformation
occurs Cream become gritty and cosmetically unacceptable.
12. Decomposition of Products
• Chemical substance undergo changes due to careless storage and presence of air, light and oxygen.
• All chemicals should be stored in tightly closed containers made of dark glass and extremes of
temperature should be avoided.
• Eg: Soln. of KOH absorbs atmospheric CO2 and exerts a solvent action on lead containing glass,
therefore preserved in lead free air tight bottles of green glass.
• Deliquescent substances, absorb water from the atmosphere and get liquefied. Eg: Pellets of Sodium
hydroxide are deliquescent.
• Sunlight affects many chemicals. Eg: Bismuth carbonate turns black on exposure to sunlight for a long
period, so should be stored in a dark place.
12-01-2024
Dept. of P. Chemistry, KCP 15

16. 13. Accidental Substitution or Deliberate Adulteration
• Accidental substitution can be prevented by storing toxic substances separately.
• Deliberate adulteration by cheaper, spurious, inferior, defective or harmful substances is a
common practice in case of scarcity and price of drug is high.
• Eg: The expensive potassium bromide may be adulterated with sodium bromide.
12-01-2024
Dept. of P. Chemistry, KCP 16

17. SOURCES OF IMPURITIES
Raw
Materials
Method of
Manufacturing
Manufacturing
Hazards
Instability of
Products
• Reagents used
• Intermediate products
• Reagents used to
eliminate impurities
• Solvents used
• Atmospheric
contamination
 Contamination from
matter
 Cross contamination
 Contamination by
Microbes
 Errors in
Manufacturing
 Errors in storage and
packaging
o Chemical
instabilities
o Physical
instabilities
o Reaction with
container
o Temperature
12-01-2024
Dept. of P. Chemistry, KCP 17

18. EFFECT OF IMPURITIES
Impurities having toxic effects may be injurious to health, if present above certain limits.
Traces of impurities, may exert a cumulative toxic effect after a certain time.
Impurities may lower the active strength of the substance.
Impurity may decrease shelf life of substance.
Impurity may cause incompatibility with other substances.
Impurities may cause a physical or chemical change in the properties of the substance, so making the
substance medicinally useless.
May cause change in color, odour and taste.
12-01-2024
Dept. of P. Chemistry, KCP 18

19. DETERMINATION OF IMPURITIES (Test for Purity)
1. Colour, Odour and Taste
2. Physico-chemical constants (Iodine value, saponification value, melting point, refractive index
etc.)
3. Acidity, alkalinity and pH
4. Insoluble residue
5. Humidity (Estimation of moisture)
6. Cations and anions
7. Ash value
8. Loss on drying and Ignition
9. Organic and Carbonisable substances
10. Assay
12-01-2024
Dept. of P. Chemistry, KCP 19

20. Think like a proton, Always positive……
12-01-2024
Dept. of P. Chemistry, KCP
20