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5
General Information
(vi) Biological contamination i.e., contamination by microbes
(vii) Packaging
1.5.2 Types of Impurities
Impurities can be classified into the following categories:
(a) Organic impurities
(b) Inorganic impurities
(c) Residual solvents
(d) Extraneous or foreign matter
(a) Organic Impurities
Organic impurities can arise during the manufacturing process and storage of the drug
substance. They can be identified or unidentified, volatile or nonvolatile.
(b) Inorganic Impurities
Inorganic impurities also derive from the manufacturing processes used for bulk drugs.
Mostly they are the traces of inorganic reagents used in manufacturing or the elemental impurities
arising from the vessels. They are normally known and identified.
(c) Residual Solvents
These are the traces of solvents used in the manufacturing process or contamination from the
atmosphere. As per ICH guidelines they are categorized as class-I, class-II, and class-III solvents
depending on their toxicity profile.
(d) Extraneous or Foreign Matter
Any foreign matter in product associated with objectionable conditions or practices in
production, storage, or distribution; included are filth, decomposed material (decayed tissues due
to parasitic or nonparasitic causes), and miscellaneous matter such as sand and soil, glass, rust, or
other foreign substances. Bacterial counts are excluded.
1.5.3 Acceptance Criteria for Impurities
It is recommended that the specifications for a drug substance should include, where
applicable:
Each identified specified impurity.
Each unidentified impurity.
Total impurities.
6
A Textbook of Pharmaceutical
Chemistry
Residual solvents.
Inorganic impurities.
For a drug product, it should include:
Each specified degradation product.
Any unspecified degradation product.
Total degradation products.
The limits of impurities depend on the toxicity of the impurity and the dose of the drug.
1.6 STORAGE CONDITIONS IN PHARMACEUTICALS
Proper storage of pharmaceuticals from the manufacturing unit till it reaches the consumer is
very important. The loss of potency due to improper storage may influence the efficacy and safety
of pharmaceuticals. Pharmaceutical products require controlled storage and transit conditions to
ensure that their quality is not compromised. Storage is an important aspect of the total drug
control system. Proper environmental control (i.e., temperature, light, humidity, conditions of
sanitation, ventilation and segregation) must be maintained wherever drugs and supplies are
stored on the premises. Following are the temperature conditions defined in Indian
Pharmacopoeia.
Sr. No. Conditions Justification
1. Cold condition
Between 2-8C not exceeding 8C
2. Cool condition
Any temperature between 8-25C
3. Room temperature Working area temperature
4. Warm condition
Any temperature between 30-40C
5. Excessive heat condition
Any temperature above 40C
1.7 SOLUBILITY IN PHARMACEUTICALS
Solubility is the intrinsic property of a solid, liquid, or a gaseous chemical substance called
solute to be dissolved in another solid, liquid, or gaseous chemical called a solvent. Solubility of a
drug is very important in designing its formulation. It is also an important factor in
pharmacokinetics i.e., absorption, distribution, and excretion of the drug. The solubility of a
substance fundamentally depends on the solvent used as well as on temperature and pressure.
Following are the solubility terms defined in Indian Pharmacopoeia.
7
General Information
Sr. No. Solubility Parts
1. Very soluble less than 1 part
2. Freely soluble from 1 to 10 parts
3. Soluble from 10 to 30 parts
4. Sparingly soluble from 30 to 100 parts
5. Slightly soluble from 100 to 1000 parts
6. Very slightly soluble from 1000 to 10,000 parts
7. Practically insoluble more than 10,000 parts
General Information
8
Chapter
Limit Tests
Limit tests are performed to monitor the levels of trace elements, ions, impurities in the drug
substances or drug products.
2.1 LIMIT TEST FOR HEAVY METALS
Heavy metals are generally defined as metals with relatively high density, atomic weights, or
atomic numbers.
These tests are based on the reaction of metallic impurities with hydrogen sulfide in acidic
conditions to form a brownish color solution. Heavy metals that respond to this test are lead,
bismuth, mercury, arsenic, cadmium, silver, copper, and molybdenum. The metallic impurities in
substances are expressed as parts of lead per million of the substance. The limit given as per I.P.
is 20 parts per million (20 µg/g).
Procedure
As per I.P. (Indian Pharmacopoeia), three methods are used for limit test of heavy metals
detection.
Method-I
This method is mainly used for substances that produce clear colorless solutions under
specific condition.
Test Sample Standard Solution
1. Prepare the solution as per the monograph and
transfer 25 mL of it in color comparison tube or
Nessler’s cylinder.
2. Adjust the pH between 3 to 4 by adding dilute acetic
acid solution or dilute ammonia solution.
3. Dilute with water up to 35 mL.
4. Add freshly prepared 10 mL of hydrogen sulfide
solution.
5. Dilute with water up to 50 mL.
1. Take 2 mL of standard lead solution and dilute to 25
mL with water in color comparison tube or
Nessler’s cylinder.
2. Adjust the pH between 3 to 4 by adding dilute acetic
acid solution or dilute ammonia solution.
3. Dilute with water up to 35 mL.
4. Add freshly prepared 10 mL of hydrogen sulfide
solution.
5. Dilute with water up to 50 mL.
2
9
Limit Tests
6. Allow to stand for 5 minutes.
7. View downwards over a white surface.
6. Allow to stand for 5 minutes.
7. View downwards over a white surface.
Observation
The color produced in the sample solution should be less intense than a standard solution. If
the color produced in the sample solution is less intense than the standard solution, the sample
passes/complies with the limit test for heavy metals and vice versa.
Method II
This method is used for the substance which does not produce a clear colorless solution
under a given conditions.
Test Sample Standard Solution
1. Accurately weigh the test substance, moisten with
sulfuric acid and ignite on a low flame to complete
char. Add few drops of nitric acid, heat to 500C.
Allow to cool and add 4 mL of HCl and evaporate to
dryness. Moisten the residue with 10 mL of HCl and
digest for 2 minutes. Neutralize with ammonia
solution and make slightly acidic with acetic acid.
2. Adjust the pH between 3 to 4 by adding dilute acetic
acid solution or dilute ammonia solution.
3. Dilute with water up to 35 mL.
4. Add freshly prepared 10 mL of hydrogen sulfide
solution.
5. Dilute with water up to 50 mL.
6. Allow to stand for 5 minutes.
7. View downwards over a white surface.
1. Take 2 mL of standard lead solution and dilute to 25
mL with water.
2. Adjust the pH between 3 to 4 by adding dilute acetic
acid solution or dilute ammonia solution.
3. Dilute with water up to 35 mL.
4. Add freshly prepared 10 mL of hydrogen sulfide
solution.
5. Dilute with water up to 50 mL.
6. Allow to stand for 5 minutes.
7. View downwards over a white surface.
Observation
The color produced in the sample solution should be less intense than a standard solution. If
the color produced in the sample solution is less intense than the standard solution, the sample
passes/complies with the limit test for heavy metals and vice versa.
Method III
This method is used for the substance which produces a clear colorless solution in sodium
hydroxide solution.
Test Sample Standard Solution
1. Prepare the solution as per the monograph and
transfer 25 mL of it in color comparison tube or
Nessler’s cylinder.
2. Add 5 mL of dilute sodium hydroxide solution and
make up the volume to 50 mL with water.
1. Take 2 mL of standard lead solution in color
comparison tube or Nessler’s cylinder.
2. Add 5 mL of dilute sodium hydroxide solution and
make up the volume to 50 mL with water.
10
A Textbook of Pharmaceutical
Chemistry
3. Add 5 drops of sodium sulfide solution.
4. Mix and set aside for 5 minutes.
5. View downwards over a white surface.
3. Add 5 drops of sodium sulfide solution.
4. Mix and set aside for 5 min.
5. View downwards over a white surface.
Observation
The color produced in the sample solution should be less intense than a standard solution. If
the color produced in the sample solution is less intense than the standard solution, the sample
passes/complies with the limit test for heavy metals and vice versa.
2.2 LIMIT TEST FOR CHLORIDE
Apparatus Required
(i) Nessler’s cylinders
(ii) Glass rod
(iii) Stand
Chemicals Required
(i) Dilute nitric acid
(ii) Silver nitrate
(iii) Sodium chloride
Principle of Limit Test for Chloride
It is based upon the chemical reaction between silver nitrate and soluble chloride in presence
of dilute nitric acid to give opalescence due to the formation of silver chloride. The opalescence
produced in the test solution is compared with the standard solution. If the opalescence in the
sample is less dense than the standard, it passes/complies with the test. If it is denser than the
standard, it fails the test.
Reaction Mechanism
3
dil.HNO
3 3
Cl + AgNO AgCl + NO
Procedure
Take two 50 mL Nessler’s cylinders. Label one as ‘Test’ and the other as ‘Standard’.
Test Sample Standard Solution
1. Dissolve the specified quantity of the substance in
distilled water in Nessler’s cylinder.
2. Add 10 mL of dil. HNO
3
and make up with water up
to 50 mL.
1. Place 1 mL of 0.05845% w/v solution of sodium
chloride in Nessler’s cylinder.
2. Add 10 mL of dil. HNO
3
and make up with water up
to 50 mL.
11
Limit Tests
3. Add 1 mL of silver nitrate solution.
4. Stir with glass rod and allow to stand for 5 minutes.
3. Add 1 mL of silver nitrate solution.
4. Stir with glass rod and allow to stand for 5 minutes.
2.3 LIMIT TEST FOR SULFATE
Apparatus Required
(i) Nessler’s cylinders
(ii) Glass rod
(iii) Stand
Chemicals Required
(i) Dilute hydrochloric acid
(ii) Barium sulfate reagent (Mix 15 mL of 0.5 M BaCl
2
, 55 mL of water, and 20 mL of
sulfate-free alcohol and add 5 mL of 0.0181% w/v potassium sulfate. Dilute to 10 mL
with water and mix; dilute to 100 ml (instead of 10 mL)).
Principle of Limit Test for Sulfate
It is based upon the chemical reaction between barium chloride and soluble sulfate in
presence of dilute hydrochloric acid. The turbidity formed in the test solution is compared with
the standard solution. Barium sulfate reagent contains barium chloride, sulfate-free alcohol, and a
small quantity of potassium sulfate. The inclusion of a small quantity of potassium sulfate in the
reagent increases the sensitivity of the test. Alcohol prevents supersaturation and helps to develop
more uniform turbidity. If the turbidity produced in the test solution is more intense than the
standard solution, the sample fails the test. Otherwise, it passes/complies with the test.
Reaction Mechanism
dil.HCl
2
4 2 4
SO + BaCl BaSO + 2Cl
Procedure
Take two 50 mL Nessler’s cylinders. Label one as ‘Test’ and the other as ‘Standard’.
Test Sample Standard Solution
1. Dissolve the sample in distilled water and transfer
to a Nessler’s cylinder.
2. Add 2 mL of dilute hydrochloric acid, dilute to 45
mL with water and 5 mL of barium sulfate reagent.
3. Stir immediately with glass rod and allow to stand
for 5 minutes.
1. Transfer 1 mL of 0.1089% w/v solution of potassium
sulfate to a Nessler’s cylinder.
2. Add 2 mL of dilute HCl, dilute to 45 mL with water
and add 5 mL of barium sulfate reagent.
3. Stir immediately with a glass rod and allow to stand
for 5 minutes.
12
A Textbook of Pharmaceutical
Chemistry
2.4 LIMIT TEST FOR IRON
Apparatus Required
(i) Nessler’s cylinders
(ii) Glass rod
(iii) Stand
Chemicals Required
(i) Standard iron solution: (Dissolve 0.1726 gm of ferric ammonium sulfate in 10 mL of 0.1
N H
2
SO
4
and add sufficient water to produce 1000 mL.)
0.1N H
2
SO
4
(4.904 gm of conc. sulfuric acid in 1000 mL of water.)
(ii) Iron-free citric acid
(iii) Thioglycolic acid
(iv) Ammonia solution
Reaction Mechanism
+3 +3
2 2
Ferric iron
Thioglycollic acid
2
2
2
Ferrous thioglycollate
2Fe + 2CH SH.COOH 2Fe + S – CH – COOH
|
S – CH – COO 2H
CH SH OCO
Fe
COO HS– CH
Principle of Limit Test for Iron
The test is based on the reaction between ferrous iron and thioglycolic acid in the presence of
ammonia, where a pale pink to deep reddish-purple color is produced. Ferric iron is reduced to
ferrous iron by the thioglycolic acid and the compound produced is ferrous thioglycollate. Citric
acid forms a soluble complex with iron and prevents its precipitation by ammonia as ferrous
hydroxide. Ferrous thioglycollate is colorless in neutral or acid solutions. The color develops only
in the presence of alkali. It is stable in the absence of air but fades when exposed to air due to
oxidation to the ferric compound. Therefore the colors should be compared immediately after the
time allowed for the full development of color is over.
13
Limit Tests
Procedure
Take two 50 mL Nessler’s cylinders. Label one as ‘Test’ and the other as ‘Standard’.
Test Sample Standard Solution
1. Dissolve a specified quantity of the substance in 20
mL of water and transfer to Nessler’s cylinder.
2. Add 2 mL of a 20% w/v solution of iron free citric
acid, 0.1 mL of thioglycollic acid and mix.
3. Make alkaline with iron free ammonia solution and
dilute to 50 mL with water and allow to stand for 5
minutes.
1. Dilute 2 mL of standard iron solution with 20 mL of
water in a Nessler’s cylinder.
2. Add 2 mL of a 20% w/v solution of iron free citric
acid, 0.1 mL of thioglycollic acid and mix.
3. Make alkaline with iron free ammonia solution and
dilute to 50 mL with water and allow to stand for 5
minutes.
2.5 LIMIT TEST FOR LEAD
Apparatus Required
(i) Nessler’s cylinders
(ii) Glass rod
(iii) Stand
Chemicals Required
(i) Dilute acetic acid
(ii) Dilute ammonia
(iii) Hydrogen sulfide solution (Saturated H
2
S)
(iv) Standard lead solution
Lead Nitrate Stock Solution
Dissolve 0.1598 gm of lead nitrate in 100 mL of water; add 1 mL of a con. nitric acid and
dilute to 1000 mL with water.
Standard Lead Solution
Dilute 10 mL of the lead nitrate stock solution to 100 mL with water (20 ppm of lead).
Principle
It is based on the reaction between the solution of lead and a saturated solution of hydrogen
sulfide. In acidic media, it produces reddish/black color which is compared with color obtained
with standard lead nitrate solution.
Reaction Mechanism
Pb + H
2
S
PbS + H
2
14
A Textbook of Pharmaceutical
Chemistry
Procedure
Take two 50 mL Nessler’s cylinders. Label one as ‘Test’ and the other as ‘Standard’.
Test Sample Standard Solution
1. Place 25 mL of the solution in Nessler’s cylinder and
adjust the pH 3 to 4 using dilute acetic acid or dilute
ammonia solution.
2. Dilute to 35 mL with water and mix.
3. Add 10 mL of freshly prepared H
2
S solution.
4. Dilute to 50 mL with water. Mix well and allow to
stand for five minutes.
1. Place 2 mL of standard lead solution in a Nessler’s
cylinder and dilute to 25 mL with water. Adjust the
pH 3 to 4 by using dilute acetic acid or dilute
ammonia solution.
2. Dilute to 35 mL with water and mix.
3. Add 10 mL of freshly prepared H
2
S solution.
4. Dilute to 50 mL with water. Mix well and allow to
stand for five minutes.
2.6 LIMIT TEST FOR ARSENIC
The arsenic limit test is designed to monitor the allowable limit of arsenic in a given test
substance. The limit is expressed in terms of arsenic trioxide (As
2
O
3
). It is determined by a
special apparatus, known as the Gutzeit apparatus.
Lead
acetate
cotton
plug
Rubber
bang
Generator
bottle
Clip
Mercury chloride paper
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