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Introduction to Pharmaceutical Chemistry 17
Observation:
The purple color produced in sample solution should not be greater than standard solution.
If purple color produced in sample solution is less than the standard solution, then the sample will
pass the limit test of iron and vice versa.
Reasons:
Citric acid helps precipitation of iron by ammonia by forming a complex with it.
Thioglycolic acid helps to oxidize iron (II) to iron (III).
Iron Standard Solution:
Weigh 0.1726 g of ferric ammonium sulphate, and dissolve it in 10 ml of 0.1 N sulphuric acid
and sufficient water to produce 1000 ml. Each ml of this solution contains 0.02 mg of Fe.
1.4.6 Limit Test for Heavy Metals
Principle:
Limit test of heavy metals determine the content of metallic impurities with hydrogen sulfide
in acidic medium to form brownish color solution. Metals that respond to this test are lead,
mercury, bismuth, arsenic, antimony, tin, cadmium, silver, copper and molybdenum. The metallic
impurities in substances are expressed as parts of lead per million parts of the substance. The
usual limit as per Indian Pharmacopoeia is 20 ppm.
Procedure:
The Indian Pharmacopoeia has adopted three methods for the limit test of heavy metals.
Method 1: Used for the substance which gives clear colorless solution under the specific
condition.
Limit Test for Heavy Metals:
Test Sample
Standard Compound
1. Solution is prepared as per the monograph
and 25 ml is transferred in Nessler’s
cylinder.
1. Take 2 ml of standard lead solution and
dilute with 25 ml with water.
2. Adjust the pH between 3 to 4 by adding
dilute acetic acid ‘Sp’ or dilute ammonia
solution ‘Sp’.
2. Adjust the pH between 3 to 4 by adding
dilute acetic acid ‘Sp’ or dilute ammonia
solution ‘Sp’.
3. Dilute with water to 35 ml.
3. Dilute with water to 35 ml.
4. Add freshly prepared 10 ml of hydrogen
sulphide solution.
4. Add freshly prepared 10 ml of hydrogen
sulphide solution.
5. Dilute with water to 50 ml.
5. Dilute with water to 50 ml.
6. Allow to stand for five minutes.
6. Allow to stand for five minutes.
7. View downwards over a white surface.
7. View downwards over a white surface.
18 Text Book of Pharmaceutical Chemistry
Observation:
The color appeared in test solution should not be greater than standard solution. If color
produced in sample solution is less than the standard solution, the sample will pass the limit test
of heavy metals and vice versa.
Method II: Used for the substance which do not give clear colorless solution under the specific
condition.
Limit Test for Heavy Metals:
Test Sample
Standard Compound
1. Weigh specific quantity of test substance,
moisten with sulphuric acid and ignite on a
low flame till completely charred. Add few
drops of nitric acid and heat to 500°C.
Allow cooling and adding 4 ml of
hydrochloric acid and evaporate to
dryness. Moisten the residue with 10 ml of
hydrochloric acid and digest for 2 minutes.
Neutralize with ammonia solution and
make just acid with acetic acid.
1. Take 2 ml of standard lead solution and
dilute to 25 ml with water.
2. Adjust the pH between 3 to 4 and filter if
necessary.
2. Adjust the pH between 3 to 4 by adding
dilute acetic acid ‘Sp’ or dilute ammonia
solution ‘Sp’.
3. Dilute with water to 35 ml.
3. Dilute with water to 35 ml.
4. Add freshly prepared 10 ml of hydrogen
sulphide solution.
4. Add freshly prepared 10 ml of hydrogen
sulphide solution.
5. Dilute with water to 50 ml.
5. Dilute with water to 50 ml.
6. Allow to stand for 5 minutes.
6. Allow to stand for 5 minutes.
7. View downwards over a white surface
7. View downwards over a white surface.
Observation:
The color appeared in test solution should not be greater than standard solution. If color
produced in sample solution is less than the standard solution, then the sample will pass the limit
test of heavy metal and vice versa.
Method III: Used for the substance which gives clear colorless solution in sodium hydroxide
solution.
Introduction to Pharmaceutical Chemistry 19
Limit Test for Heavy Metals:
Test Sample
Standard Compound
1. Solution is prepared as per the monograph
and 25 ml is transferred in Nessler’s
cylinder or weigh specific amount of
substance, dissolve in 20 ml of water and
add 5 ml of dilute sodium hydroxide
solution.
1. Take 2 ml of standard lead solution.
2. Make up the volume to 50 ml with water.
2. Add 5 ml of dilute sodium hydroxide
solution and make up the volume to 50 ml
with water.
3. Mix and set aside for 5 minutes.
3. Mix and set aside for 5 minutes.
4. View downwards over a white surface.
4. View downwards over a white surface
Observation:
The color appeared in test solution should not be greater than standard solution. If color
produced in sample solution is less than the standard solution, then the sample will pass the limit
test of heavy metals and vice versa.
1.4.7 Limit Test for Arsenic
Arsenic is a well-known undesirable and harmful impurity which is present in medicinal
substance. In the limit test of arsenic, all arsenic present is converted into arsenic gas (AsH
3
) by
reduction with zinc and hydrochloric acid.
Principle:
Limit test of arsenic is based on the reaction of arsenic gas with hydrogen ion to form yellow
stain on mercuric chloride paper in the presence of reducing agents like potassium iodide. It is
also called as Gutzeit test and requires special apparatus.
When the sample is dissolved in acid, the arsenic present in the sample gets converted to
Arsenic acid. Arsenic, present as arsenic acid (H
3
AsO
4
) in the sample, is reduced to arsenious
acid (H
3
AsO
3
) by reducing agents like potassium iodide, stannous acid, zinc, hydrochloric acid,
etc. Arsenious acid is further reduced to arsine (gas) (AsH
3
) by hydrogen and reacts with mercuric
chloride paper to give a yellow stain.
H
3
AsO
4
+ H
2
SnO
2
→ H
3
AsO
3
+ H
2
SnO
3
Arsenic acid Arsenious acid
H
3
AsO
3
+ 3H
2
→ AsH
3
+ 3H
2
O
Arsenious acid Arsine
The extent of yellow stain on mercuric chloride paper will depend upon the quantity of
arsenic present in the sample.
20 Text Book of Pharmaceutical Chemistry
Apparatus:
➢ The apparatus is composed of a wide-mouthed glass bottle of 120 ml capacity having
mouth of about 2.5 cm in diameter. This bottle is fitted with a rubber bung through
which passes a glass tube, 20 cm long. External diameter = 0.8 cm and Internal diameter
= 0.65 cm.
➢ The tube is constricted at its lower end extremity to about 1 mm diameter and there is
blown a hole, not less than 2 mm in diameter, in the side of the tube near the constricted
part.
➢ The upper end of the glass tube is fitted with two rubber bungs (25 mm × 25 mm), each
having a hole bored centrally and exactly 6.5 mm in diameter.
➢ One of the bungs has been fitted to the upper end of the tube, while the second bung has
to be fitted upon the first bung in such a way that the mercuric chloride paper gets
exactly sandwiched between the central perforations of the two.
➢ The bungs are kept in close contact by using rubber band or spring clip in such a manner
that the gas evolved from the bottle must have to pass through the 0.65 mm internal
circle of mercuric chloride paper.
➢ During the test, the evolved gases have been passing through the side hole, the lower
hole serving as an exit for water which condenses in the constricted part of the tube.
➢ An important feature has been the standardization of the area of Mercuric chloride paper
which is exposed to the reaction of arsine gas.
Preparation of Standard Arsenic Solution (10 ppm As):
Dissolve 0.330 g of arsenic trioxide in 5 ml of 2 M sodium hydroxide and dilute to 250.0 ml
with water. Dilute 1 volume of this solution to 100 volumes with water.
Fig. 1.2: Apparatus for Arsenic Limit Test
Introduction to Pharmaceutical Chemistry 21
Procedure: Limit Test for Arsenic:
Test Sample
Standard Compound
1. The test solution is prepared by dissolving
specific amount in water and stannated
HCl (arsenic-free) and kept in a wide-
mouthed bottle.
1. A known quantity of dilute arsenic
solution in water and stannated HCl
(arsenic-free) is kept in wide-mouthed
bottle.
2. To this solution add 1 g of KI.
2. To this solution, add 1 g of KI.
3. Add 5 ml of stannous chloride acid
solution.
3. Add 5 ml of stannous chloride acid
solution.
4. Add 10 g of granulated zinc is added (all
this reagents must be arsenic free).
4. Add 10 g of zinc is added (all these
reagents must be arsenic-free).
5. Keep the solution aside for 40 minutes.
5. Keep the solution aside for 40 minutes.
6. Stain obtained on mercuric chloride paper
is compared with standard solution.
6. Compare the stain obtained on mercuric
chloride paper with standard solution
Observation:
Stain obtained on mercuric chloride paper is compared with standard solution. If the stain
produced by test is no deeper than standard stain, then sample completes the limit test for arsenic.
Inference:
After 40 minutes, if the intensity of the yellow stain produced in the standard is more than
that in the test, then the sample complies with the limit test of lead.
1.5 EXERCISE
A. Long Answer Type Questions
1. Discus the various sources of impurities present in the pharmaceutical substances.
2. Describe the procedure for the limit test for Arsenic.
3. Write a note on limit test of heavy metal.
4. Describe in brief the scope and objectives of pharmaceutical chemistry.
5. Write short notes on:
(a) Accuracy
(b) Precision
(c) Significant figures
6. Write the classification of errors with examples.
7. Write in brief rules for calculation of significant figures.
22 Text Book of Pharmaceutical Chemistry
B. Short Answer Type Questions
1. Explain limit test.
2. Give the principle for the limit test for iron
3. Define sources of impurities.
4. Define significant figure.
5. Give the method for limit test of sulphate.
6. What is the main scope of pharmaceutical chemistry?
7. Write about random or indeterminate errors.
8. Define precision.
C. Fill in the Blanks
1. Gutzeit apparatus is used in the limit test of ___________.
2. Sodium fluoride is used as a ___________
3. Pale pink to deep reddish purple color is produced in the limit test of ___________.
4. ___________ is defined as a how close a measurement is to the correct or accepted
value of the quantity being measured.
5. Errors can be classified into ___________ and ___________ errors.
Answers:
1. Arsenic, 2. Dental product, 3. Iron, 4. Accuracy, 5. determinate and indeterminate.
Chapter
2
VOLUMETRIC AND
GRAVIMETRIC ANALYSIS
STRUCTURE
2.1 Introduction to Pharmaceutical Analysis
2.2 Scope of Analytical Chemistry
2.3 Different Techniques of Analysis
2.4 Fundamental/Basic Principles Used in Volumetric Analysis
2.5 Different Types of Volumetric Analysis
2.6 Modern Concept of Acid and Bases
2.7 pH, pOH and Buffer Solution
2.8 Acid-Base Indicators
2.9 Theories of Acid-Base Indicators
2.10 Classification of Acid-Base Titrations
2.11 Types of Non-aqueous Solvents
2.12 Classification of Ionizing Solvents
2.13 Leveling and Differentiating Effect
2.14 Detection of End Point in Non-aqueous Titration
2.15 Acidimetric and Alkalimetric Titration
2.16 Assay of Sodium Benzoate
2.17 Types of Precipitation Titration
2.18 Types of Complexometric Titration
2.19 Metal Ion Indicators
2.20 Masking and Demasking Agents
2.21 Preparation and Standardization of 0.05 M Disodium Edetate Solution
2.22 Estimation of Magnesium Sulphate
2.23 Oxidation-Reduction Reaction (Redox Titration)
2.24 Redox Reaction
24 Text Book of Pharmaceutical Chemistry
2.25 Oxidation Number (Oxidation State)
2.26 Redox Titration
2.27 Redox Indicators
2.28 Principle of Gravimetric Analysis
2.29 Types of Gravimetric Analysis
2.30 Steps Involved in Precipitation Gravimetry
2.31 Purity of Precipitate
2.32 Exercise
OBJECTIVES
Volumetric Analysis: Fundamentals of Volumetric Analysis, Acid-Base Titration, Non-aqueous
Titration, Precipitation Titration, Complexometric Titration, Redox Titration.
Gravimetric Analysis: Principle and Method.
PART 1
VOLUMETRIC ANALYSIS
2.1 INTRODUCTION TO PHARMACEUTICAL ANALYSIS
Pharmaceutical analysis is a branch of chemistry that involves a series of processes for
identification, determination, quantization, purification, and structure elucidation of the given
compound used in the formulation of pharmaceutical products. Analysis can be done by using
various techniques and often used for the separation of the components from the mixture and for
the determination of the structure of the compounds. Pharmaceutical analysis is categorized into
two types: (1) qualitative (identification) and (2) quantitative (estimation).
1. Qualitative (identification):
This method of analysis is used for the identification of substances or components present in
the natural/synthetic samples. In this method, an unknown compound is analyzed to indicate
whether any specific chemical substance or component is present in the sample or not. Qualitative
analysis generally expresses the melting point, changes in color, odor, limit tests, reactivity,
boiling point and precipitation.
2. Quantitative (estimation):
This technique of analysis is mainly used to determine the quantity of compound or substance
present in the sample. In this method of analysis, the amount or concentration of an analyte may
be determined (estimated) and expressed as a numerical value in appropriate units.
Volumetric and Gravimetric Analysis 25
2.2 SCOPE OF ANALYTICAL CHEMISTRY
Analytical chemistry plays an important role in the pharmacy and pharmaceutical industries
for analysis of assay and purity of the drugs by using various instrumental techniques such as
titrimetric, spectroscopic, chromatographic and electrophoresis method of chemical analysis. The
scope of analytical chemistry in various fields is listed as follows:
➢ Analytical chemistry is concerned with qualitative and quantitative analysis of
substances.
➢ The importance of analytical chemistry lies in drug discovery, isolation and
standardization.
➢ Estimation of biological samples.
➢ It is used in food determination.
➢ It is important in quality control and quality assurance.
➢ It is also of great importance in different research areas.
➢ It is extensively used in new drug discovery and development.
➢ It is broadly concerned with the validation of analytical equipments.
➢ It is used in assay or analyses of the quality and quantity of chemical substances.
2.3 DIFFERENT TECHNIQUES OF ANALYSIS
26 Text Book of Pharmaceutical Chemistry
2.4 FUNDAMENTAL/BASIC PRINCIPLES USED IN VOLUMETRIC ANALYSIS
Volumetric analysis is a quantitative analytical method; also known as titrimetric analysis.
This method is used to measure the volume of a solution whose concentration is known and is
applied to the concentration of an analyte or known solution. In other words, in volumetric
analysis, measuring the volume of a second substance that combines with the first in known
proportions is known as volumetric analysis.
The various apparatus required for volumetric analysis are as follows:
➢ Weighing machine with a chemical balance.
➢ Pipette, burette measuring flasks, and measuring cylinders.
➢ Flasks for general titration, beaker, tile, glass rod, funnel, weighing bottle, and wash
bottle.
Basic Principles of Volumetric Analysis:
➢ The solution which we want to analyze contains a chemical of unknown amount.
➢ For the end-point, a reagent with an unknown concentration reacts with the chemical of
an unknown amount in the presence of an indicator (generally phenolphthalein) to show
the end-point.
➢ The reaction between the solution and the reagent is completed by titration which is used
to measure the volumes.
➢ The solution and the amount of reagent is shown by the volume and concentration of
reagent used in the titration.
➢ The mole fraction of the equation determines the amount of an unknown chemical in the
specific volume of solution. When the end-point of the reaction is reached, the volume
of reactant consumed is measured and applied to carry volumetric analysis calculations
of the analyte by the following formula.
Ca = Ct Vt M / Va
Where,
Ca is the analyte concentration, typically in molarity.
Ct is the titrant concentration, typically in molarity.
V is the volume of the titrant which is used, typically in litres.
M is the mole ratio of the analyte and reactant from the balanced equation.
V is the volume of the analyte, typically in litres.
Numerous non-acid-base titrations require a constant pH throughout the reaction.
Therefore, a buffer solution can be added to the titration chamber to maintain the pH
value.