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35
Titrations
Sequestering Agent (Solubilising Agent)
These agents form water-soluble chelates with metals. Mainly used for removal of water
hardness or to remove dirt from clothes by forming soluble complexes.
Metal Ion Indicators (Metallochromic Indicators)
The indicators used in complexometric titrations are called metallochromic indicators. It is
an ionochromic dye that undergoes a definite color change in presence of a specific metal ion. It
forms a weak complex with metal ions.
These indicators should have the following ideal characteristics
The color reaction should be specific.
The metal-indicator complex must be less stable than the metal-EDTA complex.
The indicator must be very sensitive to metal ions.
Indicators used in complexometric titration are shown below:
Sr. No. Name of Indicators Color Change pH Range Metals Detected
1 Mordant black-II Red to Blue 6-7 Ca, Ba, Mg, Zn, Cd,
Mn, Pb, Hg
Eriochrome black T
Solochrome black T
2 Murexide or Ammonium
purpurate
Violet to Blue 12 Ca, Cu, Co
3 Catechol violet Violet to Red 8-10 Mn, Mg, Fe, Co, Pb
4 Methyl blue Blue to Yellow 4-5 Pb, Zn, Cd, Hg
Thymol blue Blue to Grey 10-12
5 Alizarin Red to Yellow 4.3 Pb, Zn, Co, Mg, Cu
6 Sodium alizarin sulfonate Blue to Red 4 Al, Thorium
7 Xylenol orange Lemon to Yellow 1-3 Bi, Thorium
4-5 Pb, Zn
5-6 Cd, Hg
Preparation of 0.05M Disodium EDTA Solution
Dissolve 18.6 g of disodium EDTA in water and make up the volume to 1000 mL.
Standardization of 0.05M Disodium EDTA Solution (As per USP)
Accurately weigh about 0.2 g of calcium carbonate previously dried at 110 C for 2 hours.
Add 10 mL of water and 2 mL of dilute HCl acid shake to dissolve and dilute with water to about
100 mL. Add about 30 mL of disodium EDTA solution from a burette. Add 15 mL of sodium
36
A Textbook of Pharmaceutical
Chemistry
hydroxide TS and 300 mg of hydroxy naphthol blue and continue the titration with disodium
EDTA solution to form a blue color as an endpoint.
Factor: 0.0050 g of calcium carbonate is equivalent to 1 ml of 0.05 M disodium EDTA.
M =
3
______ g CaCO × 1000
100.0869 × ______ mL EDTA Vol.
Types of Complexometric Titration
Let us know about different ways in which we can use EDTA in titrations.
1. Direct Titration
It is the simplest and the most convenient method in which the standard solution of EDTA is
slowly added to the metal ion solution till the endpoint is achieved. It is similar to simple acid-
base titrations. For this method to be useful, the complex formation constant must be large and the
indicator must provide a very distinct color change. A standardized solution of EDTA is needed.
Some important metal ions which could be determined directly by the complexometric titration
are copper, calcium, barium, bromine, zinc, cadmium, mercury, aluminum, stannous (tin), lead,
bismuth, chromium, iron, cobalt, nickel, palladium, etc. However, the presence of other ions may
cause interference and need to be suitably handled.
2. Back Titration
In this method, an excess of a standard solution of EDTA is added to the metal solution
being determined to complex all the metal ions present in the solution. The excess of EDTA left
after the complex formation with the metal is back titrated with a standard solution of another
metal ion. This method becomes necessary if the analyte precipitates in the absence of EDTA or
reacts too slowly with EDTA or it blocks the indicator.
For example, determination of manganese (Mn) is done by this method because a direct
titration is not possible due to precipitation of manganese hydroxide i.e., Mn(OH)
2
. The excess
EDTA remaining after complex formation is back titrated with a standard zinc solution using
eriochrome black T as an indicator.
3. Replacement Titration
This type is used when direct or back titrations do not give sharp endpoints or when there is
no suitable indicator for the analysis. The metal to be analyzed is added to a metal-EDTA
complex. The analyte ion displaces EDTA from the metal and the metal is subsequently titrated
with standard EDTA solution.
For example in the determination of Mn an excess of Mg-EDTA chelate is added to Mn
solution. The Mn ions quantitatively displace Mg from Mg-EDTA complex because Mn forms a
more stable complex with EDTA. The free Mg metal is then directly titrated with a standard
solution of EDTA using eriochrome black T as an indicator.
37
Titrations
Calcium, lead, and mercury are also determined by this method.
4. Indirect Titration
Certain anions that form a precipitate with metal cations and do not react with EDTA can be
analyzed by indirect method. The anion is first precipitated with a metal cation and the precipitate
is washed and boiled with an excess of disodium EDTA solution to form the metal complex. The
protons from disodium EDTA are displaced by metal and titrated with alkali. Therefore, this
method is also called alkalimetric titration.
For example, barbiturates can be determined by this method.
Applications of Complexometric Titration:
Complexometric titrations are widely used in the pharmaceutical industry because of the
very small quantity of samples is required.
Ability to introduce ions into a cell in case of deficiencies.
To determine the hardness of the water.
Ability to titrate the number of ions available in a living cell.
4.8 GRAVIMETRY
Gravimetric analysis determines the analyte based on the mass of the solid formed. It is one
of the most accurate analytical methods.
It involves the isolation and weighing of an analyte in its pure form.
Types of Gravimetric Analysis
There are four fundamental types of gravimetric analysis.
(a) Physical Gravimetry
It is most commonly used in environmental engineering. It involves the physical separation
of matter.
E.g., Surfactants, oil, grease, etc.
(b) Thermogravimetry
It is a technique in which the mass of a substance is measured as a function of temperature.
E.g., Glass and volatile solids
(c) Electrodeposition
It involves the electrochemical reduction of metal ions at a cathode and the deposition of
ions on it.
38
A Textbook of Pharmaceutical
Chemistry
E.g., Environmental engineering
(d) Precipitation Gravimetry
It involves the formation of precipitate of an analyte.
E.g., Determination of aluminum
Ideal Characteristics for Precipitation Gravimetry
The factors which determine a successful analysis by precipitation gravimetry are:
The precipitate must be formed quantitatively
The precipitate must be formed within a time limit.
The precipitate should be slightly soluble
Particles of precipitate should be of such diameter that they do not pass through the
filtering media.
The precipitate should be easily and quickly filterable.
The precipitate must be free from impurities.
Following steps are involved in gravimetric analysis:
(i) Sampling
(ii) Precipitation
(iii) Digestion
(iv) Completion of precipitation
(v) Filtration
(vi) Washing
(vii) Drying
(viii) Ignition
(ix) Weighing
(x) Calculation
(i) Sampling
The first step is to accurately weigh and dissolve the given sample to prepare its solution.
39
Titrations
(ii) Precipitation
The positive and negative ions in the solution react with another substance to form a
sparingly soluble substance called a precipitate. Generally, precipitation is carried out in hot
solutions because solubility increases with temperature. Precipitation is more effective in dilute
solutions.
Co-precipitation
The precipitate is contaminated by substances that are normally soluble in the solution under
the condition of precipitation. It occurs by occlusion or adsorption process.
Post-precipitation
The process in which an impurity is deposited after the precipitate formation of the desired
substance is called post precipitation.
Factors Affecting Precipitation
Choice of precipitant
Amount of precipitant
Temperature
pH
Complex formation
(iii) Digestion (Ostwald Ripening)
The smaller particles have higher solubility. As a result, the solution becomes supersaturated
for the larger particles. This results in the deposition of the dissolved particles on the larger
particles and increases particle size. This is known as digestion, aging, or Ostwald ripening.
(iv) Completion of precipitation
After complete precipitation, there is an addition of two to three drops of precipitating
reagent if turbidity develops, again add precipitating reagent and check for completion of
precipitation.
(v) Filtration
Filtration is a separation technique to separate the precipitate from the mother liquor.
Generally, Whatman filter paper, Gooch crucibles, Sintered glass crucible, etc. are used for
filtration.
(vi) Washing
The washing of precipitate is normally done by water or electrolytes. Mainly wash liquid has
a higher solubility for impurities and lower solubility for precipitate of an analyte.
40
A Textbook of Pharmaceutical
Chemistry
(vii) Drying
It is a prime important step to remove all water or liquid in the precipitate to get the proper
weight of an analyte.
(viii) Ignition
Ignition is carried out in an oven at temperature 373 – 423 K (100 – 150C) to remove water
and cooled in a desiccator.
(ix) Weighing
Generally, analytical or microbalances are used to weigh the dried precipitate.
(x) Calculation
The analyte in the sample is calculated from the weight of the precipitate. It gives the
quantitative weight of certain analytes to be determined.
Gravimetric factor (GF) = Weight of substance sought/Substance weight
Formula:
% A = Weight of precipitate × GF × 100/Weight of sample
E.g., Determination of aluminum, calcium metal by gravimetric analysis.
4.9 DIAZOTIZATION TITRATION
Diazotization titrations are carried out for the estimation of drugs containing a primary
aromatic amino group. Several drugs contain either primary aromatic amino groups or other
groups that can be converted to have such groups by the simple reaction.
E.g., hydrolysis, reduction, etc.
The resulting aromatic amino group is diazotized by reaction with sodium nitrite solution in
cold acid solution. The nitrous acid formed diazotizes the compound. The endpoint can be
determined using external indicators such as starch iodide paper.
Alternatively, the potentiometric method or dead stop endpoint technique of determining
endpoint can also be carried out.
The principle can be explained with the help of titration of Benzocaine by this technique.
41
Titrations
NH
2
COOC
2
H
5
NaNO
2
+ HCl
N
COOC
2
H
5
+
N
Cl
+ NaCl + H
2
O
0 - 15
0
C
The addition of sodium nitrite to hydrochloric acid causes the formation of nitrous acid. This
nitrous acid diazotizes the aromatic amino group. After the end point, excess nitrous acid formed
is detected by the instant formation of blue color with starch iodide paper. Starch iodide paper is
prepared by immersing a filter paper in starch mucilage and potassium iodide solution.
The color change of indicator paper is because of the reaction:
KI + HCl
KCl + HI
2HI + 2HNO
2
I
2
+ 2H
2
O
The iodine formed reacts with starch mucilage to give the blue color.
In the dead stop endpoint technique, a potential of 30 – 50 mV is applied across two
platinum electrodes. An automatic pipette is used for the delivery of nitrite solution. At the
endpoint, the delivery of nitrite solution stops automatically.
Applications
1. Benzocaine, dapsone, primaquine phosphate, suramin determination.
2. All sulpha drugs contain free aromatic amino groups like sulfacetamide sodium,
sulphadiazine, sulphaguanidine, etc.
3. Conversion to an amino group by chemical reactions like:
(a) By reduction: Drug containing aromatic nitro group which can be reduced using a
reducing agent to get an aromatic amino group. E.g., Metronidazole, Secnidazole,
Chloramphenicol, etc.
(b) Hydrolysis: These drugs are acetyl, succinyl, or phthalyl derivatives of amino groups.
After hydrolysis to free amino group titrated with nitrite solution.
Preparation of 0.1M Sodium Nitrite Solution
Dissolve 7.5 g of sodium nitrite in 1000 mL of purified water.
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A Textbook of Pharmaceutical
Chemistry
Standardization of 0.1M Sodium Nitrite Solution
Weigh accurately about 0.5 g of sulfanilamide previously dried at 105C for three hours and
dissolve in 50 mL of water, add 20 mL of hydrochloric acid, stir until the clear solution is formed
and cool to 0-15C. Titrate with 0.1M sodium nitrite solution.
Factor: 0.01722 g of sulfanilamide is equivalent to each mL of 0.1 M NaNO
2
.
M =
2
______ g sulfanilamide × 1000
172.2 × ______ mL NaNO solution
General Information
43
Chapter
Nomenclature of
Organic Chemical
Systems
5.1 COMMON NAME/TRIVIAL NAME SYSTEM
It is a common name used to recognize any chemical compound simply but it conveys little
information about the structure.
E.g., Phenol, Ethanol, etc.
5.2 IUPAC NOMENCLATURE (INTERNATIONAL UNION
OF PURE AND APPLIED CHEMISTRY)
(a) Aliphatic Compounds
Homologous series of hydrocarbons.
Number of Carbon Atoms Name of Hydrocarbons
1 Methane
2 Ethane
3 Propane
4 Butane
5 Pentane
6 Hexane
7 Heptane
8 Octane
9 Nonane
10 Decane
11 Undecane
12 Dodecane
5
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A Textbook of Pharmaceutical
Chemistry
Common rules for IUPAC nomenclature.
First, identify the longest carbon chain. This chain is called the parent chain.
Identify all of the substituents.
Number the carbons of the parent chain from the end that gives the substituents the
lowest numbers.
If the same substituent occurs more than once, the location of each point on which the
substituent occurs is given.
If there are two or more different substituents they are listed in alphabetical order using
the base name.
There are no spaces in the name.
CH
3
CHH
3
C
OH
CH3
CH
H
3
C
CHH
3
CH
2
C
H
2
C CH
3
2-Propanol 3-ethyl-2-methyl hexane
Alkanes-saturated Hydrocarbons
The names of the substituents formed by the removal of one hydrogen from the end of the
chain are represented by changing the suffix -ane to -yl.
CH3
H
2
C
CH
3
CH3
CH
CH
3
Cl
Propane Propyl chloride
Alkyl Halides
The halogen is treated as a substituent on an alkane chain.
CH3
CH
Cl CH
3
H
3
C
C
Br
CH
3
CH
3
2-Chloro-propane 2-Bromo-2-methyl propane
CH
3
CH
3
CH
3
CH
3
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