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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5265_Библиотеки_им_академика_М_И_Перельмана.pdf
Volumetric and Gravimetric Analysis 37
HCl + NaOH → NaCl + H
2
O
Fig. 2.1: Neutralization curve (Strong acid + Strong base)
The pH is initially very low due to the high concentration of hydrogen ions (H
+
) in the
reaction flask. Initially, the pH rises very slowly 1 to 4. When NaOH is added in amount up to
10 ml, the pH raises suddenly to 7. As more NaOH is added, the pH rises to around 10. The end-
point of titration is shown by this sudden change in pH from 4 to 10, where the curve is
practically flat. At pH 7, the titration comes to an end-point.
Therefore, the end-point in strong acid and strong base titration is the point of neutrality.
Upon more addition of base, introduce OH
−
ion concentration, the pH increases slowly after
sudden jump. The indicator used in strong acid-strong base titration is with the pH range (4 to 10)
such as methyl orange, methyl red, phenol red and phenolphthalein.
Weak Acid and Strong Base Titration
Titration of a weak acid with a strong base is concerned with the direct transfer of protons
from the weak acid to the hydroxide ion. Assume the analyte is acetic acid (weak acid) and the
titrant is sodium hydroxide (NaOH) (strong base). The graph (Fig. 2.2) depicts the relationship
between the pH of the analyte and the volume of NaOH added from the burette.
1. Acetic acid is a weak acid. So, the starting pH is higher than what we noticed in
previous case where we had a strong acid (HCl).
2. During titration, e.g., after adding NaOH, neutralization of acid occurs and pH
increases. However, formation of salt (CH
3
COONa) decreases the ionization of weak
acid.
CH
3
COOH ↔ CH
3
COO
−
+ H
+
CH
3
COONa → Na
+
+ CH
3
COO
−
Additionally, hydrolysis of salt (CH
3
COONa) increases the concentration of OH
−
that raises
the pH.
CH
3
COONa + H
2
O → CH
3
COOH + Na
+
+ OH
−
38 Text Book of Pharmaceutical Chemistry
The indicator of pH range 8.2-10 is used for this type of titration, e.g., Phenolphthalein,
Thymol blue, etc.
Fig. 2.2: Neutralization curve (Weak acid + Strong base)
Weak Base and Strong Acid Titration
Titration between 0.1 N ammonium hydroxide (weak base) and 0.1 N hydrochloric acid
(strong acid) is performed. Change in pH against the volume of titrant addition is represented in
the graph (Fig. 2.3).
NH
4
OH + HCl → NH
4
Cl + H
2
O
In strong acid-weak base titration, starting pH is normally higher than 7 (11-12) and
decreases rapidly with the additions of acid. As the equivalence point is reached, the pH will
change more gradually. In strong acid-weak base titrations, the equivalence point pH is not 7 but
below it (4 to 6) due to the production of a conjugate acid during the titration.
As a result, in this plot, the chemical indicators methyl red (pH range 4.2 to 6.3) or methyl
orange (pH range 3 to 4.4) would be appropriate. It will shift from a basic to an acidic color.
Fig. 2.3: Neutralization curve (Weak base + Strong acid)
Volumetric and Gravimetric Analysis 39
Weak Acid and Weak Base
Titration of weak acid and weak base occurs between 0.1 N acetic acid CH
3
COOH (weak
acid) and 0.1 N ammonium hydroxide NH
4
OH (weak base). When plotting the pH of the analyte
versus the volume of acetic acid added from the burette, the titration curve is shown in Fig. 2.4.
CH
3
COOH + NH
4
OH → CH
3
COONH
4
+ H
2
O
There is no immediate change in pH when titrating a weak base with a weak acid. Hence, no
sharp end-point is detected with any of the common indicators.
Fig. 2.4: Neutralization curve (Weak acid + Weak base)
2.11 TYPES OF NON-AQUEOUS SOLVENTS
Solvents are classified into various classes on the basis of properties of the solvents. The most
suitable classification of solvents is based on the electrolytic characteristics of the solvents. The
following methods have been used to classify the solvents:
(a) Non-ionizing solvents or non-polar liquids: These solvents are also known as aprotic
solvents because these solvents contain no hydrogen in their structure. These solvents
have very little dielectric constant, e.g., benzene (C
6
H
6
), carbon tetrachloride (CCI
4
),
etc.
(b) Ionizing solvents or polar liquids: These solvents have large dipole moments. They
contain bonds between atoms with very different electronegativities, such as oxygen and
hydrogen. Examples of such solvents are H
2
SO
4
, H
2
F
2
, CH
3
COOH, H
2
O, liq. NH
3
, liq.
SO
2
, pyridine, BrF
3
, HgBr
2
, CH
3
OH, etc.
2.12 CLASSIFICATION OF IONIZING SOLVENTS
Ionizing solvents are classified in the following ways:
1. Aprotic Solvent
2. Protogenic Solvent
3. Protophillic Solvent
4. Amphiprotic Solvent
40 Text Book of Pharmaceutical Chemistry
1. Aprotic Solvent
Aprotic solvents are chemically inert and are neutral in charge. These solvents have low
dielectric constant and do not react with acid or base. Therefore, they do not favor ionization.
They are not acidic or basic (inert solvent), e.g., Chloroform, Benzene, Dioxan, Ethyl acetate, etc.
2. Protogenic Solvent
Protogenic solvents are acidic in nature and have the tendency to donate protons. These
solvents are used to dissolve basic analyte. They have high dielectric constant and ionized. These
solvents have a tendency to donate protons, e.g., H
2
SO
4
, H
2
F
2
, CH
3
COOH, formic acid, propanoic
acid, etc.
3. Protophillic Solvent
Protophillic solvents are basic in nature. They have high affinity for proton. These solvents
tend to react with the acids they come in contact with, leading to the formation of solvated
protons, e.g., amines and ketone, pyridine, ethylene diamine and DMF.
4. Amphiprotic Solvent
Amphiprotic solvents are the solvents that combine the properties of both protophilic and
protogenic solvents. It means that amphiprotic solvents are both acidic and basic in nature. They
donate H
+
ion and act as an acid, and accept H
+
ion and act as a base, e.g., alcohol and water.
➢ Water accepts H
+
, therefore acts as a base.
H
2
O + HCl → H
3
O
+
+ Cl
−
➢ Water donates H
+
, therefore acts as an acid.
H
2
O + NH
3
→ NH
4
+
+ OH
−
Solvents Used in Non-aqueous Titration
Sr.
No.
Type of
Solvent
Characteristics
Example
1
Aprotic
solvent
➢ Chemically inert in nature
➢ Neutral in charge
➢ Neither acidic nor basic
➢ Have low dielectric constant
C
6
H
6
, CHCl
3
, C
4
H
8
O
2
,
C
4
H
4
Cl
2
,
2
Protogenic
solvent
➢ Acidic in nature
➢ Readily donate proton
➢ Have a leveling effect on the bases
➢ Applied to increase the alkalinity of
weak acids and strengthen weak bases
H
2
SO
4
, H
2
F
2
, H
3
COOH,
HCOOH
3
Protophilic
solvent
➢ Basic in nature
➢ Have a high tendency to accept
protons
Amines liquid,
ammonia, Pyridine,
DMF Ethylenediamine
4
Amphiprotic
solvent
➢ Have both acidic and basic properties
➢ Have property of both protophilic as
well as protogenic solvents
Acetic acid and alcohols
Volumetric and Gravimetric Analysis 41
2.13 LEVELING AND DIFFERENTIATING EFFECT
Leveling effect applies to the effect of solvent on the properties of acids and bases. It is also
called as solvent leveling. In a leveling solvent, various acids are completely dissociated and are
thus of the same strength. The strength of a strong acid is leveled by the basicity of the solvent;
likewise, the strength of a strong base is leveled by the acidity of the solvent.
If a strong acid (HA) is dissolved in water, it reacts with it and accepts a proton to
form hydronium ion (H
3
O
+
). HA is very much stronger acid as compared to H
3
O
+
. Thus, no acid
stronger than H
3
O
+
exists in H
2
O.
HA + H
2
O → A
−
+ H
3
O
+
Example: Loss of proton in case of perchloric acid (HClO
4
) is very much greater than that of
H
3
O
+
. Hence, HClO
4
is completely ionized in water and are all equally strong acids.
HClO
4
+ H
2
O → H
3
O
+
+ ClO
4
−
On the other hand, differentiating solvents are chemical solvents that cause various acids to
dissociate at different degrees, and therefore, have different strengths.
Example: In case of anhydrous acetic acid (CH
3
COOH) as a solvent, it is weaker proton acceptor
in comparison to water. Thus, strong acids like HCl and HClO
4
partially dissociate into ions in
anhydrous acetic acid and their strengths are unequal. When strong acids are mixed with this sort
of solvent, they have varying strengths.
Acetic acid (weakly basic solvent) has less tendency than water (more strongly basic) to
accept a proton. In the same way, a weakly acidic solvent has less tendency to donate protons
than a strong acid.
2.14 DETECTION OF END-POINT IN NON-AQUEOUS TITRATION
End-point Detection
End-point detection is critical for titration. It ensures that the reaction is completed and the
result is accurate. Two methods are used to determine the end-point:
(a) Visual indicators
(b) Electrochemistry
(a) Visual Indicators
At the end-point, observe for a color change or precipitation.
The addition of an external or self-indicator to the reaction process allows the progress of the
reaction to be monitored.
In non-aqueous titration, visual indicators have been found to be the most appropriate for the
detection of end-point. These indicators observe a color change or precipitation at the end-point.
The following are the primary indicators used in non-aqueous titration:
42 Text Book of Pharmaceutical Chemistry
➢ Crystal Violet: It is used as a 0.5% (w/v) solution in glacial acetic acid. Its color change
is from violet (basic medium) through blue, followed by green, then to greenish-yellow
(acidic medium). It is generally used for the titration of pyridine with perchloric acid.
➢ Methyl Red: It is used as a 0.2% (w/v) solution in dioxane with a yellow (acidic
medium) to red (basic medium) color change.
➢ 1-Naphtholbenzein: It is used as a 0.2% (w/v) solution in acetic acid with a yellow
(acidic medium) to green (basic medium) color. It produces sharp end-points in
nitromethane containing acetic anhydride for titrations of weak bases against perchloric
acid.
➢ Oracet Blue B: It is used as a 0.5% (w/v) solution in acetic acid. It is examined to be
superior to that of crystal violet for titrations of bases in acetic acid with standard
perchloric acid. It gives the end-point from blue (acidic medium) to pink (basic
medium).
➢ Thymol Blue: It is used as 0.2% (w/v) solution in methanol. It is used for titrations of
substances acting as acids in Dimethylformamide solution. The end-point changes from
yellow to blue.
➢ Methyl Violet: It is used as 0.2% (w/v) solution in chlorobenzene. The end-point color
changes from violet (acidic medium) to blue (basic medium).
➢ Quinaldine Red: It is used as 0.1% w/v solution in ethanol. The end-point color
changes from purple red (acidic medium) to pale green (basic medium). It is used for the
determination of the drug substance in dimethylformamide (DMF).
(b) Electrochemistry
➢ Potentiometry: The end-point is detected by using indicator electrodes and reference
electrode.
➢ Conductometry: Conductometry measures conductivity to monitor a progress of
chemical reaction. It is applied to analyze the end-point of titrations that include ions.
➢ Amperometry: It measures change in current between electrodes in solution.
2.15 ACIDIMETRIC AND ALKALIMETRIC TITRATION
Acidimetry (Titration of Bases)
Acidimetry is the analytical technique used for the measurement of the strength of acids. It is
the part of volumetric analysis by which an acid solution at known concentration, along with a
specific indicator, is used to titrate a base solution and thus work out its concentration.
Volumetric and Gravimetric Analysis 43
List of Various Cognate Determinations using Different Indicators
Sr.
No.
Compound
Medium
Indicator
Titrant
Category
1
Adrenalin – 0.3 g
Glacial acetic
acid
Crystal
violet
0.1 N Perchloric
acid
Sympathomimetic
2
Amantadine
Glacial acetic
acid and
mercuric acid
Crystal
violet
0.1 N Perchloric
acid
Antiviral
3
Atropine sulphate
Glacial acetic
acid
–
0.1 N Perchloric
acid
Anticholinergic
4
Chlordiazepoxide
Chloroform
Methyl red
0.1 N Perchloric
acid
Antianxiety
5
Ethambutol
Glacial acetic
acid
Crystal
violet
0.1 N Perchloric
acid
Anti-tubercular
6
Chlorpromazine
HCl
Glacial acetic
acid and
mercuric acid
Crystal
violet and
Methyl
orange
0.1 N Perchloric
acid
Antipsychotic
7
Verapamil HCl
Glacial acetic
acid and
mercuric acid
Crystal
violet
0.1 N Perchloric
acid
Calcium channel
blockers
Alkalimetry (Titration of Acid)
Alkalimetry is the technique of measuring the strength of base of a solution using an acid
standard solution. It is the part of volumetric analysis by which a basic solution at known
concentration, along with a specific indicator, is used to titrate an acidic solution, and thus, work
out its concentration.
Weakly acidic substances may be titrated efficiently by use of a suitable non-aqueous solvent
with a sharp end-point. The wide variety of such organic compounds include amino acids, acids,
acid halides, anhydrides, enols (barbiturates), xanthines, sulphonamides, phenols, imides, and
lastly, the organic salts of inorganic acids.
Alkalimetric Assay: Non-aqueous Titration using Sodium Methoxide/
Lithium Methoxide Either Potentiometrically or Titrimetrically
Sr.
No.
Name of
Compound
Indicator
Titrant
Category
1
Phenobarbital
sodium
Quinaldine red
0.1 M Sodium
Methoxide
Sedative hypnotic
2
Nalidixic acid
Thymolphthalein
0.1 M Sodium
Methoxide
Antibacterial
3
Allopurinol
Thymol blue
0.1 M Sodium
Methoxide
Xanthine oxidase
inhibitor
4
5-fluorouracil
Thymol blue
0.1 M Tetra butyl
ammonium hydroxide
Anticancer
5
Bendroflumethiazide
Azo violet
0.1 M Sodium
Methoxide
Antihypertensive
44 Text Book of Pharmaceutical Chemistry
2.16 ASSAY OF SODIUM BENZOATE
Sodium Benzoate:
Sodium benzoate has chemical formula C
7
H
5
O
2
Na with m.wt. 144.1. It is the sodium salt of
benzoic acid and exists in this form when dissolved in water.
Properties:
It occurs as white, odorless or nearly odorless granules, crystalline powder, or flakes.
1 g dissolves in 2 ml of water, in 75 ml of alcohol, and in 50 ml of 90% alcohol.
Procedure:
Weigh 0.25 g of sodium benzoate and transfer to a beaker. Add 20 ml of glacial acetic acid.
Stir until it completely dissolved. Add 2 drops of crystal violet as indicator and titrate with 0.1 N
perchloric acid. The end-point will be blue to bluish green color.
Principle of Precipitation Titration:
Precipitation titration is a type of titration in which the titrant reacts with analyte to form an
insoluble substance called precipitate. It continues till the last amount of analyte is consumed.
Example: A precipitation reaction occurs when water solutions of two different ionic compounds
are mixed and an insoluble solid separates out of solution.
AgNO
3 +
NaCl → AgCl + NaNO
3
The main principle of precipitation titrations is that the amount of precipitating reagent or
precipitant added is equivalent to the amount of substance precipitated.
Characteristics of Precipitation Titration:
➢ They are fast, and the stoichiometry is well-known and reproducible (no secondary
reactions of interference).
➢ They are complete or can be quantified depending on the amount of solubility product.
(In general, a precipitation titration is considered complete when Kps < 10-8.)
➢ An indicator can be used to find the equivalence point or titration end-point which, for
this type of titration, corresponds to when precipitation of the analyte under analysis is
complete.
2.17 TYPES OF PRECIPITATION TITRATION
2.17.1 Argentometric Titration
Argentometric titration is a method of titration which contains silver (I) ion. This method is
use to determine the amount of chloride present in a sample. In this method, sample solution is
titrated against a solution of silver nitrate of known concentration. Silver (I) and chloride ions
react to give the insoluble silver chloride.
Volumetric and Gravimetric Analysis 45
The important precipitation reaction used in this titration is that of silver with a range of
anions. These anions include: Halides (Cl
–
, Br
–
and I
–
) and Pseudo halides (S
2–
, HS
–
, CN
–
and
SCN
–
).
Methods of Precipitation Titration
According to end-point detection method, three methods are widely used depending on the
type of application. These are:
1. Mohr’s Method
2. Fajan’s Method
3. Volhard’s Method
1. Mohr’s Method
Mohr’s method is used to determine the chloride ion concentration of a solution by titration
with silver nitrate. When the silver nitrate solution is added, a precipitate of silver chloride is
forms. The titration end-point arises when all the chloride ions are precipitated. Subsequently,
excess of silver ions react with the chromate ions as the indicator, potassium chromate, to form a
reddish precipitate of silver chromate.
The direct method utilizes potassium chromate (CrO
4
2–
) in the titration of (Cl
–
, Br
–
and CN
–
)
ions (analyte) with a silver nitrate standard solution (titrant).
NaCl + AgNO
3
→ AgCl (precipitate) + NaNO
3
2AgNO
3
+ K
2
CrO
4
(precipitate) + 2KNO
3
Theory:
After all chlorides precipitate as silver chloride (AgCl) and when all Cl
–
is consumed, the first
excess of Ag
+
reacts with the chromate ions (CrO
4
2–
) indicator to produce red silver chromate as a
secondary precipitate.
Ag
+
(aq) + Cl
–
(aq) → AgCl (s)
White precipitate
Mohr’s method is a direct titration method in which a red silver chromate precipitates
Ag
2
CrO
4
(s) forms at the end-point. This method must be performed in a neutral to alkaline
condition (pH of 08.00).
2Ag
+
(aq) + CrO
4
2–
(aq) → Ag
2
CrO
4
(s)
Procedure:
Preparation of 0.1 N Silver Nitrate: Weigh 4.284 g of finely powdered silver nitrate and
dissolve in 250 ml of distilled water for the preparation of 0.1 N silver nitrate (AgNO
3
).
Assay Procedure of Potassium Chloride:
Reaction medium: Neutral.
Indicator: 1 ml of K
2
Cr
2
O
7
is added to the conical flask.
46 Text Book of Pharmaceutical Chemistry
Sample solution: Sample solution is prepared by dissolving 0.25 g of potassium chloride (KCl)
in 50 ml of water.
Standard solution: Burette is filled with 0.1 N AgNO
3
.
End-point detection: Appearance of reddish precipitate of silver chromate
Advantages of Mohr’s Method:
➢ Mohr’s method is a simple method of titration as it does not consume time. Therefore,
there is no need for more titrations.
➢ Potassium chromate is used as the indicator which is easily available and affordable.
➢ This method is a simple, direct and accurate for chloride determination.
Disadvantages of Mohr’s Method:
➢ This method is applicable only for titration of chloride, bromide and cyanide alone.
➢ In this method, errors are found due to the need of excess titrant before the end-point
color is visible.
For this method, acidic solution is required. Hence, it cannot take place in basic or neutral
solutions.
2. Fajan’s Method
Fajan’s method was introduced by Kazimierz Fajans in 1923. In this method, silver ions
titrated with halide or thiocyanate ions in the presence of adsorption indicator is called Fajan’s
method. This method is also called as indicator adsorption method as adsorption of indicator takes
place at end-point.
This is the direct titration method which uses certain dyes as internal adsorption indicators.
The indicators are absorbed by the precipitate, and at the end-point, color changes. This method is
commonly used for the quantitative analysis of halide ions or thiocyanate ions. It involves
titration of AgNO
3
with Cl
–
ions in the presence of adsorption indicator. Here, Cl
–
ion solution
with indicator is taken in titration flask and AgNO
3
kept in burette.
Types of Adsorption Indicators:
There are two types of adsorption indicators:
1. Acid dyes: Fluorescein and Eosin as sodium salts.
2. Basic dyes: Rhodamine 6G or Phenosafranine as halogen salts.
Indicator
Color Change
Application
Fluorescein
Yellowish green to pink
(0.2% solution used for titration).
It is used for the estimation of all
halides Cl, Br and I
–
(pH 7-10).
Eosin
Pink to reddish violet
(0.1% solution used for titration).
It is used for the estimation of Br, I
–
and SCN.
Diiododimethyl
Fluorescein
Orange to blue.
It is used for the estimation of I
–
only
(pH 4-7).
Dichloro
Fluorescein
Yellowish green to red
(0.1% solution used for titration).
It is used for the estimation of Cl
–
and
Br
–
(pH 4-7).