Pharmaceutical Analytical Chemistry I

(Pharm D- clinical)
Lecture I&II
 General Introduction about the Quantitative Analysis
Analytical Chemistry
1- Qualitative Analysis:
It is the identification, separation and confirmation of the
constituents of a substance or mixtures of substances.

2- Quantitative Analysis:
It is concerned with the methods of determining the
concentration of these constituents of a substance or
mixtures of substances. The aim of the quantitative analysis
is to determine the quantity and the purity of the samples to
be analyzed.
In this course, the principle underlying the quantitative
analysis will be considered.
Methods Used in Quantitative Analysis:
They are classified according to:

1- Sample concentration:
Macro; for determination of quantities 100 mg or
more.
Semi- micro; for determination of quantities ranging
from 10 mg to 100 mg.
Micro; for determination of quantities not exceeding 1
mg.

2- The kind of the analyzed sample:

Food analysis.
Water analysis.
Drug analysis.
3- The process of the final measurement:
Volumetric or Titrimetric Analysis:
It depends on measuring the volume of both the analyzed
sample and the standard solution needed for complete
reaction with this sample.
The term titration means controlled addition of the standard
solution to a solution sample until the reaction is complete.

Gravimetric Analysis:
It depends on converting the sample to an insoluble form.
The separated precipitate is dried or ignited, possibly to
another form, and is accurately weighed. From the weight of
the precipitate and knowledge of its composition, the weight
of the analyte in the desired form is calculated.
Instrumental Analysis:
It depends on measuring some physical properties that are
quantitatively related to the concentration of the sample to
be analyzed using certain instruments.
This course will involve the volumetric or titrimetric analysis
which is more commonly employed in the analytical
laboratories, since it is much easier compared with the two
other methods.
Types of Reactions Used in Titrimetric Analysis:
A- Ionic Combination Reactions:
These reactions depend on the formation of slightly ionized or slightly soluble
product. This type of reaction involves:
1- Neutralization Reactions:
It involves the union of hydrogen and hydroxyl ions to form water which is very
slightly ionized:
H+ + OH- → H2O
2- Precipitation Reactions:
It involves the formation of slightly soluble salts:
Ag+ + Cl- → AgCl↓
Ba2+ + SO42- → BaSO4↓
3- Complexation Reactions:
It involves the formation of slightly ionized complexes:
Ag+ + 2CN- → [Ag(CN)2-]

B- Electron Transfer Reactions:

These reactions involve the transfer of one or more electrons.
Theses reactions occur if one reactant is an oxidizing agent and the other is a
reducing agent:
Ce4+ + Fe2+ → Ce3+ + Fe3+
Requirements of Titrimetric Analysis:
1- The reaction between the sample and the standard must
be simple and can be expressed by a chemical equation.
2- The reaction should be single, i.e.: with no side reactions.
3- A suitable standard solution must be available as a titrant
for the sample.
4- The end point of the reaction must be easily detected.
5- The reaction must be rapid or a catalyst is used.

Titrimetric methods need the following:

1- Calibrated measuring vessels; including burettes, pipettes
and measuring flasks.
2- Substances of known purity for the preparation of the
standard solutions.
3- Visual indicators or instruments to detect the end point.
To understand the concept of the titrimetric analysis, some
definitions are needed:
Titration:
It is the process of measuring the volume of titrant needed to
reach the end point.
Standard Solution:
It is a solution of exact known concentration.
Titrant:
It is the standard solution which is used to titrate the sample.
Equivalence Point:
It is the point at which the reaction between the sample and the
standard is complete.
End Point:
It is the point at which the indicator changes its color.
Indicator:
It is a chemical substance that responds to the end point by
changing colors.
Types of Standard Solutions:
1- Empirical Standard Solutions:
These solutions are prepared in a concentration that is
each 1ml of this solution reacts with definite amount of the
sample. They are used for the determination of a specific
sample.
2- Molar Standard Solutions (M):
These are solutions that contain gram Molecular Weight
in each liter.

3- Normal Standard Solutions (N):

These are solutions that contain gram Equivalent Weight
in each liter.
Calculating the Equivalent Weights:
Equivalent Weight of Acids:
Eq.wt = Molecular weight / Number of replaceable H+

Examples:
Eq.wt of HCl = M.wt / 1
Eq.wt of H2SO4 = M.wt / 2

Equivalent Weight of Bases:

Eq.wt = Molecular weight / Number of replaceable OH-

Examples:
Eq.wt of NaOH = M.wt / 1
Eq.wt of Ba(OH)2 = M.wt / 2

Equivalent Weight of Salts:

Eq.wt = Molecular weight / Number of ions X Valency

Examples:
Eq.wt of Na2CO3 = M.wt / 1 X 2
• Types of Chemical Standards:
1- Primary Standards:
• They are substances of definitely known composition and high
purity.
• Primary Standard should have the following characteristics:
• Easily obtained in a very high grade of purity and of known
composition.
• Easily tested for impurities.
• Stable; non volatile, non hygroscopic, non efflorescent.
• Reacts stoichiometrically; in a quantitative way according to a
balanced chemical equation.
• Readily soluble in solvents.
• Has high equivalent weight to minimize weighing errors.
• Examples:
• Potassium acid phthalate, benzoic acid, anhydrous sodium
carbonate
 2- Secondary Standards:
They are substances which do not fulfill all the previous requirements
and whose content of the active substance can be found by
comparison against primary standards.

Examples:
Oxalic acid and borax.

Preparation of Standard Solutions:

Standard solutions are prepared by either of two ways:

Direct Method:
An accurately weighed amount of the solute is dissolved and made up
to the required volume in a volumetric flask.
The solute must be of primary standard quality

Indirect Method:
If the solute is not of primary standard quality, an approximate
concentration will be obtained which is standardized against a primary
standard.
Acid –Base Titration in
Aqueous Medium
Acid - Base Titration in Aqueous Medium
Many of the reactions of qualitative and quantitative
analysis take place in aqueous solutions. It is therefore
necessary to have a general knowledge of the conditions
which exist in such solutions.
Electrolyte solution did allow the current to pass, i.e. they
conduct the electric current. Examples of such solution are
mineral acids, caustic alkalis and salts.
Electrolytic Dissociation Theory:
When an electrolyte is dissolved in water, it dissociates into
positively charged fragments "Cations" and negatively
charged fragments "Anions":
For each concentration there is a state of a reversible
equilibrium between un-dissociated molecules and ions:
Molecules ⇋ Cations + Anions
Degree of Dissociation:
Arrhenius introduced a quantity "ɑ" called the degree of
dissociation:
ɑ= Number of dissociated solute molecules
Total number of solute molecules before
dissociation
According to the value of "ɑ", electrolytes can be classified
into:
Strong Electrolytes:
If the value of ɑ is unity or near to unity.
Examples:
ɑ = 0.92 HCl
ɑ = 0.91 NaOH
Weak Electrolytes:
If the value of ɑ is far from unity.
Examples:
ɑ = 0.001 H3BO3
ɑ = 0.013 NH4OH
ɑ = 0.01 HgCl2
Acid – Base Theories
Arrhenius Theory:
An acid: any substance ionizes to give H+
A base : any substance ionizes to give OH-
The theory suffers several points of weakness:
It didn't discus the role of solvent in the ionization process.
Some compounds contain no OH-, and are more basic than
NaOH.
Bronsted - Lowry Theory:
An acid: substance that donates H+
A base : substance that accepts H+
When the acid gives the proton, the remaining species has a
certain proton affinity and hence is a base. This base is known as
the conjugate base of the acid:
Acid ⇋ Proton + Conjugate Base
Exemples:
HCl ⇋ H+ + Cl-
HAc ⇋ H+ + Ac-
H2O ⇋ H+ + OH-
The stronger the acid, the weaker its conjugate base.

The solvent, in this theory, is involved in the reaction as an acid

or a base:

HCl + H2O ⇋ Cl- + H3O+

(acid) (base)

NH3 + H2O ⇋ NH4+ + OH-

(base) (acid)
Lewis Theory:
Lewis defined a base as a substance that contains an atom with
unshared electron pair e.g.: N, O, P, S, while the acid is the
substance that accepts this electron pair.
An acid: substance that accepts electrons.
A base : substance that donates electrons.
Example:
H+ + :O-H- ⇋ H: O-H
This theory explains the following:
Compounds containing no OH- and react as a base e.g.: NH3

Compounds containing no H+ and react as an acid

e.g.:BCl3
Buffer Solutions
Definition:
These are solutions which resist the change in pH upon
addition of small amount of acids or bases.

Types of Buffers:
1- Acidic Buffers:
They consist of weak acid and its salt.
Example:
Acetic acid – Sodium acetate.

2- Basic Buffers:
They consist of weak base and its salt.
Example:
Ammonium hydroxide – Ammonium chloride.
Mechanism of Action of Buffers:
Acidic Buffers (HAc – NaAc):

Upon addition of strong acid:

H+ + Ac- ⇋ HAc "weak acid"
The strong acid, therefore, is converted to a
weakly dissociated acid.
So the pH remains almost constant.

Upon addition of strong base:

OH- + HAc ⇋ Ac- + H2O "neutral"
The strong base, therefore, is converted to water.
So the pH remains almost constant.
Basic Buffers (NH4OH - NH4Cl):
Upon addition of strong acid:
H+ + NH4OH ⇋ NH4+ + H2O "neutral"
The strong acid, therefore, is converted to water.
So the pH remains almost constant.

Upon addition of strong base:

OH- + NH4+ ⇋ NH4OH "weak base"
The strong base, therefore, is converted to a
weakly dissociated base.
So the pH remains almost constant.
Henderson Equation for Calculating the
pH of Buffers:
pH of Acidic Buffers:
Example: HAc - NaAc
HA ⇋ H+ + A-
Ka = [H+] [A-] / [HA]
-log Ka = -log [H+] - log [A-] / [HA]
pKa = pH - log [salt] / [acid]
pH = pKa + log [salt] / [acid]
pH of Basic Buffers:
Example: NH4OH – NH4Cl
Buffer Capacity:
It is the magnitude of the resistance of a buffer to
the change in pH.
β = Δ B/Δ pH

Where:
β is the buffer capacity.
Δ B is the change in mg equivalent of strong
acid or base added.
Δ pH is the change in pH.
The higher the buffer capacity, the more efficient
the buffer.
The higher the concentration of the two
components of the buffer, the higher the buffer
capacity.
Buffer ratio:
It is the [salt] / [acid] ratio.

Maximum Buffer Capacity:

It occurs when the [salt] = [acid].
Thus, pH = Pka

Adequate Buffer Capacity:

The ratio of [salt] / [acid] should not exceed
1/10 or 10/1 to obtain adequate buffer
capacity.
Thus, pH = pKa ± 1
Examples:
1- Calculate the pH of a buffer solution containing 0.1M
acetic acid and 0.1M sodium acetate,(pKa = 4.76).
Solution:
pH = pKa + log [salt] / [acid]
pH = 4.76 + log 1/1
pH = 4.76

2- Calculate the pH of a buffer solution containing 0.01M

ammonium hydroxide and 0.1M ammonium
chloride,(pKb = 4.76).
Solution:
pH = pKw – pKb - log [salt] / [base]
pH = 14 – 4.76 - log 0.1/ 0.01
pH = 8.24
 Types of Indicators:
1- Color Indicators
These are weak organic acids or bases with high molecular weight
which change their colors according to the change in pH.

They are two types:

One color indicator, e.g. phenolphthalein.
Two colors indicator, e.g. methyl orange.

2- Fluorescent Indicators:
These are organic compounds which emit fluorescence at certain pH.
e.g. fluorescene.

3- Turbidity Indicators
These are weak organic acids or bases that form colloidal precipitate at
certain pH.
e.g. iso-nitro acetyl p-amino azo-benzene.
4- Screened Indicators:
In some indicators as M.O. the color change is not easily detected
specially in artificial light
A sharper end point or color change may be obtained by using a
suitable mixture of the indicator & different dye
Example:
Methyl orange and indigocarmine.
The dye acts as a screen making the color change sharp at pH 4.
Color change: from yellowish green (alkaline) to violet color (acid).
5- Mixed Indicators:
A sharper color change may be obtained by using a mixture of two
indicators having similar pH range but showing contrasting
colors.
Example:
Thymol blue (pH: 1-2), Cresol red (pH: 0.5-2).
Color changes: from yellow (acid) to violet (alkaline).
6- Universal Indicators:
Several indicators are mixed together (6-7); the color change
will then extend over a wide range. They are not suitable for
quantitative determination but are used for rough pH
determination.
Theories of Color Indicators:
Ostwald Theory:
This theory considered the color indicators as weak acids or weak
bases in which the un-dissociated molecules have different color
from the dissociated ions:

Acid Indicator; e.g. ph.ph:

HIn ⇋ H+ + In-
Acidic un-dissociated Indicator Dissociated Ions

"Colorless" "Red"

Basic Indicator; e.g. M.O:

InOH ⇋ OH- + In+
Basic un-dissociated Indicator Dissociated Ions

"Yellow" "Red"
Color Change of Some Common Indicators:
1- Phenolphthalein; (pH range: 8.3-10):
2- Methyl Orange; (pH range: 3.3- 4.4):