PRINCIPLES OF CHEMICAL EQUILIBRA

COURSE OUTLINE
*General Concepts
*Ionization Constants, Ionic strength
*Acid/Base Equilibra
*pH and Buffers
*Theory of Indicators

GENERAL CONCEPTS OF CHEMICAL EQUILIBRA

Reversible Process and Law of Mass Action
Equilibrium is a state of equality of forces while dynamic equilibrium can occur during a
physical or chemical change. In physical equilibrium there is no change in composition of
the substances involved in the reaction.
E,g. NaCl (solid) ↔ NaCl (solution) While in chemical equilibrium the reactants undergo a
change in composition to form products which are reconverted to the reactants at the same
rate.
Many chemical reactions do not go to completion as indicated by the equation representing
them. More often than not such reactions proceed in both forward and backward direction
according to experimental conditions. Such reactions are said to be reversible. A reversible
reaction is in dynamic equilibrium when both the forward and backward reactions are
occurring at the same rate. They can only reach dynamic equilibrium in a closed system.
All chemical reactions proceed in both directions if the products of the reaction are not
removed as they are formed (closed system). However, there are some reactions which
proceed nearly to completion. These are referred to as Irreversible reactions (Burning of
piece of paper, metabolism of glucose (C6H12O6 + 6O2 → 6CO2 + 6H2O). The irreversible
reactions occur so that the reactants are completely consumed in the reaction.
Chemical equilibrium is concerned with reversible reactions
CH3COOH + H2O ↔ H3O+ + CH3COO-
Acid base Hydroxonium Conjugate base
So, in reversible reaction, the products recombine to form the reactants. A state of
equilibrium is established when the rate of the forward reaction is equal to the rate of
backward reactions. In the effect, equilibrium maybe defined as a balance between two
opposing forces or actions. Chemical equilibrium maintains a constant in the concentration
of the reacting substances.

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According to the Law of Mass Action or Law of Chemical equilibrium which states that at
constant temperature, the rate of reaction is proportional to the product of active masses of
each of the reactants, each activity being raised to the power equal to the number of moles of
the substances in the reaction.
mA + nB → Product
r α [A]m[B]n
r = K [A]m[B]n
K = Velocity constant, rate constant or proportionality constant

mA + nB ↔ pC + qD (r1 and r2)

Forward reaction, r1 = K1[A]m[B]n
Backward reaction, r2 = K2[C]p[D]q

Therefore K1/K2 = [C]p[D]q

[A]m[B]n
K1/K2 = K = Equilibrium Constant
For a reversible reaction K is therefore the ratio of the concentration of the substances on the
right hand side (RHS) to that on the left hand side (LHS) of the reaction. The term speed or
rate or velocity has the same meaning. However, the concentration of the products and the
reactants are not necessarily equal at equilibrium but the speed, rate or velocity of the forward
and backward reactions are the same.
For a reaction in which more than two substances react
A +B +C↔D + E
K = [D][E]
[A][B][C]
When two or more molecules of substances are in a reaction
E.g. A + 3B ↔ 2C
K= [C]2
[A][B]3
FACTORS AFFECTING ESTABLISHED EQUILIBRIUM
According to Le-Chartelier’s Law or Principle which states that if an external constraint such
as a change in temperature, pressure and concentration is imposed on a chemical system in
equilibrium, the equilibrium will shift so as to annul or neutralize the constraint. As such
established equilibrium may be shifted by variation in experimental conditions. A variation

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in temperature, pressure (if a gas is involved) and concentration will cause a change in
equilibrium. It is important to note that variation in temperature will affect the numerical
value of the equilibrium constant as well as causing a shift in equilibrium. Variation of other
factors will cause a shift in equilibrium but will not affect the numerical value of equilibrium
constant. Catalysts have no effect on the position of equilibrium.
Equilibrium in Solid System
The concentration of undissolved solids in suspension and mixtures cannot be varied. So
solid reactants and products are omitted from the equilibrium constant equation. It is also of
note that the concentration of water is excluded from the equation because they are presence
in large volume.

Theories of Acids, Bases and Salts

Arrhenius Theory. Arrhenius, a Swedish Chemist in 19th century (1880-1890) defined acid
as a substance that produces hydrogen ion in aqueous solution and a base as a substance that
yields hydroxyl ions in aqueous solution.
HCl + H 2 O ↔ H 3 O+ + Cl-
This definition was found to be inadequate because it did not account for manifestation of
acid-base reactions in non-aqueous solutions. The second problem is that some compounds
act as bases but do not contain Hydroxyl ions. E.g. (NH3 and Na2CO3)
Bronsted-Lowry in 1923 gave a more satisfactory and generalized definition of acids as
substances charged, or uncharged capable of producing a proton i.e. a proton donors while a
base is a substance charged or uncharged capable of accepting a proton from an acid.
A ↔ H+ + B
HCl ↔ H+ + Cl- Fe3+ + e- ↔ Fe2+
NH4+ ↔ H+ + NH3 Oxidant Reductant
HCO3- ↔ H+ + CO3-
H2 O ↔ H+ -OH

Please note that an acid will not release a proton unless a base capable of accepting it is
simultaneously present.
NH3 + H2O ↔ NH4+ + OH-
NH4+ + H2O ↔ NH3 + H3O+
CH3COOH + H2O ↔ CH3COO- + H2O
The limitation of this definition is that the proton concept of acids/bases does not provide
basic reason for proton transfer hence does not explain how substances such as SO32- , BCl3
and CO2 etc none of which is capable of donating a proton but behave as acids.

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 GN Lewis in 1923 suggested the 3rd definition of acids and bases. He provided answers for
these observations by defining acid as a substance capable of sharing or accepting a pair of
electrons made available by another substances called a base thereby forming a co-ordinate
covalent bond. A base is a substance that donates a share in its electron pair to the acid.
Acid (electron pair acceptor); a base (electron pair donor).
BCl3 + NH3 ↔ BCl3:NH3

COMPARISON OF ACID-BASE THEORIES

Theory Acid Base

Arrhenius Proton Donor in aq. solution OH is released in aq. solution

Bronsted-Lowry Proton Donor Proton acceptor

Lewis Electron pair acceptor Electron pair Donor

The relative strength of acids and bases are measured by the ability of these substances to
give up and take on protons. HCl acid is a strong acid in water because it readily releases its
proton in aqueous solution whereas acetic acid is a weak acid since it gives up its proton only
to a small extent. The strength of an acid or base varies with the solvent. HCl is a weak acid
in glacial acetic acid while acetic acid is a strong acid in liquid ammonia. Also, the strength
of an acid depends not only on its ability to give up a proton, but also on the ability of the
solvent to accept the proton from the acid. This is referred to as Basic strength of the
solvent.

Classification of Solvents
On the basis of the forces of interaction occurring in solvents, they are broadly classified as
(a) Polar Solvents. They are made up of strong dipolar molecules having hydrogen
bonding. E.g H2O, H2O2.
(b) Semi-polar Solvents. They are also made up of strong dipolar molecules but which
do not form hydrogen bonding. E.g. Acetone
(c) Non-polar Solvents. They are made up of molecules having a small or no dipolar
character. E.g. Benzene, mineral oil.
Solvents are also classified based on their affinity for proton
(1) Protophilic Solvent:- A solvent capable of accepting proton from solute. E.g. Liq.
NH3, Ether
(2) Protogenic Solvent:- A proton donating solvent. E.g HCl, H2SO4
(3) Amphiprotic Solvent:- A Solvent capable of acting as both proton acceptor and
proton donor. E.g. Water and alcohol

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 (4) Aprotic Solvent: A solvent that neither accept nor donate protons. E.g.
Hydrocarbons

IONIC STRENGTH OF ELECTROLYTES (µ)

It is a measure of the intensity of electric field in a solution. It is use to evaluate electrostatic
interaction between ions in strong electrolytes or for solution of weak electrolytes together
with its salts or other electrolytes (Buffers)
Debye-Huckel Theory relates the activity coefficient of electrolyte to the number and charge
of all the ions in the solution by using the concept of ionic strength designated by µ. The
ionic strength is half the summation of molar concentration of the ion to the square of
the valency or charge.
µ = ½Ɛ(Mi Zi2) Mi = molar concentration
Zi2 = square of the valency or charge
For electrolyte composed of univalent cation and univalent anion called (Uniunivalent or 1:1
electrolyte), the ionic strength is identical with Molarity. E,g. NaCl
For bivalent cation and univalent anion (Biunivalent or 2:1 electrolyte) or univalent cation
and bivalent anion (1:2 electrolyte, the ionic strength is 3 times the molarity.
For bivalent cation and bivalent anion (2:2 electrolyte), the ionic strength is 4 times the
molarity. Ionic strength is additive.
Examples
(1) 0.08M NaCl ↔ Na+ + Cl-
µ= 0.08 (1 x 12 + 1 x 12)
2
= 0.08

(2) 0.2M CaSO4 ↔ Ca2+ + SO42-

µ = 0.2 ( 1 x 22 + 1 x 22)
2
= 0.8
(3) 0.03M K3PO4 ↔ 3K+ + PO43-
µ= 0.03 (3 x 12 + 1 x 32)
2
5
 = 0.18

IONIZATION OR DISSOCIATION OF WATER

It is a known fact that water is a poor conductor of electricity but pure water does ionize
through a process called autoprotolysis. In the ionization of water, the liberated hydrogen
atom or proton does not exist freely but combine with another molecule of water given rise to
hydroxonium. Water then acts as a base being a proton acceptor
2 H2O ↔ H3O+ + OH-
HCl + H2O ↔ H3O+ + Cl-
On the other hand, Water may also act an acid being a proton donor. Hence water is
Amphiprotic.
H2 O + NH3 ↔ NH4+ + OH-
Apply the law of mass action to this reaction, gives the following
K = [H3O+][OH-]
[H2O]2
Since the concentration of water is very much greater than either hydroxonium or hydroxyl
group concentration, it is considered to be constant.
K = Kw = [H+][OH-] This is called ionic product of water or auto-protolysis constant or
dissociation constant of water. Kw varies with temperature , at 25o C, it is approximately
equal to 1 x 10-14
Kw = [H+][OH-] = 10-14
A solution in which the [H+] or [H3O+] is equal to [OH-] is termed a neutral solution.
[H+] = [OH-] =√1 x 10-14 = 1x 10-7 mole/litre or M

IONIZATION OF ACIDS AND BASES

Acids and bases are classified as strong or weak acids and strong or weak bases according to
how extensively or slightly ionized in aqueous solutions
E.g HCl and Acetic acid
HCl is a better conductor of electricity, reacts more readily with metals, catalyze certain
reactions more efficiently and possesses a more acidic taste than the acetic acid. The
differences in the properties of the two acids is attributed to the differences in the
concentration of hydrogen or hydroxonium ion. Likewise, most of the difference between
NaOH and Ammonia solutions are attributed to the higher OH- ion concentration in the
former.

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The ionization of incompletely or slightly ionized acid may be considered a reversible
reaction of the type below
HB + H2O ↔ H 3 O+ + B -
Applying the law of mass action to this reaction gives
Ka = [H3O+][B-]
[HB][H2O] [H2O] is constant

Ka = [H3O+][B-]
[HB]
Bases
B- + H2O ↔ HB + OH- E.g. NH3 + H2O ↔ NH4+ + OH-

Kb = [HB][OH-]
[B-]
Multiplying these two constants gives
Kw = Ka *Kb i.e. Ka xKb = [H3O+][B-] x [HB][OH-]
[HB] [B-]

Ka x Kb = [H3O+][OH-] = Kw
Note
The numerical value of most dissociation constants are very small numbers, hence it is
convenient to employ logarithm when using them

pK = -logK therefore pKw = pKa + pKb

Substance Ka Pka
Benzoic acid 6.25 x 10-5 4.20
Phenol 1.0 x 10-10 10.0
Salicylic acid 10.05 x 10-3 2.98
4 x 10-10 13.40

IONIZATION OF POLYPROTIC ELECTROLYTES

Acids which are capable of donating more than one proton are termed Polyprotic acids or
polybasic acids. The ionization occurs in 3 stages. E.g. Phosphoric acid H3PO4, Citric acid

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and Tartaric acid while a base that can accept more than a proton is referred to as Polyacidic
base
Example
Write the ionization of Phosphoric acid H3PO4 and apply the law of mass action to find the
overall ionization constant K
Hints H3PO4 + H2O ↔ (k1) H2PO4- + H3O+
H2PO4- + H2O ↔ (k2) HPO42- + H3O+
HPO42- + H2O ↔ (K3) PO43- + H3O+

Applying the law

K1 = [H2PO4-][H3O+] K2 = [HPO42-][H3O+]
[H3PO4] [H2PO4-]

K3 = [PO43- ][H3O+]
[HPO42- ]
K = K1 x K2 x K3 = [H2PO4-][H3O+] x [HPO42-][H3O+] x [PO43-][H3O+]
[H3PO4] [H2PO4-] [HPO42-]

= [H3O+]3[PO43- ]

[H3PO4]
H3PO4 + 3H2O ↔ PO43- + 3H3O+

Note
The lower the pKa, the stronger is the acid; the larger the pKa value of a base, the stronger the
base.
The basic drug is virtually, completely ionized at pHs up to 2 units below its pKa, and
virtually unionized at pHs greater than 2 units above its pKa.
The acidic drug is virtually, completely unionized at pHs up to 2 units below its pka and
virtually, completely ionized at pHs greater than 2 units above its pKa
Both acidic and basic drugs are exactly 50 % ionized at their pKa values.

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AMPHOLYTES

Compounds that can function as either as acids or as bases are called Ampholytes. They
are said to be Amphoteric in nature
E.g. Amino acids and Proteins
Glycine NH2CH2COOH

+NH
3CH2COOH (acid) + H2O (base) ↔ +NH3CH2COO- + H 3 O+
+NH
3CH2COO
- + H2O (base) ↔ NH2CH2COO- + H 3 O+

The species +NH3CH2COO- is amphoteric because it reacts as an acid in above

equation by donating its proton and as a base by accepting a proton from water as shown
below
+NH
3CH2COO
- + H2 O ↔ +NH CH COOH
3 2 + OH-

This specie is also called a Zwitterion.

pH
in the previous lecture, the operator p, which was introduced to mean negative logarithm. pH
may be defined as a negative logarithm of the hydrogen or hydroxonium ion value
concentration.

pH = - log[H+] .
The larger the value of pH, the smaller is the [H+] ion concentration. The solution with the
lower pH is more acidic and the one with the higher pH is more alkaline.

Example
Calculate the pH of a hydroxonium ion conc of 1 x 10-4 g-ion/litre
pH = -log [1x10-4] = 4

pOH
pOH = -log[OH-]
Since pKa + pKb = pKw

pH + pOH = pKw

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Example calculate the pH of a 0.005M solution of NaOH solution
pOH = -log[0.005] = 2.30
pH = Pkw - pOH = 14.00 – 2.30 = 11.70

pH OF WEAK ACIDS AND BASES

A weak acid is one that is not completely dissociated that is the undissociated species can be
diluted in solution. The extent of dissociation is characterized by ka. Assuming the initial
concentration in g/L is C. The concentration of undissociated acid at equilibrium will be
almost the same as the initial concentration because of the diminutive ion dissociation.
HA ↔ H+ + A-
[HA] = [A-][H+] This result is also obtained by noting that each molecule of HA
dissociates to yield one H+ and one A-, hence [H+] = [A-]
Ka = [A-][H+] Since [HA] = C
[HA]

Ka = [H+]2 = [H+]2
[HA] C
KaC = [H+]2
[H+] = √KaC Take logarithm of both sides
Log[H+] = ½logKa + ½logC Multiply by –ve
-Log[H+] = - ½logKa - ½logC

pH = ½pKa - ½logC
Therefore if the concentration of acid and dissociation constants are known, it is possible to
calculate the pH of the solution.

FOR WEAK BASE

B + H2 O ↔ BH+ + -OH

Kb = [BH+][OH-] kb = [-OH]2
[B] C
KbC = [-OH]2
[OH-] = √KbC

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Log[OH-] = ½logKb + ½logC x -ve
- Log[OH-] = -½logKb - ½logC

pOH = ½pKb - ½logC pkw = pH + pOH

Example: Calculate the pH of 0.1N Acetic acid which has pKa of 4.75
Solution pH = ½pKa - ½logC
pH = ½ x 4.75 - ½ Log 0.1
= 2.38 + 0.5 = 2.88

pKw = pH + pOH pOH = ½pKb - ½logC

pH = pKw - pOH
pH = pKw - pOH = pKw - ½pKb + ½logC

pH = pKw - ½pKb + ½logC

BUFFERS AND BUFFERING AGENTS

The terms buffer, buffer solution, or buffered solution are used with reference to hydrogen
ion concentration or pH. This refers to the ability of a system or solutions of compounds or
mixtures of compounds to resist changes in their pH upon addition of small quantities of an
acid, alkaline or on diluting it with solvent. H2O and neutral salt are unbuffered because the
minute trace of HCl or NaOH when added to it causes a corresponding large increase in [H+]
and [OH] respectively. They have no ability to resist change in H+ or OH concentration.
But certain substances or a concentration of substances impart to the system the ability
to maintain a desired pH at a relatively constant levels upon addition of acids or bases.
These substances are called buffers and their ability to resist changes in pH is known as
Buffer action, and their efficiency is measured by the function known as Buffer capacity or
buffer index or Buffer value or Buffer efficiency.
E.g. A solution of NaCl has a pH value of 7. Addition of even 1mL of 1NHCl solution to
1Litre of NaCl solution lowers its pH value from 7 to about 3. Similarly, addition of even 1
mL of 1N NaOH solution to 1Litre of NaCl solution raises its pH to about 11. NaCl solution
is therefore not a buffer solution because its devoid of buffer action.
Most buffers or buffer solutions usually consists of a mixture of a weak acid and one of its
salts or a weak base and one of its salts. An example of a buffer is a mixture of a weak acid
(Acetic acid) and its salts (Na. Acetate). Acetic acid is slightly dissociated in solution while

11
Sodium acetate being a salt is almost completely dissociated. The mixture thus consists of
CH3COOH molecules as well as CH3COO- and Na+ ion.
CH3COONa ↔ Na+ + CH3COO-
CH3COOH + H2O ↔ H30+ + CH3COO-
If a strong acid is added to the mixture, the H+ ion supplied by the acid are immediately mop
up by CH3COO- ions to form the very slightly dissociated CH3COOH
CH3COO- + H30+ ↔ CH3COOH + H2 0
The H+ ions are thus neutralized by the acetate ions present in the mixture and there is very
little change in the pH value of the mixture.
On the other hand, if a strong base is added, the OH- ions provided by the base are thus
neutralized by acetic acid present in the mixture and again there is very little change in the
pH of the solution.
CH3COOH + -OH ↔ CH3COO- + H20

Likewise, a mixture of a weak base and its salt (NH4OH and NH4Cl) behave in a similar
manner.
NH4Cl ↔ NH4+ + Cl-
NH3 + H20 ↔ NH4+ + -OH The mixture contains undissociated NH4OH as well
as NH4 and Cl ions. If a strong acid is added to the mixture, the H+ ions supplied by the
+ -

acid is neutralized by the base NH4OH

NH4OH + H+ → NH4+ + H20
On the other hand, if a strong base is added, the OH ions are neutralized by NH4+ ions
forming a very slightly dissociated NH4OH
NH4+ + -OH → NH4OH In both cases, there is very little change in the pH.

Similarly, for the phosphate buffer system which contains a monobasic potassium phosphate
KH2PO4 and dibasic potassium PO4 (K2HPO4)
KH2PO4 = K+ + H2PO4-
K2HPO4 = 2K+ + HPO42-
When -OH ion is added, the H2PO4- absolved it to form HPO42-
H2PO4- + -OH ↔ HPO42- + H2O
And when hydroxonium ion H3O+ is added the following occurs
HPO42- + H3O+ → H2PO4- + H2O

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The most common salt used to prepare buffer solutions are 1) Acetate 2) Borate 3) Citrate
4) Phosphate 5) phthalates

Importance of Buffers in quantitative Analytical Chemistry

1. Ensure proper progress of a reaction by removing H3O+ & -OH reaction products as they
are being formed.
2. Control the level of pH during a precipitation process/stability of formulations
3. Maintain a required level of pH in order to guarantee the proper reactions of an indicator
substances
4. Used in titration processes.

BUFFER EQUATION FOR A WEAK ACID; ITS SALTS AND COMMON ION
EFFECT
Using the example of the effect of addition of sodium acetate on the ionization of acetic acid.
Both sodium acetate and acetic acid have an ion common between them (CH3COO-)
The dissociation constant for the acid is given by
CH3COOH + H2O ↔ CH3COO- + H3O+
Ka = [CH3COO-][H3O+]
[CH3COOH]
If sodium acetate is added to the acetic acid solution, it ionizes to give acetate ions.
CH3COONa ↔ CH3COO- + Na+
This causes a momentary increase in the concentration of CH3COO- in the solution. To re-
establish the dissociation constant for the solution, the H+ ion term in the numerator is
consumed. This results in the increase in the concentration of acetic acid in the denominator.
Thus the reaction
H3O+ + CH3COO- ↔ CH3COOH + H2O is favored and the constant ka remains
unaltered. In other words, the ionization of acetic acid is repressed upon addition of the
common acetate ion to the solution and this is known as the COMMON ION EFFECT

CH3COOH + H2 O ↔ CH3COO- + H3 O+
Ka = [CH3COO-][H3O+]
[CH3COOH]

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[H3O+] = Ka [CH3COOH]
[CH3COO-] Since acetic acid ionizes only slightly, the concentration of
acetic acid may be considered to represent the total concentration of acid in the solution.
Hence, the term [CH3COOH] can be replaced with [Acid]. Similarly since acetate ion is
contributed almost entirely by the salt, sodium acetate, the term [CH3COO-] may be replaced
by [Salt]
[H3O+] = Ka [Acid]
[Salt]

Take –Log of the expression

-Log[H3O+] = -LogKa - log[Acid] + log[Salt]
pH = pKa + Log [Salt]
[Acid]
pH = pKa + Log [ionized]
[unionized]

This is known as the buffer equation or the Henderson-Hasselbalch Equation for a weak
acid and its salt. The equation describes the relationship between ionized and unionized
species of a weak electrolyte. The Buffer equation is a useful expression used in the
preparation of buffered pharmaceutical solutions. It is satisfactory for calculations within the
pH range of 4 to 10

BUFFER EQUATION FOR A WEAK BASE AND ITS SALT

Although buffers are not usually prepared using weak bases and their salts because of their
poor stability but certain pharmaceutical solutions such as a solution of Ephedrine bas and
Ephedrine HCl which are mixtures of weak bases and their salts are often encountered.
The buffer equation of weak base and its salt can be derived in similar manner.
NH3 + H2O ↔ NH4+ + -OH

Kb = [NH4+][-OH] [NH4+] = [Salt] [ionized]

[H3N] [NH3] = [Base] [unionized]
[-OH] = Kb [Base]……………………………………………………….(1)
[Salt]
Since Kw = [H3O+][-OH]

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[-OH] = Kw ……………………………………………………………(ii)
[H3O+]

Substituting equation (ii) in (i)

Kw = kb [Base]
[H3O+] [Salt]
Take Logarithm of both sides and rearrange
LogKw - log[H3O+] = LogKb + Log[Base] - Log[Salt]
-Log[H3O+] = -logKw + logKb + log[Base] - log[Salt]

pH = pKw - pKb + Log[Base] [Unionized]

[Salt] [Ionized]

BUFFER CAPACITY
Buffer capacity is usually defined as the number of moles of a strong base required to change
the pH of one litre of solution by one unit. It is a measure of magnitude of resistance to
change in pH on addition of a base.
ß = ΔB
ΔpH
ßmax = 0.576C C = total buffer concentration (the sum of the molar concentrations of
the acid and the salt.
TYPES OF BUFFERS
1. BIOLOGICAL BUFFERS. The pH of blood is maintained at about 7.4 by primary
buffer components in the plasma (carbonic acid-carbonate, the acid/alkaline sodium salts of
phosphoric acid) and secondary buffer components in the erythrocytes.(oxy-haemoglobin-
haemoglobin and acid/alkaline potassium salt of phosphoric acid). The physiological pH
range of blood is 7.0 to 7.8. When the pH of the blood decreases or rises beyond this range,
life is in danger.
The pH of Lacrimal fluids or tears is about 7.4 with a range of 7.0 to 8.0. tears have been
found to have a great degree of buffer capacity. The average pH of urine is about 6.0 with a
range of 4.5 to 7.8.

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2. PHARMACEUTICAL BUFFERS
Buffers are used in the manufacture or formulation of pharmaceutical preparations in which
the pH must be maintained at a relatively constant level in order to ensure maximum stability
or for maintaining the pH of the product within the optimal physiological pH range. Buffers
are used in Ophthalmic, parenteral preparations, in creams and ointments.
CONDITIONS FOR PREPARATION OF PHARMACEUTICAL BUFFERS
The following steps are used for the preparation of buffers
1. A weak acid should be selected having a pKa approximately equal to the pH at which the
buffer is to be used. This will give the maximum buffer capacity.
2. The ratio of the conjugate salt and acid required to attain the desired pH may be calculated
for the buffer equation which gives a fairly good approximation within the pH of 4 to 10.0
3. Individual concentrations of the buffer salt should then be considered to obtain the desired
buffer capacity. Usually a concentration of 0.05 to 0.5M is sufficiently corresponding to a
buffer capacity of 0.01 to 0.1
4. Easy availability of the buffer components
5. They should be compatible with the drug
6. The buffer must be stable
On the final note, the pH and buffer capacity of the prepared system should be determined
experimentally using a reliable pH meter indicator paper or machine since theoretical values
may differ slightly from the experimentally determined ones.

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INDICATORS
Indicators are used internally to locate the equivalence points and or end points of
neutralization titrations. Equivalence point, or stoichiometric point of a chemical reaction is
the point at which chemically equivalent quantities of reactants have been mixed. End point
of a titration is the point at which the indicator changes colour. Where the indicator substance
used reacts by changing its colour at the exact equivalence point of the titration then, the end
point and equivalence point coincide. Where the indicator reacts appreciably before or after
the exact equivalence, it means the end point has been determined, which, in this instance,
does not coincide with the equivalence point. Where there exists a lack of coincidence
between the end point and the equivalence point volumes of titration, the titration is said to
suffer from a titration error and hence requires the use of an indicator-blank correction in
order to correct the volume of titration for the end point to the titrant volume corresponding
to the equivalence point.
Indicators act as weak acids or weak bases in aqueous solution. According to original theory
of Ostwald, the colour changes of indicators are due to changes in ionization, the ion having
one colour and undissociated salt colourless. The proportion of free indicator represented as
[HIn] to ionized indicator [In-] being connected with changes in hydrogen ion concentration
by the mass action equation is shown below
HIn + H2O ↔ H 3 O+ + In-
Km = [H3O+][In-]
[HIn]

[H3O+] = Km [HIn]
[In-]
-Log[H3O+] = -LogKm + log[In-]
[HIn]
pH = pKm + log[In-]
[HIn]
Usually in titrations, the indicator will be chosen so that pK = pH for then, the colour will be
half way between the acidic and alkaline extremes since [HIn]=[In-]. This is sometimes
called the change-point of the indicator.
In line with the early theories of Barnthsen, Friedlander and Watt, colour in organic
compounds is associated with the presence of certain unsaturated “Chromophores” such as
C=C, C=O,N=O and N=N, especially when intensified by “auxochromes” such as NH2 and
OH. It has been discovered that the colour changes of many indicators could be explained as
resulting from the transformation of a Benzenoid structure into a Quinonoid, or vice versa,
with changes in the hydrogen ion concentration of the solution.

17
 Benzenoid form Quinonoid form
Colourless
Coloured

Classification of indicators
1. The Phthaleins e.g. Phenolphthalein. It is colourless in acid or neutral solution and
becomes red in slightly alkaline solution. The red colour fades in strongly alkaline solution
as shown below.

18
 OH

O
CO

C CO 2-

C
Lactone, colourless OH
in acid solution
Quinonoid salt
red in alkaline sol
O-

O-
CO 2-

OH
O-

Phenolic salt of Carbinol, colourless

in strongly alkaline solution

2. The Azos. E,g Methyl Orange. It is yellow in alkaline solution and present as the salt
of sulphonic acid. The yellow colour being due to the -N:N- group. On addition of acids,
there is a change in structure to a red quinonoid form

-O2S N=N- N(CH 3)2

Azoid form
yellow in neutral or +
alkaline solution
NH N= =N(CH 3)2

Quinonoid form, red in acid solution

19
3. The sulfonphthalein E.g Phenol red, Nitrophenol or phenolsulfophthalein

HO NO 2 -
O NO 2

Almost colourless in Deep yellow in alkaline

acidic solution solution

Common name colour change colour change

range in pH
Methyl Violet Yellow to blue 0.00 - 1.6
Methyl Orange Red to yellow 4.2 - 6.2
Litmus Paper Red to blue 4.5 - 8.3
Phenolphthalein colourless to red 8.3 10.0
Bromo cresol green Yellow to blue 3.8 - 5.4

Factors affecting indicator use

1. Indicator selection. It must have a colour change range in pH which coincides with the
pH which occurs close to or around the equivalence point pH of the titration
2. Quantity of Indicator. In order to avoid large amount of titrant in the indicator colour
change reaction, relative to the equivalence point volume, the amount of the indicator used
should be as small as is conveniently possible.
3. Colour change detection. The first colour change that can be clearly detected is taken as
the indicator of colour changes. Any operator should rely on his ability to judge colour
change.
4. Effect of temperature. Increase in temperature increases the degree of ionization of
indicator hence promote quick colour change.
5. The effect of impurities such as colloids or other adsorbent

20
MARTIN’S Physical pharmacy and pharmaceutical sciences. Physical chemical and
Biopharmaceutical principles in pharmaceutical Sciences 5th Edition, Patrick J. Sinko,
Lippincott Williams & Wilkins. 2006

21
 Topic 10 – Thermodynamics
Revision Notes

1) Enthalpy Changes

• An enthalpy change is a change in heat energy measured at constant pressure.

• Enthalpy changes refer to the chemicals not the surroundings.
• The symbol for an enthalpy change is ∆H (∆ = change, H = heat energy)
• The units for enthalpy change are kJ mol-1

2) Entropy and Free-energy

• As a general rule, once an exothermic reaction has started it produces enough

energy to keep it going e.g. burning methane
• Similarly, an endothermic reaction requires constant heating and will stop if the heat
is removed e.g. thermal decomposition of copper carbonate
• However, some endothermic reactions will keep going without being heated e.g.
NaHCO 3 and HCl. The enthalpy change is not the only factor to be considered when
deciding whether a reaction is possible

a) Entropy

• Entropy is measure of the disorder of a system. It has the symbol S and units
of J K-1 mol-1 (note that this is J not kJ)
• Considering the states of matter, a solid is the most ordered and has the
lowest entropy. A gas is the most disordered state and has the highest
entropy
• At absolute zero (-273 °C or 0 K), particles stop moving and have zero
entropy

b) Entropy changes

• Entropy changes are calculated using the following formula

∆S = Σ S(products) - Σ S(reactants)

• A reaction that produces a gas will have a positive entropy change because
disorder has increased
• Melting and boiling have positive entropy changes. Boiling has a bigger
entropy change than melting because gases are much more disordered than
liquids and solids

c) Feasibility

• For a chemical reaction to be feasible (possible) the amount of disorder in

the universe must not decrease
• Fortunately, we do not have to do measurements on the universe to find out
whether a reaction is feasible. Instead we define a quantity called the free
energy change, ΔG, and it can be shown that disorder in the universe does
not decrease if ΔG is less than or equal to zero for the reaction
 • ΔG is calculated using the following formula

ΔG = ΔH – TΔS (T is temperature in K)

• It follows from this formula that feasibility is dependent on temperature

• An exothermic reaction with a positive entropy change will be feasible at all
temperatures
• An endothermic reaction with a negative entropy change will be infeasible at
all temperatures
• An exothermic reaction with a reduction in entropy will become feasible at
low temperatures (when ΔH outweighs TΔS) – see example below
• An endothermic reaction with an increase in entropy will become feasible at
high temperatures (when TΔS outweighs ΔH)
• In the last two cases, the temperature at which the reaction becomes
feasible is when ΔG =0 (i.e. ΔH = TΔS, or T = ΔH/ΔS)

Example

TiO 2 (s) + C(s) + 2Cl 2 (g) → TiCl 4 (l) + CO 2 (g)

For this reaction, ΔH = -258 kJ mol-1 and ΔS = -35.6 J K-1 mol-1

Calculate the temperature at which this reaction ceases to be feasible

T = ΔH/ΔS
= (-258 x 1000)/-35.6 (common mistake is to leave out x 1000)
= 7247K (infeasible above this temperature)

• For changes of state, such as melting and boiling, ΔG = 0 and the two states are in
equilibrium

3) Born-Haber cycles

a) General

• Born-Haber cycles show the steps involved in forming an ionic solid either
directly from its elements or indirectly via the formation of gaseous atoms
and ions
• The indirect route involves the following steps: atomisation of the metal,
ionisation of the metal, atomisation of the non-metal, electron affinity of the
non-metal and lattice formation. It is recommended that this sequence is
followed every time a cycle is drawn
• Born-Haber cycles allow missing enthalpy values to be calculated using
Hess’s Law (which states that enthalpy change is independent of route)

b) Equations for Born-Haber Cycles

The steps involved in forming NaCl(s) by both routes and their associated enthalpy
changes are shown below.

• Formation, ΔH f e.g. Na(s) + ½Cl 2 (g) → NaCl(s)

• Atomisation of the metal, ΔH at e.g. Na(s) → Na(g)
• Ionisation of the metal, ΔH i1 e.g. Na(g) → Na+(g) + e-
• Atomisation of the non-metal, ΔH i1 e.g. ½Cl 2 (g) → Cl(g)
• Electron affinity of the non-metal, ΔH ea1 e.g. Cl(g) + e- → Cl-(g)
 • Lattice formation , ΔH LE e.g. Na+(g) + Cl-(g) → NaCl(s)

Hess’s Law says:

ΔH f = ΔH at (Na) + ΔH i1 + ΔH at (Cl) + ΔH ea1 + ΔH LE

• Atomisation enthalpies of non-metals are per atom e.g. 121 kJ mol-1 for Cl,
so twice this for Cl 2 (g) → 2Cl(g)
• A Group II metal has two ionisation enthalpies which will be shown as
separate steps in the cycle. The second ionisation enthalpy is larger than the
first because the electron is lost from a particle that is already positive which
means that the outer electron is more firmly attracted to the nucleus
• A Group VI non-metal has two electron affinities which will be shown as
separate steps in the cycle.
• The first electron affinity is exothermic due to the attraction between the
nucleus and the external electron
• The second electron affinity is endothermic because the negative ion repels
the negatively charged electron
• Lattice formation is an exothermic process, ΔH LE is negative; lattice
dissociation is endothermic, ΔH LE is positive. Both lattice enthalpies have the
same numerical value but have opposite signs

4) Enthalpies of Solution

The steps involved in forming NaCl(aq) are shown below.

• Solution, ΔH sol e.g. NaCl(s) → Na+(aq) + Cl-(aq)

• Lattice dissociation or formation, ΔH latt e.g. NaCl(s) → Na+(g) + Cl-(g)
or Na+(g) + Cl-(g) → NaCl(s)
• Hydration of the metal ion, ΔH hyd e.g. Na+(g) → Na+(aq)
• Hydration of the non-metal ion, ΔH hyd e.g. Cl-(g) → Cl-(aq)

If given lattice formation enthalpy use:

ΔH sol + ΔH LE form = ΔH hyd (Na+) + ΔH hyd (Cl-)

If given lattice dissociation enthalpy, either change sign to –ve and do above
calculation or leave sign +ve and use:

ΔH sol = ΔH hyd (Na+) + ΔH hyd (Cl-) + ΔH LE diss

5) Effect of ionic charge and ionic radius

• As ionic charge increases, lattice enthalpy becomes more exothermic e.g.

MgCl 2 has a more exothermic lattice enthalpy than NaCl because Mg2+ has a
higher charge than Na+. This is due to a stronger electrostatic attraction
between the positive and negative ions
• As ionic radius decreases, lattice enthalpy becomes more exothermic e.g.
MgO has a more exothermic lattice enthalpy than CaO because Mg2+ has a
smaller ionic radius than Ca2+. In MgO the ions are closer together so the
positive and negative ions are more strongly attracted to one another
• The same factors apply when comparing hydration enthalpies but in this case
the comparison is between the attraction of the ions to the appropriate end
of a water molecule
6) Perfect Ionic Model

• Lattice enthalpy (LE) is a measure of the strength of attraction between ions. The
more negative the lattice enthalpy of formation, the stronger the attraction and the
stronger the ionic bonding.

• The lattice enthalpy values obtained by using Born-Haber cycles are determined by
experiment and reflect the actual value.

• It is also possible to calculate the lattice enthalpy by visualizing the ionic lattice as
made up of perfectly spherical ions in a lattice (the perfect ionic model).

• In some ionic compounds, the experimental lattice enthalpy of formation is more

negative than predicted by the perfect ionic model i.e. the compound is more stable
than expected. (When considering lattice enthalpy of dissociation, the experimental
value will be more positive than the calculated value.)

• This discrepancy is caused by covalent character which exists in the ionic lattice. This
covalent character makes the forces in the lattice stronger than purely ionic forces
(i.e. there is extra bonding)

• The covalent character is caused by polarisation of ions

• The extent of the polarisation depends on how much the cation pulls on the
electrons; the polarising power, and on how much the anion allows the electrons to
be pulled away: the polarisability.

• Polarising power is increased by higher positive charge and smaller cation.

• Polarisability is increased by higher negative charge and larger anion

Compound Experimental LE value / Theoretical LE value Difference in LE

kJmol-1 / kJmol-1 values / kJmol-1
MgF 2 -2957 -2913 44
MgI 2 -2327 -1944 383

• In the above example, F- is small and not significantly polarized by Mg2+ whereas I- is
large and more polarisable leading to increased covalent character and a more
negative LE than predicted by the perfect ionic model.
6) Dissolving

• When positive ions dissolve, there is an attraction between the ion and the δ- O of a
water molecule
• When negative ions dissolve, there is an attraction between the ion and the δ+ H of
a water molecule
• These are called ion-dipole attractions
 THERMODYNAMIC - SAMPLE QUESTIONS

(Dr. D.K. Adeyemi)

1. The enthalpy of vaporization of diethyl ether was 42 KJ/mol at its B.Pt of 30.6 0C.
Determine the entropy change for the conversion.
2. The enthalpy of combustion of glucose was -1720 KJ/mol. Determine the calorific value
given that the molecular mass is180g/mol
3. Given that the enthalpy of the reaction 2NH3 ----- 3H2 +N2 is -642 KJmol -1. Calculate the
enthalpy of formation of ammonia
4. When 36.0 g of glucose (molar mass 180 g/mol) was completely burnt, the heat released
was used to raise the temperature of 2.5g of water from 60 to 950C, assume that the
energy conversion is 75% efficient, use this information to determine the enthalpy of
combustion (C =4.18J/g K)
5. Calculate the internal energy change for a thermodynamic system which absorbs 100 J of
heat and does equivalent work of 472 J on its surroundings.
6. Define the terms below with example i open systems ii. adiabatic process iii. enthalpy
of formation iv. state function
7. Given that enthalpy change for the reaction 2H2 (g) + 02 (g) →2H20 (l) is ΔH = 285.6
KJmol -1. Determine the enthalpy of formation of water
8. Given that the heat liberated on burning completely 23g of ethanol and 35g of LPG
(butane) were -305.3 and -951.2 kJ respectively. Determine the enthalpy of combustion
and calorific value of each fuel and compare their efficiency rate
9. Calculate the entropy change of fusion and vaporization of naphthalene. Given that ΔH
fusion = 6.40 kJ/mol, m.pt = - 50.6 oC, ΔH vap = 20.4 kJ/mol, b.pt = - 30.5 oC
10. State the zeroth, first, second and third laws of thermodynamics
11. Consider the reaction, TiO2(s) + C(s) + 2Cl2(g) → TiCl4(l) + CO2(g)
ΔH = -258 kJ mol-1 and ΔS = -35.6 J K-1 mol-1. Calculate the temperature at which this
reaction ceases to be feasible.
12. Explain with equation each of the following enthalpy changes
a. Lattice enthalpy b. enthalpy of neutralization c. enthalpy of solution
13. List any five thermodynamic processes in Pharmacy.
14. List any 2 applications and limitations of thermodynamics.
15. A student measures out 35 cm3 of 2.4 mol/dm3 NaOH and 35 cm3 of 2.4 mol/dm3 HCl, on
mixing the two solutions, the temperature rises by 16.50 C. Given that the specific heat
capacity of the mixture is 4.18 J/g K, and assume that density of the mixture is 1.0g/cm3.
Calculate the enthalpy of neutralization in KJ/mol.
16. Construct an energy cycle relating enthalpy of solution of MgCl2, lattice enthalpy, and
enthalpy of hydration of the ions. Determine the lattice energy, given that the enthalpy of
solution of Mg (OH)2 is -152 KJ/mol, while enthalpy of hydration of Mg2+ and OH- are
-1926 and -460 KJ/mol respectively.