Intermolecular Forces and Phase Equilibria

Intermolecular force (IMF)
and Phase Equilibria
Getahun Paulos (B.Pharm; MSc;

PhD)
Asst. Professor of Pharmaceutics
1 phase rule 01/18/2022

Outline
2
 Introduction to intermolecular force of interaction (IMF)
 The phase rule
 Phase equilibria of single, two and three component systems
(principles and applications)
01/18/2022
Introduction to IMF
3
 Intermolecular forces
 Forces of attraction or repulsion which act b/n neighboring
particles, molecules or ions.
 Manifested by
 aggregationsof molecules in gases, liquids & solids
 Cohesion and adhesion b/n molecules
 The strengths of Intermolecular forces are weak

compared to the intramolecular forces (see figure below)
 Dear student, what are intramolecular forces?
01/18/2022
Introduction to IMF…
4
Intramolecular force between HCl molecules. H-Cl --- H-Cl

3.3 kJ/mol (to separate molecules)
 +
 -  + -
431 kJ/mol (to break covalent bond)

Introduction to IMF…
5
 The knowledge of intermolecular force is important

for understanding:
 The properties of gases, liquids, and solids
 The properties of interfacial phenomena
 Flocculation in suspensions & stabilization of emulsion
 Compaction of powders in capsules, and
 The compression or granules to form tablets.
phase rule 01/18/2022

Types of attractive intermolecular forces
6
1. Van der waals forces

2. Ion-dipole and ion-induced dipole force
3. Hydrogen bonds
01/18/2022
1. Van der waals forces
7
Van der Waals forces

 Occurs between neighboring molecules
 These forces can be divided into three categories:

(1) Dipole-Dipole,
(2) Dipole-Induced Dipole, and
(3) Induced dipole-Induced dipole

Van der waals forces…
8
A. Dipole-Dipole Forces (Keesom forces)

 Dipole-Dipole: Occurs between two polar molecules
 A molecule is called Dipole if a molecule acts as if it has a
positive and negative pole (polar molecules)
 Why Dipole? Due to the difference b/n the electro-negativities of the atoms
 Example: The dipole-dipole interaction in HCl is only 3.3 kJ/mol
(The covalent bonds in HCl are 130 times as strong)
 hydrogen chloride boils at -85.0oC. 01/18/2022
B. Dipole-Induced Dipole Forces (Debye force)
9
 Occurs between polar & non-polar molecules

 Permanent dipoles are capable of inducing an electric dipole in nonpolar
molecules
 For Example, what would happen if we mixed HCl with argon, which has no
dipole moment?
+ HCl - Ar
 By distorting the distribution of electrons around the argon atom, the polar HCl
molecule induces a small dipole moment
 This force is very weak, with a bond energy of about 1 kJ/mol
 E.g., H2O---O2 01/18/2022

10
C. Induced Dipole-Induced Dipole Forces (London dispersion)

 Force of attraction b/n two non-polar molecules such as hydrogen
gas, carbon tetrachloride, & benzene
 How these attraction occur?
 Movement of the electrons around the nuclei of a pair of neighboring
atoms can become synchronized so that each atom simultaneously
obtains an induced dipole moment.
 These fluctuations in electron density occur constantly, creating an
attraction between pairs of atoms.
 Example: helium -- only 0.076 kJ/mol
He He
2. Ion-dipole & ion-induced dipole force
11
A. An ion-dipole force
 an ion and a polar molecule interacting. + - +
 Example: NaCl and water Na+ H2O
 Na+ ---H2O and Cl- --- H2O
B. An ion-induced dipole force

 an ion and a non-polar molecule interacting.
 Like a dipole-induced dipole force, the charge of the ion causes a distortion of
the electron cloud on the non-polar molecule.
 Example: iodide complex, - + - +
I2 - K+I3- +
I2 + K+I- K +I 3 -
 Because the charge of any ion is much greater than the charge of a
dipole moment, these forces are stronger than other IMF
01/18/2022
3. Hydrogen bonding
12
 It is the strongest type of dipole-dipole attractions.
 The interaction b/n a molecule containing a H-atom & a

strongly electronegative atom such as fluorine, oxygen, or
nitrogen
 Because of small size of a hydrogen atom and its large
electrostatic field, it can move in close to the
electronegative atom and form an electrostatic type of
union- hydrogen bridge.
01/18/2022
H-bonding
13
 For example,
 hydrogen bond exists in ice and in liquid water;
 it accounts for many of the unusual properties of
water including
 high dielectric constant,
 low vapor pressure and
 high boiling point.
H-bonding
 Salicylic acid showing intermolecular and intramolecular

hydrogen bonding
15
Phase equilibria

Contents of Presentation
16
 Phase and Phase rule

 One component systems
 Two component systems
 Three component systems

Phase
17
• What is phase?
• Phase is a homogenous, physically distinct, mechanically separable
portion of a material that is separated from other parts of the system
by definite boundaries.
• Examples
– How many phases we have in the Mixture of two immiscible liquids?
– Two phases: aqueous phase and oily phase
OIL
– A mixture of gases: how many phases?
– One phase water
• Two or more phases are said to be in equilibrium when the rate
of formation/disappearance of the two phases is equal. E.g.
water-oil system
– It is a dynamic equilibrium phase rule 01/18/2022
Phase rule
18
Phase rule
• Gibbs Phase rule (it is formulated by J. Willard Gibbs in
1876)
– It is a device for relating the effect of the least number of
independent (intensive) variables upon the various phases
that can exist in an equilibrium system containing a given
number of components.
– Examples of intensive variables are temperature, pressure
concentration, viscosity, density, refractive index, etc.
• Mathematically it is expressed as:
F=C-P+2
Phase rule…
19
Where,
 P is the number of phases in equilibrium
 C is the number of components

 it is the smallest number of chemical constituents of each
phase in the system at equilibrium expressed in the form of
chemical formula or equation.
 Example:
 How many components are there in the case of ice-water-
vapour system?
 How many components are there when NaCl(s) dissolved in
H2O?
Phase rule…
20
 F is the number of degrees of freedom:

 the least number of intensive variables that must be fixed
to describe the system completely.
 Example: A system containing liquid water and vapour, F

is 1. How F = 1? Please calculate
– One variable should be defined to get the two phases in
equilibrium.
– Or only one variable should be specified to describe the system
completely
One component system
21 phase rule 01/18/2022

One component systems
22
 In one component systems, the maximum F is 2

(i.e., when P is 1)
F =C-P+2 = 1-1+2 = 2
 Temperature and pressure are the two intensive variables
affecting the equilibrium
 One component system is illustrated by

 Phase diagrams of water
 It can be represented by ordinary rectangular coordinate plane.
 Using the above degree of freedom (F = 2)

One component: Phase diagram of water
23

One component systems…
24
1. Regions (areas) on the diagram

 Each region corresponds to one phase (liquid, ice or
vapour)
 F is 2 (bivariant)
 Temperature and pressure should be specified to

describe the system completely.
 One can vary both P and T independently without
changing the existing phase

25
2. Lines between the regions (AO, BO and CO)

 Known as phase transition curves
 Two phases exist in equilibrium ,
 F =1,univariant
 Only one variable (T or P) -specified to describe the system
lying on any of the lines completely.
 by stating the T, the system is completely defined because the P
under which the two phases coexist is also defined.
 The two variables cannot be varied independently; otherwise a
change from two-phase region to a single-phase system will
occur.
26
Curve AO
 Known as vapour pressure curve
 Vapour and liquid water coexist in equilibrium
 Boiling point of water lies on this curve and it
increases as pressure increases.

 It has important application in steam sterilization

27
Curve BO
• Known as melting point/fusion/ curve
• Liquid water and ice coexist in equilibrium
• The negative slope of this curve shows that melting point of
water decreases as pressure increases

• unlike most substances, liquid water is denser than ice
Curve CO
 Known as sublimation curve
 Ice and vapour coexist in equilibrium (below the triple point)
 This curve has important application in freeze-drying
(lyophilization)
28
3. The triple point

 The three phases exist in equilibrium
 It is at 0.098OC and 4.54 mmHg (0.006 atm)
 The degree of freedom is zero (invariant)=
F=1-3+2=0
 There is no degree of freedom. If we attempt to
vary the particular conditions of T or P necessary
to maintain this system, we will lose a phase.

Two component system
29 phase rule 01/18/2022

Two Component (Binary)
30
systems
• In two component systems, the max. F is 3 (P is 1) F= c-
p+2= 2-1 +2 = 3
• T, P and C the 3 variables affecting the equilibrium
A. binary systems containing liquid phases

• Two liquids could be:
– Miscible in all proportions. eg. Water and ethanol

– Practically immiscible. eg. Water & fixed oils, water & mercury
– Partially miscible. eg. Phenol and water, water and ether, water
and acetone, water and benzene, Triethylamine and water,
Nicotine and water etc.
• Solubility of partially miscible liquids depend on intensive
variables phase rule 01/18/2022
Two component system…
31
 In cases where partial miscibility occurs under normal

conditions the degree of miscibility is usually dependent on
the Temperature
 Dependency can described by means of phase diagrams, which
are graphs of T vs Composition at constant P
 Pressure is kept constant in two component system in order to

represent the system in planar form
 The partially miscible systems may be divided into the following

types
01/18/2022
1. Systems showing an increase in miscibility with
rise in temperature
32
Phase diagram of phenol-

water system

bimodal curve/bimodal/ or phase boundary
33
 Upper consulate temperature (critical solution), the maximum

T at which two phase region exists
 Line bc drawn across the region containing two phases is
termed as tie line
 It is always parallel to the base line
 Starting at point a (pure water) at 50 OC, the addition of phenol

to fixed weight of water results in one phase up to point b
01/18/2022
bimodal curve/bimodal/ or phase boundary
34
• At point b minute amount of 2nd phase appears at

bottom, at conc. of 11% by wt. of phenol in water.
– The analysis of this 2nd phase (phenol-rich phase) shows
that it contains 63% by wt. phenol in water (denoted by
point c).
– The 1st phase is known as water-rich phase and contains
11% by wt. of phenol (denoted by point b)
• Once the conc. of phenol exceeds 63%, a single
phenol-rich liquid phase is formed

The tie line
35
The parallel line drawn across the region containing the two
conjugates phases (at a given T)
 All systems prepared on a tie line, will separate into two
conjugate phases of :
 constant composition but the relative amount (proportion) is not
constant. For example:
 any system represented by a point on the line bc, at 50oC, gives a
pair of conjugate phases whose composition is b and c
 If we prepare a system containing 24% by wt of phenol &76% by
wt of water (point d), we get 2 phases
 Upper phase (A) has a composition of 11% phenol in water (point b)
 Lower layer (B) contains 63% phenol (point c)
The tie line
36
• The tie line can be used to calculate:

– The relative proportions (weights) of the two phases
– The amount of each phase and amount of each
component (in each phase)
 Tie line can be used to determine the weight

and composition of the phases

The tie line
37
Lever rule
 Let the water-rich phase and phenol-rich phase be phase A and
phase B, respectively. At point b
Weight of phase A Length of dc


Weight of phase B Length of bd
– It is possible measure lenght dc & bd using ruler (cm).
It is more convenient to take % by wt. of phenol from
x-axis
01/18/2022
The tie line
38
Example 1
At point d = 24%
b = 11%, c = 63%,
bc 6324 39 3
  
bd 2411 13 1
 For every 10 g of a liquid system in equilibrium

at point d
 Phase A = 7.5 g & Phase B = 2.5 g
01/18/2022
The tie line
39
 At point f =50%
fc 6350 13 1
  
bf 5011 39 3
 For every 10 g of system f

b= 11%  Phase Ae== 37%
2.5 g & phase B 7.5 g c= 63%
ec 6337 26
At Point e = 37 %
  1 1/1= 50/50

be 3711 26
 Equal weight of phase A & phase B 01/18/2022
The tie line
40
Example 2,
• Let us suppose that we prepared a system containing 24g
of phenol & 76g water, warmed to 50oC & let to reach at
equilibrium
 Calculate
 The weight of each phase.
11% 24% 63%
A/B = 63-24/ 24-11 = 39/13= 3/1= 75%/25%= 75g/25g
 The amount of phenol in each phase.
 The amount of water in each phase.

The tie line
41
Answer
 On separation of the two phases, we would find 75g of phase
A (containing 11% of phenol) and 25g phase B (containing
63% of phenol)
 Phase A contains a total of (11x75)/100= 8.25g of phenol

 Phase B contains a total of (63x25)/100= 15.75g of phenol
 Total of 24g phenol
• if u calculate the water part , you will find
 phase A contains 66.75g of water
 Phase B contains 9.25g of water

42
 At 30 oC
 7%24% 70%
 24% phenol with 76% water mixed
 What is the weight of each layer
 A/B = 70-24/24-7 = 46/ 17= 2.7/1= A=2.7/3.7=73g, B=
1/3.7=27g
 Calculate the weight of phenol in each layer?
 Phenol in water rich layer (73g)= 5.11g= 7% 0f 73= 5.11g
 Phenol in phenol rich layer (27g)= 70% x 27g= 18.9g

Upper critical solution temperature
43
 Is, the upper consolute T, max. T at which the two

conjugate phases exist
 It is 66.8OC for phenol water system
 Above this T, they are miscible (only one phase exists)
 As the temperature decreases, the positive deviation from
Raoult's law occurs and result in a decrease in miscibility
sufficient to cause the separation of the mixture into two
phases.

2. Systems showing a decrease in miscibility with
rise in temperature
44
 A few mixtures, which probably

involve compound formation,
exhibit a lower critical solution
temperature (CST),
 e.g. triethylamine plus water (20 OC),
paraldehyde plus water
 The formation of a compound
produces a negative deviation from
Raoult's law, & miscibility
therefore increases as the
temperature falls
3. Systems showing upper and lower critical solution
temperature
45
 Some mixtures have

both upper & lower
critical solution T
 Nicotine-water system
(208OC & 60.8OC,
respectively)

The effects of additives on critical solution
temperature (CST)
46
Type of Solubility of additive in Effect on CST Effect on

CST each component miscibility
Upper Approx. equally soluble in Lowered Increased
both components
Upper Readily soluble in one Raised Decreased
component but not in other
Lower Approx. equally soluble in Raised Increased
both components
Lower Readily soluble in one Lowered Decreased
component but not in other

B. Two component systems containing solid and liquid phases: Eutectic mixtures
47
 The two components are

 miscible in the liquid state and
 insoluble (partially soluble) in solid state
 Such systems are:
 Salol-thymol and
 Salol- camphor
 Phase diagram of Salol-thymol system

Eutectic Mixtures
48
 Eutectic mixtures are formed when the drug and

polymer are miscible in their molten state, but on
cooling, they crystallize as two distinct components
with negligible miscibility.
 When a drug (A) and a carrier (B) are co-melted at
their eutectic composition defined by point ‘e’, as
shown schematically in Figure, the melting point of
the mixture is lower than the melting point of either
drug or carrier alone.

49

50

Eutectic Mixtures
51
 There are four regions on this phase diagram

I. a single liquid phase (1 phase)
II. solid salol in equilibrium with a conjugate liquid
phase (2 phases)
III. solid thymol in equilibrium with a conjugate liquid
phase (2 phases)
IV. the two components existing as pure solid phases (2
phases)

Eutectic Mixtures
52
 Those regions containing two phases (ii, iii, iv) are

comparable to phenol water system. i.e, it is
possible to calculate the wt. of each
phases/components by using the knowledge of tie
lines and phase boundaries.

Eutectic Mixtures
53
 Assume we prepare a system containing 60% by wt

thymol in salol and raised T to 50OC (point x). On
cooling a sequence of phase changes is observed.
 Up to T1 (29oC), only one liquid phase exists (salol
dissolved in thymol)
 At T1 solid thymol starts to form and as a result two phases
exist (solid thymol and liquid phase)
 At T2 (25oC), the system X1 is composed of liquid phase, a1
is 53% (thymol in salol) and b1 (100% solid thymol)
 The wt ratio of a1 to b1 is (100-60)/(60-53)= 40/7= 5.71:1

Eutectic Mixtures
54
• At T3 (20oC), the system X2 is composed of liquid

phase, a2 is 45% (thymol in salol) and b2 (100% solid
thymol)
– The wt ratio of a2 to b2 is (100-60)/(60-45)= 40/15= 2.67:1
• At T4 (15oC), the system X3 is composed of liquid
phase, a3 is 37% (thymol in salol) and b2 (100% solid
thymol)

Eutectic Mixtures
55
• Below 13OC (eutectic T) the liquid phase disappears and the

system contains an equilibrium mixture of pure solid thymol
and pure solid salol.
– Thus, 10oC, the system X4 is composed of pure solid salol, a 4 &
pure solid thymol, b4 (100% solid thymol)
• A similar sequence of phase change is observed if system Y is

cooled in a similar manner.
– Solid salol starts to form after the phase boundary
– The liquid phase is thymol dissolved in salol
Eutectic Mixtures
56
• The lowest point at which liquid phase exists is

known as eutectic point.
– At this point three phases coexist: liquid, solid thymol &
solid salol
– The mixture having the lowest melting point is known as
eutectic mixture.
– For salol-thymol system it is at 13 OC and 34% by wt
thymol.
– Melting point of mixtures of substances exhibiting
eutectics is always less than that of the pure components.

Eutectic Mixtures
57
Application of eutectics
 improve solubility and hence absorption of poorly
water soluble drugs (solid dispersions)

 Example: the absorption of griseofulvin-succinic acid
mixture is 6-7 times that of pure griseofulvin.
Other substances exhibiting eutectics are salol-

camphor, CAF-urea, procaine- lignocaine, asprin-
paracetamol, sulfathizole-urea, etc.

Three component system
58 phase rule 01/18/2022

Three component (ternary) systems
59
 For a three component system the maximum

degree of freedom (when p =1) is 4
 T, P and C of the two components should be
defined to describe the system completely.
 Considering condensed phases and keeping T
constant, the effect of conc. on the phase equilibria
can be presented using triangular coordinate
system.

60

61 phase rule 01/18/2022
Rules related to triangular diagrams
62
1. Each of the three corners (apexes of the triangle)

represent 100% by wt of one component and 0% of the
other two components
2. The three lines joining the corner points represent two-
component mixtures of the three possible combinations
– AB, BC and AC represent two component system mixtures of
A & B, B &C and A & C, respectively
3. The area with in the triangle represents all the possible
combinations of the three components.
– Point X represents 15% B, 55% A and 30% C

63
4. Any line drawn parallel to one side represents

ternary systems in which the proportion (%) of
one component is constant
 Line HI contains 20% C and varying proportions of A
&B

64
Ternary systems with one pair of partially miscible

liquids.
Example
 Benzene-water-ethanol system
 Benzene and water are partially miscible

 Ethanol (blending agent)
 Chloroform-water-acetic acid
 Chloroform and water are partially miscible
 Acetic acid (blending agent)

65

66
 Water–propanol–heptane
01/18/2022
67
 Oil-Alcohol-Water
01/18/2022
68

69
 A, B and C represent water, alcohol & benzene

respectively.
 Two conjugate phases or single phase will appear
depending on the proportion of the two and conc. of
ethanol.
 a and c are limits of solubility of C in A and A in C
respectively.
 The curve afdeic is the binodal curve. It represents the
extent of the two phase region.
 The tie lines with in the bimodal are not necessarily
parallel to each other and to the base line.01/18/2022
phase rule
70
 The effect of ethanol is similar to the effect of temperature in

phenol water system.
 It increases the solubility of benzene in water
 Mixture of water & intermediately polar organic solvents increases
solubility of poorly water soluble drugs.
 Such solvents are known as consolvents
 Examples water-ethnaol, water-glycerol, water-propylene glycol.,Water-
sorbitol, etc.
 Effect of temperature
 It increases solubility
 For most ternary systems, the bimodal region (two phase region) is
reduced as temperature increases
Ternary systems with two pairs of partially miscible liquids
71
 There are two binodal curves

 The tie line still exists in the two phase region and rule
of tie lines still apply
 Number of degrees of F(under constant T & P):
 1 in two phase region (Only conc. of one of the 3 components
needs to be specified to describe the system completely).
 2 in one phase region (only conc. of two of the 3 components
needs to be specified to describe the system completely).
 Example
 System of water, phenol and aniline

Ternary systems with three pairs of partially miscible liquids
72
 There are three binodal curves

 Example
 Succinic nitrile-water-ether system
 The tie line still exists in the two phase region and rule of tie lines
still apply
 At low temperature (low miscibility) three conjugate phases will
exsit at the centre of the triangle.
 Number of degrees of freedom(under constant T & P:
 0 in three phase region (invariant)
 1 in two phase region (Only conc. of one of the 3 components needs to be
specified to describe the system completely).
 2 in one phase region (only conc. of two of the 3 components needs to be
specified to describe the system completely).

Intermolecular Forces and Phase Equilibria

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Intermolecular Forces and Phase Equilibria

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Intermolecular force (IMF)

and Phase Equilibria

Getahun Paulos (B.Pharm; MSc;

1 phase rule 01/18/2022

 Introduction to intermolecular force of interaction (IMF)

 The phase rule

 Phase equilibria of single, two and three component systems

(principles and applications)

 The strengths of Intermolecular forces are weak

Intramolecular force between HCl molecules. H-Cl --- H-Cl

431 kJ/mol (to break covalent bond)

 The knowledge of intermolecular force is important

phase rule 01/18/2022

1. Van der waals forces

Van der Waals forces

 These forces can be divided into three categories:

phase rule 01/18/2022

A. Dipole-Dipole Forces (Keesom forces)

 Occurs between polar & non-polar molecules

 E.g., H2O---O2 01/18/2022

C. Induced Dipole-Induced Dipole Forces (London dispersion)

B. An ion-induced dipole force

 It is the strongest type of dipole-dipole attractions.

 The interaction b/n a molecule containing a H-atom & a

 Salicylic acid showing intermolecular and intramolecular

phase rule 01/18/2022

 Phase and Phase rule

phase rule 01/18/2022

 C is the number of components

 F is the number of degrees of freedom:

 Example: A system containing liquid water and vapour, F

21 phase rule 01/18/2022

 In one component systems, the maximum F is 2

 One component system is illustrated by

phase rule 01/18/2022

phase rule 01/18/2022

1. Regions (areas) on the diagram

 Temperature and pressure should be specified to

phase rule 01/18/2022

2. Lines between the regions (AO, BO and CO)

 Vapour and liquid water coexist in equilibrium

 Boiling point of water lies on this curve and it

increases as pressure increases.

phase rule 01/18/2022

• Liquid water and ice coexist in equilibrium

• The negative slope of this curve shows that melting point of

water decreases as pressure increases

 Ice and vapour coexist in equilibrium (below the triple point)

 This curve has important application in freeze-drying

3. The triple point

phase rule 01/18/2022

29 phase rule 01/18/2022

A. binary systems containing liquid phases

– Miscible in all proportions. eg. Water and ethanol

 In cases where partial miscibility occurs under normal

 Pressure is kept constant in two component system in order to

 The partially miscible systems may be divided into the following

Phase diagram of phenol-

phase rule 01/18/2022

 Upper consulate temperature (critical solution), the maximum

 It is always parallel to the base line

 Starting at point a (pure water) at 50 OC, the addition of phenol