Intramolecular and

intermolecular Bonds
Atoms can form stable units called molecules by
sharing or donating & accepting electrons .

The formation of molecules is the result of

intramolecular bonding (within the molecule).
Covalent Bond
 covalent bond, also called a molecular bond,
is a chemical bond that involves the sharing of
electron pairs between atoms. These electron
pairs are known as shared pairs or bonding
pairs, and the stable balance of attractive and
repulsive forces between atoms, when they
share electrons, is known as covalent bonding.

 Example: hydrogen (H2) →

 The electrons are attracted simultaneously by
the positive charges of the two hydrogen nuclei.
This attraction that bonds the electrons to both
nuclei is the force holding the atoms together.
Covalent Bond
 Examples
Ionic Bond
 An ionic bond is a chemical bond formed by the
electrostatic attraction between positive and negative
ions.

 Ions form due to valency changes in an atom.

 The atom that loses electrons become a cation (+ve

ion), and the atom that gains electrons becomes an anion
(-ve ion).

 Ionic bonds are considerably stronger than many of the

forces described before and can even be stronger than
covalent.
 Ionic Bond
 Any given ion tends to attract as many neighboring ions of
opposite charge as possible.

 When large numbers of ions gather together, they form an

ionic solid. The solid normally has a regular, crystalline
structure.

 Ionic compounds result when a metal reacts with a

nonmetal

 Example : Magnesium Fluoride, NaCl, a crystalline solid

material
 Binding forces between molecules

 In order for molecules to exist in aggregates in gases,

liquids and solids , intermolecular forces must exist.
 An understanding of intermolecular forces is important in
the study of pharmaceutical systems interfacial phenomena,
flocculation in suspensions, stabilization of emulsions,
compaction of powders in capsules, dispersion of powders
or liquid droplets in aerosols, the compression of granules
to form tablets. And the stability of biomolecular products
during production, formulation, and storage.
Repulsive and attractive forces
 When molecules interact, both repulsive and attractive
forces operate.

 As two molecules are brought close together, the

opposite charges in the two molecules are closer
together than the like charges and cause the molecules to
attract one another.
 The force is repulsive when the molecules are brought
close enough together that the outer charge clouds of the
molecules touch, and this causes the molecules to repel
each other.
 molecules to interact, these forces must be balanced in
an energetically favored arrangement.
balance distance
( 3 - 4 ) x 10 -8 cm
 Intermolecular forces

1. Van der Waals forces

2. Ion- dipole forces
3. Ion-ion interactions
4. Hydrogen bonds
 Intermolecular forces can be
divided into two types:
Cohesive forces: this term is used when
like molecules attract each other
Adhesive forces: this term is used when
different molecules attract each other
 Van der waals forces
 are weak forces that involve the dispersion of
charge across a molecule called a dipole.

Permanent dipole
In a permanent dipole, as illustrated by the
peptide bond, the electronegative oxygen draws
the pair of electrons in the carbon–oxygen
double bond closer to the oxygen nucleus.
 The bond then becomes polarized due to the
fact that the oxygen atom is strongly pulling the
nitrogen lone pair of electrons toward the
carbon atom, thus creating a partial double
bond.

 the nucleus of the nitrogen atom pulls the

electron pair involved in the nitrogen–hydrogen
bond closer to itself and creates a partial
positive charge on the hydrogen.
 Induced dipole
 the ability of a permanent dipole to
polarize charge in a neighboring neutral
molecule.
 two neighboring neutral molecules induce
partial charge distributions.
 Van der waals forces includes:

1. Dipole-dipole interaction ( keesom).

2. Dipole – induced dipole interaction

(Debye).

3. Induced dipole – Induced dipole

interaction (london).
 Van der Waals forces
dipole-dipole interaction ( keesom).
weak interaction associate dipolar molecules

 Dipolar molecules frequently tend to align

themselves with their neighbors, so that the
negative pole of one molecule points toward the
positive pole of the next.
 dipole-induced dipole interaction (Debye ).
 Permanent dipoles are capable of inducing an
electric dipole in nonpolar molecules which are
easily polarizable. When an oxygen molecule
comes close to a polar H2O molecule, the
electrons can shift to one side of the nucleus to
produce a very small dipole moment that lasts
for only an instant.
• Induced dipole-induced dipole interaction
(London).

• which are weak electrostatic force by which

nonpolar molecules such as hydrogen gas,
carbon tetrachloride and benzene attract one
another.

• The London force is sufficient to bring about the

condensation of nonpolar gas molecules so as
to form liquids and solids when molecules are
brought close to one another.
 Ion-dipole/ induced dipole forces :
 Ion-dipole force : Attraction occurs between
polar molecules (permanent dipoles) and ions.
 The attraction occurs because ions have a stronger
charge than dipoles, so a partially charged end of a
dipole will attract to an ion.
Account for the solubility of ionic crystalline
substances in water, the cation for example attracting
the relatively negative oxygen atom of the water and the
anion attracting the hydrogen atoms of the dipolar water
molecules .

 Example: NaCl dissolved in water:

 Na+ is attracted to the δ- oxygen of water
 Cl- is attracted to the δ+ hydrogens of water
 Ion–induced dipole force: Attraction occurs
between nonpolar molecules and ions .

 Ion-induced dipole forces are involved in the formation of

the iodide complex.
 Reaction accounts for the solubility of iodine in a
solution of potassium iodide.
Ion – dipole force

Ion – dipole force

 Ion–Ion Interactions:
 An ionic, electrovalent bond between two counter
ions is the strongest bonding interaction and can
persist over the longest distance.

 Ion–ion interactions exist in salt formation &

influence pharmaceutical systems.

 A cation on one compound will interact with an anion

on another compound.

 Ion–ion interactions can also be repulsive when two

ions of like charge are brought closely together.
Ion – ion interaction
 Hydrogen bonds
• The interaction between a molecule containing a
hydrogen atom and a strongly electronegative
atom such as F, O or N

• Because of the 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
known as hydrogen bond.

• Hydrogen bonds exist between some alcohol

molecules, carboxylic acids , aldehydes , esters and
polypeptides .
 One sixth of the hydrogen bonds of ice are
broken when water passes into the liquid state,
and all the bonds are destroyed when it
vaporizes.
 Bond energies serve as a measure of the
strength of bonds.

 Hydrogen bonds are relatively weak, having a

bond energy of about 2 to 8 kcal/mol as
compared with a value of about 50-100 kcal/mol
for the covalent bond and well over 100
kcal/mol for the ionic bond
 States of matter
• Gaseous, solids and liquids are the three
states of matter.
 As the temperature of a solid substance is
raised, the atoms acquire sufficient energy
to disrupt the ordered arrangement of the
lattice and pass into the liquid form. Finally,
when sufficient energy is supplied, the atoms
or molecules pass into the gaseous state.
The gaseous state
 The gaseous state
• Gas molecules travel in random paths and collide not
only with one another but also with the walls of the
container in which they are confined.
• Volume, is usually expressed in liters or cubic
centimeters (1 cm3 = 1 mL).
 The temperature involved in the gas equations is
given according the absolute or Kelvin scale.
 Zero degrees on the centigrade scale is equal to
273.15 Kelvin (K).
• Pressure measures force per unit area SI units of
pascal (1 N/m2) and Cgs system units of dynes/cm2.
• Pressure is also recorded in atmospheres or in
millimeters of mercury (1 atm = 740 mmHg).
The gaseous state
 The ideal gas law : the gas laws formulated by Boyle,
Charles, and Gay-Lussac refer to an ideal situation
where
 no intermolecular interactions exist and collisions
are perfectly elastic, and thus
 no energy is exchanged upon collision.

 Boyle’s law relates the volume and pressure of a given

mass of gas at constant temperature,
 The law of Gay-Lussac and Charles states that
the volume and absolute temperature of a given
mass of gas at constant pressure are directly
proportional,

 These equations can be combined to obtain the

familiar relationship . In this equation P1, V1, and
T1 are the values under one set of conditions
and P2, V2, and T2 the values under another set.
From the last equation, it is seen that PV/T under one set of
conditions is equal to PV/T under another set, and so on. Thus, one
reasons that although P, V, and T change, the ratio PV/T is constant
and can be expressed mathematically as

(molar gas constant)

In which R is the constant value for the PV/T ratio of an

ideal gas. This equation is correct only for 1 mole (i.e., 1 g
molecular weight) of gas, for n moles it becomes
 It is known as the general ideal gas law, and because it
relates the specific conditions or state, that is, the pressure,
volume, and temperature of a given mass of gas, it is called
the equation of state of an ideal gas.

 Real gases do not interact without energy exchange, and

therefore do not follow the laws of Boyle and of Gay-
Lussac and Charles as ideal gases are assumed to do.
 To obtain a numerical value for R.
If 1 mole of an ideal gas is chosen, its volume under
standard conditions of temperature and pressure
(i.e., at 0◦C and 760 mm Hg) has been found by
experiment to be 22.414 liters. Substituting this
value in the equation, we obtain:

1 atm × 22.414 liters = 1 mole × R × 273.16 K

R = 0.08205 liter atm/mole K

 Or in joules unit :
R = 8.314 joules/mole K
 Molecular Weight
 The approximate molecular weight of a gas can be
determined by use of the ideal gas law.

 The number of moles of gas n is replaced by its

equivalent (wt/M.W), in which g is the number of
grams of gas and M.W is the molecular weight:
The liquid state
The liquid state
 When a gas is cooled, it loses some of its kinetic energy in
the form of heat, and the velocity of molecules decreases.
 If pressure is applied to the gas, the molecules are brought
within the sphere of the van der Waals interaction forces
and pass into the liquid state (Liquefaction of Gases).

 Liquids are considerably denser than gases and occupy a

definite volume.

 The transitions from a gas to a liquid (condensation) and

from a liquid to a solid (freezing) depend on the
temperature and the pressure.
 Condensation occurs when a vapour is cooled or
compressed.
 If the temperature is elevated sufficiently, a value is
reached above which it is impossible to liquefy a gas
irrespective of the pressure applied. This temperature,
above which a liquid can no longer exist, is known as the
critical temperature.

 The pressure required to liquefy a gas at its critical

temperature is the critical pressure, which is also the
highest vapor pressure that the liquid can have. The
further a gas is cooled below its critical temperature, the
less pressure is required to liquefy it.

 The critical temperature of water is 374◦C, or 647 K, and

its critical pressure is 218 atm, whereas the corresponding
values for helium are 5.2 K and 2.26 atm. WHY ??
• The critical temperature serves as a rough measure
of the attractive forces between molecules
because at temperatures above the critical value, the
molecules possess sufficient kinetic energy so that
no amount of pressure can bring them within the
range of attractive forces that cause the atoms or
molecules to “stick” together.
• The high critical values for water result from the
strong dipolar forces (hydrogen bonding)
between the molecules.
• Conversely, only the weak London force attracts
helium molecules, and, consequently, this element
must be cooled to the extremely low
temperature of 5.2 K before it can be liquefied. Above
this critical temperature, helium remains a gas no
matter what the pressure.
Aerosols
• Gases can be liquefied under high pressures in a closed
chamber as long as the chamber is maintained below the
critical temperature.

• When the pressure is reduced, the molecules expand

and the liquid reverts to a gas. This reversible change of
state is the basic principle involved in the preparation of
pharmaceutical aerosols.

• In such products, a drug is dissolved or suspended in a

propellant, a material that is liquid under the
pressure conditions existing inside the container
but that forms a gas under normal atmospheric
conditions.
 Aerosolised drugs are prescribed for use in a range of
inhaler devices and systems.

 The container is so designed that, by depressing a valve,

some of the drug–propellant mixture is expelled
owing to the excess pressure inside the container.

 If the drug is nonvolatile, it forms a fine spray as it

leaves the valve orifice; at the same time, the liquid
propellant vaporizes off.

 Chlorofluorocarbons and hydrofluorocarbons

have traditionally been utilized as propellants in these
products because of their physicochemical properties.
However, in the face of increasing environmental
concerns (ozone depletion) and legislation , the use
of chlorofluorocarbons and hydrofluorocarbons is
tightly regulated. This has led researchers to identify
additional propellants, which has led to the increased
use of other gases such as nitrogen and carbon
dioxide.

Part of the propellant is in the gaseous state and

exerts the pressure necessary to extrude the drug,

whereas the remainder is in the liquid state and

provides a solution or suspension vehicle for the
drug.
Vapor Pressure of Liquids
 When a liquid is placed in an evacuated
container at a constant temperature, the
molecules with the highest energies break away
from the surface of the liquid and pass into the
gaseous state, and some of the molecules
subsequently return to the liquid state, or
condense. When the rate of condensation
equals the rate of vaporization at a definite
temperature, the vapor becomes saturated and
a dynamic equilibrium is established. The
pressure of the saturated vapor above the liquid
is then known as the equilibrium vapor pressure
 If a liquid is placed in an open container
and heated until the vapor pressure
equals the atmospheric pressure, the
vapor will form bubbles that rise rapidly
through the liquid and escape into the
gaseous state. The temperature at which
the vapor pressure of the liquid equals
the external or atmospheric pressure is
known as the boiling point.
 The heat that is absorbed when water
vaporizes at the normal boiling point (i.e.,
the heat of vaporization at 100◦C) is 539
cal/g or about 9720 cal/mole. For
benzene, the heat of vaporization is 91.4
cal/g at the normal boiling point of
80.2◦C. These quantities of heat, known as
latent heats of vaporization, are taken up
when the liquids vaporize and are liberated
when the vapors condense to liquids.
 Therefore, the boiling point of a compound, like
the heat of vaporization and the vapor pressure
at a definite temperature, provides a rough
indication of the magnitude of the attractive
forces.
 The boiling points of normal hydrocarbons,
simple alcohols, and carboxylic acids increase
with molecular weight because the attractive
van der Waals forces become greater with
increasing numbers of atoms. Branching of the
chain produces a less compact molecule with
reduced intermolecular attraction, and a
decrease in the boiling point results
Solids
 Solids, unlike liquids and gases, have
definite shapes and an orderly
arrangement of units
 It can be
1. Crystalline solids
2. Polymorphism
3. Amorphous Solids
Crystalline Solids
 Crystalline solids is a solid material arranged in
an ordered pattern and show definite melting
points, passing rather sharply from the solid to the liquid
state.

 The units that constitute the crystal structure can be

atoms, molecules, or ions

 In molecular crystals the molecules are held

together by van der Waals forces, and hydrogen
bonding, which are weak binding and account for soft
crystal with low melting points of these crystals.

 Solid carbon dioxide, hydrogen chloride, and

naphthalene form crystals composed of molecules
 Whereas ionic and atomic crystals in general are
hard and brittle and have high melting points.

 The sodium chloride crystal, consists of a cubic lattice

of sodium ions and chloride ions, the binding force of
the crystal being the electrostatic attraction of the
oppositely charged ions.

 In diamond and graphite, the lattice units consist of

atoms held together by covalent bonds.
 Polymorphism
 Some elemental substances, such as carbon and
sulfur, may exist in more than one crystalline
form this refer to polymorphism

 Polymorphs have different stabilities and may

spontaneously convert from the metastable
form at a temperature to the stable form.

 They also exhibit different melting points, x-ray

crystal diffraction patterns and solubilities, even
though they are chemically identical.
 Theobroma oil, or cacao butter, is a polymorphous
natural fat. it consists mainly of a single glyceride, it melts
to a large degree over a narrow temperature range
(34◦C–36◦C).

 Theobroma oil is capable of existing in four polymorphic

forms:
1. the unstable gamma form, melting at 18◦C;
2. the alpha form, melting at 22◦C;
3. the beta prime form, melting at 28◦C; and
4. the stable beta form, melting at 34.5◦C.

 What is the relationship between polymorphism and the

preparation of cacao butter suppositories ???
 If theobroma oil is heated to the point at which it is
completely liquefied (about 35◦C), the nuclei of the stable
beta crystals are destroyed and the mass does not
crystallize until it is supercooled to about 15◦C.

 The crystals that form are the metastable gamma, alpha,

and beta prime forms, and the suppositories melt at 23◦C
to 24◦C or at ordinary room temperature.

 The proper method of preparation involves melting cacao

butter at the lowest possible temperature, about
33◦C. The mass is sufficiently fluid to pour, yet the crystal
nuclei of the stable beta form are not lost. When the mass
is chilled in the mold, a stable suppository, consisting of
beta crystals and melting at 34.5◦C, is produced.
Amorphous Solids
 They lack order in their structure, so they do not have
definite melting points and other properties in crystalline
solids.

 Whether a drug is amorphous or crystalline has been

shown to affect its therapeutic activity.

 Thus, the crystalline form of the antibiotic novobiocin

acid is poorly absorbed and has no activity, whereas
the amorphous form is readily absorbed and
therapeutically active.

 This is due to differences in rate of dissolution. Once

dissolved, the molecules exhibit no memory of their origin.
Melting Point and Heat of Fusion
 The temperature at which a liquid passes into the solid
state is known as the freezing point.

 It is also the melting point of a pure crystalline compound.

The freezing point or melting point of a pure
crystalline solid is strictly defined as the temperature at
which the pure liquid and solid exist in equilibrium.

 In practice, it is taken as the temperature of the

equilibrium mixture at an external pressure of 1 atm;
this is sometimes known as the normal freezing or
melting point.
 The heat of fusion may be considered as the heat required to
increase the interatomic or intermolecular distances in
crystals, thus allowing melting (increased molecular motion) to
occur.
 A crystal that is bound together by weak forces generally has a
low heat of fusion and a low melting point, whereas one bound
together by strong forces has a high heat of fusion and a high
melting point.
 Because polymorphic forms represent different molecular
arrangements leading to different crystalline forms of the same
compound, it is obvious that different intermolecular forces will
account for these different forms. Then consider polymorph A,
which is held together by higher attractive forces than is
polymorph B. It is obvious that more heat will be required to break
down the attractive forces in polymorph A, and thus its melting
temperature will be higher than that of polymorph B.
liquid crystalline state
 A fourth state of matter is the liquid crystalline state or
mesophase. The term liquid crystal is an apparent
contradiction, but it is useful in a descriptive sense
because materials in this state are in many ways
intermediate between the liquid and solid states.
 Because of their intermediate nature, liquid crystals
have some of the properties of liquids and some of the
properties of solids. For example, liquid crystals are
mobile and thus can be considered to have the flow
properties of liquids. At the same time they possess the
property of being birefringent, a property associated
with crystals. In birefringence, the light passing through a
material is divided into two components with different
velocities and hence different refractive indices.
Liquid crystalline state. (a) Smectic structure;
(b) nematic structure.
 Supercritical fluids
 Supercritical fluids have properties that are intermediate
between those of liquids and gases, having better ability to
permeate solid substances (gaslike) and having high
densities that can be regulated by pressure (liquidlike).

 A supercritical fluid formed from the gaseous state where

the gas is held under a combination of temperatures and
pressures that exceed the critical point of a
substance (Fig. 2–16).

 a gas that is brought above its critical temperature Tc will

still behave as a gas irrespective of the applied pressure; the
critical pressure (Pc) is the minimum pressure required to
liquefy a gas at a given temperature.
Supercritical fluids
 As the pressure is raised higher,

 the density of the gas can increase without a significant

increase in the viscosity

 the ability of the supercritical fluid to dissolve

compounds also increases.

 A gas that may have little to no ability to dissolve a

compound under ambient conditions can completely
dissolve the compound under high pressure in the
supercritical range.
Supercritical fluids
 Figure 2–17 illustrates this phenomenon with
CO2, where CO2 held at the same temperature can
dissolve different chemical classes from a natural
product source when the pressure is increased.

 It is also important to note that more than one gas or

even the addition of a solvent (termed a cosolvent)
such as water and/or ethanol can be made to increase
the ability of the supercritical fluid to dissolve
compounds.
Supercritical fluids
Several common uses for supercritical fluids
including :
1. extraction,
2. crystallization, and
3. the preparation of formulations

 Supercritical fluids offer several advantages over

traditional methodologies:
1. The potential for low temperature extractions and
purification of compounds (consider heat added for
distillation procedures),
2. Solvent volatility under ambient conditions, selectivity of
the extracted compounds (Fig. 2–17), and
3. lower energy requirement and lower viscosity than
solvents.