Faculty of Pharmaceutical Sciences

UNIT II (States of Matter and Physicochemical properties of drug molecules)

Class Content C.V.S. Subramanyam Patrick J. Sinko.
No. (2017) Essentials of Martin’s Physical
Physical Pharmacy. Pharmacy and
2nd Ed. Vallabh Pharmaceutical
Prakashan. [Link] Sciences. 6th Ed.
Lippincott Williams
& Wilkins. [Link]
1. State of matter- forces of 18-20, 94 39 – 45,
interaction Changes in the
state of matter
2. Changes in the state of 40 - 51 55 - 57
matter, vapor pressure
3. Latent heats, vapor 43 70 – 75, 93 -- 94
pressure, Eutectic mixtures
4. Sublimation critical point, 94 - 105 86 – 88, 97
phase equilibria and phase
rule
5. Gases, aerosols – inhalers, 55 - 61 56 - 57
6. Relative humidity Liquid 51 - 53 76 - 78
complexes, liquid crystals,
glassy states
7. Solid crystalline, 62 - 75 60 - 68
amorphous &
polymorphism.
8. Physicochemical 167 – 170, 181 - 185 152 – 154, 196 -
properties of drug 197
molecules: Refractive
index- determinations and
applications
Faculty of Pharmaceutical Sciences

9. Optical rotation 186 - 189 199 - 201

10. Dielectric constant- 171 - 173 155 - 158
determinations and
applications
11. Dipole moment- 174 - 178 155, 161
determinations and
applications
12. Dissociation constant, 292 - 314 276 - 281
determinations and
applications
 Faculty of Pharmaceutical Sciences

Introduction
➢ Matter can exist in one of three main states: solid, liquid, or gas.
➢ Solid matter is composed of tightly packed particles. A solid will retain its shape;
the particles are not free to move around.
➢ Liquid matter is made of more loosely packed particles. It will take the shape of
its container. Particles can move about within a liquid, but they are packed
densely enough that volume is maintained.
➢ Gaseous matter is composed of particles packed so loosely that it has neither a
defined shape nor a defined volume. A gas can be compressed.

Gas, liquid, and solid are known as the three states of matter or material, but each
of solid and liquid states may exist in one or more forms. Thus, another term is
required to describe the various forms, and the term phase is used. Each distinct
form is called a phase; however, the concept of phase defined as a homogeneous
portion of a system extends beyond a single material, because a phase may also
involve several materials. For example, a homogeneous solution of any number of
substances is a one-phase system. Phase is a concept used to explain many physical
and chemical changes (reactions).
• A solid has a definite shape and volume. A liquid has a definite volume but it
takes the shape of a container whereas a gas fills the entire volume of a
container. You already know that diamond and graphite are solids made up of
the element carbon; they are two phases of carbon, but both are solids. Solids
are divided into subclasses of amorphous (or glassy) solids and crystalline solids.
Arrangements of atoms or molecules in crystalline solids are repeated regularly
over a very long range of millions of atoms, but their arrangements in
amorphous solids are somewhat random or short range of say some tens or
hundreds of atoms.
• In general, there is only one liquid phase of a material. However, there are two
forms of liquid helium; each have some unique properties. Thus, the two forms
are different (liquid) phases of helium. At a definite temperature and pressure,
the two phases co-exist.
 Faculty of Pharmaceutical Sciences

• So far, all gases behave alike as do mixtures of gases. Thus, a gas is usually
considered as a phase.
The Concept of Phase
A phase is a distinct and homogeneous state of a system with no visible boundary
separating it into parts.
Water, H2O, is such a common substance that its gas (steam), liquid (water), and
solid (ice) phases are widely known. An ice water mixture has two phases, as do
systems containing ice-and-vapor, and water-and-vapor. To recognize the vapor
system in these systems may require a keen observation, because the vapor usually
blends with air, and is not detected directly.
We know that several solids may exist for a substance, and each of the solid forms
is also called a phase. Diamond and graphite are the most quoted examples; both
are solid carbon, but they have different crystal shapes, colors, and structures. They
represent two different phases of carbon. Ice is another example, under 1 atm, ice
has hexagonal symmetry, while cubic ice is formed under high pressure. In fact,
there are at least eight different types of ice, each being a solid phase.
When water and alcohol is mixed, regardless of the relative amounts that has been
use, they are fully miscible. The resulting mixture has only one phase (a solution).
However, water and oil are normally immiscible, and their boundary of separation
is visible; they form a two-phase system. Sometimes boundary cannot be "seen",
and will need scientific reasoning to realize the number of phases present in
system.
Phase term is useful because it can be used to explain many phenomena.
Phase Transitions
The conversion between these phases is called a phase transition. A state change
of any material due to temperature or pressure change is a phase transition. A
phase transition is a physical change (or reaction). The following diagram illustrates
the key phase transitions:
 Faculty of Pharmaceutical Sciences

Liquid to Gas
Vaporization of a sample of liquid is a phase transition from the liquid phase to the
gas phase. There are two types of vaporization: evaporation and boiling.
• Evaporation occurs at temperatures below the boiling point, and occurs on the
liquid’s surface. For molecules of a liquid to evaporate, they must be located
near the surface, be moving in the proper direction, and have sufficient kinetic
energy to overcome intermolecular forces present in the liquid phase.
• Boiling, by contrast, is a rapid vaporization that occurs at or above the boiling
temperature and at or below the liquid’s surface.
Vapor pressure
In much the same way that tea spreads out from a tea bag once the bag is immersed
in water, molecules that are confined within a phase will tend to spread themselves
(and the thermal energy they carry with them) as widely as possible. This
fundamental law of nature is manifested in what is called the “escaping tendency”
of the molecules from the phase. The escaping tendency is of fundamental
importance in understanding all chemical equilibria and transformations.
It is possible to observe the tendency of molecules to escape into the gas phase
from a solid or liquid by placing the substance in a closed, evacuated container
connected to a manometer for measuring gas pressure.

The vapor pressure is a direct measure of the escaping tendency of molecules from
a condensed state of matter.

Boiling
 Faculty of Pharmaceutical Sciences

The boiling point is the temperature at which the vapor pressure of the liquid
is equal to the pressure exerted on the liquid by the surrounding environment (air).
The escaping tendency of molecules from a phase always increases with
temperature; therefore, the vapor pressure of a liquid will be greater at higher
temperatures. The variation of vapor pressure with temperature is not linear.
Because the typical pressure at the earth’s surface is 1 atm (760 torr), this is the
vapor pressure that a liquid must equal in order for it to be at its normal boiling
point.
The vapor pressure of a liquid is determined by the attractive forces that act on the
molecules at the surface of a liquid. In a very small drop, the liquid surface is curved
in such a way that each molecule experiences fewer nearest-neighbor attractions
than is the case for the bulk liquid. The outermost molecules of the liquid are bound
to the droplet less tightly, and the drop has a larger vapor pressure than does the
bulk liquid. If the vapor pressure of the drop is greater than the partial pressure of
vapor in the gas phase, the drop will evaporate.
Supercritical Fluids
A supercritical fluid is a substance at a temperature and pressure above its critical
point, where distinct liquid and gas phases do not exist.

Properties of Supercritical Fluids

A supercritical fluid is any substance at a temperature and pressure above its critical
point, where distinct liquid and gas phases do not exist. This can be rationalized by
thinking that at high enough temperatures (above the critical temperature) the
kinetic energy of the molecules is high enough to overcome any intermolecular
forces that would condense the sample into the liquid phase. On the other hand,
high enough pressures (above the critical pressure) would not allow a sample to
stay in the pure gaseous state. Therefore, a balance between these two tendencies
is achieved and the substance exists in a state between a gas and a liquid.
 Faculty of Pharmaceutical Sciences

Phase Diagram for a Substance: The figure highlights the critical point, above which
(in either temperature or pressure) the substance does not exist in either the liquid
or gas phase. Under those conditions it is called a “supercritical fluid,” and has
properties between those of a liquid and a gas.

Liquid to Solid Phase Transition

Freezing is a phase transition in which a liquid turn into a solid when its
temperature is lowered to its freezing point.
Freezing, or solidification, is a phase transition in which a liquid turn into a solid
when its temperature is lowered to or below its freezing point. All known liquids,
except helium, freeze when the temperature is low enough. (Liquid helium remains
a liquid at atmospheric pressure even at absolute zero, and can be solidified only
under higher pressure.)
For most substances, the melting and freezing points are the same temperature;
however, certain substances possess different solid-liquid transition temperatures.
For example, agar displays a hysteresis in its melting and freezing temperatures: it
melts at 85 °C (185 °F) and solidifies between 31 °C and 40 °C (89.6 °F to 104 °F).
Most liquids freeze by crystallization, the formation of a crystalline solid from the
uniform liquid.
Freezing is almost always an exothermic process, meaning that as liquid changes
into solid, heat is released. This may seem counterintuitive, since the temperature
of the material does not rise during freezing (except if the liquid is supercooled).
 Faculty of Pharmaceutical Sciences

But heat must be continually removed from the freezing liquid, or the freezing
process will stop. The energy released upon freezing, known as the enthalpy of
fusion, is a latent heat and is exactly the same as the energy required to melt the
same amount of the solid.

Nucleation
This is a first-order thermodynamic phase transition, which means that as long as
solid and liquid coexist, the equilibrium temperature of the system remains
constant and equal to the melting point. Crystallization consists of two major
events: nucleation and crystal growth. Nucleation is the step in which the
molecules start to gather into clusters (on the scale of nanometers), arranging
themselves in the periodic pattern that defines the crystal structure. The crystal
growth is the subsequent growth of the nuclei that succeed in achieving and
surpassing the critical cluster size.

Solid to Gas Phase Transition

Sublimation is the phase transition from the solid to the gaseous phase, without
passing through an intermediate liquid phase.
Sublimation is the process of transformation directly from the solid phase to the
gaseous phase, without passing through an intermediate liquid phase. It is an
endothermic phase transition that occurs at temperatures and pressures below a
substance ‘s triple point (the temperature and pressure at which all three phases
coexist) in its phase diagram.
At a given temperature, most chemical compounds and elements can possess one
of the three different states of matter at different pressures. In these cases, the
transition from the solid to the gaseous state requires an intermediate liquid state.
But at temperatures below that of the triple point, a decrease in pressure will result
in a phase transition directly from the solid to the gaseous. Also, at pressures below
the triple point pressure, an increase in temperature will result in a solid being
converted to gas without passing through the liquid region.
 Faculty of Pharmaceutical Sciences

Phase Diagram of a Pure Substance: Notice the triple point of the substance. At
temperatures and pressures below those of the triple point, a phase change
between the solid and gas phases can take place.
For some substances, such as carbon and arsenic, sublimation is much easier than
evaporation. This is because the pressure of their triple point is very high and it is
difficult to obtain them as liquids. The solid has such high vapor pressures that
heating leads to a substantial amount of direct vaporization even before the
melting point is reached.
The process of sublimation requires additional energy and is therefore an
endothermic change. The enthalpy of sublimation (also called heat of sublimation)
can be calculated as the sum of the enthalpy of fusion and the enthalpy of
vaporization.

ΔHsub = ΔHfus + ΔHvap

The reverse process of sublimation is deposition (i.e., gas to solid). For example,
solid iodine, I2, is easily sublimed at temperatures around 100°C. Even ice has a
measurable vapor pressure near its freezing point, as evidenced by the tendency
of snow to evaporate in cold dry weather. There are other solids whose vapor
pressure overtakes that of the liquid before melting can occur. Such substances
sublime; a common example is solid carbon dioxide (dry ice) at 1 atm of
atmospheric pressure.
 Faculty of Pharmaceutical Sciences

States of matter: it can also be classified as:

1. Gaseous state
2. Liquid state
3. Solid and crystalline state
4. Liquid crystalline state
Gas: Gases can be expanded infinitively, therefore gases can fill containers and take
their volume and shape. Gases diffuse and mix evenly and rapidly. Gases have much
lower densities than liquids and solids (There is a lot of free space in a gas,
therefore; It is the most compressible state of matter).
General properties of gas:
• Gas molecules travel in random paths and collide with one another and with the
walls of the container in which they are confined
• A gas exerts a pressure (a force per unit area) expressed in dynes/cm2,
atmospheres or in mmHg (1 atm = 760 mmHg = 760 Torr).
• Gases have volumes that is expressed in liters or cubic centimeters (1 cm3 = 1
mL).
• The temperature involved in the gas equations is expressed by the absolute or
Kelvin scale (0°C=273.15 K (Kelvin)).

Ideal gas: Ideal gas is a gas where no intermolecular interactions exist and collisions
are perfectly elastic, and thus no energy is exchanged during collision. The
properties of the ideal gas can be described by the general ideal gas law, which are
derived from Boyle, Charles and Gay-Lussac laws
Ideal gas properties:
• The particles of the gas do not attract one another (no intermolecular forces),
but instead move with complete independence; this statement applies only at
low pressures.
 Faculty of Pharmaceutical Sciences

• The total volume of gases molecules is so small as to be negligible in relation to

the volume of the space in which the molecules are confined while the real gases
composed of molecules of finite volume.
• The particles exhibit continuous random motion owing to their kinetic energy.
The average kinetic energy, E, is directly proportional to the absolute
temperature of the gas.
• The molecules exhibit perfect elasticity; that is, there is no net loss of speed or
transfer of energy after they collide with one another and with the molecules in
the walls of the confining vessel.
• The ideal gas can be compressed or cooled but without liquification (remain gas)
while the real gas can be compressed, cooled and converted to liquid
(liquification).

Boyle’s law: It states that the volume and pressure of a given mass of gas is
inversely proportional (i.e. when the pressure of a gas increases, its volume
decreases).
P ∝ 1/V or P ∝ K / V
P1 V1 = P2 V2 ------- (1)
P = pressure, K = constant, V = volume
Charles law: It states that the volume and absolute temperature of a given mass of
gas at constant pressure are directly proportional (i.e when the temperature of a
gas increases, its volume increases as well).
V ∝ T or V ∝ K T
V1 / T1 = V2 / T2 ------- (2)
T = Temperature in Kelvin
Gay-Lussac law: The law of Gay-Lussac states that the pressure and absolute
temperature of a given mass of gas at constant volume are directly proportional
(i.e when the temperature of a gas increases, its pressure increases as well).
P ∝ T or P ∝ K T
 Faculty of Pharmaceutical Sciences

P1 / T1 = P2 / T2 ------- (3)
Boyle, Gay-Lussac and Charles law can be combined to obtain the relationship:
P1 V1/ T1 = P2 V2 / T2 ------ (4)
Ideal gas law: General ideal gas law (also called equation of state) relates the
specific conditions, that is, the pressure, volume, and temperature of a given mass
of gas.
P1 V1/ T1 = P2 V2 / T2 means, PV / T = R
R = the molar gas constant value for the PV/T ratio of an ideal gas.
For n moles it becomes:
PV = n R T ------- (5)
Molar gas constant: The volume of 1 mole of an ideal gas under standard
conditions of temperature and pressure (i.e., at 0°C and 1 atm) has been found by
experiment to be 22.414 liters. Substituting this value in general ideal gas law:
R = P V / T = (1 x 22.4) / 273
R = 0.08205 atm L/mole K
The molar gas constant can also be expressed by energy units:
R = 8.314 Joules/mole K or
R = 8.314 × 107 erg/mole K
Kinetic molecular theory explains the behavior of gases according to the ideal gas
law:
• Gases are composed of particles called atoms or molecules, the total volume of
which is so small (negligible) in relation to the volume of the space in which the
molecules are confined.
• Gas molecules exert neither attractive nor repulsive forces on one another.
• The particles exhibit continuous random motion. The average kinetic energy, E,
is directly proportional to the absolute temperature of the gas, or E = (3/2) RT.
 Faculty of Pharmaceutical Sciences

• The molecules exhibit perfect elasticity; there is no net loss of speed or transfer
of energy after they collide with one another and with the walls of the confining
vessel.

Real gases do not interact without energy exchange, and therefore do not follow
the laws of Boyle, Charles, and Gay-Lussac. Real gases are not composed of
infinitely small and perfectly elastic non-attracting spheres. They are composed of
molecules of a finite volume that tend to attract one another. The significant
molecular volume and the intermolecular attractions between gas molecules affect
both the volume and the pressure of a real gas respectively.
The influence of non-ideality is greater when the gas is compressed (At high
pressure and low temperature).
Liquification of gases
Liquefaction of gases is the process by which substances in their gaseous state are
converted to the liquid state. When pressure on a gas is increased, its molecules
closer together, and its temperature is reduced, which removes enough energy to
make it change from the gaseous to the liquid state.
Critical Temperature and Pressure
Two important properties of gases are important in developing methods for their
liquefaction: critical temperature and critical pressure. The critical temperature of
a gas is the temperature at or above which no amount of pressure, however great,
will cause the gas to liquefy. The minimum pressure required to liquefy the gas at
the critical temperature is called the critical pressure.
For example, the critical temperature for carbon dioxide is 304K (87.8°F [31°C]).
That means that no amount of pressure applied to a sample of carbon dioxide gas
at or above 304K (87.8°F [31°C]) will cause the gas to liquefy. At or below that
temperature, however, the gas can be liquefied provided sufficient pressure is
applied. The corresponding critical pressure for carbon dioxide at 304K (87.8°F
[31°C]) is 72.9 atmospheres. In other words, the application of a pressure of 72.9
atmospheres of pressure on a sample of carbon dioxide gas at 304K (87.8°F [31°C])
will cause the gas to liquefy.
 Faculty of Pharmaceutical Sciences

Differences in critical temperatures among gases means that some gases are easier
to liquify than are others. The critical temperature of carbon dioxide is high enough
so that it can be liquified relatively easily at or near room temperature. By
comparison, the critical temperature of nitrogen gas is 126K (-232.6°F [-147°C]) and
that of helium is 5.3K (-449.9°F [-267.7°C]). Liquefying gases such as nitrogen and
helium obviously present much greater difficulties than does the liquefaction of
carbon dioxide.
Heating Curve for Water
Water transitions from ice to liquid to water vapor as heat is added to it.
Like many substances, water can exist in different phases of matter: liquid, solid,
and gas. A heating curve shows how the temperature changes as a substance is
heated up at a constant rate.
Drawing a Heating Curve
Temperature is plotted on the y-axis, while the x-axis represents the heat that has
been added. A constant rate of heating is assumed, so that one can also think of
the x-axis as the amount of time that goes by as a substance is heated. There are
two main observations on the measured curve:
• regions where the temperature increases as heat is added
• plateaus where the temperature stays constant.
It is at those plateaus that a phase change occurs.
 Faculty of Pharmaceutical Sciences

Heating Curve of Water: The phase transitions of water.

Analysis of a Heating Curve
Looking from left to right on the graph, there are five distinct parts to the heating
curve:
a) Solid ice is heated and the temperature increases until the normal
freezing/melting point of zero degrees Celsius is reached. The amount of heat
added, q, can be computed by: q = m ⋅ CH2O(s)⋅ ΔTq, where m is the mass of the
sample of water, C is the specific heat capacity of solid water, or ice, and ΔTΔT is
the change in temperature during the process.
b) The first phase change is melting; as a substance melts, the temperature stays
the same. For water, this occurs at 0o C. The above equation (described in part
1 of the curve) cannot be used for this part of the curve because the change in
temperature is zero. Instead, use the heat of fusion (ΔHfusion ) to calculate how
much heat was involved in that process: q = m ⋅ ΔHfusion, where m is the mass of
the sample of water.
c) After all of the solid substance has melted into liquid, the temperature of the
liquid begins to increase as heat is absorbed. It is then possible to calculate the
heat absorbed by: q = m ⋅ CH2O(l)⋅ ΔT. Note that the specific heat capacity of
liquid water is different than that of ice.
 Faculty of Pharmaceutical Sciences

d) The liquid will begin to boil when enough heat has been absorbed by the
solution that the temperature reaches the boiling point, where again, the
temperature remains constant until all of the liquid has become gaseous water.
At the atmospheric pressure of 1 atm, this phase transition occurs at 100o C (the
normal boiling point of water). Liquid water becomes water vapor or steam
when it enters the gaseous phase. Use the heat of vaporization (ΔHvap) to
calculate how much heat was absorbed in this process: q = m ⋅ CH2O(g) ⋅ ΔTq,
where m is the mass of the sample of water.
e) After all of the liquid has been converted to gas, the temperature will continue
to increase as heat as added. Again, the heat added that results in a certain
change temperature is given by: q = m ⋅ CH2O(g) ⋅ ΔT. Note that the specific heat
capacity of gaseous water is different than that of ice or liquid water.
f) Water has a high boiling point because of the presence of extensive hydrogen
bonding interactions between the water molecules in the liquid phase (water is
both a strong hydrogen bond donor and acceptor). When heat is first applied to
water, it must break the intermolecular hydrogen bonds within the sample.
After breaking the bonds, heat is then absorbed and converted to increased
kinetic energy of the molecules in order to vaporize them.

Vapor pressure
The vapor pressure of a liquid is the equilibrium pressure of a vapor above its liquid
(or solid); that is, the pressure of the vapor resulting from evaporation of a liquid
(or solid) above a sample of the liquid (or solid) in a closed container. The vapor
pressure of a liquid varies with its temperature. As the temperature of a liquid or
solid increases its vapor pressure also increases. Conversely, vapor pressure
decreases as the temperature decreases.
The vapor pressure of a liquid can be measured in a variety of ways. A simple
measurement involves injecting a little of the liquid into a closed flask connected
to a manometer.
Definition: The pressure exerted by the gas in equilibrium with a solid or liquid in a
closed container at a given temperature is called the vapor pressure. The line on
the graph shows the boiling temperature for water.
 Faculty of Pharmaceutical Sciences

Factors That Affect Vapor Pressure

Surface Area: the surface area of the solid or liquid in contact with the gas has no
effect on the vapor pressure.
Types of Molecules: the types of molecules that make up a solid or liquid determine
its vapor pressure. If the intermolecular forces between molecules are:
Relatively strong, the vapor pressure will be relatively low.
Relatively weak, the vapor pressure will be relatively high.
Example: Ethyl ether (C4H10O) Pvapor (25oC) = 520 torr. The relatively weak dipole-
dipole forces and London dispersion forces between molecules results in a much
higher vapor pressure. Ethyl alcohol (C2H6O) Pvapor (25oC) = 75 torr. Although dipole-
dipole forces and London dispersion forces also exist between ethyl alcohol
molecules, the strong hydrogen bonding interactions are responsible for the much
lower vapor pressure compared to ethyl ether.
Temperature: at a higher temperature, more molecules have enough energy to
escape from the liquid or solid. At a lower temperature, fewer molecules have
sufficient energy to escape from the liquid or solid.
Crystalline and Amorphous Solids
 Faculty of Pharmaceutical Sciences

Crystalline solids have regular ordered arrays of components held together by

uniform intermolecular forces, whereas the components of amorphous solids are
not arranged in regular arrays.
Types of Crystals
Ionic Crystals
Ions in ionic crystals are bound together by electrostatic attraction. Ions bound
together by electrostatic attraction form ionic crystals. Their arrangement varies
depending on the ions’ sizes or the radius ratio (the ratio of the radii of the positive
to the negative ion). A simple cubic crystal lattice has ions equally spaced in 3D at
90° angles.
Stability of ionic solids depends on lattice energy, which is released in the form of
heat when two ions are brought together to form a solid. Lattice energy is the sum
of all the interactions within the crystal.
The properties of ionic crystals reflect the strong interactions that exist between
the ions. They are very poor conductors of electricity, have strong absorption of
infrared radiation, and are easily cleaved. These solids tend to be quite hard and
have high melting points.
An ionic crystal consists of ions bound together by electrostatic attraction. The
arrangement of ions in a regular, geometric structure is called a crystal lattice.
Examples of such crystals are the alkali halides, for example: potassium fluoride
(KF), potassium chloride (KCl), potassium bromide (KBr), potassium iodide (KI),
sodium fluoride (NaF) and other combinations of sodium, cesium, rubidium, or
lithium ions with fluoride, bromide, chloride or iodide ions
These solids tend to be quite hard and have high melting points, reflecting the
strong forces between oppositely-charged ions. The exact arrangement of ions in a
lattice varies according to the size of the ions in the crystal.
Covalent Crystals
Atoms in covalent solids are covalently bonded with their neighbors, creating, in
effect, one giant molecule. Covalent (or network) solids are extended- lattice
compounds, in which each atom is covalently bonded to its nearest neighbors.
Because there are no delocalized electrons, covalent solids do not conduct
electricity.
 Faculty of Pharmaceutical Sciences

The rearranging or breaking of covalent bonds requires large amounts of energy;

therefore, covalent solids have high melting points. Covalent bonds are extremely
strong, so covalent solids are very hard. Generally, covalent solids are insoluble due
to the difficulty of solvating very large molecules.
Diamond is the hardest material known, while cubic boron nitride (BN) is the
second-hardest. Silicon carbide (SiC) is very structurally complex and has at least 70
crystalline forms.
A covalent bond is a chemical bond that involves the sharing of pairs of electrons
between atoms. This sharing results in a stable balance of attractive and repulsive
forces between those atoms. Covalent solids are a class of extended-lattice
compounds in which each atom is covalently bonded to its nearest neighbors. This
means that the entire crystal is, in effect, one giant molecule. The extraordinarily
strong binding forces that join all adjacent atoms account for the extreme hardness
of these solids. They cannot be broken or abraded without breaking a large number
of covalent chemical bonds. Similarly, a covalent solid cannot “melt” in the usual
sense, since the entire crystal is one giant molecule. When heated to very high
temperatures, these solids usually decompose into their elements.
Another property of covalent network solid is poor electrical conductivity, since
there are no delocalized electrons. When molten, unlike ionic compounds, the
substance is still unable to conduct electricity, since the macromolecule consists of
uncharged atoms rather than ions. (This is also contrary to most forms of metallic
bonds.)
Boron nitride (BN) is similar to carbon because it exists as a diamond-like cubic
polymorph as well as in a hexagonal form similar to graphite. Cubic boron nitride is
the second-hardest material after diamond, and it is used in industrial abrasives
and cutting tools.
Molecular Crystals
Molecules held together by van der Waals forces form molecular solids. A
molecular solid is composed of molecules held together by van der Waals forces.
Its properties are dictated by the weak nature of these intermolecular forces.
Molecular solids are soft, often volatile, have low melting temperatures, and are
electrical insulators.
 Faculty of Pharmaceutical Sciences

Classes of molecular solids include organic compounds composed of carbon and

hydrogen, fullerenes, halogens (F, Cl, etc.), chalcogens (O, S, etc.), and pnictogens
(N, P, etc.).
Larger molecules are less volatile and have higher melting points because their
dispersion forces increase with the larger number of atoms. Decrease in binding of
outer electrons to the nucleus also increases van der Waals-type interactions of the
atom due to its increased polarizability.
Liquids and solids composed of molecules are held together by van der Waals (or
intermolecular) forces, and many of their properties reflect this weak binding.
Molecular solids tend to be soft or deformable, have low melting points, and are
often sufficiently volatile to evaporate directly into the gas phase. This latter
property often gives such solids a distinctive odor. Whereas the characteristic
melting point of metals and ionic solids is ~1000 °C, most molecular solids melt well
below ~300 °C. Thus, many corresponding substances are either liquid (water) or
gaseous (oxygen) at room temperature.

Molecular solids also have relatively low density and hardness. The elements
involved are light, and the intermolecular bonds are relatively long and are
therefore weak. Because of the charge neutrality of the constituent molecules, and
because of the long distance between them, molecular solids are electrical
insulators.
Because dispersion forces and the other van der Waals forces increase with the
number of atoms, large molecules are generally less volatile, and have higher
melting points than smaller ones. Also, as one moves down a column in the periodic
table, the outer electrons are more loosely bound to the nucleus, increasing the
polarizability of the atom, and thus its propensity to van der Waals-type
interactions. This effect is particularly apparent in the increase in boiling points of
the successively heavier noble gas elements.
Metallic Crystals
Metallic crystals are held together by metallic bonds, electrostatic interactions
between cations and delocalized electrons. Atoms in metals lose electrons to form
cations. Delocalized electrons surround the ions. Metallic bonds (electrostatic
 Faculty of Pharmaceutical Sciences

interactions between the ions and the electron cloud) hold the metallic solid
together. Atoms are arranged like closely packed spheres.
Because outer electrons of metal atoms are delocalized and highly mobile, metals
have electrical and thermal conductivity. The free electron model can be used to
calculate electrical conductivity as well as the electrons’ contribution to the heat
capacity and heat conductivity of metals.
Metals are ductile, or capable of plastic deformation. Hooke’s law describes
reversible elastic deformation in metals, in which the stress is linearly proportional
to the strain. Forces larger than the elastic limit, or heat, may cause an irreversible
deformation of the object.
In general, metals are denser than nonmetals. This is due to the tightly packed
crystal lattice of the metallic structure. The larger the amounts of delocalized
electrons, the stronger the metallic bonds are.
In a metal, atoms readily lose electrons to form positive ions (cations). These ions
are surrounded by delocalized electrons, which are responsible for conductivity.
The solid produced is held together by electrostatic interactions between the ions
and the electron cloud. These interactions are called metallic bonds. Metallic
bonding accounts for many physical properties of metals, such as strength,
malleability, ductility, thermal and electrical conductivity, opacity, and luster.
Understood as the sharing of “free” electrons among a lattice of positively charged
ions (cations), metallic bonding is sometimes compared to the bonding of molten
salts; however, this simplistic view holds true for very few metals. In a quantum-
mechanical view, the conducting electrons spread their density equally over all
atoms that function as neutral (non-charged) entities.
Atoms in metals are arranged like closely-packed spheres, and two packing
patterns are particularly common: body-centered cubic, wherein each metal is
surrounded by eight equivalent metals, and face-centered cubic, in which the
metals are surrounded by six neighboring atoms. Several metals adopt both
structures, depending on the temperature.
Metals in general have high electrical conductivity, high thermal conductivity, and
high density. They typically are deformable (malleable) under stress, without
cleaving. Some metals (the alkali and alkaline earth metals) have low density, low
 Faculty of Pharmaceutical Sciences

hardness, and low melting points. In terms of optical properties, metals are
opaque, shiny, and lustrous.
Melting Point and Strength
The strength of a metal derives from the electrostatic attraction between the
lattice of positive ions and the “sea” of valence electrons in which they are
immersed. The larger the nuclear charge (atomic number) of the atomic nucleus,
and the smaller the atom’s size, the greater this attraction. In general, the transition
metals with their valence-level d electrons are stronger and have higher melting
points: Ex: Fe - 1539°C, Re - 3180 °C, Os - 2727 °C, W - 3380°C.
The majority of metals have higher densities than the majority of nonmetals.
Nonetheless, there is wide variation in the densities of metals. Lithium (Li) is the
least dense solid element, and osmium (Os) is the densest. The metals of groups IA
and IIA are referred to as the light metals because they are exceptions to this
generalization. The high density of most metals is due to the tightly packed crystal
lattice of the metallic structure.
Electrical Conductivity:
In order for a substance to conduct electricity, it must contain charged particles
(charge carriers) that are sufficiently mobile to move in response to an applied
electric field. In the case of ionic compounds in water solutions, the ions themselves
serve this function. The same thing holds true of ionic compounds when melted.
Ionic solids contain the same charge carriers, but because they are fixed in place,
these solids are insulators.
In metals, the charge carriers are the electrons, and because they move freely
through the lattice, metals are highly conductive. The very low mass and inertia of
the electrons allows them to conduct high-frequency alternating currents,
something that electrolytic solutions cannot do.
Electrical conductivity, as well as the electrons’ contribution to the heat capacity
and heat conductivity of metals, can be calculated from the free electron model,
which does not take the detailed structure of the ion lattice into account.
Mechanical properties
 Faculty of Pharmaceutical Sciences

Mechanical properties of metals include malleability and ductility, meaning the

capacity for plastic deformation. Reversible elastic deformation in metals can be
described by Hooke’s Law for restoring forces, in which the stress is linearly
proportional to the strain. Applied heat, or forces larger than the elastic limit, may
cause an irreversible deformation of the object, known as plastic deformation or
plasticity.
Metallic solids are known and valued for these qualities, which derive from the non-
directional nature of the attractions between the atomic nuclei and the sea of
electrons. The bonding within ionic or covalent solids may be stronger, but it is also
directional, making these solids brittle and subject to fracture when struck with a
hammer, for example. A metal, by contrast, is more likely to be simply deformed
or dented.
Although metals are black due to their ability to absorb all wavelengths equally,
gold (Au) has a distinctive color. According to the theory of special relativity,
increased mass of inner-shell electrons that have very high momentum causes
orbitals to contract. Because outer electrons are less affected, blue-light absorption
is increased, resulting in enhanced reflection of yellow and red light.
Eutectic mixtures
A eutectic mixture is defined as a mixture of two or more components which usually
do not interact to form a new chemical compound but, which at certain ratios,
inhibit the crystallization process of one another resulting in a system having a
lower melting point than either of the components.
Eutectic mixtures, can be formed between Active Pharmaceutical Ingredients
(APIs), between APIs and excipient or between excipient; thereby providing a vast
scope for its applications in pharmaceutical industry.
Eutectic mixture formation is usually, governed by following factors:
• The components must be miscible in liquid state and mostly immiscible in solid
state.
• Intimate contact between eutectic forming materials is necessary for contact
induced melting point depression.
• The components should have chemical groups that can interact to form physical
bonds such has intermolecular hydrogen bonding etc.
Faculty of Pharmaceutical Sciences

• The molecules which are in accordance to modified Vant Hoff’s equation can
form eutectic mixtures.

Applications of Eutectic Mixtures in Pharmaceutical Industry: During pre

formulation stage, compatibility studies between APIs and excipient play a crucial
role in excipient selection. Testing for eutectic mixture formation can help in
anticipation of probable physical incompatibility between drug and excipient
molecules. Eutectic mixtures are commonly used in drug designing and delivery
processes for various routes of administration. (Table 1) lists few examples of
eutectic mixtures and their application. During manufacturing of pharmaceutical
dosage form, it is extremely necessary to anticipate the formation of eutectics and
avoid manufacturing problems if any. For example, during tablet compaction the
heat produced in the punch and die cavities may lead to fusion or melting of tablet
powder compacts leading to manufacturing defects. Thus knowledge of eutectic
points of powder components may help avoid these problems. During
pharmaceutical analysis, understanding of eutectic mixtures can help in the
identification of compounds having similar melting points. Compounds having
similar melting points, as a rule will have different eutectic point with a common
other component. This knowledge could be used to identify compounds like
Ergotamine, Allobarbital etc. (Table 2). The listed drugs can be distinguished by
their tendency to form eutectic mixtures with Benzanilide.
Faculty of Pharmaceutical Sciences

Table 1: Applications of eutectic mixtures in formulation development

Table 2: Eutectic Temperature of Drugs with Benzanilide

Phase Equilibria & The Phase Rule
Water and ice in hot summer is 3 phase system. Suspension consist of solid drug in
liquid and evaporation may take place.
Phase Equilibrium: A stable phase structure with lowest free-energy (internal
energy) of a system, and also randomness or disorder of the atoms or molecules
(entropy).
Any change in Temperature, Composition, and Pressure causes an increase in free
energy and away from equilibrium thus forcing a move to another ‘state’.
 Faculty of Pharmaceutical Sciences

The phase rule: A relationship between number of intensive variables

(temperature, concentration, density and pressure) that can be changed without
changing the equilibrium state of the system,
A phase is defined as any homogeneous and physically distinct part of a system
which is separated from other parts of the system by interfaces.
➢ A phase may be gas, liquid or solid.
➢ A gas or a gaseous mixture is a single phase.
➢ Totally miscible liquids constitute a single phase.
➢ In an immiscible liquid system, each layer is counted as a separate phase.
➢ Every solid constitutes a single phase except when a solid solution is formed.
➢ A solid solution is considered as a single phase.
➢ Each polymorphic form constitutes a separate phase.
a) Liquid water, pieces of ice and water vapor are present together. The number
of phases is 3 as each form is a separate phase. Ice in the system is a single phase
even if it is present as a number of pieces.
b) Calcium carbonate undergoes thermal decomposition. The chemical reaction is:
CaCO3 (s) CaO(s) + CO2 (g) Number of phases = 3 : This system consists of
2 solid phases, CaCO3 and CaO and one gaseous phase, that of CO2 .
c) A solution of NaCl in water Number of phases = 1

Components
The number of components of a system at equilibrium is the smallest number of
independently varying chemical constituents using which the composition of each
and every phase in the system can be expressed.
Examples: Counting the number of components
a) The Sulphur system is a one component system. All the phases, monoclinic,
rhombic, liquid and vapor – can be expressed in terms of the single constituent
– Sulphur.
b) A mixture of ethanol and water is an example of a two component system. We
need both ethanol and water to express its composition.
Degrees of freedom (or variance)
Faculty of Pharmaceutical Sciences

The degrees of freedom or variance of a system is defined as the minimum number

of variables such as temperature, pressure and concentration which must be fixed
in order to define the system completely.
F=C–P+2
Where, F = degree of freedom
C = number of components
P = number of phases

Fig: Phase diagram or pressure v/s temp diagram for the water system.
 Faculty of Pharmaceutical Sciences

Two component system

For two component system F can be 3, (3D model is needed), e.g. Temperature,
pressure and concentration, fix p = 1atm, the vapor phase is neglected, and F is
reduced to 2.
For three component system the pressure and temperature are fixed.
Sublimation critical point
Sublimation critical point refers to the maximum or minimum temperature and
pressure beyond which the state of the matter cannot be changed.
Sublimation is the process of transition of solid matter directly into gas without it
being converted into its liquid form.
 Faculty of Pharmaceutical Sciences

This process occurs at a particular temperature or pressure and beyond that

temperature or pressure the process of sublimation cannot be carried out.
This point is the Critical point.
Dry ice is a substance which sublimates at a temperature of -78.5℃ . It is known as
liquid nitrogen but it is seen in vapor state which consists of carbon dioxide gas and
cold and humid air.
Gases, aerosols – inhalers,
An aerosols consists of extremely fine solid or liquid particles that remain
suspended in a gas or air, called propellant. Propellant is an inert substance. Fog
and smoke are examples of natural aerosols. Pharmaceutical aerosols means fine
particles of drug or medicine (either solid or liquid, or both) that is kept in a
container under pressure and that is released as a fine spray when a button is
pressed.
Types of Aerosols
Aerosols consist of two-phase (gas and liquid) or three-phase (gas, liquid, and solid
or liquid) systems. The two-phase aerosol consists of a solution of active
ingredients in liquefied propellant and the vaporized propellant. The solvent is
composed of the propellant or a mixture of the propellant and cosolvents such as
alcohol, propylene glycol, and polyethylene glycols, which are often used to
enhance the solubility of the active ingredients.
Three-phase systems consist of a suspension or emulsion of the active ingredient(s)
in addition to the vaporized propellants. A suspension consists of the active
ingredient(s) that may be dispersed in the propellant system with the aid of suitable
excipients such as wetting agents and/or solid carriers such as talc or colloidal
silicas.
A foam aerosol is an emulsion containing one or more active ingredients,
surfactants, aqueous or nonaqueous liquids, and the propellants. If the propellant
is in the internal (discontinuous) phase (i.e., of the oil-in-water type), a stable foam
is discharged; and if the propellant is in the external (continuous) phase (i.e., of the
water-in-oil type), a spray or a quick-breaking foam is discharged.
 Faculty of Pharmaceutical Sciences

Types of pharmaceutical aerosols

Generally, pharmaceutical aerosols are stored in two types of inhalers viz.,
Metered-Dose Inhalers (MDIs) and Dry Powder Inhalers (DPIs). MDIs and DPIs
deliver a specific quantity of drug to the lungs through pulmonary tracks on
external surface of body parts. Both types of products are used to treat lung
diseases characterized by obstruction of airflow and shortness of breath, including
asthma and chronic obstructive pulmonary disease (COPD), as well as respiratory
infections and cystic fibrosis. The inhalation route offers further potential for
systemic drug delivery.
MDIs
The MDI is used to provide a certain dose of an aerosol of medication. It is likely to
be either: Salbutamol/Ventolin (blue), Salmeterol/Serevent (green), or one that
includes a small dose of steroid such as Fluticasone/Flixotide (orange), Seretide
(purple), Becotide/Clenil (brown), Alvesco/Ciclesonide (red) or Fostair (pink). These
work by relaxing the muscles of the large airways and/or reducing the inflammation
of the airways.
Dry powder inhalers
Dry powder inhalers are an alternative to the aerosol-based inhalers commonly
MDIs, that deliver a powder dosage form to the lungs. Most DPIs include an active
ingredient and one or more excipient to aid powder dispersion and flow. The
powder dose from a DPI can be analyzed on the PSA300 image analysis system. The
optimum aerodynamic particle size distribution for most inhalation aerosols is very
important and these are generally are in the range of 1-5 µm.
Working of aerosol
The delivery of contents of aerosol depends on its valve assembly, containers, and
actuators as well as on the propellant. Their functions are discussed below. The two
components of aerosol are product concentrate and propellant. The product
concentrate contains the therapeutically active ingredients. The propellant having
vapour pressure greater than atmospheric pressure at 400?? is develop required
pressure in the container to expel the product concentrate in the desired form viz.,
spray, mist, solid, foam, stream etc. Sometimes the propellant also act as a solvent
or vehicle for the drug concentrate.
 Faculty of Pharmaceutical Sciences

1 – container, 2 – deep pipe, 3 – valve, 4 – actuator, 5 – drug and liquid propellant,

6 – propellant vapor, 7 – spray jet
Figure: components of aerosol
The various components of an aerosols is shown in above Figure. Container (item
no. 1) is made up of metal viz. aluminum, tin-plated alloys, glass or plastic
depending on the nature of drug and its size is designed as per the number of doses
and other requirement. The purpose of the container is to hold or store the
aerosols. Normally, it is perfectly and safely sealed. No drug or propellant can
escape.
A deep pipe (item no. 2) is inserted from the bottom most position of the container.
A suitable valve (item no. 3) is attached at the top through which the deep pipe is
attached. The function of the valve for delivering the contents. Different types of
valves are used. Continuous spray valves continuously spray the medicine,
metering valves, when open it spray metered amount of medicine through the exit
tube on the side of the valve normally remain safely closed.
A spring holds the valve tightly in place. The valve is operated through a push
button type actuator (item no. 4) which is normally remain in its ‘up’ position. The
function of the actuator is to open the valve and produce required types of
discharge. The drug (item no. 5, either liquid or solid powder) is kept in suspense
or in solution of a propellant (item no. 6) whose vapor occupies the empty space of
the container and its vapor creates pressure inside the container. The function of
Faculty of Pharmaceutical Sciences

the propellant is to develop pressure within the container and to expel the product.
Different types of propellants are used. Tri-chloro-fluoro-methane, di-chloro-di-
fluoro-methane are most commonly used.
When the actuator button is pressed towards bottom, the spring is compressed
and it allows to open the valve. The pressurized drug and propellant escape through
an opening at the top of the valve as aerosol or mist jet. Again when the actuator
button released, the spring expands and close the valve.
Drug delivery to the lungs is an attractive route for local treatment of pulmonary
disease such as asthma, and chronic obstructive pulmonary disorder (COPD), and
also delivering drugs systemically. In particular, significant research and
development efforts have been put into dry powder aerosols, which require no
propellant, have superior chemical stability compared with solution, and are easy
for patients to use. There are two types of dry powder inhalers, passive or breath
actuated devices, and active devices. With passive devices, the energy for
dispersion is generated by the patient's inspiratory effort. In contrast, active
devices minimize inspiratory effort by using an independent means (motor or
compressed gas) to fluidize the powder. In the literature, the active devices have
also been referred to the third generation DPI.
Clinical efficacy of inhaled therapeutics is governed by lung deposition, which
depends on the aerosol properties. For DPIs, the aerosol properties are related to
the dispersion of the powder, governed by the complex interaction between
patient inspiratory flow rate, the device, and the formulation. The effect of these
variables on deposition in the lungs can be examined by in vivo lung deposition
studies.
The product concentrate in the container is in equilibrium between liquid &
gaseous state. When actuator is pressed the valve opens. Since the product is under
pressure, the vapor above the liquid concentrate pushes the products down. Then
the product gets expelled through dip-tube from the container.
Production of aerosol
Pressure filling method: In this method, the products concentrate is placed in the
container and closed with the valve. The product is maintained below critical
temperature/slightly below boiling point (critical temperature is defined as the
temperature above which the liquid can no longer exist as liquid or in easy term,
Faculty of Pharmaceutical Sciences

temperature above which liquid show properties which are intermediate between
gas & liquid). The propellant gets liquefied in the container.
Applications
Administration of drugs from an aerosols is very easy and they can be applied
directly on the affected parts or abraded skin introduced into body cavity and
passages. When sprayed on skin, some of propellants (e.g., ethyl chloride) cool the
tissue due to sudden expansion of propellant. For these reasons, pharmaceutical
aerosols has a wide range of applications in the treatment of a patient due to its
beneficial effect over the other dosage form. It is used very effective treatment of
illness of asthma and chronic obstructive pulmonary disease (COPD). In a recent
study, it has been observed that inline dry powder inhalers offer a potentially
effective option to deliver high dose inhaled medications simultaneously with
mechanical ventilation. Inline DPI which are actuated using a low volume of air (LV-
DPI) are available for efficiently deliver pharmaceutical aerosols during low flow
nasal cannula (LFNC) therapy. Pharmaceutical aerosols are also very effective in the
treatment of diseases like diabetes, angina pectoris and many others.

Advantages
Pharmaceutical aerosols are gaining popularity due to certain advantages. These
are as follows:
• Pharmaceutical aerosols are easy to apply.
• Aerosol administration gives very efficient and quick relief.
• The stability of drug is enhanced by storing in MDIs and DPIs since the drug is
not comes in contact atmospheric oxygen and moisture.
• The drug can be directly applied to the affected areas.
• Administration of drug by aerosol is a rapid process.
• It protects the drug from gastrointestinal tract degradation.
• Hepatic first pass metabolism can be avoided.
• Aerosols can be used for both systemic and local applications.
• A sterile dose of drug is dispensed and also the contamination of drug is
prevented.

Relative humidity
 Faculty of Pharmaceutical Sciences

Relative Humidity - a dimensionless ratio, expressed in percent, of the amount of

atmospheric moisture present relative to the amount that would be present if the
air were saturated. Since the latter amount is dependent on temperature, relative
humidity is a function of both moisture content and temperature. As such, relative
humidity by itself does not directly indicate the actual amount of atmospheric
moisture present.
The amount of water vapor in the air at any given time is usually less than that
required to saturate the air. The relative humidity is the percent of saturation
humidity, generally calculated in relation to saturated vapor density.

There are three main measurements of humidity: relative, absolute and specific.
Absolute humidity (units are grams of water vapor per cubic meter volume of air)
is a measure of the actual amount of water vapor in the air, regardless of the air's
temperature. The higher the amount of water vapor, the higher the absolute
humidity. For example, a maximum of about 30 grams of water vapor can exist in a
cubic meter volume of air with a temperature in the middle 80s.
Relative humidity, expressed as a percent, is a measure of the amount of water
vapor that air is holding compared the amount it can hold at a specific temperature.
Warm air can possess more water vapor (moisture) than cold air, so with the same
amount of absolute/specific humidity, air will have a higher relative humidity. A
relative humidity of 50% means the air holds on that day (specific temperature)
holds 50% of water needed for the air to be saturated. Saturated air has a relative
humidity of 100%.
The relative humidity of an air-water mixture is also defined as the ratio of the
partial pressure of water vapor in the mixture to the saturated vapor pressure of
water at a given temperature. Thus, the relative humidity of air is a function of both
water content and temperature.
Specific humidity refers to the weight of water vapor contained in a unit weight
(amount) of air (expressed as grams of water vapor per kilogram of air). Absolute
and specific humidity are quite similar in concept.

Dew Point
Faculty of Pharmaceutical Sciences

Dew Point is the temperature at which air is saturated with water and condensation
begins. The higher the dew point rises, the greater the amount of moisture in the
air.

Relationship between Dew Point and Relative Humidity

Compared to relative humidity, dew point is frequently cited as a more accurate
way of measuring the humidity and comfort of the air, since it is an absolute
measurement (unlike relative humidity).
The relative humidity is 100 percent when the dew point and the temperature are
the same. If the temperature drops any further, condensation will result, and liquid
water will begin to form.
If the relative humidity is 100 percent (i.e., dew point temperature and actual air
temperature are the same), this does not necessarily mean that precipitation will
occur. It simply means that the maximum amount of moisture is in the air at the
particular temperature the air is at. Saturation may result in fog on the ground and
clouds aloft (which consist of tiny water droplets suspended in the air).
While dew point gives one a quick idea of moisture content in the air, relative
humidity does not since the humidity is relative to the air temperature. In other
words, relative humidity cannot be determined from knowing the dew point alone,
the actual air temperature must also be known.
Relative humidity is also approximately the ratio of the actual to the saturation
vapor pressure.
RH = (Actual Vapor Pressure) / (Saturation Vapor Pressure) X 100%
Where actual vapor pressure is a measurement of the amount of water vapor in a
volume of air and increases as the amount of water vapor increases. Saturated
vapor pressure is the maximum VP that can exist at any given temperature.

A hygrometer is an instrument used to measure relative humidity

The simplest hygrometer - a sling psychrometer - consists of two thermometers
mounted together with a handle attached on a chain. One thermometer is
ordinary. The other has a cloth wick over its bulb and is called a wet-bulb
thermometer.
 Faculty of Pharmaceutical Sciences

A psychrometer also called a sling psychrometer has two thermometers attached.

One is dry (often called the dry bulb thermometer) and measures the actual air
temperature. The other called the wet bulb thermometer has a has a wet cloth at
the tip. As water molecules evaporate from the surface of the wet bulb they will
take heat with them lowering the reading on the thermometer. The rate of
evaporation depends on the vapor pressure or amount of water vapor in the air. At
100% relative humidity no water will evaporate from the wet bulb and the readings
on both thermometers will be the same. Comparing the two temperatures in a
chart will give the relative humidity.

Liquid complexes,
Complex fluids are binary mixtures that have a coexistence between two phases:
solid-liquid (suspensions or solutions of macromolecules such as polymers), solid-
gas (granular), liquid-gas (foams) and liquid-liquid(emulsions). They exhibit unusual
mechanical responses to applied stress or strain due to the geometrical constraints
that the phase coexistence imposes. The mechanical response includes transitions
between solid-like and fluid-like behavior as well as fluctuations. Their
mechanical properties can be attributed to characteristics such as high disorder,
caging, and clustering on multiple length scales.
Shaving cream is an example of a complex fluid. Without stress, the foam appears
to be a solid: it does not flow and can support (very) light loads. However, when
adequate stress is applied, shaving cream flows easily like a fluid. On the level of
individual bubbles, the flow is due to rearrangements of small collections of
bubbles. On this scale, the flow is not smooth, but instead consists of fluctuations
due to rearrangements of the bubbles and releases of stress. These fluctuations are
similar to the fluctuations that are studied in earthquakes.

Liquid crystals,
Liquid Crystal is neither fully liquid nor fully solid (crystal) but it is an intermediate
of these two different states. The most important property that differentiates
solids and liquids is a flow property. Liquid flow and acquire shape of the container,
whereas a solid does not flow and tend to retain their shape. This phenomenon is
due to arrangement of molecules in liquid and solid crystal. In crystal the molecules
 Faculty of Pharmaceutical Sciences

are arranged in three-dimensional order whereas in liquid they are not. The order
in crystal is usually both, positional and orientational. So, the molecules are
constrained both to occupy specific sites in a lattice and to point their molecular
axes in specific directions.
As the temperature of substance increases, its molecules are vibrating more
vigorously. So, by the time these vibrations overcome the forces that hold the
molecules in place (lattice), and start to move. In the liquid state this motion
overcomes the intermolecular forces that maintain a crystalline state, and the
molecules move (diffuse) into random positions without pattern in location
(positional) or orientation.
In material that forms liquid crystals, the intermolecular forces are not the same in
all directions. In some directions the forces are weaker than in other directions. On
heating such a material, the increased molecular motion overcomes the weaker
forces first, but its molecules remain bound by the stronger forces. This produces a
two-dimensional molecular arrangement that is random in some directions and
regular in others. The two-dimensional arrangement of molecules in flowing
condition constitutes one type of liquid crystal.
The molecules in two-dimensional arrangement in layers, but within each layer,
they arrange in random positions, although they remain more or less parallel to
each other. Within layers, the molecules can slide around each other and the layers
can slide over one another. Thus, molecular mobility produces the fluidity
characteristic of a liquid, called anisotropic liquid or mesophase or mesomorphic
or mesogenic or nonamphiphilic etc. Thus the fluidity character of a substance
conforms that, the fourth state rather new physically distinct state of matter (three
of solid, liquid & gaseous) must exist in few compounds, between the isotropic
liquid and a crystalline solid phases known as liquid crystalline state and the
substance is called a liquid crystal or mesogen or nonamphiphile etc.
Classification
Liquid crystals are classified into two main categories.
• Thermotropic liquid crystals or Non-amphiphilic liquid crystals.
• Lyotropic liquid crystal or amphiphilic liquid crystals.
 Faculty of Pharmaceutical Sciences

This classification is based on the manner in which the liquid crystalline state is
formed or the manner in which three-dimensional array in crystalline structure of
the matter is broken. Crystalline structure of matter can be broken either by
heating the substance or by dissolving the substance in the suitable solvent. Thus
this mesmorphic state is achieved by applying heat. Thus, if mesophase is obtained
by heating, is called ‘Thermotropic liquid crystal’. If the mesomorphic state is
achieved by way of salvation, (i.e., Phenomenon of attraction between solvent and
solute.) than it is called ‘Lyotropic liquid crystals’. Gray and Windsor preferred the
terms non-amphiphilic and amphiphilic liquid crystal respectively.

Application of liquid crystals: Liquid crystal application find in all science faculties
likes Physical, Chemical, Space, Engineering, Mathematics Biology, etc.

• The most common application of liquid crystal technology is ‘Liquid Crystal

Displays’ (LCDs). LCDs are useful in electronic appliances like, Digital watches,
Pocket calculators, View cameras, compact and large flat screen televisions, etc.
• The twisted nematic (TN) represent the first successful application of liquid
crystals. In this archetypal device the liquid crystal is confined between crossed
polarizers and birefringence controlled electrically. It is very useful in watches,
calculators, compact TVs, etc.
• Ferroelectric liquid crystals (FLCs) also exhibit a spontaneous helixing of the
polarization, so that over macroscopic distances the polarization averages to
zero. Since the coupling of the polarization to applied fields is linear in the field,
this means that FLCs can be made switch quickly and in a bipolar manner. It is
very useful in video camera.
• Polymer-dispersed liquid crystal display (PDLC) is under active development. In
this kind of display, very small bubbled of liquid crystal are produced inside a
transparent polymer and it works as polarizer. PDLCs are very bright because
polarizers are not needed. They are useful in projection television.
• Electrically controlled birefringence (ECB) is a very small part of the liquid crystal
materials market and normally large dielectric anisotropy and birefringence
materials are desired.
 Faculty of Pharmaceutical Sciences

Glassy states
Cooling of a liquid to well below its equilibrium melting temperature without
crystallization retains the molecular disorder and may allow freezing of the
molecules to their random positions and formation of a solid-like but disordered,
non-crystalline glass. The solid-liquid transformation of the amorphous material is
known as glass transition. Glass transition is one of the most important
physicochemical characteristics of non-crystalline, amorphous solids. It governs
functional characteristics and plasticization of synthetic polymers as well as
inorganic glasses. Both the supercooled, amorphous liquid (rubbery, leathery, etc.)
and glassy states are thermodynamically nonequilibrium states, and their
properties are time-dependent.

The glass transition is reversible, and it occurs over a temperature range. Well
below the glass transition, molecules are frozen in their positions, and their
molecular motions are limited to rotations and vibrations, which results in the
solid-like characteristics of the material. When a glass is heated to above the glass
transition, molecules gain translational mobility and enter the supercooled, liquid-
like state with a concomitant appearance of viscous flow. In cooling to below the
glass transition, the amorphous material vitrifies to a solid-like, brittle, and
transparent structure typical of the glassy state. These properties and significant
differences of the solid- and liquid-like states of amorphous materials make the
glass transition perhaps the most important state transition responsible for
processing, stability, and quality characteristics of food materials.

The easily fusible "polar" glasses of the first group are characterized by the
cessation of the rotation vibrational motion of the molecular dipoles in a definite
{critical) temperature region. This results in stabilization of chain-like structures of
polar molecules rigidly associated (by means of the dipoles). The second group
consists of organic glassy polymerization products, which have in the stabilized
state a fibrous structure of rigid valency-bonded carbon atoms with small side
branches in the form of hydrogen atoms or of more complex radicals. The most
extensive third group of glasses is composed of refractory inorganic compounds of
multivalent elements. These glasses in the stabilized state have the most
 Faculty of Pharmaceutical Sciences

thermostable chemical structure in the form of a three-dimensional rigid atomic

valency-bonded spatial network.

Crystalline solids
A crystal or crystalline solid is a solid material whose constituents, such as atoms,
molecules or ions, are arranged in a highly ordered microscopic structure, forming
a crystal lattice that extends in all directions. Example: diamond, quartz.
Properties of crystalline solid
• These solids have a particular three-dimensional geometrical structure.
• The arrangement order of the ions in crystalline solids is of long order.
• The strength of all the bonds between different ions, molecules and atoms is
equal.
• Melting point of crystalline solids is extremely sharp. Mainly the reason is that
the heating breaks the bonds at the same time.
• The physical properties like thermal conductivity, electrical conductivity,
refractive index and mechanical strength of crystalline solids are different along
different directions.
• These solids are the most stable solids as compared to other solids.

Amorphous solid
An amorphous or non-crystalline solid is a solid that lacks the long-range order
characteristic of a crystal. Example: glass, plastic.
Amorphous solids as a first approximation may be considered supercooled liquids
in which the molecules are arranged in a somewhat random manner as in the liquid
state. Substances such as glass, pitch, and many synthetic plastics are amorphous
solids. They differ from crystalline solids in that they tend to flow when subjected
to sufficient pressure over a period of time and they do not have definite melting
points.
Amorphous substances, as well as cubic crystals, are usually isotropic, that is, they
exhibit similar properties in all directions. Crystals other than cubic are anisotropic,
showing different characteristics (electric conductance, refractive index, crystal
 Faculty of Pharmaceutical Sciences

growth, rate of solubility) in various directions along the crystal. It is not always
possible to determine by casual observation whether a substance is crystalline or
amorphous. Beeswax and paraffin, although they appear to be amorphous, assume
crystalline arrangements when heated and then allowed to cool slowly. Petrolatum
contains both crystalline and amorphous constituents. Some amorphous materials,
such as glass, may crystallize after long standing. Whether a drug is amorphous or
crystalline has been shown to affect its therapeutic activity. 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 the differences in the rate of dissolution. Once dissolved, the
molecules exhibit no memory of their origin.
Difference between crystalline and amorphous solids
Crystalline solids Amorphous solids
The particles in the constituent are
Crystals have definite and regular
arranged irregularly. They do not have
geometry and have long range as well as
any definite geometry and have short
short range order of constituent particles.
range order.
Crystals possess high melting points. They are devoid of sharp melting points.
The crystals external forms have No external regularity in their form when
regularity when these are formed. these amorphous solids are formed.
They give a clean surface after cleavage Usually the amorphous solids exhibit
with knife. irregular cut.
Amorphous solids do not possess any
They have definite heat of fusion.
particular heat of fusion.
Crystalline solids are very rigid and their Amorphous solid do not exhibit rigidity.
molecules cannot be deformed by mild Deformation could be done by bending or
distorting force. compressing them.
Crystalline solids are considered as true Amorphous solids are considered as
solid. super cooled liquids or also pseudo solids.
Crystalline solids display anisotropism. Amorphous solids display isotropism.

Polymorphism
 Faculty of Pharmaceutical Sciences

When a particular substance exists in more than one crystalline form, the property
is called polymorphism. Example: Calcium carbonate exists in two crystalline forms
called calcite and aragonite.
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 and diffraction patterns and solubilities, even though
they are chemically identical.
The formation of polymorphs of a compound may depend upon several variables
pertaining to the crystallization process, including:
• Solvent differences (the packing of a crystal might be different from a polar
versus a nonpolar solvent).
• Temperature
• Geometry of the covalent bond (are the molecules rigid, plane or free, flexible
• Pressure

Theobroma oil is capable of existing in four polymorphic forms: the unstable

gamma form, melting at 18°C; the alpha form, melting at 22°C; the beta prime form,
melting at 28°C; and the stable beta form, melting at 34.5°C.
Different polymorphs = different solubilities
Ex: slightly soluble drugs effects rate of dissolution. Ex: chloramphenicol palmitate
has a significant influence on biological activity.
The transition temperature in polymorphism is important because it helps
characterize the system and determine the more stable form at temperatures of
interest. At their transition temperatures, polymorphs have the same free energy
(i.e., the forms are in equilibrium with each other), identical solubilities in a
particular solvent, and identical vapor pressures.
Principle of Polymorphism: When each of two polymorphs is thermodynamically
stable in a definite range of temperature and pressure, the pair is said to be
enantiotropy. When one of two polymorphs are thermodynamically unstable at all
temperatures below the melting point, the two are said to be monotropic.
 Faculty of Pharmaceutical Sciences

Solvates Because many pharmaceutical solids are often synthesized by standard

organic chemical methods, purified, and then crystallized out of different solvents,
residual solvents can be trapped in the crystalline lattice. This creates a cocrystal,
as described previously, termed a solvate. The presence of the residual solvent may
dramatically affect the crystalline structure of the solid depending on the types of
intermolecular interactions that the solvent may have with the crystalline solid.
Cocrystals
Cocrystals are crystalline materials composed of two or more molecules held
together within the same crystal lattice. Cocrystallisation is significant in the
pharmaceutical industry, where drug molecules are screened for cocrystal
formation in order to improve their solubility, stability and bioavailability. This has
the added advantage of increasing the number of crystal forms that can be
considered for drug formulation while simultaneously maximizing patent
protection.
Pharmaceutical cocrystals could be used to improve the physicochemical
properties of active pharmaceutical ingredients
Pharmaceutical cocrystals are well-defined crystalline solids generated from active
pharmaceutical ingredients (API) and cocrystal formers (CCF). In recent years,
identification and development of pharmaceutical cocrystals gained increasing
interest in the pharmaceutical industry. The approach of cocrystal formation can
diversify the solid form choices and increase the chances to identify suitable
development candidates, especially for APIs with no crystalline form, nonionizable
functional groups, or low pKa values (to maintain as a stable salt). Examples of
pharmaceutical cocrystals have been demonstrated in the literature to provide
improved properties such as physical stability, dissolution rate, and solubility, and
thus they can be used as an alternative solid dosage form for an API.
In the last years, the formation of pharmaceutical cocrystals has gained an
increased interest as a means of optimizing the physicochemical properties of solid
dosage forms. Apart from potential improvements in solubility, dissolution rate,
bioavailability and physical stability, pharmaceutical cocrystals frequently enhance
 Faculty of Pharmaceutical Sciences

other essential properties of the APIs such as hygroscopicity, chemical stability,

compressibility and flowability.
Amorphous polymorphism
The amorphous form does not possess a defined order in its arrangement.
Although the amorphous form is the most soluble form, it exhibits the lowest
stability. Amorphous compounds are produced in the conditions when
precipitation is kinetically faster than crystallization and crystalline disorder caused
by processing (i.e. milling or micronisation).
It is also possible that more than one distinct amorphous phase may be formed
from the same substance. In analogy with the phenomenon of crystalline
polymorphism, this behavior has been termed “amorphous polymorphism”.
Significance: Amorphous materials can significantly increase bioavailability of
poorly-water soluble drugs. Understanding the crystallization of amorphous
material is crucial for process development.
Physical Properties of Substances In the field of thermodynamics, physical
properties of systems are classified as extensive properties, which depend on the
quantity of the matter in the system (e.g., mass and volume), and intensive
properties, which are independent of the amount of the substances in the system
(e.g., temperature, pressure, density, surface tension, and viscosity of a pure
liquid). The physical properties of substances can be classified as:
a) Colligative properties depend mainly on the number of particles in a solution.
Such as osmotic pressure, vapor pressure lowering, freezing point depression,
and boiling point elevation. In considering the colligative properties of solid-in-
liquid solutions, it is assumed that the solute is nonvolatile and that the pressure
of the vapor above the solution is provided entirely by the solvent.
b) Additive properties depend on the total contribution of the atoms in the
molecule or on the sum of the properties of the constituents in a solution such
as molecular weight.
c) Constitutive properties depend on the arrangement and to a lesser extent on
the number and kind of atoms within a molecule. These properties give clues to
 Faculty of Pharmaceutical Sciences

the constitution of individual compounds and groups of molecules in a system.

Many physical properties may be partly additive and partly constitutive. The
refraction of light, electric properties, surface and interfacial characteristics, and
the solubility of drugs are at least in part constitutive and in part additive
properties

Refractive index
Refractive index is defined as “The ratio of speed of light in vacuum to its speed in
a specific medium”.
The speed of light in a medium depends on the properties of the medium. In
electromagnetic waves, the speed is dependent on the optical density of the
medium. Optical density is the tendency of the atoms in a material to restore the
absorbed electromagnetic energy. The more optically dense material is, the slower
the speed of light. One such indicator of the optical density of a medium is the
refractive index.
Refractive index is the measure of bending of a light ray when passing from one
medium to another. It can also be defined as the ratio of the velocity of a light ray
in an empty space to the velocity of light in a substance.
Refractive index, represented by symbol n, is the velocity of light in vacuum divided
by the velocity of light in a medium. The formula of the refractive index is as follows:
n = c/v
The refractive index of a medium can be calculated using this formula
where n is the refractive index of the medium
c is the velocity of light in vacuum
v is the velocity of light in the medium
Refractive index is dimensionless. It is a number that indicates the number of times
slower than a light wave would be in the material than it is in a vacuum
 Faculty of Pharmaceutical Sciences

The speed of light is faster in water. The refractive index of water is 1.3 and the
refractive index of glass is 1.5. From the equation n = c/v, we know that the
refractive index of a medium is inversely proportional to the velocity of light in that
medium. Hence, light travels faster in water.
The vacuum has a refractive index of 1. The refractive index of other materials can
be calculated from the above equation. Higher the refractive index, higher the
optical density and slower is the speed of light. The table below lists the refractive
index of different media.
Material Refractive Index
Air 1.0003
Water 1.333
Diamond 2.417
Ice 1.31
Ethyl Alcohol 1.36

Refraction is the bending of the path of a light wave as it passes across the
boundary separating two media. Refraction is caused by the change in speed
experienced by a wave when it changes medium. The tendency of a ray of light to
bend one direction or another is dependent upon whether the light wave speeds
up or slows down upon crossing the boundary. The speed of a light wave is
dependent upon the optical density of the material through which it moves. For
this reason, the direction that the path of a light wave bends depends on whether
the light wave is traveling from a more dense (slow) medium to a less dense (fast)
medium or from a less dense medium to a more dense medium.
This relationship between the angles of incidence and refraction and the indices of
refraction of the two media is known as Snell's Law. Snell's law applies to the
refraction of light in any situation, regardless of what the two media are.
 Faculty of Pharmaceutical Sciences

ϴi = angle of incidence
ϴx = angle of refraction
As per Snell’s law: n1 . Sin ϴi = n2 . Sin ϴx
Where, n1 = refractive index of air (medium 1)
n2 = refractive index of water (medium 2)
Snell’s law can also be defined as “The ratio of the sine of the angle of incidence to
the sine of the angle of refraction is a constant, for the light of a given color and for
the given pair of media”. Snell’s law formula is expressed as:
Sin i / Sin r = constant = μ
Where i is the angle of incidence and r is the angle of refraction. This constant value
is called the refractive index of the second medium with respect to the first.
Applications of Snell’s Law Formula in Real Life:
• Snell’s law has a wide range of applications in physics especially in the branch
of optics. It is used in optical apparatus such as eyeglasses, contact lenses,
cameras, rainbows. There is an instrument called a refractometer that uses
Snell’s law to calculate the refractive index of liquids. It is used all the time in
the candy-making industry.
Faculty of Pharmaceutical Sciences

• The refractive index of a material medium is an important optical parameter

since it exhibits the optical properties of the material.
• Its values are often required to interpret various types of spectroscopic data.
Such as DOAS, ES, RPFTS, IRRS, PWMS.
• It is used to calculate the focusing power of lenses, and the dispersive power of
prisms.
• The refractive index coefficients are important parameters in the design of a
solid-state laser.
• The adulteration problem is increasing day by day and hence simple, automatic
and accurate measurement of the refractive index of materials is of great
importance these days.

An interesting case of refraction can occur when light travels from a medium of
larger to smaller index. The light ray can actually bend so much that it never goes
beyond the boundary between the two media. This case of refraction is called total
internal reflection.
Refractometer
The instrument used to measure refractive index is called as Refractometer.
Type of refractometer: Following types of refractometer are used
• Abbe refractometer
• Handheld refractometers
• Digital refractometer
• Automatic refractometer
• Process refractometer

Abbe refractometer: The Abbe refractometer, named after its inventor Ernst Abbe
(1840-1905), was the first laboratory instrument for the precise determination of
the refractive index of liquids. The measuring principle of an Abbe refractometer is
based on the principle of total reflection.
Abbe refractometers are used for measuring liquids. The reference media glasses
(prisms) can be selected with high refractive indices. The light from a radiation
source is reflected by a mirror and hits a double prism. A few drops of the sample
 Faculty of Pharmaceutical Sciences

are placed between this so-called Abbe double prism. The incident light beams pass
through the double prism and sample only if their angles of incidence at the
interface are less than the critical angle of total reflection. A microscope and a
mirror with a suitable mechanism are used to determine the light / dark boundary
line (shadow line).
The operator of the Abbe refractometer adjusts the mirror with the help of a rotary
knob until the light / dark boundary is located at the intersection of the
microscope’s crosshairs. The corresponding refractive indices can then be read
from a Vernier scale. Since the light / dark boundary is very low in contrast, it can
be only approximately determined manually. The accuracy of the classical Abbe
refractometer is nD = 0.0002, where the fourth decimal place is determined by
averaging a large number of individual measurements. The results depend on the
interpretation of the user, and often differ between users.
Semi-automatic refractometers are equipped with a digital display of the
measurement data and thus allow more consistent reading of measurement data.
A manual adjustment of this equipment is still necessary, however, so that
measurement results obtained continue to depend on the interpretation and the
skill of the measured person.

Optical rotation
Many substances possess the inherent property to rotate the plane of incident
polarized light; this property is called optical activity. The measurement of optical
activity is used for pharmacopeial purposes mainly to establish the identity of the
substance. It may also be employed to test the purity of the substance (absence of
optically non-active foreign substances) and as an assay procedure.

The optical rotation is the angle through which the plane of polarization is rotated
when polarized light passes through a layer of a liquid. Substances are described as
dextrorotatory or levorotatory according to whether the plane of polarization is
rotated clockwise or counterclockwise, respectively, as determined by viewing
towards the light source. Dextrorotation is designated (+) and levorotation is
designated (-). In the International Pharmacopoeia the optical rotation (α) is
expressed in angular degrees. In the SI, the angle of optical rotation is expressed in
radians (rad).
 Faculty of Pharmaceutical Sciences

The measurement of optical rotation should be carried out at the temperature

indicated in the monograph, usually at 20-25 °C. Some substances have large
temperature coefficients and for them special care should be taken to adjust the
temperature indicated.

Specific optical rotation (specific rotation)

The specific optical rotation of a liquid substance is the angle of rotation measured
as specified in the monograph, calculated with reference to a layer 100 mm thick,
and divided by the relative density (specific gravity) measured at the temperature
at which the rotation is measured.

The specific optical rotation of a solid is the angle of rotation measured as specified
in the monograph, and calculated with reference to a layer 100 mm thick of a
solution containing 1 g of the substance per mL.

Specific rotation = 10,000 a / l c = 10,000 a / l d p

where a is the observed rotation, l is the length of the observed layer in mm, c is
the number of g of substance contained in 100 mL of solution, d is the relative
density and p is the number of g of substance contained in 100 g of solution.

Following equation is used to calculate the specific optical rotation from

experimental data:

αobs = observed optical rotation

c = the concentration of the solution in grams per milliliter
l = the length of the tube in decimeters (1 dm=10 cm)
The observed specific rotation [α]obs depends on the length of the tube, the
wavelength that it is used for the acquisition, the concentration of the optical active
compound (enantiomer), and to a certain degree on the temperature as well.
 Faculty of Pharmaceutical Sciences

However, the temperature effect is very difficult to specify since it differs for each
compound.

Optical rotation is measured with a polarimeter. The zero point of the polarimeter
is determined with the tube empty but closed for liquid substances and filled with
the specified solvent for solutions of solid substances. The components of
polarimeter are: a light source - (usually a sodium lamp), a polarizer, a tube for
holding sample in the light beam- a sample cell, an analyzer- second polarizer, and
a scale- to measure the rotation of plane polarized light.

Schematic of a polarimeter: If no or optically inactive sample is present in the tube

and the instrument is reading zero (0o), the axes of plane polarized light and the
analyzer is exactly parallel. The observer will detect maximum amount (100%
transmittance) of light passing through. If the sample is optically active the plane
of plane polarized light will be rotated as it passes through the tube. In order to
detect the maximum brightness of the light (i.e. 100% transmittance) observer will
have to rotate the axis of the analyzer in either clockwise or counterclockwise
direction. If the analyzer is rotated in a clockwise direction, the rotation (α in
degree) is said to be positive (+), and such substance are called dextrorotatory. If
the rotation is counterclockwise, the α is negative (–), and such substances are
called levorotatory.
 Faculty of Pharmaceutical Sciences

A light wave is an electromagnetic wave that travels through the vacuum of outer
space. Light waves are produced by vibrating electric charges. An electromagnetic
wave is a transverse wave that has both an electric and a magnetic component. A
light wave that is vibrating in more than one plane is referred to as unpolarized
light. Light emitted by the sun, by a lamp in the classroom, or by a candle flame is
unpolarized light. Such light waves are created by electric charges that vibrate in a
variety of directions, thus creating an electromagnetic wave that vibrates in a
variety of directions. It is possible to transform unpolarized light into polarized light.
Polarized light waves are light waves in which the vibrations occur in a single plane.
The process of transforming unpolarized light into polarized light is known as
polarization.
Application of optical rotation and polarimetry
• Optical rotation is a method to tell how pure the chiral substance is.
• Polarimetric method is a simple and accurate means for determination of
structure in micro analysis of expensive and non-duplicable samples.
• It is employed in quality control, process control and research in the
pharmaceutical, chemical, essential oil, flavor and food industries.
• It can be used for research purpose in isolating and identifying unknowns,
crystallized from various solvents or separated by HPLC.
• It can also be used in evaluating and characterizing optically active compounds
by measuring their specific rotation and comparing this value with the
theoretical values found in literature.
• It can be used for investigating kinetic reactions by measuring optical rotation
as a function of time and also in monitoring changes in concentration of an
optically active component in a reaction mixture, as in enzymatic cleavage.
• It can determine product purity by measuring specific rotation and optical
rotation of: Amino acids, Amino sugars, Analgesics, Antibiotics Cocaine,
Dextrose Diuretics Serums Steroids Tranquilizers Vitamins.
• Polarimetry can be utilize for incoming raw materials inspection of Camphor,
Citric acid, Glycerol, Lavender oil, Lemon oil, Orange oil, Spearmint oil etc.
 Faculty of Pharmaceutical Sciences

Dielectric constant

Dielectrics are materials that don’t allow current to flow. They are more often
called insulators because they are the exact opposite of conductors. But usually
when people call insulators “dielectrics,” it’s because they want to draw attention
to a special property shared by all insulators i.e. polarizability.

When a battery is connected to a conductor, the potential difference of the two

poles of the battery pushes on all the charges in the conductor, which in turn causes
them to drift slowly through the material creating a current through the conductor.
This happens because the outer electrons in a conductor are not attached to
particular nuclei, they can wander freely throughout the entire material. In a
dielectric, the charges are valence electrons that are stuck inside atoms of a crystal
or polymer, and so current doesn’t flow at all. The electric field,
however, still exerts a force on the charges. While the individual electrons remain
tied to their parent atoms, they prefer to stay on the side of the atom that’s closer
to the positive terminal. Electrons wanted to come out from their parent atoms but
remain inside because of electrostatic forces that bind valence electrons to
nucleus.

Because the external field causes the electrons in each atom to congregate on one
side of the nucleus, the atoms are polarized, meaning they have a positive pole and
a negative pole that are oriented with the direction of the electric field. If a large
enough electric field is applied to a dielectric, the forces that want to push the
electrons can actually overcome the force that binds them to the atomic nucleus,
resulting in the electrons being came out from parent atom. Large electric fields
ionize the atoms of a dielectric. This means large electric fields create free charges
(electrons in this case) that are able to move freely through the material and carry
current. This process is called dielectric breakdown because the dielectric
transitions from being an insulator to a conductor. In most real-world capacitors,
dielectric breakdown results in a spark and damage to the capacitor.

So, dielectric is a material which has poor electrical conductivity but inherits an
ability to store an electrical charge (due to Dielectric polarization). Thus, exhibiting
 Faculty of Pharmaceutical Sciences

only displacement current making it ideal to build a capacitor; to store and return
electrical energy.

Dielectric Constant of a substance can be defined as “The ratio of the permittivity

of the substance to the permittivity of the free space”. It expresses the extent to
which a material can hold electric flux in it. It is mathematically expressed as:

κ = ε / ε0
Where,

• κ is the dielectric constant

• 𝜺 is the permittivity of the substance

• 𝜺0 is the permittivity of the free space

As it is the ratio of two like entities, it is a unitless, dimensionless quantity.

The relative permittivity of a dielectric substance is also called a Dielectric Constant,

expressed using Greek letter kappa ‘κ’.

Theory behind Dielectric Constant

This is a prime parameter to characterizes a capacitor. A capacitor is an electronic

component designed to store electric charge. This is widely built by sandwiching a
dielectric insulating plate in between the metal conducting plates. The dielectric
property plays a major role in the functioning of a capacitor.

The layer made up of dielectric material decides, how effectively the capacitor can
store the charge. Picking the right dielectric material is crucial. Thus, we can also
define it as ‘the ratio of the electric field without a dielectric(E0) to the net field with
a dielectric(E).’

κ = Eo / E

Here, the value of E0 always greater than or equal to E. Thus, the value of a dielectric
constant is always greater than 1.
 Faculty of Pharmaceutical Sciences

Greater the value of κ more charge can be stored in a capacitor.

In the capacitor, the capacitance is given by
C = κ C0

Thus, filling the gap between the plates completely by dielectric material will
increase its capacitance by the factor of dielectric constant value.
In the parallel plate capacitor, the capacitance is given by:

C = κ ε0 A d

Where,
C is the capacitance of the parallel plate capacitor.
κ is the dielectric constant.
𝜺0 is the permittivity of the free space.
A is the area of parallel conducting plates.
D is the separation between parallel conducting plates

The capacitance value can be maximized by increasing the value of the dielectric
constant and by decreasing the separation between the parallel conducting plates.

Thus, the value of the dielectric constant is crucial in building various electronic
components. Dielectric Constants of few materials are vacuum (1.00), air (1.00059),
water (80) and paper (3.6).

Dipole moment

When atoms in a molecule share electron unequally, they create what is called a
dipole moment. This occurs when one atom is more electronegative than another,
resulting in that atom pulling more tightly on the shared pair of electrons, or when
one atom has a lone pair of electrons and the difference of electronegativity vector
points in the same way. One of the most common examples is the water molecule,
made up of one oxygen atom and two hydrogen atoms. The differences in
electronegativity and lone electrons give oxygen a partial negative charge and each
hydrogen a partial positive charge.
 Faculty of Pharmaceutical Sciences

A dipole moment arises in any system in which there is a separation of charge. They
can, therefore, arise in ionic bonds as well as in covalent bonds. Dipole moments
occur due to the difference in electronegativity between two chemically bonded
atoms.
A bond dipole moment is a measure of the polarity of a chemical bond between
two atoms in a molecule. It involves the concept of electric dipole moment, which
is a measure of the separation of negative and positive charges in a system.
The bond dipole moment is a vector quantity since it has both magnitude and
direction. An illustration describing the dipole moment that arises in an HCl
(hydrochloric acid) molecule is provided below.

It can be noted that the symbols 𝛿+ and 𝛿– represent the two electric charges that
arise in a molecule which are equal in magnitude but are of opposite signs. They
are separated by a set distance, which is commonly denoted by ‘d’.

• The dipole moment of a single bond in a polyatomic molecule is known as the

bond dipole moment and it is different from the dipole moment of the molecule
as a whole.
• It is a vector quantity, i.e. it has magnitude as well as definite directions.
• Being a vector quantity, it can also be zero as the two oppositely acting bond
dipoles can cancel each other.
• By convention, it is denoted by a small arrow with its tail on the negative center
and its head on the positive center.
• In chemistry, the dipole moment is represented by a slight variation of the arrow
symbol. It is denoted by a cross on the positive center and arrowhead on the
negative center. This arrow symbolizes the shift of electron density in the
molecule.
• In the case of a polyatomic molecule, the dipole moment of the molecule is the
vector sum of the all present bond dipoles in the molecule.

Factors affecting dipole moment: Dipole moments increase with ionic bond
character and decrease with covalent bond character. It when there is a separation
 Faculty of Pharmaceutical Sciences

of charge. So, can occur between two ions in an ionic bond or between atoms in a
covalent bond; dipole moments arise from differences in electronegativity. The
larger the difference in electronegativity, the larger the dipole moment. The
distance between the charge separation is also a deciding factor into the size of the
dipole moment. The dipole moment is a measure of the polarity of the molecule.

Dipole Moment Formula

A dipole moment is the product of the magnitude of the charge and the distance
between the centers of the positive and negative charges. It is denoted by the
Greek letter ‘µ’. Mathematically,

Dipole Moment (µ) = Charge (Q) * distance of separation (r)

It is measured in Debye units denoted by ‘D’. 1 D = 3.33564 × 10-30 C.m
where C is Coulomb and m denotes a meter.

The bond dipole moment that arises in a chemical bond between two atoms of
different electronegativities can be expressed as follows:

μ=𝛿.d

Where, μ is the bond dipole moment, 𝛿 is the magnitude of the partial charges
𝛿+ and 𝛿–, and d is the distance between 𝛿+ and 𝛿–.

The bond dipole moment (μ) is also a vector quantity, whose direction is parallel to
the bond axis. In chemistry, the arrows that are drawn in order to represent dipole
moments begin at the positive charge and end at the negative charge.

When two atoms of varying electronegativities interact, the electrons tend to move
from their initial positions to come closer to the more electronegative atom. This
movement of electrons can be represented via the bond dipole moment.

The absolute value of the difference in electronegativity (ΔEN) of two bonded

atoms provides a rough measure of the polarity to be expected in the bond and,
thus, the bond type. When the difference is very small or zero, the bond is covalent
and nonpolar. When it is large, the bond is polar covalent or ionic. So,
Faculty of Pharmaceutical Sciences

electronegativity and bond polarity plays an important role in formation of dipole

moment.
Examples: Dipole moment of BeF2
In a beryllium fluoride molecule, the bond angle between the two beryllium-
fluorine bonds is 180o. Fluorine, being the more electronegative atom, shifts the
electron density towards itself. The individual bond dipole moments in a
BeF2 molecule are illustrated below.

Bond dipoles in BeF2

Total bond moment in BeF2

From above example, it can be understood that the two individual bond dipole
moments cancel each other out in a BeF2 molecule because they are equal in
magnitude but are opposite in direction. Therefore, the net dipole moment of a
BeF2 molecule is zero.
Dipole moment of H2O (Water)
In a water molecule, the electrons are localized around the oxygen atom since it is
much more electronegative than the hydrogen atom. However, the presence of a
lone pair of electrons in the oxygen atom causes the water molecule to have a bent
shape (as per the VSEPR theory). Therefore, the individual bond dipole moments
do not cancel each other out as is the case in the BeF2 molecule. An illustration
describing the dipole moment in a water molecule is provided below.
Faculty of Pharmaceutical Sciences

The bond angle in a water molecule is 104.5o. The individual bond moment of an
oxygen-hydrogen bond is 1.5 D. The net dipole moment in a water molecule is
found to be 1.84D.
Significance or applications of dipole moment
• Distinction between polar and non-polar molecules: Dipole moment is the scalar
product of charge and displacement between two poles. i.e., μ = Q × d, it means
dipole moment helps to predict whether a molecule is polar or non- polar means
the magnitude of dipole moment is directly proportional to polarity of molecule.
For non - polar molecule dipole moment is always zero.
• Ionic character in a molecule: The percentage of ionic character is calculated
with help of dipole moment. i.e., % of ionic character = μ(observed) /μ(ionic) ×
100
• Symmetrical molecules have zero dipole moment. For example: - BF3 , CH4 , etc
has zero dipole moment because these molecules are symmetrical and number
of lone pairs is zero in central atom.
• It helps to distinguish between Ortho, meta and para isomers. Dipole moment
of para molecule is zero. Dipole moment of Ortho is greater than that of meta
isomer.
• Degree of polarity in a molecule: Greater is the value of dipole moment, greater
is the degree of polarity. This relationship specially holds true for diatomic
molecules. HF (1.78D) is more polar than HCl (1.07D).
• Shapes of molecules: Water and carbon dioxide have dipole moments 1.85 D
and 0 respectively. Thus, water has angular shape whereas carbon dioxide has
linear shape.

Dissociation constant
 Faculty of Pharmaceutical Sciences

The acid-base dissociation constant (pKa) of a drug is a key physicochemical

parameter influencing many biopharmaceutical characteristics.

To determine if an acid is weak or strong is by comparing the dissociation constants

of the acids. The dissociation constant is the ratio of dissociated ions (products) to
original acid (reactants). It is abbreviated as Ka.

An acid dissociation constant (Ka) is a quantitative measure of the strength of an

acid in solution.

pKa The logarithmic constant (pKa) is equal to -log10(Ka).

The larger the value of pKa, the smaller the extent of dissociation. A weak acid has
a pKa value in the approximate range of -2 to 12 in water. Acids with a pKa value of
less than about -2 are said to be strong acids. A strong acid is almost completely
dissociated in aqueous solution; it is dissociated to the extent that the
concentration of the undissociated acid becomes undetectable. pKa values for
strong acids can be estimated by theoretical means or by extrapolating from
measurements in non-aqueous solvents with a smaller dissociation constant, such
as acetonitrile and dimethyl sulfoxide.

The dissociation constant specifies the tendency of a substance MxNy to reversibly

dissociate (separate) in a solution (often aqueous) into smaller components M
and N:

The dissociation constant is denoted Kd and is calculated by

where A represents the activity of a species, and [M], [N], and [MxNy] are the molar
concentrations of the entities M, N, and MxNy. Because water is the solvent, and
 Faculty of Pharmaceutical Sciences

the solution is assumed to be dilute, the water is assumed to be pure, and the
activity of pure water is defined as 1. The activities of the solutes are approximated
with molarities.

The dissociation constant is an immediate consequence of the law of mass

action which describes equilibria in a more general way. The dissociation constant
is also sometimes called ionization constant when applied to salts. The inverse of
the dissociation constant is called association constant.

Dissociation constant of water

The value of Kw changes considerably with temperature.

Acid dissociation constant, Ka

Faculty of Pharmaceutical Sciences

The acid dissociation constant (Ka) is a quantitative measure of the strength of an

acid in solution. It can be derived in following way:

The greater the dissociation constant of an acid the stronger the acid. Polyprotic
acids (e.g. carbonic acid or phosphoric acid) show several dissociation constants,
because more than one proton can be separated (one after the other).

Base dissociation constant, Kb

For a drug molecule that is weak base

 Faculty of Pharmaceutical Sciences

Factors affecting dissociation constant

1. Temperature: The major factors which affect affinity and dissociation constant
are temperature and the presence of a catalyst. In general, the rate of any
reaction is determined by the Arrhenius equation:

k = A e -Ea/RT

k is rate constant
A is pre-exponential factor constant, which is different for every chemical reaction,
and which equates to the frequency of molecular collisions in the correct
orientation
Ea is the activation energy for the reaction
R is universal gas constant
T is temperature in kelvin
Normally dissociation happened at 20 or 25ᵒC.
If reaction is exothermic, the dissociation constant will rise with increasing
temperature.
If reaction is endothermic, the dissociation constant will fall with increasing
temperature.
2. Nature of solute:

Consider the general equation for acid dissociation equilibria.

Acid + Solvent ⇌ Conjugated base of acid + Protonated solvent

 Faculty of Pharmaceutical Sciences

Usually, acid dissociation depends on three factors: properties of acid itself,

properties of solvent which acts as base, and temperature.

However, there are also many factors involved in properties of acid.

a) Inductive effect. Having electronegative atom nearby in structure makes bonds

between acidic proton and the rest of molecules weaker as those atoms will pull
electron density toward themselves. Therefore, its proton will be more easily to
come off, making it stronger. This explains why sulfuric acid is more acidic than
sulfurous acid, and also why fluoroacetic acid is more acidic than acetic acid.

b) Resonance effect. If its conjugate base is stabilized by resonance, acid will be

stronger as it prefers more to stay as conjugate base. This is the reason for acidity
of phenols compared to alcohols.

c) s-character. Proton connected to sp carbon will be more acidic than those

connected to sp2 or sp3, as bonding electrons will be closer to carbon in sp than
sp2 and sp3, making C-H weaker.

3. Nature of solvent: The solvent affects the dissociation to a large extent. Solvents
having high dielectric constant can weaken the interionic forces and separate
the ions in water. For example, water
4. Concentration of substance: if the concentration of the substance is less, then
the dissociation is promoted to a larger extent. As the solvent available is large,
the inter-ionic forces can be broken. Thus, promotes the dissociation.

Difference between pka (dissociation constant) and partition coefficient (logP)

pka (dissociation constant) Partition coefficient (logP)

The pka or (dissociation constant) is a Partition coefficient or log P is a

measure of strength of an acid or base. measure how well a substance
It allows to determine the charge on a partitions between oil and water.
molecule at a particular pH.
Faculty of Pharmaceutical Sciences

High valve indicates weak acid and low If logP value is more means more
value indicate strong acid lipophilic if less means less lipophilic.

pka can be measured by using any one of the following methods:

• Potentiometric titration,
• Spectrophotometric methods,
• Conductivity method,
• Solubility method

Conductivity method: In this method degree of dissociation can be obtained from

conductivity experiments using formula:

α = Ʌc / Ʌ ∞

Ʌ c = equivalent conductance of the ions at a given concentration, c, S.m² / gram-

Eq, Ʌ ∞ = equivalent conductance at infinite dilution, S.m² / gram-Eq

The equivalent conductance (Ʌ) is calculated from specific conductance by

following equation:

Ʌ = specific conductance / 1000 x conc. of electrolyte

Ʌ = k / 1000 c

Conductance of a solution is measured using a conductivity bridge, i.e. conductivity

meter.

As per Ostwald's dilution law,

Kₐ = α²c/ (1 – α)

If degree of dissociation is known, dissociation constant can be calculated.

Advantages: Acceptable for acid and all those having pkₐ value in the range of 1.89
– 5.15. For this range give results of highest precision.
Faculty of Pharmaceutical Sciences

Disadvantages: Not suitable for strong bases. Tedious and time consuming. Carbon
dioxide free and deionized water should be used. Not suitable for second ionization
constant of a substance with two ionizing group.

Applications

The concept of the dissociation constant is applied in various fields of chemistry

and pharmacology. In protein-ligand binding the dissociation constant describes
the affinity between a protein and a ligand. A small dissociation constant indicates
a more tightly bound the ligand. In the case of antibody-antigen binding the
inverted dissociation constant is used and is called affinity constant.

• The absorption of drugs in gastrointestinal tract can be predicted using

dissociation constant of the drug and pH of different sites of GIT.
• The concentration of preservatives such as benzoic acid required to preserve
solutions and emulsions can be predicted.
• The acid base dissociation constant (pka) of a drug is key physico-chemical
parameter to influencing many biopharmaceutical characteristics.
• The knowledge of pka values is important for quantitative evaluation of systems
involving acid – base equilibria in solution.
• Dissociation constant is also essential for working with buffers. The design of
these solutions depends on the knowledge of pka value of their components.
• pH of solution can be calculated. A pH indicator is weak acid or a weak base
which changes color in the transition pH range i.e. about pka ± 1.