States of Matter & Properties of Matter

Relative humidity (RH)

• Humidity is the concentration of water
vapor present in the air. (g/m3)
• The amount of water vapor in the air at any
given time is usually less than that required to
saturate the air.
• RH is a ratio, expressed in percent (%), of the
amount of atmospheric moisture present relative
to the amount that would be present if the air
were saturated.
• Dew point is the temperature at which the water vapor
commence to condense.

Method of Determination of RH:

Dew point method, the dew is found
on the walls of container at the
temperature, where the air is in contact
with it, and gets saturated.
Psychrometric method both the dry
bulb and wet bulb temperatures are
determined. By determining the wet
bulb temperature, humidity of dry air
and relative humidity can bre
calculated with the help of humidity
chart.
Liquid complexes:
• Complex fluids are gases or liquids that contain
particles of other substances dispersed within
them.
• Complex fluids are binary mixtures that have
coexistence between two phases: solid–liquid
(suspensions or solutions of macromolecules
such as polymers), solid–gas (granular), liquid–
gas (foams) or liquid–liquid (emulsions).
Liquid crystals: 
• The liquid crystal state is a distinct state of
matter observed between the crystalline solid
and liquid states. 
Characteristics of Liquid Crystal State:
1. The molecules of liquid crystal point along a
common axis. This is in contrast to liquid phase
molecules, which have no intrinsic order, whereas solid
state molecules are highly ordered.

2. Most liquid crystal compounds exhibit

polymorphism.

3. They are anisotropic in nature and their properties

depend upon the direction along which they are
measured.
Types of Liquid crystals:
• Thermotropic Liquid Crystals – Liquid crystals are said to be
thermotropic if liquid crystalline properties depend on the
temperature.
• Nematic Liquid Crystals: Here the molecules (mesogens) have
no positional order, but they have long-range orientational order
• Smectic Liquid Crystals: In this, the mesogens have both
positional order and orientational order.
• Cholestric liquid Crystals: The cholestric phase can be defined
as a special type of nematic liquid crystals in which thin layers of the
parallel mesogens have their longitudinal axes rotated in adjacent
layers at certain angle.
• Lyotropic Liquid Crystals: Liquid crystals which are prepared by
mixing two or more substances, of which one is a polar molecule,
are known as lyotropic liquid crystals.
Glassy state
• The glassy state of materials refers to non equilibrium,
solid state, such as is typical of inorganic glasses, synthetic
noncrystalline polymers and food components.
• Characteristics of the glassy state include transparency,
solid appearance and brittleness.
• In such systems, molecules have no ordered structure and
the volume of the system is larger than that of crystalline
systems with the same composition. These systems are
often referred to as amorphous (i.e., disordered) solids
(e.g., glass) or super cooled liquids (e.g., rubber, leather,
syrup).
Schematic two-dimensional Illustration of the atomic
arrangement in (1) crystal and (2) glass
Glassy state
• All the glass is considered to be a non-conducting transparent
solid, it is actually a type of solid matter.
• It can neither be considered as a typical solid nor a typical liquid.
• The atoms and molecules in most solids are arranged in an
orderly manner whereas in Glassy materials these are highly
disorder.
• Glassy materials however, have some short range order as in the
case of polymers.
• Glassy materials also do not have a specific melting point but
these slowly and gradually liquefy on heating.
• Structurally Glassy materials can be considered to be made up of
a random selection of polyhedral molecules linked together at
their corners.
Glassy state
• Certain materials can easily be converted to a Glassy state
while other pose great difficulty and certain materials cannot
be converted at all.
• Although the theory behind this behaviour is not very clear, it
has been shown that material which can be converted to glassy
state have a very high viscosity at their melting point which
inhibits the formation of an ordered structure
• Although the most common materials which can be converted
to Glassy state are the metal oxides ,even materials such as
Steel can be converted to the Glassy state if it is cooled very
quickly. This technique produces glasses since the material
solidifies even before it gets chances to develop a crystalline
structure.
 SOLIDS & CRYSTALLINE STATE
Pharmaceutical Drugs: more than 80% are solid formulations
 Solids and the crystalline state
• A crystalline solid possesses rigid and long-range
order.

• In a crystalline solid, atoms, molecules or ions occupy

specific (predictable) positions.

• An amorphous solid does not possess a well-defined

arrangement and long-range molecular order.
Classification of Solids
A unit cell is the basic repeating structural unit of a
crystalline solid.

lattice
point
At lattice points:
• Atoms
• Molecules
• Ions

Unit Cell Unit cells in 3 dimensions

The crystal lattice of sodium
chloride NaCl

Na Cl
 Crystal forms
The various crystal forms are divide to basic 7 unit according to
its symmetry iodoform
NaCl urea

iodine

Be3Al2(SiO3)6
sucrose Boric acid
Ionic Crystals
Types of Crystals
• Lattice points occupied by cations and anions
• Held together by electrostatic attraction
• Hard, brittle, high melting point
• Poor conductor of heat and electricity

CsCl ZnS CaF2

Covalent Crystals
• Lattice points occupied by atoms
• Held together by covalent bonds
• Hard, high melting point
• Poor conductor of heat and electricity

carbon
atoms

diamond
graphite
Metallic Crystals
• Lattice points occupied by metal atoms
• Held together by metallic bonds
• Soft to hard, low to high melting point
• Good conductors of heat and electricity

nucleus &
inner shell e-

mobile “sea”
of e-

Cross Section of a Metallic Crystal

 Polymorphism
• Some elemental substance such
as C and S ,may exist in more
than one crystalline form and
are said to be allotropic, which
is a special case of
polymorphism

• Polymorphism is the ability of a

substance to exist in more than
one crystal structure
 Polymorphism is the ability of a substance to exist in
more than one crystal structure

 Polymorphs: when two crystals have the same chemical

composition but different internal structure (molecular
packing –molecular conformation or / and inter or intra
molecular interactions)modifications or polymorphs or
forms

 Pseudo polymorphs : different crystal forms have

molecules of the same given substances and also contain
molecules of solvent incorporated into a unique
structure (solvates or hydrates (water))
 The most common example of polymorphism

carbon
atoms

High T and p
diamond graphite

Diamond is metastable and converts very slowly to graphite

 Solid State : Polymorphs

Mono-component systems:
Polymorphs

Multi-component systems
 Cocrystal
• The simplest definition of a cocrystal is a crystalline
structure made up of two or more components in a
definite stoichiometric ratio, where each component
is defined as either an atom, ion, or molecule.
 Principle of polymorphism

• When the change from one form to another is

reversible, it is said to be enantiotropic.
Carbamazepine

• When the transition takes place in one direction only

—for example, from a metastable to a stable form—
the change is said to be monotropic.
Chloramphenical palmitiate, Metozolone
 Solvates
• Pharmaceutical synthesis include purification and
crystallization, residual solvent can be trapped in the
lattice.
 This result in the formation of cocrystal or solvate.

• The presence of residual solvent may affect

dramatically the crystalline structure of the solid
depending on the type of inter. molecular forces that
the solvent may have with crystalline solid
 Polymorphism
 Melting point  Photochemical reactivity
 Vapor pressure  Thermal stability
 Hardness  Filtration and drying
 Optical, electrical characteristics
magnetic properties  Dissolution rate
 Color  Bioavailability
 IR spectra  Physical and chemical
 NMR spectra stability

Solubility and melting point are very important in

pharmaceutical processes including dissolution
and formulation.
 Amorphous Solid
• An amorphous solid does not possess a well-defined
arrangement and long-range molecular order.
• Amorphous substances, as well as cubic crystal, are isotropic,
that is, they exhibit similar properties in all direction.

AMORPHOUS SOLIDS
      Solids that don’t have a definite geometrical shape are known as
Amorphous Solids.
1. In these solids particles are randomly arranged in three dimension.
2. They don’t have sharp melting points.
3. Amorphous solids are formed due to sudden cooling of liquid.
4. Amorphous solids melt over a wide range of temperature
 Amorphous or crystalline & therapeutic
activity
• The crystalline from of the antibiotic novobiocin acid
is poorly absorbed and has no activity, where the
amorphous form is readily absorbed and
therapeutically active, due to different dissolution
rate.
 Crystallization
General crystallization conditions
􀁺Solvents –different polarities
􀁺Concentration of the solutions (super saturated,
saturated, diluted)
􀁺Cooling speed (quenching, slow)
􀁺Temperature (room or lower than room temperature)
 Polymorphism and Industry/
Pharmaceutical

API Final Form

Crystallization Granulation

Filtration Drying

Drying Compaction

Milling Tableting

Bulk API Drug Product

Stability
 Polymorphism and Industry/
Pharmaceutical
• Fluoxetine HCl, the
active ingredient in
the antidepressant
drug Prozac.

• co crystal which
will have increased
solubility
compared to the
crystalline form
 Celecoxib
• CELECOXIB is a nonsteroidal anti-inflammatory drug

• However it was found that the higher bioavailability was shown by the
amorphous state

• The downfall of the amorphous state was its stability.

• This was due to the structural relaxation.

• This was enhanced by mixing it with polymers like PVP, which helped in
stabilizing the amorphous system (Piyush Gupta et al. 2004, Piyush Gupta
et al. 2005).

• A new solid state form was developed by Pharmacia

 Furosemide

Two forms with significantly differing aqueous solubility

and dissolution rate
Oral bioavailability compromised

Giron lists >20 excipients that display polymorphism,

including
– Lactose (anhydrous; also monohydrate)
– Aspartame (anhydrous; hydrate forms)
– Magnesium stearate (can affect lubrication of tablets)
Physical Properties of Drug Molecules
Physical properties of Drug Molecules
• Physical properties are properties than can be measured
or observed without changing the chemical composition
of the substance.
• Some physical properties of drug molecules and solvents
are:
o Molecular volume
o Dipole moment
o Optical rotation
o Viscosity
o Surface tension
o Refractive index
o Dielectric constant
Applications:

o Identification of drugs
o Determination of percentage composition of
drugs
o Drug synthesis
o Elucidation of the structure of molecules
o Formulation of dosage forms
o Evaluation of drug action
Refractive index:

• The ratio between the speed of light in medium

to speed in a vacuum is the refractive index.
• Refractive index is defined as “the ratio of the
speed of light in a vacuum to its speed in a
specific medium”.
• Optical density is the tendency of the atoms in a
material to restore the absorbed electromagnetic
energy
• Snell’s law states that the refractive indes (n) of
the liquid is a constant ratio of the angle of
incidence to that of the refraction.

• It is given by:

𝑛 = sin 𝑖 / sin r

Where,
i is angle of incidence
r is angle of refraction
Measurement of Refractive Index:
Refractive index is determined by using instrument
called refractometer.
o Abbes refractometer
Mostly used- Quick & Convenient

o Immersion refractometer &

o Pulfrich refractometer

Figure: Angles of Incidence and Refraction

Reference liquids for calibration of Abbes’ refractometer
Applications of refractive index
• RI is a fundamental physical property - identify a particular
substance, confirm its purity, or measure its concentration.
• RI values are useful in determination of molecular weights and
structures of organic compounds from their molar refraction values.
• Refractive index is used to measure refraction characteristics of
solids, liquids, and gases.
• Measure the concentration of a solute in an aqueous solution.
• Determine the sugar content in solution of sugar
• Alcohol content in bioproduction
• Dielectric constant and molar polarizibility values can be obtained
from the refractive index.
• RI of a substance is the most important property of any optical
system that uses refraction for example, lenses and prisms.
 Optical rotation:
oOrdinary light – vibrations - distributed in all directions in a plane
perpendicular to the direction of propagation, called as unpolarised light.
oWhen the vibrations of light are restricted (Polarized – Nicol Prism) to
only one plane, the light is said to be polarized light.

Optically Active Substances - Some

substances rotates the plane of polarized
light are called as.

This property of optically active substance is

measured as angle of rotation.

Figure: Ordinary and polarized light

Optical rotation:
• The optical rotation (α) is the angle through
which the plane of polarization is rotated when
polarized light passes through a layer of liquid.

optically active
substances :
• Lactic acid,
• Tartaric acid,
• 2-methyl -1-butanol etc.
Leavo rotatory (l) Dextro rotatory (d)
or (−) substance or (+) substance
Laevulose Dextrose
(fructose) (Glucose)
Optical rotation:
The angle of rotation is normally expressed as specific rotation (α) and
mathematical expression is

Reason for Optical rotation:

• left and right polarized light travel through an optically active substance at
different velocities.
• Optical activity is considered to be due to the interaction of plane
polarized radiations with electrons in molecules which shows electronic
polarization. This interaction rotates the direction of vibration of radiation
by altering electric field.
Optical rotation:
o Optically active substances can be categorized in to two
types:
1. Those which are optically active only in the crystal state due
to their characteristic crystal structure and becomes optically
inactive in the fused or dissolved state, for example, sodium
chlorate, quartz crystal etc and,
2. Those which shows optical activity in all states viz.
Crystalline (solid), fused (liquid) and gaseous state, due to
their structural configurations.
Polarimeter:

Figure: Schematic of Polarimeter

Application of Optical rotation:
o Studying the structure of anisotropic substances, and for
checking the purity and identifying chiral mixtures.
o Determination of Adulterations in the optically active
substances. For example, optical rotation of honey is
opposite to that of sugar due to the presence of fructose
and glucose and hence can be determined from the optical
rotation.
o Polarimetry is used in the analysis of various drugs and
pharmaceutical formulations such as Adrenaline
Bitartarate, anticoagulant Citrate Dextrose Solution,
Dextran 40 Injection, Dextrose Injection, Sodium
Chloride and Dextrose injection etc.
Dielectric Constant (ε)
• It is a very important property of liquids. Liquids have
capacity to separate ions and keep them in solution. This
capacity is measured in terms of dielectric constant
values.
• Water has a dielectric constant of 80, alcohol has a
dielectric constant of 25 and chloroform has a dielectric
constant of 5.
• It is influenced by intermolecular and interatomic
attraction.
Dielectric Constant (ε)
Parallel plate condenser is used for understanding the
concept.
Condenser is one that can store electricity
Electricity in condenser (coulombs) α Potential diff (volt)

Electricity in condenser q = connstant x Potential diff, v

constant is Capacitance: C = q/v

The ratio of capacitance of test substance

(Cx) divided by the capacitance of
reference substance is termed as dielectric
constant.

ε = Cx/Co
Figure: Parallel Plate Condenser
Dielectric Constant (ε)
• Dielectric constant is a physicochemical property of a
solvent relating to the amount of energy required to
separate two oppositely charged regions in the solvent as
compared with the energy required to separate the same
in the vacuum.
Importance of Dielectric Constant (ε)
o Polarity of Solvent.
o Solubilisation of drug
 The higher the dielectric constant, the higher is the capacity to
dissolve polar substances. Water has a high dielectric constant and
can dissolve sodium chloride easily when compared with alcohol and
chloroform.
 Polar substances dissolve in liquids having high dielectric constant
values.
 Non – polar substances dissolve in liquids having low dielectric
constant values.
o Selection of solvent