1. Physicochemical Properties
of Drug Molecule
Mahakal Institute of
Pharmaceutical Studies, Ujjain
Subject: Physical Pharmacy-I
Unit II Part II
2. The molecular structure of the compound uniquely defines all its physical, chemical and
biological properties. It is generally recognized that physicochemical properties play an
important role in product development including studies on biological performance of
drugs. A study of the physical properties of drug molecules is a prerequisite for product
preformulation, formulation development and optimizing storage and usage conditions. It
often leads to a better understanding of the relationship between molecular structure and
drug action. The most important physical properties related to product formulation and
biological performance is summarized below:
Physical properties of substances may be classified in to three types;
(i) Additive Properties: Additive properties are derived from sum of the properties of
individual properties of atoms or functional groups present within the molecule. The
examples of this type are mass or molecular weight, volume etc.
(ii) Constitutive Properties: These properties are depending on the structural arrangement
of atoms and functional groups as well as bond structure that exists within the molecules.
The examples of this type are optical activity, surface tension, viscosity etc.
(iii) Colligative Properties: Colligative properties are defined as the properties which
depend upon the total number of non-volatile solute particles present in the solution. Dilute
solutions which contain negligibly small amount of non-volatile solute exhibit colligative
properties. The examples of these properties are lowering of vapour pressure, freezing
point depression, boiling point elevation and osmotic pressure. These properties are used
to determine molecular weights of compounds.
5. Light passes more slowly through a substance than through a vacuum. As light
enters a denser substance, the advancing waves interact with the atoms in the
substance at the interface and throughout the thickness of the substance. These
interactions modify the light waves by absorbing energy, resulting in the waves
being closer together by reducing the speed and shortening the wavelength. If the
light enters the denser substance at an angle, one part of the wave slows down
more quickly as it passes the interface, and this produces a bending of the wave
toward the interface. This phenomenon is called refraction. The relative value of
the effect of refraction between two substances is given by the refractive index.
Refractive index is determined by using instrument called refractometer. Abbes
refractometer, immersion refractometer and Pulfrich refractometer are used for this
purpose. Abbes refractometer is commonly used at laboratory scale because of its
advantages over other refractometers. It is most convenient, reliable and simple
instrument with small sample size requirement suitable for range of substances. Ordinary
light source, easy maintenance and economy and easy determinations are some of the
other advantages of this instrument. The components of Abbes refractometers include
light reflection mirror, dispersion compensator, telescope, and index arm and prism box.
• Refractive index is a fundamental physical property of a substance
• It is often used to analyze and identify a particular substance, confirm its
purity, or measure its concentration.
• Refractive index 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.
• Most commonly it is used to measure the concentration of a solute in an
aqueous solution. For a solution of sugar, the refractive index can be
used to determine the sugar content. Similarly alcohol content in
bioproduction is also determined from the refractometry.
• Dielectric constant and molar polarizibility values can be obtained from
the refractive index.
• Refractive index of a material is the most important property of any optical
system that uses refraction for example, lenses and prisms.
10. When a monochromatic polarized beam of light is passed
through a solution of a substance in the plane of the
polarized light is turned through a certain angle, such
substance is said to be optical active and the phenomenon is
called as optical activity.
The velocity of plane polarized light can become
slower or faster as it passes through a sample, similar to
refraction. This change in velocity results in refraction of
the polarized light in a particular direction for an optically
active substance. A clockwise rotation in the planar light, as
observed looking into the beam of polarized light, defines a
substance as dextrorotatory. When the plane of light is
rotated by the sample in a counterclockwise manner, the
sample is defined as a levorotatory substance. A
dextrorotatory substance, produces an angle of rotation, α,
that is defined as positive, whereas the levorotatory
substance, which rotates the beam to the left, has an α that
is defined as negative. Molecules that have an asymmetric
center (chiral) and therefore lack symmetry about a single
plane are optically active, whereas symmetric molecules
(achiral) are optically inactive and consequently do not
rotate the plane of polarized light.
11. Specific rotation: Specific rotation is the angle of rotation of the plane of
polarised light caused by 1 decimeter columns of solution containing 1
gram of the substance per cubic centimeter.
The relation of optical rotation, α, and specific rotation, [α]T
λ , is summarized
by Biot’s law:
Measurement of orientation of plane polarized light is called polarimetry, and the
instrument used is called a polarimeter. The simplest polarimeter, consists of
monochromatic light source, a polarizer, a sample cell, a second polarizer which is called
the analyzer and a light detector. Polariser and analyzer are made up of Nicol prisms.
When analyzer is oriented 90° to the polarizer no light reaches to the detector. When an
optically active substance is placed in the sample cell and beam of light is passed
through, it rotates the polarization of the light reaching the analyzer so that there is a
component that reaches the detector. The angle that the analyzer must be rotated from the
original position is the optical rotation.
• Specific rotation can be used to evaluate and characterize optically active compounds.
• It is used to investigate kinetic reactions by measuring optical rotation as a function of
• It can be used to monitor changes in concentration of an optically active component in
a reaction mixture as in enzymatic cleavage.
• It can analyze molecular structure by plotting optical rotator dispersion curves over
wide range of wavelengths.
• It can be used to distinguish between optical isomers
Quality and process control applications: Specific rotation in quality and process
control both in laboratory or on-line in the factory for compound like pharmaceuticals,
essential oils, flavors, food and chemicals. Few examples are listed below: t
• Pharmaceuticals: Amino acid, antibiotics, dextrose, steroids, amino sugars, cocaine,
• Flavors and essential oils: orange oil, lavender oil, spearmint oil, lemon oil, camphor,
• Food products: carbohydrates, lactose, raffinose, fructose, levulose, sucrose, glucose,
maltose, xylose, natural monosaccharides etc.
• Chemicals: Biopolymers, Natural polymers, synthetic polymers etc.
15. Dielectric constant is defined as the ratio of the energy to separate two opposite
charges in presence of solvent to vacuum.
Let us consider a salt sodium chloride comprised of sodium ion (positive ion) and the
chloride ion (negative ion). If this salt is placed in the water, the positive ion and the
negative ion will be separated by the energy (solvent effect) of water. Similarly, the
same salt is placed in vacuum to separate the opposite charges. The relative energy
required to separate the charges is measured. The dielectric constant of water is 78.5.
According to above discussion, it can be said that water has 78.5 times more capacity to
separate the sodium and chloride ions under the same conditions in vacuum. The ratio
of first conductance to second conductance gives dielectric constant of the material.
Dielectric constant is the property of solvent. It affects the solubility of the drugs. Water
being polar substance may affect the solubility of polar or non polar drugs. As the
dielectric constant value of solvent increases, it has more capacity to dissolve the polar
drugs. Each drug has highest solubility in a solvent of a particular dielectric constant.
The parallel plates are separated by some medium across a distance r and connected to
voltage supply source. The electricity will flow across the plates from left to right through the
battery until potential difference of the plates equals that of the battery which is supplying the
initial potential difference. The capacitance, C, is equal to the amount of electric charge, q,
stored on the plates, divided by V, the potential difference, between the plates.
The Co is used as capacitance reference medium on which to compare other mediums. The Co
is the capacitance between the plates when a vacuum fills the space between the plates. The
ratio of capacitance of test material (Cm) divided by the capacitance
of reference material is termed as dielectric constant.
1. The ease of solution of salt soluble like water & glycerin explain based
on high dielectric constant.
2. More polar is the solvent higher the dielectric constant.
3. Dielectric constants are related dipole-dipole interactions and full
induced dipole-dipole interaction.
4. Solvents with large dipole moment will have large dielectric constant.
5. As the temperature increases the dielectric constant of dipolar solvent
will tend to decrease.
20. Dipole is a pair of separated opposite electric charges. Electric dipole is an assemblage of
atoms or subatomic particles having equal electric charges of opposite sign separated by a
finite distance. Dipoles are characterized by their dipole moment, a vector quantity with a
magnitude equal to the product of charge or magnetic strength of one of the poles and the
distance separating the two poles.
μ = q × r
where, μ is dipole moment, q is charge on atom and r is distance of separation of charge. The
direction of the dipole moment corresponds for electric dipoles, to the direction from the
negative to the positive charge. The direction of an electric field is defined as the direction of
the force on a positive charge, electric field lines away from a positive charge and toward a
Molecular Dipoles: Many molecules have dipole moments due to non-uniform distributions
of positive and negative charges on its various atoms. In the case of HCl, the bonding
electron pair is not shared equally rather is attracted towards the more electronegative
chlorine atom due to its higher electro-negativity which pulls the electrons towards it. It
leads to development of positive charge to H atom and negative charge to chlorine atom. A
molecule having positive and negative charges at either terminal is referred as electric
dipoles or just dipole. Dipole moments are often stated in Debyes; The SI unit is the
21. Molecular dipoles are of three types:
Permanent dipoles: These occur when two atoms
in a molecule have substantially different electro-
negativity with one atom attracting electrons more
than another becoming more electronegative, while
other atom becomes more electropositive.
Instantaneous dipoles: These occur due to chance
when electrons happen to be more concentrated in
one place than another in a molecule, creating a
Induced dipole: These occur when one molecule
with a permanent dipole repels another molecule’s
electrons, inducing a dipole moment in that
• The structure of the molecule can be confirmed from the dipole moment values,
for example, chlorobenzene, benzene, carbon dioxide etc.
• The cis and trans isomers can be differentiated form dipole moment values, for
example, cis and trans dichloroethylene.
• Dipole moments can be used to determine percent ionic characteristic of bond of
the molecule, e.g. H-Cl a covalent bond, ionic characteristic is 17%.
• Permanent dipole moments can be correlated with the biological activities to
obtain information about the physical parameters of molecules.
• The more soluble the molecule the easier it passes the lipoidal membrane of
insects and attacks the insect’s nervous system. Therefore, the lower is the dipole
moment the greater is the insecticidal action.
• For example, p, m and o isomers of DDT show different insecticidal activities due
to their differences in permanent dipole moment as p- isomer shows µ=1.1 and has
predominant toxicity, o-isomer shows µ = 1.5 with intermediate toxicity while m-
isomer shows µ = 1.9 with least toxicity. The variations in activities of different
isomers are due to the greater solubilities in non-polar solvents.
24. Dissociation is the process by which a chemical compound breaks-up into simpler
constituents as a result of either added energy (dissociation by heat), or the effect of a
solvent on a dissolved polar compound (electrolytic dissociation). It may occur in the
gaseous, solid, or liquid state, or in solution.
Dissociation constant is a constant whose numerical value depends on the equilibrium
between the undissociated and dissociated forms of a molecule. A higher value indicates
greater dissociation. The equilibrium constant of such a dissociation is called the acid
dissociation constant or acidity constant, given by
Dissociation constant are related to physiological and pharmaceutical activities, solubility,
rate of the solution, side of binding (protein binding) and rate absorption of the drug.
Example: Rate and extent absorption of weakly acidic drugs take place from the stomach
region as the amount of unionized drug available is more from stomach. Similarly the
absorption of the weak bases is better from the intestine