Physical Properties of Drug Molecules
Contents of
This Chapter
• The liquid crystalline state, its properties and
significance
• Determination and applications of refractive index
• Determination and applications of dipole moment
• Determination and application of dissociation constant
• Determination and applications of optical rotation
• Determination and application of dielectric constant
Learning
Objectives
• At the end of this lecture, student will be able to
– Explain the concept of liquid crystalline state and
describe its properties and significance
– Explain the fundamental
principles of refraction
of electrons and neutrons
– Explain the relationships between atomic and molecular
forces and their response to electromagnetic energy
– Describe the fundamental principle of dissociation
constant
– Describe the
polarization of light beams and use of polarized light to study chiral
molecules
– Discuss the relationships between atomic and molecular
forces and their response to electromagnetic energy
Liquid
Crystalline State- Structure
• Liquid crystals (mesophase) are intermediate between the
liquid and solid state
• The two main types of liquid crystals are termed as:
– Sematic (soap like or grease like)
– Nematic (threadlike)
• In the sematic state molecules are mobile in two
directions and can rotate about one axis
• In the nematic state, the molecules again rotate only
about one axis but are mobile in three dimensions
• The sematic mesophase is of pharmaceutical significance
• This phase usually forms internary mixtures containing a
surfactant, water and a weakly amphiphilic or nonpolar additive
• Molecules that form mesophases are –
– Organic
– Elongated and rectilinear in shape
– Rigid
– Possesses strong dipoles and easily polarizable groups
Liquid
Crystalline State- Properties and Significance
• Because of their intermediate nature, liquid crystals have
some properties of liquids and some properties of solids
• Liquid crystals are mobile and can be considered to have
flow properties of liquids
• They exhibit birefringence where, the light passing
through a material is divided into two components with different velocities and
refractive index
• The sematic mesophase has application in the
solubilization of water insoluble materials
• Liquid crystalline phases are present in emulsions and responsible
for physical stability owing to their highly viscous nature
• The lipoidal forms of liquid crystalline state is found in
nerves, brain tissue and blood vessels
• Three components of bile (cholesterol, bile acid salt and
water) can form a sematic mesophase
• The principle of liquid crystal formation can be applied
to the solubilisation and dissolution of cholesterol
• Liquid crystals have structures that are similar to those
in cell membranes
Refractive
Index
• Light passes more slowly through a substance than through
vacuum
• When a ray passes from one medium to another it shows
refraction
• If light enters a denser substance at an angle, one part
of the wave slows down more quickly as it passes the interface
• This produces bending of the wave toward the interface,
this phenomenon is called refraction
• If the light enters a less dense substance, it is refracted
away from the interface
• 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
• The relative value of the effect of the refraction between
two substances is given by Snell’s law
• Snell’s law states that the refractive index (n) of the
liquid as a constant ratio of the sine of the angle of incidence to that of the
refraction
sin I velocity of light in the first
substance c1
n =——=
———————————————————– = ——-
sin r velocity of the light in the second substance c2
Where, sin i is the angle of the incident ray of light, sin
r is the sine of the
angle of the
refracted ray and
c1 and c2
are the speeds of the light in
the respective media
Refractive
Index- Factors Affecting
• Refractive index
varies with the wavelength of light and the temperature
• The refractive index decreases with increase in the wavelength
of light
• Refractive index of liquid decreases as the temperature
increases
• For measuring the refractive index of gases, pressure
should be held constant
Molar
Refraction
• Molar refraction Rm, is related to both the refractive
index and the molecular properties of a compound being tested
• Molar refraction is expressed by
Where, M is the molecular weight and ρ is the density of the
compound
Refractive
Index- Applications
• To identify a substance
• Measurement of purity of a substance
• Determination of concentration
• Determination of dielectric constant
• Determination of molar polarizability
• Determination of molar refraction
Refractive
Index- Determination
• Abbe’s refractometer is used to determine the refractive
index
Dipole
Moment
• Dipolar molecule is defined as the one in which the
regions of positive and negative charges are well separated
• The separation is due to uneven distribution of electrons
in the molecule
• The regions of positive and negative charges are balanced
• Examples of dipolar molecules are water, hydrochloric acid
etc.
• In water molecules, oxygen is an electronegative atom and
have a greater tendency draw the shared
pair of electrons towards it
• As a result hydrogen atom assumes positive charge
• Positive and negative centers are developed in the
molecule
• In a polar molecule, the separation of positively and
negatively charged regions are permanent and the molecule will possess a
permanent dipole moment, (μ)
Dipole
Moment- Mathematical treatment
• Dipole moment is defined as the vector equal in magnitude
to the product of electric charge and distance, having the direction of the
line joining the positive and negative centers
• Mathematically, dipole moment (μ) can be expressed as:
Dipole moment = distance X charge
μ = r X
e
SI units: cm meter X coulomb
• In CGS system the unit is debye
• 1 debye is equal to 10-18 electrostatic unit
(esu) cm or 3.34X 10-30 coulomb meter
• In an electric field, the molecules with permanent dipole moments
can also have induced dipole
• The total molar polarization, P, is the sum of induction
and permanent dipole effects:
Where P0 is the orientation polarization of the
permanent dipoles
Dipole
Moment- Applications
• Solubilisation of drugs
• Crystalline nature of solids
• Drug receptor interactions
• Therapeutic activity of the drugs
• Chemical structure of compounds
Dissociation
Constant
• About 75% of all drugs are weak bases and 20% are weak acids
• As drugs are weak electrolytes they undergo dissociation
• The degree to which drugs are ionized depends on the pH of
the solution
• The relationship between pH and drug ionization is useful
in predicting the following:
– Absorption of the drug from the site of application
– Distribution of drugs from blood into tissue and brain
– Elimination of drugs by liver and kidneys
– Estimation of solubility of drugs
– Attainment of optimum bioavailability
• The ionic equations of weak acids and bases exist in equilibrium
• Equilibrium is defined as a balance between two opposing
forces or actions
• At equilibrium, concentrations of products and reactants
remain equal
• Equilibrium is a dynamic process indicating the quality
between velocities of the forward and backward reactions
Dissociation
Constant- Ionization Constant of a Weak Acid
• The ionization of acetic acid is a reversible chemical
reaction and can be written as:
HAc + H2O <————-> H3O+ +Ac- ……….. (1)
• The equilibrium
rate constant K may be written as :
K= [H3O+ ] [Ac −]
…………..(2)
[HAc] [H2O]
• The square brackets represent the stoichiometric molar concentration
• In dilute solution, water is considered regarded as
constant
[H3O+] [Ac −]
Ka = K x constant =
———————– ……….(3)
[HAc]
• The new constant, K is denoted as ionization constant or dissociation
constant at a particular temperature
• Ka denotes the acid ionization constant
• The greater the dissociation constant of the acid, the
stronger is the acid
pKa = – log [Ka]………(4)
• The pKa is defined as the negative logarithm of acid
ionization constant
Dissociation
Constant- Ionization Constant of a Weak Base
• The ionization of ammonia (weak base) is a reversible chemical
reaction and is written as:
NH3 + H2O <———–> NH4+ + OH– ……..
(5)
• Applying the law of mass action to equation (5) gives base
ionization constant (Kb) as:
[NH4+] [OH−]
Kb =
——————– …… (6)
[NH3]
• The general expression for ionization of base B may be
written as:
[BH+] [OH−]
Kb = —————–
…………. (7)
[B−]
• The greater the dissociation constant of the base, the
stronger is the base
• pKb is defined as the negative logarithm of base
ionization constant and it is expressed by
pkb = -log [Kb]…………..(8)
Dissociation
Constant- Applications
• It is important in Hendersen-Hasselbalch equation to
calculate the extent of ionization
• The absorption of drug in GIT can be predicted
• The concentration of preservative required can be
predicted
• The pH of the solution can be calculated
• It can be used to obtain the maximal yields in the
extraction of drugs
Dissociation
Constant- Methods of Determination
• Ionization or dissociation constant can be determined by
the following methods:
– Conductivity method
– Solubility method
– Potentiometric method
– Spectrophotometric method
Optical
Rotation
• Ordinary light transmits its rays in all directions (all
planes)
• When light is allowed to pass through a polarizing prism
(Nicol prism), light vibrations in only one plane are transmitted
• Such a light beam is known as plane polarized light
• When certain substances are placed in the path of the
plane polarized light, its velocity may decrease or increase
• The change in velocity results in a corresponding change
in the rotation of plane polarized light through a certain angle called as
angle of rotation, α
• Optical activity is the ability of certain substances to
rotate the plane polarized light
• Optically active substances are the substances which can
rotate the plane polarized light either to right- side or to left- side
• When viewed through the path of beam, if the rotation of
plane polarized light takes place in clock-wise direction (towards right) it is
called Dextrorotatory
• If the rotation
of plane polarized
light takes place
in anti- clockwise direction
(towards left), then the rotation is called as Levorotatory
• A dextrorotatory substance produces an angle of rotation,
α, that is defined as positive
• 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
• Symmetric molecules (achiral) are optically inactive and
do not rotate the plane of polarized light
• Optical rotation, α, depends on density of an optically
active substance
• The specific rotation, at a specified temperature t and
wavelength λ is given by the equation
• Where l is the length in decimeters (dm) of the light path
through the sample
• g is the number of grams of optically active substance in
ν millilitre volume
Optical
Rotation- Applications
• For identification of substance
• Purity of a substance can be measured
• Concentration of a substance dissolved in a substance can
be determined
Optical
Rotation- Determination
• A polarimetry is used to measure optical activity
Dielectric
Constant
• Dielectric constant is a physical property that is
influenced by interatomic and intermolecular attractions
• It is a measure of efficiency of a substance to induce
dipoles in another molecule
• Condenser is one that can store electricity
• Condenser consists of two parallel plates separated by an
insulating medium
• Electricity that a condenser store is directly
proportional to the potential difference in volts applied across the plate
• Electricity in a condenser (coulombs) ∝
potential difference (volts)
Electricity in a condenser, q = constant x potential
difference, ν
• The constant is designated as capacitance and given as:
q
C = ——
ν
• Dielectric constant can be given as:
Cx
ε = ——-
C0
Where, ε is dielectric constant of liquid, Cx is capacitance of condenser in liquid and C0
is capacitance of condenser in vacuum
• 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 to the energy required to separate
the same in vacuum
• Dielectric constant is dimensionless because it is the ratio
of two capacitances
Dielectric
Constant in Nonpolar Compounds
• When nonpolar compounds are kept between the plates, an induced
polarization of the molecule occurs
• The induced dipole moment is proportional to the field
strength of the capacitor and the induced polarizability, αp
• The relationship can be represented as
n is the number of molecules per unit volume
Dielectric
Constant- Applications
• Measurement of polarity of a solvent
• Solubilisation of drugs
• Selection of solvents for the solubility of drugs
Summary
• Liquid crystals
(mesophase) – These are intermediate between the liquid and solid state
• The two main types of liquid crystals are termed as:
– Smectic (soap like or grease like)
– Nematic (threadlike)
• Because of their intermediate nature, liquid crystals have
some properties of liquids and some properties of solids
• Snell’s law –
Itstates that the refractive index (n) of the liquid as a constant ratio of the
sine of the angle of incidence to that of the refraction. It is given by
sin i
n = ———
sin r
• Molar refraction Rm
– Itis related to both the refractive index and the molecular properties of a
compound being tested. It is given by
• Dipolar molecule –
It is defined as the one in which the regions of positive and negative charges
are well separated
• Dipole moment-
It is defined as the vector equal in magnitude to
the product of electric charge and distance, having the direction of the line
joining the positive and negative centers
• In a polar molecule, the separation of positively and
negatively charged regions are permanent and the molecule will possess a
permanent dipole moment, μ
• Dipole moment is defined as the vector equal in magnitude
to the product of electric charge and distance, having the direction of the
line joining the positive and negative centers
• The greater the dissociation constant of the acid, the
stronger is the acid
pKa = – log [Ka]
• pKb is defined as the negative logarithm of base
ionization constant and it is expressed by
pkb = -log [Kb]
• Plane polarised
light- When light is allowed to pass through a polarizing prism (Nicol
prism), light vibrations in only one plane are transmitted, and such a light
beam is known as plane polarized light
• Optical activity –
It is the ability of certain substances to rotate the plane polarized light
• Optically active
substances – These are the substances which can rotate the plane polarized
light either to right- side or to left- side
• Dextrorotatory substances rotate the plane polarised light
towards the right, has an α, that is defined as positive
• Levorotatory substances rotate the plane polarised light towards
left, has an α, that is defined as negative
• Specific rotation –
The specific rotation, at a specified temperature t and
wavelength λ is given by the equation
• A polarimeter is used to measure optical rotation
• Dielectric constant
– It 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
to the energy required to separate the same in vacuum
• Dielectric constant can be given as:
Cx
ε = ——-
C0
• Dielectric constant is dimensionless
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