Physical properties of drug

molecules

Presented By
Prof. Salman Baig
AIKTC, School of Pharmacy,
New Panvel (India)
Physical properties of Drug Molecules
• The physical properties of substances can be classified as
• colligative,
• additive, and
• constitutive
Additive properties
• Additive properties depend on the total contribution of the atoms in
the molecules or on the sum of the properties of the constituents in a
solution.
• Example: Molecular weight (because it is the sum of the masses of
the constituent atoms)
• The total mass of the solution is the sum of the masses of the
individual components.
Colligative
• Colligative properties depend mainly on the number of particles in a
solution
• The colligative properties of solutions are osmotic pressure, vapor
pressure lowering, freezing point depression, and boiling point
elevation.
• The values of the colligative properties are approximately the same
for equal concentrations of different nonelectrolytes in solution
regardless of the species or chemical nature of the constituents.
• For non volatile solute colligative properties of solid-in-liquid
solutions may be vapor pressure.
Constitutive properties
• 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 the constitution of individual
compounds and groups of molecules in a system.
• 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.
Properties of solution
 Osmolality and osmolarity
• Osmolality and osmolarity are colligative properties that measure
the concentration of the solutes independently of their ability to
cross a cell membrane.
• The unit to express the amount of osmotically active substance in a
solution is the osmole or milliosmole:
𝟏 𝑶𝒔𝒎𝒐𝒍= 𝟏 𝒎𝒐𝒍 × 𝒏
Where 𝒏 is the number of species into which the solute is dissolved
1 Osmol = 103 mOsmol
Osmolarity is the number of osmoles of solute per L of solution
Osmolality is the number of osmoles of solute per kg of solvent
 Isosmotic Solutions
• Biological membranes do not always function as perfect
semipermeable membranes; some solutes also diffuse through
membrane
• These solutions are isosmotic but not isotonic
• These solutions have same osmolarity
 Isosmotic Solutions
• When two solutions are separated by a perfectly
semipermeable membrane and there is no net movement of
solvent molecules across the membrane, the solutions are
isosmotic (i.e. have equal osmotic pressure or osmolarity).

• Perfectly semipermeable membrane is permeable only to solvent

molecules.
 Isotonic Solutions
• When two isosmotic solutions contain solutes that can not cross the
biological membrane, they are described as isotonic with respect to that
membrane.
• Tonicity is the concentration of only that solutes which cannot cross the
membrane since these solutes exert an osmotic pressure on that
membrane.
• Isotonic solution is the
solution having the
same colligative like 0.9
g NaCI per 100 mL,
Methods to determine tonicity
• Hemolytic method
• Methods based on colligative property

-0.52°C is the freezing point of both human blood and lacrimal fluid.
This temperature corresponds to the freezing point of a 0.90% NaCI
solution, which is therefore considered to be isotonic with both blood
and lacrimal fluid
Liso Value
• Freezing point depression (𝜟𝑻𝒇) is directly proportional to
concentration of electrolyte (c)
• 𝜟𝑻𝒇 = Lc
• The Liso value for a 0.90% (0.154 M) solution of sodium chloride,
which has a freezing point depression of 0.52 °C which is thus isotonic
with body fluids, is 3.4
• Liso= 𝜟𝑻𝒇 /c
• Liso= 0.52/0.154
• Liso =3.4
Methods of Adjusting Tonicity
• In the Class I methods, sodium chloride or some other substance is
added to the solution of the drug to lower the freezing point of the
solution to -0.52 and thus make it isotonic with body fluids.
• Cryoscopic method (freezing point depression to -0.52 °C to make isotonic)
• Sodium Chloride Equivalent method.
• In the Class II methods, water is added to the drug in a sufficient
amount to form an isotonic solution. The preparation is then brought
to its final volume with an isotonic or a buffered isotonic dilution
solution.
• White-Vincent method
• Sprowls method
Methods of adjusting tonicity
• Cryoscopic Method: The freezing point depressions of a number of
drug solutions, determined experimentally or theoretically
• According to the previous section, the freezing point depressions of
drug solutions that have not been determined experimentally can be
estimated from theoretic considerations, knowing only the molecular
weight of the drug and the Liso value of the ionic class
Cryoscopic Method
• The freezing point depressions of number of drug solutions,
determined experimentally or theoretically.
• The freezing point depressions of drug solutions (that have not been
determined experimentally) can be estimated from theoretic
considerations, by knowing the molecular weight of the drug and the
Liso value of the ionic class.
 Methods of Adjusting Tonicity
Class I Method: NaCl Equivalent Method
In the NaCl equivalent method, sodium chloride or some other
substance is added to the solution of the drug to make the
concentration of the solution equivalent to 0.9% of NaCl and
thus make it isotonic with body fluids.
Sodium Chloride Equivalent Method
• The sodium chloride equivalent or, as referred to by these workers,
the "tonicic equivalent" of a drug is the amount of sodium chloride
that is equivalent to (i.e., has the same osmotic effect as) 1 gram, or
other weight unit, of the drug. The sodium chloride equivalents E, for
a number of drugs are listed in literature.
• E can be calculated from the Liso value or freezing point depression of
the drug according to the formulas derived by Goyan et al
Sodium Chloride Equivalent Method
• For a solution containing 1 g of drug in 1000 mL of solution, the
concentration c expressed in moles per liter may be written as

• C=1/M.W.

𝟏 gm
• ∆𝑻𝒇 = 𝑳𝒊𝒔𝒐
𝑴. 𝑾𝒕
𝑳𝒊𝒔𝒐
• E=17
𝑴. 𝑾𝒕
 Methods of Adjusting Tonicity

Class I Method: NaCl Equivalent Method

• The sodium chloride equivalent (E) of a drug is the amount of
sodium chloride that has the same osmotic effect of 1 g of the drug.
• E value can be obtained theoretically from Liso value and Molecular
weight of the drug

𝑳𝒊𝒔𝒐
𝑬 = 𝟏𝟕
𝑴. 𝑾𝒕
 Methods of Adjusting Tonicity
Class I Method: NaCl Equivalent Method
Example 1
Calculate the approximate E value for ephedrine sulfate (M.Wt
=428.54) (Liso = 5.8)

𝑳𝒊𝒔𝒐
𝑬 = 𝟏𝟕
𝑴. 𝑾𝒕

5.8
𝑬 = 17 × = 0.23
428.54
 Methods of Adjusting Tonicity
Class I Method: NaCl Equivalent Method
Example 2
A solution contains 1.0 g of ephedrine sulfate in a volume of 100 mL. What
quantity of sodium chloride must be added to make the solution isotonic?
E value for the drug is 0.23
The quantity of the drug is multiplied by its NaCl equivalent, E : Ephedrine
sulfate: 1 g × 0.23 = 0.23 g
The ephedrine sulfate has contributed a weight of material osmotically
equivalent to 0.23 g of NaCl.
Because a total of 0.9 g of NaCl is required for isotonicity, 0.67 g (0.90 - 0.23
g) of NaCl must be added.
 Methods of Adjusting Tonicity
White-Vincent Method
• The Class II methods of computing tonicity involve
• 1. Addition of water to the drugs to make an isotonic solution
• 2. The addition of an isotonic or isotonic-buffered diluting vehicle to
bring the solution to the final volume.
• Stimulated by the need to adjust the pH in addition to the tonicity of
ophthalmic solutions, White and Vincent“ developed a simplified
method for such calculations.
 Class II Method: White-Vincent Method

White and Vincent developed a simplified equation for calculating the

volume V (mL) of isotonic solution prepared by mixing the drug with
water.
𝑽 = 𝒘 × 𝑬 × 𝟏𝟏𝟏. 𝟏
V : w : weight (g) of the drug.
E : NaCl equivalent
 Methods of Adjusting Tonicity
Class II Method: White-Vincent Method
Example 1
How to make 30 mL of a 1% solution of procaine HCl isotonic with body fluid?
NaCl equivalent for procaine HCl is 0.21
Weight of the drug = 30 × 1% = 0.3 g
0.3×0.21=0.063 gm
0.063 gm NaCl ≈ 0.3gm drug
0.9/100 = 0.063/ 𝑽
𝑽=(0.063) × (0.9/100)
𝑽 = 𝒘 × 𝑬 × 𝟏𝟏𝟏. 𝟏
𝑽 = 0.3 × 0.21 × 111.1 = 7 ml
7 ml of water is added to the drug to make it isotonic, then enough isotonic
diluting solution is added to make 30 mL of the finished product.
 Class II Method: White-Vincent Method
Example 2
Make the following solution isotonic with body fluid:
Phenacaine HCl……………….….0.06 g
Boric acid…………………….……0.30 g
Distilled Water (q.s.) ………………100 ml
(E for Phenacaine HCl and Boric acid are 0.2 and 0.5 respectively)
𝑽 = 𝒘 × 𝑬 × 𝟏𝟏𝟏. 𝟏
𝑽Phenacaine HCL = 0.06 × 0.20 × 111.1 = 1.33 ml
𝑽Boric acid = 0.3 × 0.5 × 111.1 = 16.66 ml
𝑽Total = 1.33 + 16.66 = 18 ml
The drugs are mixed with water to make 18 mL of an isotonic solution, and
the volume of the preparation is completed to 100 mL by adding an
isotonic diluting solution.
 Methods of Adjusting Tonicity
Class II Method: Sprowls Method
Sprowls method is a simplification of White-Vincent Method in
which V values for drugs of fixed weights (0.3 g) are
calculated and constructed as a table.
 Dipole moment
• If nonpolar molecules are placed between the plates of a charged capacitor in a
suitable solvent, an induced polarization of the molecules can occur.
• This induced dipole occurs because of the separation of electric charge within the
molecule when it is placed in the electric field between the plates.
• The electrons and nuclei are displaced from their original positions in this
induction process.
• This temporary induced dipole moment is proportional to the field strength of
capacitor and the induced polarizability αp which is a characteristic property of
the molecule.
• Polarizability is defined as the ease with which an ion or molecule can be
polarized by any external force, whether it be an electric field or light energy
• Large-size anions have large polarizabilities because of their loosely held outer
electrons
Animation showing the electric field of an electric
dipole. The dipole consists of two point electric
charges of opposite polarity located close together
 Dipole moment
• In a polar molecule, the separation of positively and negatively charged regions
can be permanent, and the molecule will possess a permanent dipole moment,
µ.
• The polar molecule (water), however, tends to orient itself with its negatively
charged centers closest to positively charged centers on other molecules before
the electric field is applied, so that when the applied field is present, the
orientation is in the direction of the field.
• Permanent dipole moments can be correlated with biologic activities of certain
molecules to obtain valuable information about the relationship of physical
properties and charge separation in a class of compounds.
• For example, the insecticidal activity of the three isomers of DDT, shown in the
following structures, can be associated with their permanent dipole moments.
This may be due to the fact that greater solubility in a nonpolar solvent may be
related to a small dipole moment for a solute.
• The more soluble molecule most readily penetrates the lipoidal membranes of
the insect and attacks the enzymes of the insect's nervous system. Hence, the
lower the dipole moment of the isomer, the greater its insecticidal action.
Permanent vs Induced Dipole
• Consider two parallel conducting plates, Dielectric constant
such as the plates of an electric condenser,
which are separated by some medium Condenser
across a distance r
• Electricity will flow from one plate to other
through the battery until the potential
difference of the plates equals the potential
difference the voltage source.
• The capacitance, C (in farads), is equal to
the quantity of electric charge, q (in
coulombs), stored on the plates, divided by
the potential difference, V (in volts),
between the plates:
• C = qlV
 Dielectric constant
• When a vacuum fills the space between the plates, the
capacitance is Co hence the dielectric constant of a vacuum is
unity.
• The capacitance of the condenser filled with some material, Cx,
divided by the reference standard Co, is referred to as the
dielectric constant,
• e= Cx/Co
• The dielectric constant has no dimensions, since it is the ratio of
two capacitances
• The liquid whose dielectric constant is being measured is placed
in a glass container between the two plates during the
experiment
Permanent vs Induced Dipole
 Refractive index and Snell’s formula
• When the light passes the denser
medium, a part of the wave slows
down more quickly as it is passes
through interface which makes it to
bend toward the interface, this
phenomena is called as refraction.
• Consider the incident light is in
medium one and the refracted light
is in medium two if incident light is in
vacuum then this value is called the
absolute refractive index of medium
two.
Molar refraction, Rm
• The molar refraction, Rm , is related to both the refractive index and the
molecular properties of a compound being tested. Each constituent atom
or group contributes a portion to the final R. because it is additive-
constitutive property.
• For example, acetone has an Rm produced from three carbons (Rm =
7.254), six hydrogens (6.6), and a carbonyl oxygen (2.21) to give a total Rm.
of 16.1 cm3/mol.
• Because Rm is independent of the physical state of the molecule, this value
can often be used to distinguish between structurally different compounds,
such as keto and enol tautomers
M is the molecular weight
ρ is the density of the compound.
Abbe’s refractometer
• Abbé refractometer working principle is based on critical angle.
• Sample is kept between two prisms ‘measuring’ and ‘illuminating’.
• Light enters sample from the illuminating prism, gets refracted at
critical angle at the bottom surface of measuring prism
• Then the telescope is used to measure position of the border
between bright and light areas.
• Readings could be noted using adjacent eyepiece to view scale
Abbe’s refractometer
 Application of RI and Abbe’s refractometer
• It gives valuable information about the characteristics, purity and
composition of the substance.
• For determination of sugar concentration and alcohol content in bio
production and fermentation are carried out by refractometer.
• Refer to meters are used in controlling the analysis of commercial
products and in identifying unknown substances.
Optical rotation
• Ordinary light consist of different wavelengths which vibrate evenly
distributed in all direction in a plane perpendicular to the direction of
propagation. This light is called as unpolarised light.
• When the vibration of the light are restricted only to a single plane, the
light is said to be polarized light.
• Polarized light from monochromatic light source is called Plane Polarized
Light (PPL)
• The substances which rotate the plane of plane polarized light, are called
optically active substance and this property of rotation of plane polarized
light is called as optical activity .
• The substance which rotates the plane of polarized light to right are called
dextro rotatory and those which rotate it to left are called as levorotatory
• Angle through which PPl is rotated is angle of rotation (ϴ)
Optical rotation
Specific (optical) rotation
• When polarized light passes through an optically active substance, all
molecule in the path of light rotate the plane of polarization by a
constant amount, which is characteristic for the substance.
• The observed rotation, α in the emergent beam is proportional to the
path length, L and concentration of the substance, c.
• Specific rotation
• [α]Tλ = α /cL
• [α]20D