SOLUBILITY OF DRUGS

Prepared by:
Dr. Lalit Kumar Tyagi
Prof. & Principal

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 WHAT IS PHYSICAL PHARMACEUTICS (PHYSICAL PHARMACY)?

• Physical pharmaceutics is a pharmaceutical material

science that is concerned with the physical and
chemicals principals of materials that go into the
formulation of dosage form.
• Physical pharmaceutics introduces the physico-chemical
principals of the drugs and formulations and their
importance in designing efficient dosage form.
• Physical pharmaceutics is the study of the physical and
chemical properties of drugs and their dosage form.

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 OBJECTIVES OF PHYSICAL PHARMACEUTICS (PHYSICAL PHARMACY)

 Upon the completion of the course, student shall be

able to:
1. Understand various physicochemical properties of drug
molecules in the designing the dosage forms.
2. Know the principles of chemical kinetics & to use them
for stability testing and determination of expiry date of
formulations.
3. Demonstrate use of physicochemical properties in the
formulation development and evaluation of dosage forms.

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 SYLLABUS OF PHYSICAL PHARMACEUTICS (BP302T)
Unit-I
• Solubility of drugs: Solubility expressions, mechanisms of solute solvent
interactions, ideal solubility parameters, solvation & association, quantitative
approach to the factors influencing solubility of drugs, diffusion principles in
biological systems. Solubility of gas in liquids, solubility of liquids in liquids, (Binary
solutions, ideal solutions) Raoult’s law, real solutions. Partially miscible liquids,
Critical solution temperature and applications. Distribution law, its limitations and
applications.
Unit-II
• States of Matter and properties of matter: State of matter, changes in the state of
matter, latent heats, vapor pressure, sublimation critical point, eutectic mixtures,
gases, aerosols – inhalers, relative humidity, liquid complexes, liquid crystals, glassy
states, solid-crystalline, amorphous & polymorphism.
• Physicochemical properties of drug molecules: Refractive index, optical rotation,
dielectric constant, dipole moment, dissociation constant, determinations and
applications.

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 SYLLABUS OF PHYSICAL PHARMACEUTICS (BP302T)
Unit-III
• Surface and interfacial phenomenon: Liquid interface, surface & interfacial
tensions, surface free energy, measurement of surface & interfacial tensions,
spreading coefficient, adsorption at liquid interfaces, surface active.
Unit-IV
• Complexation and protein binding: Introduction, Classification of
Complexation, Applications, methods of analysis, protein binding,
Complexation and drug action, crystalline structures of complexes and
thermodynamic treatment of stability constants.
Unit-V
• pH, buffers and Isotonic solutions: Sorensen’s pH scale, pH determination
(electrometric and calorimetric), applications of buffers, buffer equation, buffer
capacity, buffers in pharmaceutical and biological systems, buffered isotonic
solutions.
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 SOLUBILITY OF DRUGS

Solubility is defined as the

Quantitative
concentration of solute in a saturated
Terms
solution at a certain temperature
Solubility
Solubility is defined as the
Qualitative spontaneous interaction of two or
Terms more substances to form a
homogeneous molecular dispersion

Objectives of the Solubility Chapter:

After completion of this chapter, the student should be able to:
1. Understand the various types of pharmaceutical solutions.
2. Define solubility, saturated & unsaturated solutions and polar & non polar
solvents.
3. Understand the factors controlling the solubility of strong & weak electrolytes.

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 SOLUBILITY OF DRUGS
TERMS:
• Solution: is a mixture of two or more components that form a homogenous mixture.
The components are referred to the solute and/or solutes & the solvent and/or
solvents.
• Solute: is the dissolved agent (less abundant part of the solution).
• Solvent : is the component in which the solute is dissolved (more abundant part of
the solution)
• A saturated solution: is one in which an equilibrium is established between dissolved
and undissolved solute at a definite temperature. Or A solution that contains the
maximum amount of solute at a definite temperature
• An unsaturated solution: or subsaturated solution is one containing the dissolved
solute in a concentration below that necessary for complete saturation at a definite
temperature.
• A supersaturated solution: contains more of the dissolved solute than it would
normally contain in a saturated state at a definite temperature.

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 DEGREE OF SATURATION

• Unsaturated, Saturated
or Supersaturated?

• How much solute can

be dissolved in a
solution?

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 IMPORTANCE OF THE PHENOMENON OF SOLUBILITY

Understanding the phenomenon of solubility helps the

pharmacist to:
1. Select the best solvent for a drug or a mixture of drugs.
2. Overcome problems arising during preparation of pharmaceutical
solutions.
3. Have information about the structure and intermolecular forces of
the drug.
4. Many drugs are formulated as solutions, or added as powder or
solution forms to liquids.
5. Drugs with low aqueous solubility often present problems related to
their formulation and bioavailability.

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 ADVANTAGES OF SOLUBILITY OF DRUGS
1. Increased bioavailability 2. Fast absorption
3. Patient compliance 3. No shaking

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 BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS)

• BCS is a scientific framework for

classifying drug substances
according to their aqueous solubility
and their intestinal permeability.
• BCS is a system to differentiate the
drugs on the basis of their solubility
and permeability.
• This system restricts the prediction
using the parameters solubility and
intestinal permeability.

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 SOLUBILITY EXPRESSIONS
The solubility of a drug may be expressed in a number of ways:
1. USP and National Formulary:
 List the solubility of drugs as Number of Parts of solvents required to dissolve one part of drug.
 The number of ml of solvent in which 1g of solute will dissolve.
 Substances whose solubility values are not known are described by the following terms:

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 SOLUBILITY EXPRESSIONS
2. Quantitative Terms:
In scientific and pharmaceutical field, solubility can be expressed as
following terms:

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 TYPES OF SOLUTION

Solid
Solution
SOLUTION

Liquid
Solution

Gaseous
Solution

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 MECHANISM OF SOLUBILITY

• Thermodynamic Solubility of Drugs:

• The thermodynamic solubility of a drug in a solvent is the maximum
amount of the most stable crystalline form that remains in solution in
a given volume of the solvent at a given temperature and pressure
under equilibrium conditions.

• The equilibrium involves a balance of the energy of three

interactions against each other:
(1) Solvent with solvent
(2) Solute with solute
(3) Solvent and solute

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 MECHANISM OF SOLUBILITY

• Process of
Solubilization:
• Steps of solid going into
solution.
Step-1: Holes open in the solvent
Step-2: Molecules of the solid breaks away
from the bulk
Step-3: The solid molecules is enter into
the hole in the solvent

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 MECHANISM OF SOLUBILITY

• Process of Solubilization:
• A mechanistic perspective of solubilization process for organic solute
in water involves the following steps:

1. Break up of solute-solute intermolecular bonds

2. Break up of solvent-solvent intermolecular bonds
3. Formation of cavity in solvent phase large enough to accommodate
solute molecule
4. Transfer of solute into the cavity of solvent phase
5. Formation of solute-solvent intermolecular bonds

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 MECHANISM OF SOLUBILITY

• Process of Solubilization:
• Three types of interaction in the solution process
1. Solvent-solvent interaction 2. Solute-solute interaction 3. Solvent-solute interaction

ΔHsol = ΔH1 + ΔH2 + ΔH3

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 MECHANISM OF SOLUBILITY

• Process of Solubilization:
• Enthalpy:
• The enthalpy change of solution refers to the overall amount of
heat which is released or absorbed during the dissolving process
(at constant pressure).
• The enthalpy of solution can either be positive (endothermic
reaction) or negative (exothermic reaction).
• The enthalpy of solution is commonly referred to as ΔH solution.

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 MECHANISM OF SOLUBILITY

• Solvent-Solute Interactions
• In pre- or early formulation, selection of the most suitable solvent is based on
the principle of

“like dissolves like”

• That is, a solute dissolves best in a solvent with similar chemical properties. Or
two substances with similar intermolecular forces are likely to be soluble in
each others

• Polar solutes dissolve in polar solvents. E.g salts & sugar dissolve in water.
• Non-polar solutes dissolve in non=polar solvents. Eg. Naphthalene dissolves
in benzene.

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 MECHANISM OF SOLUBILITY

• Solvent-Solute Interactions
• If the solvent is A & the solute is B, and the forces of attraction are represented
by:
• A-A, B-B and A-B,
• One of the following conditions will occur:
1. If A-A >> A-B: The solvent molecules will be attracted to each other & the
solute will be excluded. Example: Benzene & water, where benzene molecules are
unable to penetrate the closely bound water aggregates.
2. If B-B >> A-A; The solvent will not be able to break the binding forces between
solute molecules. Example NaCl in benzene, where the NaCl crystal is held by
strong electrovalent forces which cannot be broken by benzene.
3. If A-B >> A-A or B-B, or the three forces are equal: The solute will . Form a
solution. Example: NaCl in water.

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 CLASSIFICATION OF SOLVENTS & THEIR MECHANISM OF ACTION:

Solvent

Polar Non-polar Semi polar

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 CLASSIFICATION OF SOLVENTS & THEIR MECHANISM OF ACTION:

• POLAR SOLVENTS:
• The solubility of a drug is due in large measure to the polarity of the solvent, that is,
to its dipole moment.
• Polar solvents dissolve ionic solutes and other polar substances.
• The ability of the solute to form hydrogen bonds is a far more significant factor than
is the polarity as reflected in a high dipole moment
• Water dissolves phenols, alcohols and other oxygen & nitrogen containing
compounds that can form hydrogen bonds with water.

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 CLASSIFICATION OF SOLVENTS & THEIR MECHANISM OF ACTION:

• POLAR SOLVENTS:
• The solubility of a substance also depends on structural features
such as the ratio of the polar to the nonpolar groups of the
molecule.
• As the length of a nonpolar chain of an aliphatic alcohol
increases, the solubility of the compound in water decreases.
• Straight-chain monohydroxy alcohols, aldehydes, ketones, and
acids with more than four or five carbons cannot enter into the
hydrogen bonded structure of water and hence are only slightly
soluble.

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 CLASSIFICATION OF SOLVENTS & THEIR MECHANISM OF ACTION:

• POLAR SOLVENTS:
• When additional polar groups are present in the molecule, as found in propylene glycol, glycerin,
and tartaric acid, water solubility increases greatly.

• Branching of the carbon chain reduces the nonpolar effect and leads to increased water solubility.
• E. g.: Tertiary butyl alcohol is miscible in all proportions with water, whereas n-butyl alcohol
dissolves to the extent of about 8 g/100 mL of water at 20°C.

Tertiary-Butanol n-Butanol

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 CLASSIFICATION OF SOLVENTS & THEIR MECHANISM OF ACTION:

• POLAR SOLVENTS:
• Hydrogen bonding is the
attractive interaction of a
hydrogen atom with an
electronegative atom, such
as nitrogen, oxygen.
• Dipole-dipole forces are
electrostatic interactions
of permanent dipoles in
molecules.

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 CLASSIFICATION OF SOLVENTS & THEIR MECHANISM OF ACTION:

• NON-POLAR SOLVENTS:
• Non-polar solvents are unable to reduce the attraction between the ions
of strong and weak electrolytes because of the solvents' low dielectric
constants.
• They are unable to form hydrogen bonds with non-electrolytes.
• Non-polar solvents can dissolve non-polar solutes through weak van der
Waals forces
• Example: solutions of oils & fats in carbon tetrachloride or benzene.

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 CLASSIFICATION OF SOLVENTS & THEIR MECHANISM OF ACTION:

• SEMI POLAR SOLVENTS:

• Semi polar solvents, such as ketones can induce a certain
degree of polarity in non-polar solvent molecules. For example,
benzene, which is readily polarizable, becomes soluble in alcohol
• They can act as intermediate solvents to bring about miscibility of
polar & non-polar liquids.
Example: Acetone increases solubility of ether in water.
Propylene glycol has been shown to increase the mutual
solubility of water and peppermint oil and of water and benzyl
benzoate

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 POLARITY AS DIELECTRIC CONSTANT OF SOLVENT (ε)

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 POLARITY

• The solubility of the drug substance is attributable in large part to the

polarity of the solvent, often expressed in terms of dipole moment, related
to the dielectric constant.
• Solvents with high dielectric constants dissolve ionic compounds (polar
drugs) readily because of ion–dipole interactions,
• Solvents with low dielectric constants dissolve hydrophobic substances
(non-polar drugs)
• Polar solvents such as water and glycerin
• Non-polar solvents such as oils
• Solvents with intermediate dielectric constants are classified as
semipolar
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 FACTORS INFLUENCING THE SOLUBILITY OF DRUGS
1- Particle size (surface area) of drug particles:
↓Particle size → ↑ surface area→ ↑Solubility

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 FACTORS INFLUENCING THE SOLUBILITY OF DRUGS

2- Molecular Size:
• Molecular size will affect the solubility.
• Larger the molecule or higher molecular weight- Solubility.
• Larger molecules are more difficult to surround with solvent
molecules in order to solvate the substance.
• In the case of organic compounds, the amount of carbon
branching will increase the solubility since more branching will
reduce the size (or volume) of the molecule and make it easier to
solvate the molecules with solvent.

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 FACTORS INFLUENCING THE SOLUBILITY OF DRUGS

3- Boiling Point of Liquids and Melting Point of Solids:

• Both reflect the strengths of interactions between the molecules in the
pure liquid or the solid state.
• In general, aqueous solubility decreases with increasing boiling point and
melting point.

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 FACTORS INFLUENCING THE SOLUBILITY OF DRUGS

4- Influence of Substituents:
• Influence of substituents on the solubility of molecules in water can be due
to their effect on the properties of the solid or liquid.
• Substituents can be classified as either hydrophobic or hydrophilic,
depending on their polarity.
Substituents

Hydrophobic

Hydrophillic

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 FACTORS INFLUENCING THE SOLUBILITY OF DRUGS

• Polar groups such as –OH capable of hydrogen

bonding with water molecules impart high
solubility.
• Non-polar groups such as –CH3 and –Cl are
hydrophobic and impart low solubility.
• Ionization of the substituent increases solubility,
e.g. –COOH and –NH2 are slightly hydrophilic
whereas –COO– and –NH3 are very hydrophilic.

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 FACTORS INFLUENCING THE SOLUBILITY OF DRUGS

5-Temperature:
• Temperature will affect solubility. If the solution process absorbs
energy then the solubility will be increased as the temperature is
increased.
• If the solution process releases energy then the solubility will decrease
with increasing temperature.
• Generally, an increase in the temperature of the solution increases the
solubility of a solid solute.
• A few solid solutes are less soluble in warm solutions.
• For all gases, solubility decreases as the temperature of the solution
increases.
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 FACTORS INFLUENCING THE SOLUBILITY OF DRUGS

6-Crystal properties:
• Polymorphic Crystals, Solvates, Amorphous forms
• Polymorphs have the same chemical structure but
different physical properties such as: solubility,
density, hardness, and compression characteristics
• A drug that exists as an amorphous form (non
crystalline form) generally dissolves more rapidly than
the same drug in crystalline form.

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 FACTORS INFLUENCING THE SOLUBILITY OF DRUGS

7- pH:
• pH is one of the important factor influences the solubility of
most drugs that contain ionizable groups.
• Large number of drugs are weak acid or weak base.
• Solubility depends on the degree of ionization.
• Degree of ionization depends on the pH.
About 85% of marketed drugs contain functional groups that
are ionised to some extent at physiological pH (pH 1.5 – 8).

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 IONIZATION AND pH
Strong vs. weak acids and bases
1. Strong – ionized at all pHs
2. Weak – only ionized at certain pHs (most drugs are weak acids or
weak bases
3. Ionized drugs are not very lipid soluble- only nonionized form of
drug crosses membrane readily
4. Percent ionization is pH dependent
5. pKa is the negative log of the ionization constant and is equal to
the pH at which a drug is 50% ionized
6. Weak acids become highly ionized as pH increases
7. Weak bases become highly ionized as pH decreases
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 COMPUTING IONIZATION RATIOS:
• According to the Henderson-Hasselbalch equation, the difference
between the pH of the solution and the pKa of the drug is the common
logarithm of the ratio of ionized to unionized forms of the drug.
• Henderson-Hasselbalch equation will determines extent of
ionization
pKa = pH at which 50% of drug is ionized.
• FOR ACID DRUGS
log (ionized/unionized) = pH - pKa, or
ratio of ionized to unionized is 10x/ 1, where
x = pH – pKa
pH-pKa = log ([p-]/[HP])

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 COMPUTING IONIZATION RATIOS:
• FOR BASIC DRUGS
• Everything is the same except that the ratio reverses:
• Log (unionized/ionized) = pH – pKa, or
• Ratio of unionized to ionized is 10x / 1, where
• x = pH – pKa
pH-pKa = log ([B]/[BH+])
Examples:
• P weak acid, has a pKa of 5.5. Taken orally, it is in a stomach solution of pH 3.5.
• pH – pKa = 3.5 – 5.5 = -2
• Since it is an acid drug, we use the alphabetical formula ionized/unionized.
• ionized/unionized = 10-2/1= 1/100
• For every 1 molecule of P that is ionized, 100 are unionized. P in the stomach is
highly fat soluble.

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 COMPUTING IONIZATION RATIOS:

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 SOLUBILITY OF GASES IN LIQUIDS
• Solubility of a gas in a liquid is expressed as
concentration of the dissolved gas, when it is
equilibrium with pure gas above the solution.
• E.g. Fishes are able to breathe under water due
to solubility of oxygen gas in water.

Applications in Pharmacy

Preparation of Preparation of Transportation Oil Solubility

Solubility of
Reagents: Carbonated Beverages: of Anesthetic of Anesthetic
Oxygen in
e.g. Solubility of C02 in Gases through Gases
e.g. Hydrochloric Acid Blood
Water for Soda Water Blood

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 FACTOR AFFECTING SOLUBILITY OF GASES IN LIQUIDS
Pressure

Temperature Presence of
Factors Salts

Chemical
Interaction
with Solvents
1. Effect of Pressure:
• Changes in pressure have little effect on the solubility of solids and
liquids, but pressure strongly influences the solubility of gases.
• As the pressure of the gas above the liquid increases, the solubility of
the gas increases.
• As the pressure of the gas decreases, the solubility of the gas decreases.

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 FACTOR AFFECTING SOLUBILITY OF GASES IN LIQUIDS
1. Effect of Pressure:
• Carbonated beverages are a good
example.
• These drinks contain large amounts of
carbon dioxide (CO2) dissolved in water.
• The drinks are bottled under a high
pressure of CO2 gas, which forces larger
amounts of the gas into solution.
• When the container is opened, the partial
pressure of CO2 above the liquid
decreases.
• Immediately, bubbles of CO2 form in the
liquid and escape from the open bottle.

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 FACTOR AFFECTING SOLUBILITY OF GASES IN LIQUIDS
Henry’s Law:
• How is the partial pressure of carbon dioxide gas related to the solubility of CO2
in a carbonated beverage?
• The relationship is described by Henry’s law. c = kP
Where,
c is the concentration
(M) of the dissolved gas.
P is the pressure of the
gas over the solution
low high k is a Henry law
P P constant for each gas
(mol/L•atm) that
depends only on
low high temperature
c c

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 FACTOR AFFECTING SOLUBILITY OF GASES IN LIQUIDS
Henry’s Law:
• Based on the extent and nature of solubility of gases in water, it is
possible to classify the gaseous solution in to three groups:
a) First Group: These gases are sparingly soluble in water and Obey the
Henry’s law. e.g. Oxygen and Nitrogen
b) Second Group: These gases are slightly soluble in water and these
show considerable deviation from Henry’s law. e.g. C02 and
chlorine.
c) Third Group: These gases are highly soluble in water because of
specific interaction between gas and water. These do not Obey the
Henry’s law. e.g. Hydrogen Chloride and ammonia.

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 FACTOR AFFECTING SOLUBILITY OF GASES IN LIQUIDS

Henry’s Law:
• Applications of Henry’s Law:
1. It is used to estimate the solubility of gases in liquids.
2. The influence of pressure on solubility of gases is utilized in
making carbonated beverages such as: Soda, Cold drinks etc.
• Limitations of Henry’s Law: Henry’s Law is strictly applicable
when:
1. Temperature is maintained constant.
2. Gas does not involve in chemical reaction with the solvents.
3. Gas is slightly soluble in liquids (Dilute Solution).

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 FACTOR AFFECTING SOLUBILITY OF GASES IN LIQUIDS
2. Effect of Temperature:
• The effect of temperature on the solubility
of gases in liquid solvents is opposite that
of solids.
• The solubilities of most gases are greater
in cold water than in hot.
• e.g. O2 gas solubility with temperature

Solubility of gases
usually decreases with
increasing temperature.

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 FACTOR AFFECTING SOLUBILITY OF GASES IN LIQUIDS
2. Effect of Temperature:
• Applications:
1. Dissolve gas are removed by heating the solution.
2. Distilled water is maintained at 80◦C in order to make it convenient for parenteral use
because gas can not dissolve in water at that temperature.
3. Dissolved air influencing the boiling of liquids. E.g. Oxygen can be removed from aqueous
solution by bubbling a different gas such as Nitrogen through the solution. Nitrogen gas
lowers the vapor pressure of oxygen which has low solubility in water.
4. Degassing is employed, while handling solvent system in HPLC.
• Disadvantages:
1. Pharmacist should exercise caution and appreciate the effect of warm conditions, while
handling the containers of gaseous solutions. These container should be immersed in cold
water for some time to reduce the temperature and pressure of the gas before opening the
containers. E.g. Ammonia solution, Liquid bromine etc.

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 FACTOR AFFECTING SOLUBILITY OF GASES IN LIQUIDS
3. Effect of Salts:
• Addition of other substances lowers the solubility of a gas in solutions.
• Example: When a small amount of salt is added to a carbonated
solution, the gas escapes from the solution. This phenomenon is known
as Salting Out.
• Reasons: In a gaseous solution, attraction between gas and solvent is
effective. When the electrolytes are added, they establish greater
attraction with water molecules. This weakens the gas-solvent
interactions. Therefore gas release.
• E.g. Electrolytes such as: Nacl and Non-electrolytes such as:
Sucrose

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 FACTOR AFFECTING SOLUBILITY OF GASES IN LIQUIDS
4. Effect of Chemical Reaction:
• Gases such as: Hydrogen Chloride, Ammonia, and Carbon dioxide
show the deviation as a result of chemical reaction between gas and
solvent.
• For these systems, Henry’s law is not applicable.
• Due to chemical reaction, solubility of gases is Higher.
• E.g. Hydrogen chloride is about 10,000 times more soluble in water
than in liquid oxygen.
• Applications: These principles are used for the preparation of reagents
such as: concentrated solutions namely HCl, H2SO4 and Nitric Acid.

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 SOLUBILITY OF LIQUIDS IN LIQUIDS

• Frequently two or more liquids are mixed together in the

preparation of pharmaceutical products (e.g. aromatic
waters, spirits, elixirs, lotions, sprays, and medicated oils).
• Liquid–liquid systems can be divided into Three
categories according to the solubility of the substances in
one another:
1. Miscible Liquid: Miscible in all proportion e.g. water & ethyl alcohol
2. Partially Miscible Liquid: Miscible only at a certain proportion
e.g. water & phenol
3. Immiscible Liquid: Immiscible in all proportions e.g. water & mercury;
water & carbon tetra chloride
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 SOLUBILITY OF LIQUIDS IN LIQUIDS

1. Miscible Liquid:
• The components of an ideal solution are miscible in all proportions.
Such complete miscibility is also observed in some real binary
systems, e.g. ethanol and water, under normal conditions.
• Polar and semipolar solvents, such as water and alcohol, alcohol and
acetone, are said to be completely miscible because they mix in all
proportions.
• Nonpolar solvents such as benzene and CCl4 are also completely
miscible.
• These liquids are miscible because the broken attractive forces in both
pure liquids are re-established in the mixture.

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 SOLUBILITY OF LIQUIDS IN LIQUIDS
2. Partial Miscible Liquid:
• Attractions between the molecules of one component are greater than those
between its molecules and those of the other component, i.e. if a positive
deviation from Raoult's law occurs, the miscibility of the components may be
reduced.
• In cases of partial miscibility, degree of miscibility may be dependent on the
temperature:
1. Solubility  with  in temperature (water-phenol)
2. Solubility  with  in temperature (water
triethylamine)
3. Solubility  with  &  in temperature (water- nicotine)
4. Solubility not affected by temperature
In case of three component system the third liquid may influence the degree of
solubility of the 2 liquid system

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 SOLUBILITY OF LIQUIDS IN LIQUIDS
2. Partial Miscible Liquid:
• Effect of temperature variation on the degree of miscibility in these
systems is described by means of phase diagrams.

Phase diagrams
= graphs of temperature versus composition
at constant P

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 SOLUBILITY OF LIQUIDS IN LIQUIDS

1. Systems showing an increase in miscibility with rise in

temperature
 A +ve deviation from Raoult's law due to difference in the
cohesive forces that exist between the molecules of each
component in a liquid mixture.

T +ve deviation miscibility

 Each phase consists of a saturated solution of one component

in the other liquid.
 Such saturated solutions are known as conjugate solutions

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 SOLUBILITY OF LIQUIDS IN LIQUIDS
Phenol and water system phase diagram
Temperature fixed at 50 °C
Point a, system containing 100%
pure water.
Addition of phenol to water will result
in the formation of a single liquid phase
until the point b is reached.
At point b, appears a second phase.
Phase A: water rich phase containing
11% phenol
Phase B: phenol rich phase containing
63% phenol

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 SOLUBILITY OF LIQUIDS IN LIQUIDS
Phenol and water system phase diagram
 Increasing quantities of phenol,
i.e., as we proceed across the diagram from point
b to point c, we form systems in which the
amount of the phenol-rich phase (B) continually
increases.
 At the same time the amount of the water-rich
phase (A) decreases.
 Once the total conc. of phenol exceeds 63 % at
50oc a single phenol-rich liquid phase is
formed.
 At 50°C, Aqueous phase saturated with phenol:
contains 11% phenol (point b)
 Phenolic phase saturated with water: contains
63% phenol (point c)

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 SOLUBILITY OF LIQUIDS IN LIQUIDS
Phenol and water system phase diagram
 The line bc drawn across the region
containing two phases is termed a
tie line; it is always parallel to the
base line in two component
systems.
 All systems prepared on a tie line
at 50° C will separate into phases
of constant composition whose
composition is b and c. These
phases are termed conjugate
phases
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 SOLUBILITY OF LIQUIDS IN LIQUIDS
Phenol and water system phase diagram
The critical solution temperature (CST)
(upper consolute temperature):
Is the maximum temperature at which the
two phase region exists. In the case of the
phenol- water system this is 66.8° (point
h in Figure).

 All combinations of phenol and water

above this temperature are completely
miscible and yield one- phase liquid
systems

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 SOLUBILITY OF LIQUIDS IN LIQUIDS
2. Systems showing a decrease in miscibility with rise in temperature
TRIETHYLAMINE & WATER
 The solubility of liquid pairs
may increase as the
temperature is lowered
 The system will exhibit a lower
consolute temp.
 Below which the two members
are soluble in all proportions
 Above which two separate
layers are formed.

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 SOLUBILITY OF LIQUIDS IN LIQUIDS
3. Systems showing upper and lower consolute temperature
NICOTINE & WATER
 Mixtures such as nicotine & water
show both an upper and a lower
consolute temperature.
 With an intermediate temperature
region in which the two liquids are
only partially miscible.
4. Systems not showing upper and lower consolute temperature
• The pair, ethyl ether and water, has neither an upper nor a lower consolute
temperature and shows partial miscibility over the entire temperature range at
which the mixture exists.
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 SOLUBILITY OF LIQUIDS IN LIQUIDS
IDEAL SOLUTIONS OR BINARY SOLUTIONS
• Ideal Solution is one in which there is no attraction between
solute and solvent molecules.
• Ideal solution is one in which there is no change in the properties
of the components, other than dilution.
• Heat is neither evolved nor absorbed during mixing.
• They obey Raoult’s law.
• E.g.: Methanol-Water and Benzene-Toluene
• These liquids have similar properties i.e. attractive forces are in
complete uniformity.

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 SOLUBILITY OF LIQUIDS IN LIQUIDS
RAOULT’S LAW
• In ideal solutions, partial vapor pressure of each volatile
constituent is equal to the vapor pressure of the pure constituent
multiplied by its mole fraction in the solution.
• Thus, for two constituents A and B

• Where, ƤA and ƤB are the partial vapor pressures of the

constituents over the solution when the mole fraction
concentrations are XA and XB respectively

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 SOLUBILITY OF LIQUIDS IN LIQUIDS
RAOULT’S LAW
PA = XA P A0
Ideal Solution
0
PB = XB P B

PT = PA + PB
PT = XA P A0 + XB P 0B

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 SOLUBILITY OF LIQUIDS IN LIQUIDS
NON-IDEAL SOLUTIONS OR REAL SOLUTIONS
• Most liquid mixtures show varying degree of deviation from Raoult’s Law,
depending on the nature of the liquid and the temperature. These solutions
are known as Real Solutions.
• In real solutions the "cohesive“ force of attraction between A for A
exceeds the "adhesive" force of attraction existing between A and B.
• Alternatively, the attractive forces between A and B may be greater than
those between A and A or B and B.
• They do not obey Raoult's law.
• The deviations are observed because solute-solute, solute-solvent and
solvent-solvent interaction are unequal.
• Deviations: 1. Negative Deviation 2. Positive Deviation

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 SOLUBILITY OF LIQUIDS IN LIQUIDS
Negative Deviation from Raoult’s Law
• Negative deviation: When the
"adhesive" attractions between
molecules of different species exceed the
"cohesive" attractions between like
molecules, the vapor pressure of the
solution is less than that expected from
Raoult's ideal solution law, and
negative deviation occurs.
Force > Force Force
A-B A-A & B-B

• E.g. Chloroform + Acetone PT is less than

predicted by Raoults’s law
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 SOLUBILITY OF LIQUIDS IN LIQUIDS
Positive Deviation from Raoult’s Law
• Positive deviation: When the interaction between A and
B molecules is less than that between molecules of the
pure constituents (A-A or B-B), the presence of B
molecules reduces the interaction of the A-A molecules
correspondingly reduce the B- B interaction.
• Accordingly, the dissimilarity of polarities or internal
pressures of the constituents results in a greater
escaping tendency of both the A and the B
molecules.
• The partial vapor pressure of the constituents is greater
than that expected from Raoult's law, and the system is
said to be positive deviation.
Force < Force Force
A-B A-A & B-B PT is greater than
• E.g. Benzene + Ethyl Alcohol predicted by Raoults’s law
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 IDEAL SOLUBILITY PARAMETERS

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 IDEAL SOLUBILITY PARAMETERS

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 IDEAL SOLUBILITY PARAMETERS

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 IDEAL SOLUBILITY PARAMETERS

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 IDEAL SOLUBILITY PARAMETERS

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 IDEAL SOLUBILITY PARAMETERS

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 DIFFUSION PRINCIPLES IN BIOLOGICAL SYSTEM
DIFFUSION:
• Mass transfer of individual molecules of a
substance caused by random molecular
motion, associated with a driving force
such as the concentration gradient”
OR
• “A physical process that refers to the net
movement of molecules from a region of
high concentration to lower concentration
under the influence of concentration
gradient”.

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 DIFFUSION PRINCIPLES IN BIOLOGICAL SYSTEM
APPLICATIONS OF DIFFUSION PHENOMENA IN PHARMACEUTICAL SCIENCES:

• Release of drug from dosage form.

• Ultrafiltration, microfiltration, dialysis, hemodailysis.
• Permeation & distribution of drug in living tissues.
• Estimation of molecular weight of polymers.
• Prediction of absorption & elimination of drug.

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 DIFFUSION PRINCIPLES IN BIOLOGICAL SYSTEM
TYPES OF DIFFUSION:
1. Passive diffusion:
• Net moment of material from an area
of high concentration to an area of low
concentration.
• The difference between high and low
concentration is termed as
concentration gradient.
• Diffusion will continue until the
gradient has been eliminated.

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 DIFFUSION PRINCIPLES IN BIOLOGICAL SYSTEM
TYPES OF DIFFUSION:
2. Facilitated (carrier mediated) diffusion:
• It is moment of molecules across the cell
membrane via special transport proteins that
are embedded within the cellular membrane.
3. Active transport:
• Movement of molecules across a membrane
from a region of lower concentration to higher
concentration, against the concentration
gradient.
4. Filtration:
• Movement of solvent or solute molecules,
influenced by hydraulic pressure.

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 DIFFUSION PRINCIPLES IN BIOLOGICAL SYSTEM
LAWS OF DIFFUSION:
• Derived by Adolf Fick in 1856.
FICK’S FIRST LAW OF DIFFUSION:
“Diffusion f lux is directly proportional to
concentration gradient under the assumption of
steady state diffusion”
J= -D dc/dx
Where,
J= diffusion flux (g/ sq. cm/s)
D= Diffusion coefficient or diffusivity (cm sq/sec)
dc= change in concentration of material (g/cubic cm)
dx= change in distance (cm)

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 DIFFUSION PRINCIPLES IN BIOLOGICAL SYSTEM
LAWS OF DIFFUSION:
FICK’S SECOND LAW OF DIFFUSION:
“Change in concentration with time in a
particular region is proportional to the
change in concentration gradient at that
point in the system.”

dc/dt = -dJ/dx

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 DIFFUSION PRINCIPLES IN BIOLOGICAL SYSTEM
MEASUREMENT OF DIFFUSION
FRANZ DIFFUSION CELL

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 DIFFUSION PRINCIPLES IN BIOLOGICAL SYSTEM
MEASUREMENT OF DIFFUSION
PROCEDURE:
• Franz cell apparatus contain two chambers separated by a membrane.
• Donor chamber consist of known concentration of solute.
• Receptor chamber contain fluid from which samples are taken at a regular interval for
analysis.
• Temperature is maintained at 37˚C.
• Membrane may be of excised tissue, tissue constructs & cadaver tissue to synthetic
membranes.
• When experiment starts, solute from donor chamber diffuses through membrane into
receptor chamber.
• From receptor chamber, solution is periodically removed for analysis.
• The test determine amount of diffusant that has permeated the membrane.
• The solution of receptor chamber is replaced with new solution after each sampling.

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 DIFFUSION PRINCIPLES IN BIOLOGICAL SYSTEM
DIFFUSION CONTROLLED RELEASE SYSTEM
1. Reservoir (Laminated matrix) device:
• A hollow system containing an inner core surrounded in
water insoluble membrane.
• Polymer can be applied by coating or encapsulation.
• Drug partitions into membrane & exchanges with
surrounding fluid by diffusion.
• Drug will enter membrane, diffuse to periphery &
exchange with surrounding fluid.
• Polymer content in coating, thickness of coating &
hardness of microcapsules are rate controlling
parameters.
• Release follow fick’s first law of diffusion.

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 DIFFUSION PRINCIPLES IN BIOLOGICAL SYSTEM
DIFFUSION CONTROLLED RELEASE SYSTEM
2. Matrix (Monolithic) device:
• A Solid drug is dispersed or
Distributed in an insoluble matrix.
• Outer layer of drug is exposed to bathing
solution in which it is first dissolved.
Then drug diffuses out of matrix.
• Matrix diffusion system are of two
types:
(i) Rigid matrix
(ii) Swellable matrix

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 DISTRIBUTION LAW, ITS LIMITATIONS AND APPLICATIONS

NERNST’S DISTRIBUTION LAW

• If we take two immiscible solvents A and B
in a beaker, they form separate layers.
• When a solute X which is soluble in both
solvents is added, it gets distributed or
partitioned between them.
• Molecules of X pass from solvent A to B
and from solvent B to A.
• Finally a dynamic equilibrium is set up. At
equilibrium, the rate, at which molecules
of X pass from one solvent to the other is
balanced.

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 DISTRIBUTION LAW, ITS LIMITATIONS AND APPLICATIONS

STATEMENT OF NERNST’S DISTRIBUTION LAW

• Nernst (1891) studied the distribution of several solutes between different appropriate pairs of
solvents. He gave a generalization which governs the distribution of a solute between two non-
miscible solvents. This is called Nernst’s Distribution law (or Nernst’s Partition law) or
simply Distribution law or Partition law.
• If a solute X distributes itself between two immiscible solvents A and B at constant
temperature and X is in the same molecular condition in both solvents,
Concentration of X in A = KD
Concentration of X in B
• If C1 denotes the concentration of the solute in solvent A and C2 the concentration in solvent
B, Nernst’s Distribution law can be expressed as:
C1 = KD
C2
• The constant KD (or simply K) is called the Distribution coefficient or Partition coefficient
or Distribution ratio.

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 DISTRIBUTION LAW, ITS LIMITATIONS AND APPLICATIONS

LIMITATIONS OF NERNST’S DISTRIBUTION LAW

• The conditions to be satisfied for the application of the Nernst’s Distribution law are:
1. Constant temperature: The temperature is kept constant throughout the experiment.
2. Same molecular state: The molecular state of the solute is the same in the two solvents.
The law does not hold if there is association or dissociation of the solute in one of the
solvents.
3. Equilibrium concentrations: The concentrations of the solute are noted after the
equilibrium has been established.
4. Dilute solutions: The concentration of the solute in the two solvents is low. The law does
not hold when the concentrations are high.
5. Non-miscibility of solvents: The two solvents are non-miscible or only slightly soluble in
each other. The extent of mutual solubility of the solvents remains unaltered by the addition
of solute to them.

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 DISTRIBUTION LAW, ITS LIMITATIONS AND APPLICATIONS

APPLICATIONS OF NERNST’S DISTRIBUTION LAW

• There are numerous applications of distribution law in the laboratory as well as in industry:
(1) Solvent Extraction:
• This is the process used for the separation of organic substances from aqueous solutions.
• The aqueous solution is shaken with an immiscible organic solvent such as ether (or benzene) in a separatory funnel.
• The distribution ratio being in favor of ether, most of the organic substance passes into the ethereal layer.
• The ethereal layer is separated and ether distilled off. Organic substance is left behind.
(2) Partition Chromatography:
• This is a modern technique of separating a mixture of small amounts of organic materials.
• A paste of the mixture is applied at the top of a column of silica soaked in water.
• Another immiscible solvent, say hexane, is allowed to flow down the column.
• Each component of the mixture is partitioned between the stationary liquid phase (water) and the mobile liquid phase
(hexane).
• The various components of the mixture are extracted by hexane in order of their distribution coefficients.
• Thus the component with the highest distribution coefficient is first to move down in the flowing hexane which is collected
separately.
• Similarly, a component with a lower distribution ratio comes down later and is received in another vessel.

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 DISTRIBUTION LAW, ITS LIMITATIONS AND APPLICATIONS

APPLICATIONS OF NERNST’S DISTRIBUTION LAW

(3) Desilverization of Lead (Parke’s Process):
• When molten zinc is added to molten lead containing silver (argentiferous lead), zinc and lead form immiscible layers and
silver is distributed between them.
• Since the distribution ratio is about 300 in favor of zinc at 800º C, most of silver passes into the zinc layer.
• On cooling the zinc layer, an alloy of silver and zinc separates.
• The Ag-Zn alloy is distilled in a retort when zinc passes over leaving silver behind.
• The lead layer still contains unextracted silver.
• This is treated with fresh quantities of molten zinc to recover most of the silver
(4) Confirmatory Test for Bromide and Iodide:
• The salt solution is treated with chlorine water.
• Small quantity of bromine or iodine is thus liberated.
• The solution is then shaken with chloroform.
• On standing chloroform forms the lower layer.
• The free bromine or iodine being more soluble in chloroform concentrates into the lower layer, making it red for bromine
and violet for iodine.

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 DISTRIBUTION LAW, ITS LIMITATIONS AND APPLICATIONS

APPLICATIONS OF NERNST’S DISTRIBUTION LAW

(5) Determination of Solubility:
• Suppose the solubility of iodine in benzene is to be determined.
• Iodine is shaken with water and benzene.
• At equilibrium concentrations of iodine in benzene (Cb) and water (Cw) are found
experimentally and the value of distribution coefficient calculated.
Cb / Cw = Kd Sb/ Sw = Kd

• Where Sb = solubility in benzene; and Sw = solubility in water.

(6) Determination of Association

(7) Determination of Dissociation

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LLOYD INSTITUTE OF MANAGEMENT AND TECHNOLOGY (PHARM) 92