PPAR211 Solubility And Distribution Phenomena I.D.

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Importance Of Studying The Phenomenon Of SYSTEM
Solubility generally considered to be a bounded
Understanding the phenomenon of space or an exact quantity of a material
solubility helps the pharmacist to: substance.
1. Select the best solvent for a drug or a
mixture of drugs. DISPERSION
2. Overcome problems arising during consists of at least two phases with
preparation of pharmaceutical one or more dispersed (internal) phases
contained in a single continuous (external)

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solutions.
3. Have information about the structure phase.

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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
PHASE
A distinct homogeneous part of a
system separated by definite boundaries
from other parts of a system.

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often present problems related to
their formulation and bioavailability TRUE SOLUTIONS
Defined as a mixture of two or more
components that form a homogeneous
SOLUTION
molecular dispersion.
A
ID chemically and physically
homogeneous mixture of two or more
substances. LIQUID DOSAGE FORMS (based on particle
It denotes a homogeneous mixture size)
1M

that is liquid, even though it is possible to Depending on the size of the

have homogeneous mixtures that are solid dispersed particle, liquid dosage forms are
or gaseous. classified as:
• true solutions
Most important in pharmacy:
• colloidal solution
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solids in liquids
• disperse systems
liquids in liquids
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gases in liquids

Parts Of A Solution
TRUE COLLOIDAL COARSE
➢ SOLUTE – the part of a solution that
SOLUTION SOLUTION DISPERSION
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is being dissolved (usually the lesser

Homogenous Heterogenous Heterogenous
amount)
➢ SOLVENT – the part of a solution that Solution in Solutions in Solution in which
which dispersoid which a dispersoid
dissolves the solute (usually the or consists of dispersoid consists of a
greater amount) small molecules consists of a group of large
or ions (evenly single large molecules (not
Solute + Solvent = Solution distributed) molecule or evenly
group of small distributed at all)
molecules.

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 PPAR211 Solubility And Distribution Phenomena I.D.T

Particle size: Particle size: Particle size: over

0.01-1 nm; can be 1-1000 nm, 1000; can be large SOLUBILITY EXPRESSIONS
atoms, ions, dispersed, can particles or
molecules be combined or combined The USP lists the solubility of drugs
large molecules particles as: the number of ml of solvent in which 1g
Do not separate Do not separate Particles settle of solute will dissolve.
on standing on standing out
E.g. 1g of boric acid dissolves in 18 mL
Do not scatter Scatter light May scatter light, of water, and in 4 mL of glycerin.
light (Tyndall effect) but are not

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transparent
SOLUBILITY
They may pass They may pass They can’t pass

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through ordinary through through ordinary The extent to which the solute
as well as ultra ordinary filter as well as ultra dissolves is referred to as its solubility.
filters but not usually filters
through ultra Solubility refers to the maximum
filters amount of solute that can be dissolved in a
given amount of solvent

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Examples: Examples: Examples:
-Solution of NaCl -Solution of -Pharmaceutical Extent to which dissolution proceeds
in water starch suspensions and
-Milk emulsions under experimental conditions -- amount of
-Solution of -Solution of -Grain of sand in solid passing in solution with equilibrium
Glucose in water gums (?) water
ID (form saturated solution) between solution &
excess (undissolved) substance
If sugar is dissolved in water, it is
supposed that the ultimate sugar particle is
Classification Of Solutions
1M

of molecular dimensions and that a true

A. BASED ON ELEMENTAL COMPOSITION
solution is formed.
(2)
Between these two extremes lie
ORGANIC
colloidal solutions, the dispersed particles of compounds containing carbon (except
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which are larger than those of true solutions CO2, CO, carbonates and cyanides)
but smaller than the particles present in
suspensions. INORGANIC
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If very fine sand is mixed with water, compounds of other elements

including acids, bases and salts
a suspension of comparatively large
particles, each consisting of many
B. BASED ON IONIZATION/ELECTROLYTIC
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molecules, is obtained.
PROPERTY OF SOLUTE

Usp Descriptive Terms Of Solubility

ELECTROLYTIC PROPERTY – the ability of
the solution to conduct electricity

1. ELECTROLYTES – substances whose

aqueous solutions contain ions and thus
conduct electricity
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PPAR211 Solubility And Distribution Phenomena I.D.T
UNSATURATED SOLUTION
a. STRONG ELECTROLYTES – substances solution containing amount of solute
which completely dissociate into ions e.g. less than its solubility; more solute can
dissolve in it
salts, strong acids, strong bases NaCl → Na+
(aq) + Cl- (aq)
SUPERSATURATED SOLUTION
solution containing an amount of
b. WEAK ELECTROLYTES – substances solute greater than the solubility; unstable
which produce small amounts of ions; solution

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partially dissociated into ions
SOLUBILITY CURVE

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e.g. weak acids, weak bases
Any solution can be made saturated,
- CH3COOH ↔ CH3COO- (aq) + H+
unsaturated, or supersaturated by changing
(aq) the temperature.
- CH3COOH ionizes to form
CH3COO- and H+.

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While this happens, some ions also
combine to form back CH3COOH. This
results to partial dissociation
ID
2. NONELECTROLYTES – substances that
does not dissociate into ions; form non THERMODYNAMIC SOLUBILITY OF DRUGS
conducting solutions e.g. most molecular
1M

The thermodynamic solubility of a

compounds are nonelectrolytes
Examples include sugar, glycerin,
naphthalene and urea
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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

Types of Solution under equilibrium conditions.

DILUTE – solution with low solute
concentration
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The equilibrium involves a balance of the

CONCENTRATED – one with high solute energy of three interactions against each
concentration other:
(1) solvent with solvent
Types Of Solution Based On The Degree Of (2) solute with solute
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Saturation (3) solvent and solute

SATURATED SOLUTION
a solution that contains the maximum
amount of solute the solvent can dissolves;
no more solute can dissolve in it (solution in
equilibrium)
Steps of solid going into solution:
Step 1: Hole open in the solvent
Step 2: Onemolecule of the solid breaks
away from the bulk
Step 3: The solid molecule is enter into the
hole in the solvent

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PPAR211 Solubility And Distribution Phenomena
SATURATED SOLUTION
A solvent can not dissolve any more
solute
A saturated solution is at equilibrium.
Particles are dissolving and precipitating at
the same rate
NaCl(s) D Na+ (aq) + Cl- (aq)
I.D.T
↑ KE ↑ KE= ↑ motion in molecules= break
intermolecular bonds and escape from
solution
- Solid: ↑ Temp, ↑ solubility
ENDOTHERMIC REACTION (ΔHsolvation>0)
Increasing the temperature results in
a stress on the reactants side from the

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additional heat.
Le Châtelier's principle predicts that

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the system shifts toward the product side in
order to alleviate this stress.
By shifting towards the product side,
more of the solid is dissociated when
equilibrium is again established, resulting in

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increased solubility.

EXOTHERMIC REACTION
Factors Affecting Solubility
((ΔHsolvation<0ΔHsolvation<0):
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1. TEMPERATURE
Increasing the temperature results in
- Temperature will affect solubility. If the
a stress on the products side from the
solution process absorbs energy then the
additional heat.
solubility will be increased as the
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Le Châtelier's principle predicts that

temperature is increased.
- If the solution process releases energy
then the solubility will decrease with
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the system shifts toward the reactant side in
order to alleviate this stress.
By shifting towards the reactant's
side, less of the solid is dissociated when

equilibrium is again established, resulting in

increasing temperature.
decreased solubility.

- Generally, an increase in the temperature

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2. NATURE OF SOLUTE AND SOLVENT

of the solution increases the solubility of a
(SOLUTE-SOLVENT INTERACTIONS)
solid solute.
MISCIBLE LIQUIDS – pair of liquids that
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- A few solid solutes are less soluble in warm
solutions. n For all gases, solubility
decreases as the temperature of the solution
increases.
Generally, Gases:
↑ Temp, ↓ solubility,
mix in all proportion e.g. ethanol-H2O,
glycerin - alcohol, alcohol - acetone,
benzene - carbon tetrachloride
IMMISCIBLE LIQUIDS – liquids that do not
mix, e.g. oil-H2O
MISCIBILITY
➔ solubility between gases or liquids
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PPAR211 Solubility And Distribution Phenomena
The relation between the solute and
solvent is very important in determining
solubility.
STRONG SOLUTE - solvent attractions
equate to greater solubility
WEAK SOLUTE - solvent attractions equate
to lesser solubility.
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Preparation of pharmaceutical solutions
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involves mixing of 2 or more liquids.
➔ Alcohol & water to form
hydroalcoholic solutions
➔ volatile oils & water to form aromatic
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waters
➔ volatile oils & alcohols to form spirits,
elixirs
ID
Liquid-liquid systems may be divided into 2
categories:
1) Systems showing complete miscibility
1M
such as alcohol & water, glycerin & alcohol,
benzene & carbon tetrachloride.
2) Systems Showing Partial Miscibility as
phenol and water; two liquid layers are
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formed each containing some of the other
liquid in the dissolved state.
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3. “LIKE DISSOLVES LIKE”
Substances with similar
intermolecular attractive forces tend to be
soluble in one another: polar ↔ polar (salts
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& sugar dissolve in water) nonpolar ↔
nonpolar (naphthalene dissolves in benzene)
In turn, polar solutes tend to dissolve
best in polar solvents while non-polar
solutes tend to dissolve best in non-polar
solvents. In the case of a polar solute and
non-polar solvent (or vice versa), it tends to
be insoluble or only soluble to a miniscule
I.D.T
degree. A general rule to remember is, "Like
dissolves like."
4. PRESSURE (FOR GASES)
↑ pressure= ↑ concentration= ↑
solubility
Gas - molecules far apart; ↑ Kinetic
energy
Henry’s Law: Cg = kPg
Cg ≡ solubility of gas in solution
K ≡ Henry’s law constant
Pg ≡ partial pressure of the gas over
solution
HENRY’S LAW- the solubility of a gas
is directly proportional to the partial
pressure of the gas above the solution
This formula indicates that (at a
constant temperature) when the partial
pressure decreases, the concentration of gas
in the liquid decreases as well, and
consequently the solubility also decreases.
Conversely, when the partial pressure
increases in such a situation, the
concentration of gas in the liquid will
increase as well; the solubility also
increases.
Extending the implications from
Henry's law, the usefulness of Le Châtelier's
principle is enhanced in predicting the
effects of pressure on the solubility of gases.
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PPAR211 Solubility And Distribution Phenomena
When the pressure above the solution
is released (decreases), the solubility of the
gas decreases
As the temperature increases the
solubility of gases decreases
5. EFFECT OF DISSOLVED SUBSTANCE ON
SOLUBILITY
I.D.T
9. THE INFLUENCE OF SUBSTITUENTS
on the solubility of molecules in water
can be due to their effect on the properties
of the solid or liquid (for example, on its
molecular cohesion, or to the effect of the
substituent on its interaction with water
molecules).
Substituents can be classified as
either hydrophobic or hydrophilic,

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➔ presence of dissolved substance
depending on their polarity
(electrolytes) lowers solubility of gas

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(competition)
➔ ↑ dissolved substance = ↓ solubility
6. PARTICLE SIZE (SURFACE AREA) OF
Polar groups such as –OH capable of
hydrogen bonding with water molecules
impart high solubility
Non-polar groups such as –CH3 and –Cl are

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DRUG PARTICLES
hydrophobic and impart low solubility. n
↓Particle size → ↑ surface area→ ↑Solubility
Ionization of the substituent increases
7. MOLECULAR SIZE solubility, e.g. –COOH and –NH2 are slightly
ID
Molecular size will affect solubility. hydrophilic whereas –COO– and –NH3 are
The larger the molecule or the higher very hydrophilic.
its molecular weight the less soluble the
substance.
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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
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the solubility since more branching will

reduce the size (or volume) of the molecule
and make it easier to solvate the molecules
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with solvent

8. THE BOILING POINT OF LIQUIDS AND

The position of the substituent on the
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THE MELTING POINT OF SOLIDS

molecule can influence its effect on
Both reflect the strengths of
interactions between the molecules in the solubility, for example the aqueous
pure liquid or the solid state. In general, solubilities of o-, m- and p
aqueous solubility decreases with increasing dihydroxybenzenes
boiling point and melting point.

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PPAR211 Solubility And Distribution Phenomena I.D.T
10. CRYSTAL PROPERTIES
Polymorphic Crystals, Solvates,
Amorphousforms

Polymorphs have the same chemical

structure but different physical properties,
such as solubility, density, hardness, and
compression characteristics.

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A drug that exists as an amorphous

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form (non crystalline form) generally
dissolves more rapidly than the same drug
in crystalline form.
● CARBOXYLIC ACIDS with 12 to 20
11. pH carbon atoms are often referred to as

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It is one of the primary influences on fatty acids
the solubility of most drugs that contain
ionizable groups ● FATTY ACIDS containing more than
10 carbon atoms form soluble soaps
ID
Large number of drugs are weak acids
with the alkali metals. They are
or weak bases.
soluble in solvents having low
Solubility depends on the degree of dielectric constants; for example,
ionization.
1M

oleic acid (C17H33COOH) is insoluble

Degree of ionization depends on the pH in water but is soluble in alcohol and
in ether.
About 85% of marketed drugs contain
● BENZOIC ACID is soluble in sodium
functional groups that are ionized to some
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hydroxide solution
extent at physiological pH (pH 1.5 –8).
● PHENOL is weakly acidic and only
Carboxylic acids containing more than five
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slightly soluble in water but quite

carbons are relatively insoluble in water. soluble in dilute NaOH solution.
They react with dilute sodium hydroxide,
carbonates and bicarbonates to form ● Organic compounds containing a
soluble salts.
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basic nitrogen atom. Most of these

As the number of carbons in a carboxylic
acid series becomes greater, the boiling
point increases and the solubility in water
decreases.
weak electrolytes are not very soluble
in water but are soluble in dilute
solutions of acids

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PPAR211 Solubility And Distribution Phenomena
Pharmaceutical Solvents
On the basis of the forces of
interaction occurring in solvents one may
broadly classify solvents as one of three
types:
Polar Solvent
➔ those made up of strong dipolar
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molecules having hydrogen bonding
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(water or hydrogen peroxide)
Semipolar Solvent
➔ those also made up of strong dipolar
molecules but that do not form
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hydrogen bonds (acetone or pentyl
alcohol).
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Nonpolar Solvents
➔ those made up of molecules having a
small or no dipolar character
(benzene, vegetable oil, or mineral
1M
oil).
POLAR SOLVENTS
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The solubility of a drug is due in large
measure to the polarity of the solvent, that
is, to its dipole moment. Polar solvents
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dissolve ionic solutes and other polar
substances.
The ability of the solute to form
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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.
I.D.T
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.
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. 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.
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.
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.
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PPAR211 Solubility And Distribution Phenomena
They are unable to form hydrogen
bonds with non electrolytes.
Non polar solvents can dissolve non
polar solutes through weak van der Waals
forces
Examples: solutions of oils & fats in
carbon tetrachloride or benzene,
Polyethylene glycol and 400 Castor oil
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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,
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becomes soluble in alcohol.
They can act as intermediate solvents
to bring about miscibility of polar & non
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polar liquids.
Example: acetone increases solubility
of ether in water.
Propylene glycol has been shown to
1M
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
decrease, the solubility also decrease
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The solubility of the drug substance is
attributable in large part to the polarity of
I.D.T
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) n Polar solvents, with examples such
as water and glycerin;
Non-polar solvents, with examples
such as oils.
Solvents with intermediate dielectric
constants are classified as semipolar
Pharmaceutical Solvents
1. WATER — Water is a unique solvent.
Besides being a highly associated liquid,
giving rise to its high boiling point, it has
another very important property, a high
dielectric constant.
The dielectric constant indicates the
effect that a substance has, when it acts as a
medium, on the ease with which two
oppositely charged ions may be separated.
The ease of solubilizing salts in
solvents like water and glycerin can be
explained on the basis of their high
dielectric constant. Also, in general, the
more polar the solvent, the greater its
dielectric constant.
2. ALCOHOLS — Ethanol, as a solvent, is
next in importance to water.
An advantage of ethanol is that
growth of microorganisms does not occur in
solutions containing alcohol in a reasonable
concentration.
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PPAR211 Solubility And Distribution Phenomena
Resins, volatile oils, alkaloids,
glycosides, etc. are dissolved by alcohol, but
many therapeutically inert principles, such
as gums, albumin, and starch, are insoluble,
which makes it more useful as a selective
solvent.
Mixtures of water and alcohol, in
proportions varying to suit specific cases,
I.D.T
5. ISOPROPYL ALCOHOL possesses solvent
properties similar to those of ethyl alcohol
and is used instead of the latter in a number
of pharmaceutical manufacturing
operations.
It has the advantage in that the
commonly available product contains not
over 1% of water, whereas ethyl alcohol

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are used extensively. They are often referred contains about 5% water, often a

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to as hydroalcoholic solvents.
3. GLYCERIN is an excellent solvent,
although its range is not as extensive as that
of water or alcohol.
disadvantage.
Isopropyl alcohol is employed in some
liniment and lotion formulations. It cannot
be taken internally.

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In higher concentrations it has Solubility Expressions
preservative action.
It dissolves the fixed alkalies, a large
ID
number of salts, vegetable acids, pepsin,
tannin, and some active principles of plants,
but it also dissolves gums, soluble
carbohydrates, and starch.
1M

It also is of special value as a simple

solvent (as in phenol glycerite), or where the
major portion of the glycerin simply is
added as a preservative and stabilizer of
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solutions that have been prepared with

other solvents
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4. PROPYLENE GLYCOL, which has been

used widely as a substitute for glycerin, is
miscible with water, acetone, or chloroform
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in all proportions.
It is soluble in ether and will dissolve
many essential oils but is immiscible with
fixed oils. It is claimed to be as effective as
ethyl alcohol in its power of inhibiting mold
growth and fermentation.

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PPAR211 Solubility And Distribution Phenomena I.D.T

Biopharmaceutics Classification System

(BCS)
BCS is a scientific framework for
classifying Drug substances according to
their aqueous solubility and their intestinal
permeability

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Class 1
- High solubility
- High permeability
- (rapid dissolution for biowaiver)

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Class 2
- Low solubility
- High permeability
ID
Class 3
- High solubility
- Low permeability
1M

Class 4
- Low solubility
- Low permeability
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