1

Pharmaceutics-I

Solubility

Martin’s Physical Pharmacy and

21-05-2017
Pharmaceutical
Sciences
– Sinko PJ, 6th edition
P 182-195
Remington (Essential of Pharmaceutics) Dr. Muhammad Sarfraz
22 Edition Associate Professor
Solution and Phase Equilibria College of Pharmacy
Chapter 13
Page 219 Al Ain University, Al Ain, UAE.
 Solubility

• In a quantitative way: Maximum grams of solute that will

dissolve in 100 g of solvent at a given temperature

• In a qualitative way: it is the spontaneous interaction of

two or more substances (solute & solvent) to form a
homogeneous molecular dispersion
 Solubility Expressions:
a) The solubility of a drug can be expressed in terms of: -
Molarity - Molality - Mole fraction – Normality, percentage
(% w/w, % w/v, % v/v). (Chapter 1)

b) The United States Pharmacopeia (USP) describes the

solubility of drugs as parts of solvent required for one part
solute.

c) Biopharmaceutics Classification System (BCS)

 Quantification according to USP
• The United States Pharmacopeia (USP) describes the solubility
of drugs as parts of solvent required for one part solute.
Biopharmaceutics Classification System (BCS)
• BCS is a scientific framework for classifying Drug
substances according to their aqueous solubility and
their intestinal permeability.
 Types of solutions
Solutions of pharmaceutical importance includes

• Gases in liquids
• Liquids in liquids
• Solids in liquids
Gases in liquids
1-Effect of Pressure
Changing the pressure has no appreciable effect on the solubilities of either solids or
liquids in liquids. The solubilities of gases in all solvents increase, however, as the
partial pressures of the gases increase
The effect of pressure on the solubility of the gas is given by Henry's law.
which states that: “The amount of gas that will dissolve in a liquid at a given temperature
is directly proportional to the partial pressure of the gas above the liquid”
As the pressure of a gas above the liquid increases, the solubility of the gas increases.
According to Henry's Law:
Sgas = kH x Pgas
The solubility of a gas (Sgas) is directly proportional to the partial pressure of the gas (Pgas)
above the solution.

kH = Henry’s law constant for a gas; units of mol/L.atm

 9

Henry’s Law applies to gases that do not react with the solvent in which
they dissolve (or, in some cases, gases that react incompletely).

An illustration of Henry’s Law. The solubility of a gas (that does not react
completely with the solvent) increases with increasing pressure of the gas
above the solution
Using Henry’s Law to calculate gas solubility

PROBLEM: The partial pressure of carbon dioxide gas inside a bottle of cola is 4
atm at 25 oC. What is the solubility of CO2? The Henry’s law
constant for CO2 dissolved in water is 3.3 x 10-2 mol/L.atm at 25 oC.

PLAN: Knowing kH and Pgas, we can substitute into the Henry’s Law equation.

SOLUTION: S = (3.3 x 10-2 mol/L.atm)(4 atm) = 0.1 mol / L

CO2
2-Effect of Temperature
As the temperature increases the solubility of gases decreases.
Solubility of most gases decrease with a rise in temperature because of a
greater tendency of the gases to expand in comparison to the solvent.
So gases in liquids are generally the pressurized dosage forms and must be
handled with great care while exposing them to temperature

The solubility curve for gases

is the opposite of the solubility
curve for solids.

The solubility of a gas decreases as

the temperature increases.
 3-Effect of Chemical Reaction
Henry's law generally applies to gases that are only slightly soluble in
solvent and that do not act in any way with the solvent.
If any chemical reaction between a gas and a solvent greatly increases the
solubility of the gas in the solvent.
For example hydrogen chloride gas reacts with water by hydrogen bonding
when it dissolves in water. This increases the solubility of hydrogen
chloride gas in water.

4-Effect of Electrolytes and Non-electrolytes

Solubility of a gases in a solvent is generally reduced by the addition of electrolytes
such as sodium chloride or non-electrolytes such as sugar.
This is referred to as salting out.
This is due to more affinity between the solvent and the electrolyte or non-
electrolyte than between the solvent and the gas.
Factors affecting solubility of solid in liquids
 1-Particle size
Generally, a decrease in the particle size causes an increase in the
solubility. This is because a decrease in the particle size results in
increase in surface area which increases the solubility

↓Particle size → ↑ surface area→ ↑Solubility

The increase in solubility with decrease in particle size however,

ceases when the particles attain very small radius and any further
decrease in the particle size causes a decrease in solubility rather
than an increase. This is because of generation of electrical
charges on the particles.
 2- Molecular Size

• Molecular size will affect the solubility.

• The larger the molecule or the higher its molecular weight the
less soluble the substance.
• It is more difficult for solvent molecules to surround bigger
molecules

• 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
3-Boiling point of liquids and the 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.
+
4- The Influence of Substituents
The influence of substituent on the solubility of the molecules in water can be due
to their effect on the properties of the solid or liquid ( for example, on its molecular
cohesion, or due interaction of substituent with water molecules)

Substituents can be classified as either hydrophobic or hydrophilic depending on

the polarity
 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.
 5- Temperature:
• As a general concept solubility of solids increases with the increase in
temperature as they tend to dissolve with the absorption of heat. KNO3,
KBr
• This is in accordance with Le Chatelier’s Principle which states that when
a stress is applied to a system at equilibrium, the system responds in
a way that best relieves the stress.
• So in this case system tries to neutralize the increase in temperature or
constraint imposed on it by increasing the solubility of the solid when the
extra heat gets absorbed.
• It is not true for solids which dissolve with the evolution of heat. For them
what happens…………………….????
• For solids which dissolve with the evolution of heat (exothermic), an
increase in temperature causes a decrease in the solubility. Example are
Calcium Hydroxide and Calcium Sulfate.
• When heat is neither absorbed nor given off, the solubility is not
affected by variation of temperature, as is nearly the case with sodium
chloride
 Effect of temperature on the solubility of salts can be represented by the use of solubility
curves, which are plots of solubility against temperature.

After 32.5C it is converted into

anhydrous form and its
dissolution become exothermic
leading to decrease in solubility
with increase in temperature.

Below 32.5C it exist in hydrous form

and its dissolution is endothermic
leading to increase in solubility with
increase in temperature.
What mass of NaNO3 is required to
dissolve in 100 g of water at 20C?
Problem:
How much KCl will dissolve in 100g of water at
50C?
 6-Amorphous forms and Polymorphic Crystals
Crystalline solids have regular ordered arrays of components held together by uniform
intermolecular forces, whereas the components of amorphous solids are not arranged in
regular arrays

A drug that exists as an amorphous form (non crystalline form) generally dissolves
more rapidly than the same drug in crystalline form
Crystalline solids have low solubility. The insoluble nature is due to the stable crystalline
arrangement and low intermolecular forces between solvent and solute.
Amorphous Novobicin has 10 folds higher solubility than its crystalline form.

Crystalline polymorphs have the same chemical composition, but different internal
Crystal structures, and therefore possess different physicochemical properties
Chloramphenicol exist is A, B and C form and out of this B form is more stable
and most preferable.

Riboflavin has I, II and III forms, and III form shows 20 times more water
solubility than form I.
 7-Molecular structure
Slight modification in the molecular structure of the solids can lead to
marked changes in their solubility and stability in a given solvent.

1-For example, if a weak acid is converted into its salt, its ionic
dissociation in water increases markedly leading to an increase in the
interaction between the solute and the solvent which ultimately leads
to an increase in the solubility
2- Ephedrine is insoluble in water in its pure form but ephedrine-HCl is
soluble in water.
3-Phenobarbital is insoluble in water in its pure form but
phenobarbital sodium is soluble in water.
 8- Solvent Effect and Co-solvent
• The solubility of a solid depends on the nature of the solvent used.
• In general, polar solutes dissolve more readily in polar solvents and non-
polar solutes dissolve more readily in non polar solvents (like dissolves
like).
• Solubility of a solid in a solvent may be altered by the addition of some
other solvent which may bring about changes in the properties of the first
solvent.
• Very often, a mixture of solvents is used to increase the solubility of weak
electrolytes as well as non-electrolytes.
• This phenomenon of increasing solubility of poorly soluble substances by
the use of more than one solvent is known as co-solvency.
• For example, the solubility of weak electrolytes and non-polar molecules
in water may be considerably increased by the addition of co-solvents such
as Ethanol, Glycerol, Propylene Glycol and sorbitol.
 Co-Solvent illustration

• Co-solvents improve solubility between non-miscible phases, as

demonstrated by a solute dissolved in organic solvent but insoluble in
water (left). A co-solvent miscible in both phases and able to dissolve
the solute is added to form a homogeneous solution of water, organic
solvent, and compound (right).
 9- Complex formation
When a third substance is added to the solution, it will form
a complex with solute.
The Complex formation either increases or decreases the
solubility of solute

Eg: Mercuric Iodide is sparingly soluble in water, but its

solubility in water can be increased by forming the complex
with KI.
 10-Ionization of weakly acidic drugs
• According to the Bronsted-Lowry model, an acid is a substance capable of donating a proton
to another substance, such as water :If the weak acid is represented by HA, its ionization in
water may be represented by the equilibrium:
•
The equilibrium constant, Ka, is referred to as the ionization constant, dissociation constant and is given by:

The negative logarithm of Ka is referred to as pKa, i.e. pKa =–logKa. it follows that
the lower the value of pKa the stronger will be the acid and that on a log scale a
difference of one unit in pKa reflects a tenfold difference in acid strength.

Weakly acidic drugs are virtually completely unionized at pHs up to 2 units below their pKa and
virtually completely ionized at pHs greater than 2 units above their pKa. They are exactly 50% ionised at
their pKa values.
 10-Ionization of weakly basic drugs
A base is a substance capable of accepting a proton donated by another substance,
such as water: If the weak base is represented by B, its ionization in water
may be represented by the equilibrium:

The equilibrium constant, Kb, is referred to as the ionization constant, dissociation constant and is given by:

The negative logarithm of Kb is referred to as pKb, i.e. pKb = –logKb.

The percentage ionization at a given pH can be calculated from:

Percentage ionization of weakly acidic and weakly basic drugs as a function of pH.
Relationship b/w pH, pKa and Solubility of drug
• Acidic drugs, such as the non-steroidal anti-inflammatory agents, are
less soluble in acidic solutions than in alkaline solutions because the
predominant un-dissociated species.
• These un-dissociated species cannot interact with water molecules to
the same extent as the ionized form which is readily hydrated.
• The equation relating the solubility, S, of an acidic drug to the pH of
the solution is

S The total solubility of the drug (un-ionized + ionized)

The solubility of the un-ionized form of the drug
Relationship b/w pH, pKa and Solubility of drug

• Basic drugs such as ranitidine are more soluble in acidic

solutions where the ionized form of the drug is
predominant.
• The equation relating the solubility, S, of a basic drug to
the pH of the solution is:
Relationship b/w pH, pKa and Solubility of drug
• Amphoteric drugs such as the sulfonamides and tetracyclines display
both basic and acidic characteristics.
• The zwitterion has the lowest solubility, So, and the variation of
solubility with pH is given by:
Factors affecting solubility of liquid in liquids
 Solubility of liquids in liquids
 Preparation of pharmaceutical solutions involves mixing of 2 or more liquids

 Alcohol & water to form hydroalcoholic solutions

 volatile oils & water to form aromatic waters

 volatile oils & alcohols to form spirits , elixirs

Liquid-liquid systems may be divided into 2 categories:

Systems showing complete miscibility such as alcohol & water,
glycerin & alcohol, benzene & carbon tetrachloride
Systems showing Partial miscibility as phenol and water; two liquid
layers are formed each containing some of the other liquid in the
dissolved state.
The term miscibility refers to the mutual solubility of the components
in liquid-liquid systems.
 + Solubility of liquids in liquids

 Complete miscibility occurs when: The adhesive forces between different

molecules (A-B) >> cohesive forces between like molecules (A-A or B-B).

 Polar and semi-polar solvents, such as water and alcohol, glycerin and alcohol,
and alcohol and acetone, are said to be completely miscible because they mix
in all proportions.

 Nonpolar solvents such as benzene and carbon tetrachloride are also

completely miscible.
 +
Solubility of liquids in liquids
 Partial miscibility results when: Cohesive forces of the constituents of a mixture
are quite different, e.g. water (A) and hexane (B). A-A » B-B.

 When certain amounts of water and ether or water and phenol are mixed, two
liquid layers are formed, each containing some of the other liquid in the
dissolved state.

 The effect of temperature on the miscibility of two-component liquids is

expressed by phase diagrams.

 In the phase diagrams of two-component liquids, the mixture will have an upper
critical solution temperature, a lower critical solution temperature or both.
 1-Temperature
The mutual solubility of partial miscible liquid are affected by
temperature.
Type 1: In binary liquid system such as phenol-water, the solubility of two
phases increase with increase in temperature until a temperature is
reached where homogenous mixture is formed. And this temperature is
called Upper consolute Temperature (UCT).
It is define as the temperature at which two phases merge into a single
phase”
Above this temperature the phenol and water are miscible with each
other at all proportions.
50 °C

At point f

At point b

Temperature–composition diagram for the system consisting of water and

phenol
2-Concentration
 Temperature
Type 2: In binary liquid system such as
trimethylamine and water are completely miscible
by decreasing the temperature, so they have lower
consolute temperature, (LCT). Above this
temperature they are partially miscible with each
other.
This means the two components are miscible in all
proportions below the lower consolute
temperature and above this temperature the two
components produce two liquid phases LCT of 18.5°C

• Phase diagram for the system triethylamine–water showing lower consolute

temperature.
The water–triethylamine system is miscible in all mixing ratios at temperatures less
than 18 °C, but separates into two immiscible phases for a wide range of bulk
compositions as temperature increases through 19–24 °C
• Type 3: Few binary mixture such as
nicotine-water shows both UCT (208°C)
and LCT (60.8 C) with intermediate region.
Such mixture are soluble in all proportion
above UCT and below UCT, while between
UCT and LCT they are partially miscible
with each other

Nicotine–water system showing upper and

lower consolute temperatures.
Questions?