Solubility-Chapter 10 Lec.

1
Advantages of studying solubility
1-It permits us to choose the best solvent for drug or combination of drugs.
2- Overcome certain difficulties that occur in the preparation of pharmaceutical
solutions
3- Test of purity

Definitions
Solubility is defined in a qualitative way; it can be defined as the spontaneous
interaction of two or more substances to form a homogeneous molecular dispersion
, and in quantitative terms as the concentration of solute in a saturated solution at a
certain temperature
A saturated solution is one in which the solute in solution is in equilibrium with the
solid phase at certain temperature.
OR
A solution that contains the maximum amount of solute that the solvent can dissolved
at the given temprature. Any more solute added will sit as crystals on the bottom of the
container.

An unsaturated 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 is one that contains more of the dissolved solute than it
would normally contain at a definite temperature,
Supersaturated solutions are made by dissolving a solute in the solution at an elevated
temperature. If we slowly cool the mixture back to 25 °C, the solute should precipitate
But there are some example out of this rule
Ex. Sodium thiosulfate and sodium acetate can be dissolved in large amounts at an
elevated temp. and upon cooling, fail to crystallize from the solution. Nothing will
happen until you add a seed crystal. If you drop on some solute into the super
saturated solution, it will cause the rest of the salt to come out to

1
Solubility Expressions
The solubility of a drug may be expressed in a number of ways. The United States
Pharmacopeia (USP) describes the solubility of drugs as
- Parts (mls) of solvent required for one part solute.(accurate way) or
- By the use of certain general terms The USP describes solubility using the seven
groups listed in Table below.

Description Forms (Solubility Definition) Parts of Solvent Required for One Part of Solute
Very soluble (VS) <1
Freely soluble (FS) From 1 to 10
Soluble From 10 to 30
Sparingly soluble (SPS) From 30 to 100
Slightly soluble (SS) From 100 to 1000
Very slightly soluble (VSS) From 1000 to 10,000
Practically insoluble (PI) >10,000

- Solubility is also quantitatively expressed in terms of molality, molarity, and

percentage.

The process of solubility can be summerised as follow :-

1- A solute ( drug molecule)is removed from its crystal
That is mean the cohesive forces between its molecules
must be broken
2- A cavity for the molecule is created in the solvent.
3- The solute molecule is inserted into the cavity.
That is mean adhesive forces between solute and solvent must be formed

Solvent–Solute Interactions
In general the solubility of a solute in a solvent may be predicted by solute- solute,
solvent-solvent and solute-solvent interaction
- Adhesive forces  cohesive forces → increase solubility
- Crystalline solids have low solubility. The insoluble nature is due to the stable
crystalline arrangement and low intermolecular forces between solvent and solute
-  melting point → solubility (for solid)
- boiling point → miscibility ( for liquid)

Solvents
The pharmacist knows that water is a good solvent for salts, sugars, and similar
compounds, whereas mineral oil is often a solvent for substances that are normally
only slightly soluble in water. These empirical findings are summarized in the
statement, “like dissolves like.” Such a maxim is satisfying to most of us, but the
inquisitive student may be troubled by this vague idea of “likeness.”

2
Types of solvents
Polar solvents, Semipolar solvents, Nonpolar solvents

Polar Solvents
The solubility of a drug is due in large measure to the polarity of the solvent, that is, to
its dipole moment.

Measurement of polarity
Polarity of the solvents can be measured by the use of Dielectric constant €:- which
indicate the ability of solvent to separate two oppositely charged ions. The higher
dielectric constant of a solvent, the easier (higher ability) to separate two oppositely
charged ions

Dielectric
constant €
Approximate
Solvent Solute
Decreasing 80 Water Inorganic salts, organic salts Decreasing
Polarity Water
Solubility
↓ 50 Glycols Sugars, tannins ↓
30 Methyl and ethyl Caster oil, waxes
alcohols
20 Aldehydes, ketones, Resins, volatile oils, weak
and higher alcohols, electrolytes including
ethers, esters, and barbiturates, alkaloids, and
oxides phenols
5 Hexane, benzene, Fixed oils, fats, petrolatum,
carbon tetrachloride, paraffin, other hydrocarbons
ethyl ether,
petroleum ether
0 Mineral oil and fixed
vegetable oils

Polar solvents as water act as a solvent for the following compounds by the following
mechanisms
a-They dissolve ionic compounds such as sodium chloride due to their high
dielectric constant.
- They reduce the force of attraction between oppositely charged ions
(sodium chloride)insoluble in chloroform € = 5, or benzene € = 2

3
 - Polar solvents are capable of solvating molecules and ions through dipole
interaction forces (ion dipole)
The solute must be polar in nature since it must compete for the bonds that
already associated solvent molecules

b-It dissolves alcohols, aldehydes, ketones, amines, sugars due to formation of

hydrogen bonds

c- Polar solvents break covalent bonds of strong electrolytes by acid-base reaction

since these solvents are amphoteric in nature

HCl+H2O H3O+ + Cl-

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.
CH3CH2OH CH3CH2CH2 CH2CHCH2
OH OH OH OH OH
Ethanol Glycol Glycerin
lowest solubility Highest solubility

4
 Branching of the carbon chain reduces the nonpolar effect and leads to
increased water solubility. Because branching will decrease the size or
volume of the molecule and make it easier to solvate the molecule with
the solvent

CH3
CH2 C OH CH3CHCH2OH CH3CH2CH2CH2OH
CH3 CH3
Highest solubility Lowest solubility

CH3CHCH2CH3 CH3CH2CH2CH2OH
OH
More soluble

➢ Solubility is affected by molecular size of particle. The solubility of the

substance is decreased when molecules have higher molecular weight and
high molecular size because larger molecules are more difficult to be
surrounded with the solvent molecules in order to solvate substance

CH3CH2CH2OH CH3CH2CH2CH2OH
More soluble

Semipolar Solvents
Semipolar solvents, such as ketones and alcohols, can induce a certain degree of
polarity in nonpolar solvent molecules. In fact, semipolar compounds can act as
intermediate solvents to bring about miscibility of polar and nonpolar liquids.
Accordingly, acetone increases the solubility of ether in water. Other examples an
intermediate solvent action of alcohol on water–castor oil mixtures and the action of
propylene glycol on increasing the mutual solubility of water and peppermint oil and
of water and benzyl benzoate.
Nonpolar solvents:-
These solvents have the following properties:-
1- They are unable to reduce the attraction between ions of strong and weak
electrolytes because of low dielectric constant
2- Cannot break the covalent bonds
3- Cannot form hydrogen bonds
Therefore non polar solvents can dissolve the nonpolar solute by weak vander Waals
London forces