SOLUBILITY

Introduction

The therapeutic effectiveness of any drug and any new chemical entity depends upon its
bioavailability and thus ultimately upon the solubility of those drug molecules. Solubility is
one of the key parameter to achieve the desired concentration of drug in the systemic
circulation to show its pharmacological response.
Solubility

- maximum quantity of solute that can dissolve in a certain amount of solvent at a specific
temperature.

a. SOLVENT
- It is the component which forms the main constituent of a solution and it is also capable
of dissolving another substance to form a consistently disperse mixture at a molecular
level.

b. SOLUTE
- It is a substance which is present in small quantity and dissolves in the solvent

Definition of solubility
Definition Parts of solvent required for one part of solute
Very soluble <1
Freely soluble 1-10
Soluble 10-30
Sparingly soluble 30-100
Slightly soluble 100-1000
Very slightly soluble 1000-10,000
Insoluble >10,000

PROCESS OF SOLUBILISATION
The process of solubilisation involves three steps:

 The separation of solvent molecules to provide the space in the solvent for solute.
 The breaking of the intermolecular bonds or inter-ionic bonds in the solute.
 The interaction between the separated solvent molecules and the broken solute molecules
or ion.

Importance of Solubility
Solubility is one of the key parameter to achieve the desired concentration of drugs or
active ingredient in the systemic circulation, in turn, the amount of active ingredient liberated will
define how much drug is bioavailable.

Bioavailability can be defined as the rate and extent of the therapeutically active drug
that
reaches to the systemic circulation in the unchanged form and is available at the site of
action.
 The absorption of drugs from the GI tract can be affected by various factors, most
significantly by poor aqueous solubility and by the poor membrane permeability of the drug
molecule. Thus, when any drug or an active agent is administered orally, it must first get
dissolved in the gastric or in the intestinal fluids before it get permeated through the membranes
of the GIT to reach the systemic circulation. Thus, to improve the oral bioavailability of drugs or
active agents, there is a need to increase the solubility and dissolution rate of poorly water
soluble drug candidates.

FACTORS AFFECTING SOLUBILITY

There are a lot of other factors which affects the process of solubility like:

1. Particle Size
The size of the solid particles affects the solubility because with the decrease in particle
size, the surface area to volume ratio increases. The larger surface area of solute molecules
allows more interaction with the solvent.

2. Molecular Size
The molecular size will affect the solubility of the drug as larger the molecule or higher
the
molecular weight of the drug, less is the solubility of that substance. In organic compounds,
the amount of carbon branching increases the solubility because more branching will reduce
the size of molecule and also make it easier for the solvent to solvate the molecules.

3. Temperature
With the increase in temperature the process of solution absorbs the energy and thus
the
solubility will get increased but if the process of solution releases the energy with the
increase in temperature then it will decrease the solubility. Only a few solid solutes are there
which are less soluble in warm solutions. In case of gases, the solubility get decreased when
temperature of solution is increased.

4. Pressure
In case of solids and liquid solutes, there is no effect of pressure on the solubility but in
case of gaseous solutes, when the pressure is enhanced, there is an increase in the solubility
and with the decrease in pressure there is a decrease in solubility.

5. Nature of solute and solvent

There is a lot of difference in the solubility of two or more different substances on the
basis
of their natures. For example: In 100 grams of water at room temperature only 1 gram of
Lead(II)chloride can be dissolved where 200 grams of Zinc chloride can be dissolved in same
amount of water i.e. 100 grams of water at same room temperature.

6. Polarity
The polarity of solute and the solvent molecules will affect the process of solubility.
Generally, the polar solute molecules get dissolved in polar solvent system and nonpolar
solute molecules get dissolved in nonpolar solvent system. Thus if the solute molecule is
polar in nature it must have both positive and negative ends and if the solvent is also of polar
nature then it also consist of both the ends, thus the positive ends of solute molecule gets
attracted towards the negative ends of the solvent molecules. These type of attractions are
known as dipole-dipole interactions which is a type of intermolecular force.

7. Polymorphs
Solids have a rigid form and a definite shape. The shape or crystal habit of a given solid
may vary but angles between the faces remains constant. A crystal is made up of ions, atoms or
molecules in a lattice or in a regular geometric arrangement constantly repeated in three
dimensions. This repeating arrangement is known as the unit cell. The ability of a substance
to crystallize in more than one crystalline form is known as polymorphism. The polymorphs
can vary in their melting points. As, the melting point of any solid is related to its solubility,
the polymorphs will have different solubility.

8. Rate of solution
The rate of solution can be defined as the measure of how fast the substance dissolves in a
solvent. The various factors that affect the rate of solution are:-
 size of particles
 temperature
 amount of solute already dissolved
 stirring

9. Salt formation
The dissolution rate of different salts is usually different from their parent compounds.
The potassium and sodium salts of the weak acids dissolves rapidly than the pure salts.
Example, salt form of various drugs like aspirin, barbiturates, theophylline etc. Thus it is the
most effective and common method to increase the solubility as well as dissolution rate of any
acidic or basic drugs

Solubility of Liquids in Liquids

Frequently two or more liquids are mixed together in the preparation of pharmaceutical
solutions. For example, alcohol is added to water to form hydroalcoholic solutions of various
concentrations; volatile oils are mixed with water to form dilute solutions known as aromatic
waters; volatile oils are added to alcohol to yield spirits and elixirs; ether and alcohol are
combined in collodions; and various fixed oils are blended into lotions, sprays, and medicated
oils. Liquid–liquid systems can be divided into two categories according to the solubility of the
substances in one another: (a) complete miscibility and (b) partial miscibility. The term
miscibility refers to the mutual solubilities of the components in liquid–liquid systems.

Complete Miscibility
Polar and semipolar 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.
Completely miscible liquid mixtures in general create no solubility problems for the pharmacist
and need not be considered further.

Partial Miscibility
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 phenol–
water system has been discussed in prelim (under phase rule) It is sufficient here to reiterate
the following points. (a) The mutual solubilities of partially miscible liquids are influenced by
temperature. In a system such as phenol and water, the mutual solubilities of the two conjugate
phases increase with temperature until, at the critical solution temperature (or upper consolute
temperature), the compositions become identical. At this temperature, a homogeneous or
single-phase system is formed.