Solubility Determinations

Free pharmacy material

Solubility Determinations

INTRODUCTION

Solubility is defined as the amount of substance dissolved in a given quantity of solvent. This is the main basis for the development of different branches of science such as chemistry, physics, and food science, and pharmaceutical and biological sciences. Especially in pharmaceutical science, it is most important because the bioavailability of the drug depends mainly on the solubility. This solubility phenomenon mainly helps in

• Selecting the appropriate solvent
• Overcoming the problems arising during preformulation
• Providing intermolecular forces of the drug

For the solubility phenomenon, the following terms are generally used:

• Solute: the substance which is dissolved in the solvent.
• Solvent: the substance which is dissolving the solute.
• Solution: it is a homogenous mixture of two or more components, i.e., one is a solute and the other is a solvent.

CLASSIFICATION OF SOLUTIONS

Based on the saturation, the solutions are of three types:

1. Saturated solution: both the concentrations of solute and solvent are at equilibrium.
2. Supersaturated solution: solute concentration is high.
3. Unsaturated solution: solute concentration is low.

Based on the parts of the solvent required to dissolve the solute, the solutions are again classified into the following:

• Very soluble—less than one part of solvent is required
• Freely soluble—1 to 10 parts
• Soluble—10 to 30 parts
• Sparingly soluble—30 to 100 parts
• Slightly soluble—100 to 1,000 parts
• Very slightly soluble—1,000 to 10,000 parts
• Practically insoluble—more than 10,000 parts

Based on the solute dissolved in the solvent again solutions are classified into the following:

• Gases in liquids—e.g. ammonia dissolved in water
• Liquids in liquids—e.g. alcohol dissolved in water
• Solids in liquids—e.g. KOH dissolved in water

Solubility is expressed by the following terms:

• Molarity (M): This is the concentration expression which expresses moles of solute in 1 litre of solution.
• Molarity (M) = moles of solute/1 litre of solution
• Normality (N): This is also the concentration expression which expresses gram equivalent weight of solute in 1 litre of solution.
• Normality (N) = gram equivalent of solute/1 litre of solution
• Molality (m): This is the concentration expression which expresses moles of solute in 1 kg of solution.
• Molality (m) = moles of solute/1 litre of solution
• Mole fraction (XA): Mole fraction is the number of moles of one component divided by the moles of all the components of the solution. When solute A is dissolved in solvent B, it forms the solution AB. Then the mole fraction
• XA = no. of moles of A /no. of moles of AB
• The sum of all components of mole fractions must be equal to 1.
• XA + XB = 1
• Percentage (%): This will describe the amount of solute dissolved in 100 parts of solution.
• % = grams of solute/100 parts of solution
• % mass/mass (w/w) – 1 gram of the solute in 100 gram of the solution.
• % w/w = (g of solute/100 g of solution) × 100%
• % mass/volume (w/v) – 1 gram of the solute in 100 ml of the solution.
• % w/w = (g of solute/100 ml of solution) × 100%
• % volume/volume (v/v) – 1 ml of the solute in 100 ml of the solution.
• This is mainly used when the solute is liquid.
• % w/w = (ml of solute/100 ml of solution) × 100%

Mechanism of Action of the Solvent on the Solute

The solubility of the solute in the solvent mainly depends on whether the nature of the solvent is polar or non-polar. While polar solvents dissolve the ionic solutes and other polar solutes, non-polar solvents dissolve non-ionic and non-polar solutes. The mechanism of the polar solvents mainly depends on the following:

• High dielectric constant which reduces the attraction between the oppositely charged particles. For example, H2O has a dielectric constant of 80 which can dissolve the NaCl where other solvents which are of low dielectric constant should not dissolve the NaCl.
• By hydrogen bond formation
• Dipole interaction

The mechanism of the non-polar solvents depends upon the weak van der Waal's forces. For example, oils are dissolved in the carbon tetra chloride.

FACTORS AFFECTING SOLUBILITY

There are mainly three factors which affect solubility. They are as follows:

1. Temperature: solubility is directly proportional to the temperature; this means that if the tem perature increases, solubility also increases. But in some cases solubility is decreased upon increasing the temperature.
2. For example, solubility of calcium oxide decreases with increase in the temperature.
3. Nature of the solvent: polarity of the solute as well as the polarity of the solvent affects the solubility.
4. For example, polar solvents dissolve polar solutes.
5. Non-polar solvents dissolve non-polar solutes.
6. Effect of pressure: this factor mainly affects the solubility of gases. Solubility of the gases is increased by the increase in the pressure.
7. For example, carbon dioxide gas dissolves in liquids for effervescent preparations under pressure.

Mechanism of Solubility

The solute is dissolved in the solvent by the following three steps.

1. The solute particle intermolecular bonds break down between two adjacent molecules.
3. 
5. Solubility mechanism step(1)
7. In the second step, the solvent creates a gap itself to bind the solute molecule.
9. 
11. Solubility mechanism step (2)
13. Finally, the solute molecule is placed in the gap present in the solvent molecule.
15. 
17. Solubility mechanism step (3)

THEORY

The dissolving process involves the consideration of the three intermolecular attractive forces. They are as follows:

1. Solute-solvent interaction forces
2. Solvent-solvent interaction forces
3. Solute-solute interaction forces

A solute will be freely dissolved when the solute–solvent forces are greater than that of the solute–solute interactions and solvent–solvent interactions.

Solubility Rules

1. Compounds of Group I and ammonium ions are soluble.
2. Nitrates, acetates and chlorates are soluble.
3. Binary compounds of the halogens (other than F) with metals are soluble, except those of Ag, Hg (I), and Pb. Pb halides are soluble in hot water.
4. Sulphates are soluble, except those of barium, strontium, calcium, lead silver and mercury (I). The latter three are slightly soluble.
5. Except for rule 1, carbonates, hydroxides, oxides, silicates and phosphates are insoluble.
6. Sulphides are insoluble except for calcium, barium, strontium, magnesium, sodium, potassium and ammonium.

Solubility Equilibrium

When a salt dissolves in water which dissociates the salt into ions and the solution contains the equal amount of the positive and negative ions, it is called the solubility equilibrium state which is reversible.

The solubility equilibrium is denoted by the solubility product Ksp.

Ksp = [Mg+2][OH −]2

Solubility Test Methods

The solubility is determined by the two simple methods:

1. Column elution method: This method is based upon the elution of the sample in water or any other solvent from a micro column which is charged with support material.
3. 
5. Column elution method
7. Flask method: In this method, the sample is dissolved in the water at constant temperature or by increasing the temperature gradually.

Solubility Enhancement Techniques

The following are the methods to increase the solubility of the poorly soluble compounds.

• PH adjustment: The PH adjustment of the sample solution by the addition of the buffer solution increases the solubility of the poorly soluble compounds.
• Co-solvency: The solubility of the poorly soluble compounds is enhanced by the addition of co-solvents. Co-solvents are the mixture of water and water miscible solvents.

Examples:	PEG-300
	Ethanol
	Propylene glycol
	Dimethyl sulfoxide
	Dimethyl acetamide

Particle size reduction: The particle size reduction reduces the particle size and increases the surface area which improves the solubility.

Hydrotrophy: This is a solubilization process by the addition of a large amount of the second solute to the sample solution.

APPLICATIONS

• Used for the study of the bioavailability of the drug
• Used for the development of different dosage forms based on the solubility of active pharmaceutical ingredient
• Used for common salt purificationa
• Salting out of the soap
• Used in the manufacture of baking soda

REVIEW QUESTIONS

1. What is solubility?
2. Classify the solutions.
3. What are the different solubility expressions?
4. What are the different mechanisms involved in solubility?
5. What are the factors affecting solubility?
6. What are the solubility rules?
7. How do you enhance solubility?