Physical pharmacy Dr. Khaled Sh.

Shamareekh
Lectures (2)

Solubility and solutions

Determination of the solubility of a solid in a liquid

The solubility is determined when the solution becomes saturated that can be obtained either:

1. by stirring excess solute with solvent until attaining the equilibrium (for hours),

2. by warming the solvent with excess of the solute and allowing the mixture to cool.

Then, a sample is taken from the saturated solution for analysis; filtration is usually used to
separate the undissolved amount of solute.

The concentration of solute may be determined by gravimetric analysis, UV spectrophotometry

and HPLC, etc.

 Tip: the accurate determination of the solubility of a substance is one of the best
methods for determining its purity.

Factors affecting the solubility

 Temperature and heat input

In the endothermic type of dissolution, the supply of heat will increase the solubility of solute.

Conversely, in the case of exothermic dissolutions, the supply of heat will decrease the
solubility.

Most of the temperature-solubility curves are continuous. However, sudden change could
occur with some materials, if a change occurs in their nature under effect of the heat.
Physical pharmacy Dr. Khaled Sh. Shamareekh
Lectures (2)

 For example,

sodium sulfate decahydrate

Na2SO4.10H2O, its solubility
increases until 32.5 °C. Above 32.5
°C it is converted into the
anhydrous form (Na2SO4) that is of
an exothermic dissolution.

Therefore, the solubility exhibits a

change from a positive to a negative
trend as the temperature exceeds
the transition value.

 Molecular structure of solute

The influence of substituents on the Solubility curves for various substances in water

solubility in water can be due to their

effect either: 1) on the properties of the solid on its molecular cohesion or 2) on its interaction
with water molecules.

Substituents can be hydrophobic or hydrophilic:

 Polar groups, such as –OH, capable of

hydrogen bonding with water molecules
impart high solubility. For example, the
introduction of –OH to the benzene
molecule increases the water solubility
by the more than 100-fold the phenol
(benzene–OH).
Physical pharmacy Dr. Khaled Sh. Shamareekh
Lectures (2)

 Non-polar groups, such as –CH3 and –Cl, are hydrophobic and impart low solubility.
 Ionisation of the substituent increases solubility, e.g. –COOH and –NH2 are slightly
hydrophilic whereas –COO– and –NH3+ are very hydrophilic.
 The position of the substituent on the molecule can influence its effect on solubility, for
example the aqueous solubilities of pentanol isomers in table below.

Solubilities of pentanol isomers in water

 pH of solution

pH is one of the primary influences on the solubility of drugs that contain ionisable groups

Acidic drugs, such as the non-steroidal anti-inflammatory drugs (NSAIDs), are soluble in alkaline
media where the ionized form is the predominant.
Physical pharmacy Dr. Khaled Sh. Shamareekh
Lectures (2)

Basic drugs such as ranitidine are more soluble in

acidic solutions where the ionized form of the drug
is predominant.

Amphoteric drugs such as the sulfonamides and

tetracyclines display both basic and acidic
characteristics.

approaches of improvement of aqueous solubility:

 Co-solvency
- The weak electrolytes or non-polar compounds are often poorly water-soluble.

- Their solubility can be improved by addition of another solvent (called cosolvent) that is
miscible with water.

- Often, the solubility in mixed system is greater than the material's solubility in each
individual solvent.

- The most co-solvency system widely used is a water/ethanol mixture. Other suitable
solvents for use with water include sorbitol, glycerol, and propylene glycol.

Examples: 1) the solubility of cotrimoxazole is improved in a mixture of propylene glycol and

water.
2) paracetamol is formulated as an elixir using alcohol, propylene glycol and syrup.
3) betamethasone valerate is dissolved in a water/isopropyl alcohol mixture.
Physical pharmacy Dr. Khaled Sh. Shamareekh
Lectures (2)

 pH control

The solubility of drugs that are weak acids or weak bases is often poor, which is dependent on
the pH of solution.

The solubility of a weak base can be increased by lowering the pH of solution, whereas the
solubility of a weak acid is improved by increasing the pH.

The chosen pH to improve the drug solubility must do not conflict with other components and
affect their stability.

The pH of solutions could be maintained at the desired value using buffers, such as carbonate,
acetate and borate buffers.

 Complexation

In some cases, the poorly soluble drug can be interacted with a water-soluble molecule forming
a soluble intermolecular complex.

However, the formation of this complex should be reversible, allowing the free drug to be
released for offering its therapeutic effect.

The complexation of iodine with a 10-15% solution of povidone (iodine povidone) to improve
the aqueous solubility of iodine.

 Chemical modification

Chemical modification of a drug may be necessary to produce a water-soluble derivative.

Physical pharmacy Dr. Khaled Sh. Shamareekh
Lectures (2)

The chemical modification must don’t reduce the therapeutic effect of drug.

Examples include the synthesis of the sodium phosphate salts of hydrocortisone, prednisolone
and betamethasone.