where Sa is the solubility in the presence of an additive, S is the solubility in its absence, ca is the concentration of additive, and k is the salting coefficient. The sign of k is positive when the activity coefficient is increased; it is negative if the activity coefficient is decreased by the additive. The Setschenow equation frequently holds up to additive concentrations of 1 mol dm -3, a measure of the sensitivity of the activity coefficient of the solute towards the salt.


Several salts with large anions or cations which are themselves very soluble in water result in salting in, i.e. solubilisation of nonelectrolytes. Sodium benzoate and sodium p-toluenesul-fonate are good examples of such agents and are referred to as hydrotropic salts; the increase in the solubility of other solutes is known as hydrotropy. Values of k (in (mol dm -1) for three salts added to benzoic acid in aqueous solution are 0.17 for NaCl; 0.14 for KCl; and -0.22 for sodium benzoate. That is, NaCl and KCl decrease the solubility of benzoic acid, and sodium benzoate increases it.

5.2.4 The effect of pH on the solubility of ionisable drugs pH is one of the primary influences on the solubility of most drugs that contain ionisable groups. As the great majority of drugs are organic electrolytes, there are four parameters which determine their solubility:

• Their degree of ionisation

• Their molecular size

• Interactions of substituent groups with solvent

• Their crystal properties

In this section consideration is given to the solubility of weak electrolytes and the influence of pH on aqueous solubility, important in both formulation and dissolution of drugs in vivo, and ultimately and importantly their biological activity.

Acidic drugs

The object of this section is to obtain an equation to relate drug solubility to the pH of the solution and to the pKa of the drug.

Acidic drugs such as the nonsteroidal antiinflammatory agents, are less soluble in acidic solutions than in alkaline solutions because the predominant undissociated species cannot interact with water molecules to the same extent as the ionised form, which is readily hydrated.

If we represent the drug as HA and the total saturation solubility of the drug as S, and if S0 is the solubility of the undissociated species HA, it is clear that the total solubility is the sum of the solubility of the unionised and ionised species, that is

S = S0 + (concentration of ionised species)

The dissociation of the acid in water can be written

and the dissociation constant Ka is given by

Rearranging and substituting S0 for [HA] gives

0 0

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