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Many drugs are ionisable compounds and can exist as weak acids or bases. The solubility of a weak acid/base is highly dependent upon the pH of the solvent. As the pH changes along the gastrointestinal tract from the acidic conditions within the stomach to the neutral environment within the small intestine the impact of the pH of the solvent on the drug solubility needs to be understood. This is of greatest importance for weakly basic drugs as their solubility reduces within the small intestine which is the major site for drug absorption. Figure 4.2 shows the impact of pH on the solubility of a weakly acidic and a weakly basic compound.

Figure 4.2 Impact of pH on solubility of a weakly acidic and a weakly basic drug.

Very small changes in pH can have a major impact on the solubility of an ionisable drug. Solubility measurements are usually undertaken in buffered solutions to prevent small changes in pH affecting the measurement obtained.

pH solubility measurements are usually performed early in the drug development process to understand risks and whether there are drug candidates with favourable pH solubility profiles (see Chapter 7).

The pK_a of the drug is another useful drug characteristic to understand the impact of pH on solubility as this is linked via the Henderson–Hasselbach equation.

As well as the influence of pK_a on solubility it is important to note that it is the undissociated form that more readily penetrates biological tissues to exert a therapeutic effect. As the equilibrium between the dissociated and undissociated fractions is constant, it can be assumed that the undissociated permeated material will be replenished to maintain equilibrium and thus absorption can occur for both weak acids and weak bases.