Ionization and pKa Value

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Chapter: Medicinal Chemistry : Ionization and pKa Value

If the biological activity of a drug results from ions, the activity intensifies with increase in the degree of ionization.

Ionization and pKa Value


If the biological activity of a drug results from ions, the activity intensifies with increase in the degree of ionization. However, if the activity results from undissociated molecules, increase in the degree of ionization of active compounds causes a decrease in activity.

Increase in ionization intensifies a drug’s water solubility and decreases its liposolubility. In general, drugs cross cellular membranes in undissociated forms as intact molecules and act in dissociated forms as ions. This happens because the passage of ions across the cellular membrane is prevented by two factors.

1.          The cellular membrane is made up of layers of electrically charged macromolecules (lipids, proteins, and muco polysaccharide) that attract or repel ions.

2.          Hydration of ions increases their volumes rendering difficult their diffusion through pores.

Weakly acidic drugs are predominantly of the unionized form at lower pH of the gastric fluid, and absorbed from the stomach as well as intestine. Some very weak acidic drugs, such as phenytoin and many barbiturates, whose pKa values are greater than 7, are essentially unionized at all pH values. Therefore, for these weak acidic drugs transport is more rapid and independent of pH.

Most weak bases are poorly absorbed in the stomach since they are present largely in the ionized form at low pH. Strong base, those with pKa values between 5 and 11, shows pH dependent absorption. Stronger base, such as guanithidine (pKa > 11), are ionized throughout the gastrointestinal tract and tend to be poorly absorbed.




The partially lipidic nature of cellular membranes, such as the ones that enwrap the stomach, small intestine, mucosa, and nervous tissue facilitate the passage of drugs with high liposolubiltiy across them. The liposolubiltiy is affected by pH of the environmental medium and by the degree of dissociation pKa. Usually, drugs are weak acids or weak base. The degree of dissociation, pKa, is calculated from the following Henderson–Hasselbalch equation.

The biological activity of certain acids and bases is directly related to their degree of ionization. Whereas some (e.g. phenols, carboxylic acids) act in the molecular form, others (quaternary ammonium salts) act in an ionized form. In these cases, the pH plays an important role, that is, acids are more active at lower pH; bases are more active at higher pH.

           Strong acid has low pKa value

           Weak acid has high pKa value

           Strong base has high pKa value

           Weak base has low pKa value


Drug Exerting Action as Undissociated Molecules

In a large number of potent medical compounds, the dissociation plays a vital role for their respective biological characteristics. The unusual structural grouping in the tetracycline results in three distinct acidity constants in aqueous solutions of the acid salts. The particular functional groups responsible for each of the thermodynamic pKa value have been determined by Lessen et al, as described in Figure 4.1.

The approximate pKa values for each of these groups in the four commonly used tetracyclines are shown in Table 4.1.

Besides the activities of several local anaesthetics, d-tubocurarine and phenol have also been proved to be related to their degree of ionization.


Drug Exerting Action as Ionized Molecules

A plethora of medicinal compound exerts their pharmacodynamic action exclusively as the ionized molecule, namely, acetylcholine, quartenary salts as ganglionic blocking agents, muscle relaxants, and antiseptics.


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