Hoocch2nh oh

This compound can exist as a cation, as a zwitterion, or as an anion depending on the pH of the solution. The two pKa values of glycine are >2 pH units apart and hence the distribution of the ionic species will be similar to that shown in Fig. 3.7.

At a particular pH, known as the isoelectric pH or isoelectric point, pHj, the effective net charge on the molecule is zero. pHi can be calculated from pHi =

basic

Figure 3.8 Distribution of ionic species for the zwitterionic ampholyte labetalol.

Redrawn from A. Pagliara, P.-A. Carrupt, G. Caron, P. Gaillard and B. Testa, Chem. Rev., 97, 3385 (1997).

Small ApKa. In cases where the two pKa values are <<2 pH units apart there is overlap of the ionisation of the acidic and basic groups, with the result that the zwitterionic electrolyte can exist in four different electrical states - the cation, the unionised form, the zwitterion, and the anion (Scheme 3.3).

In Scheme 3.3, (ABH)& is the zwitterion and, although possessing both positive and negative charges, is essentially neutral. The unionised form, (ABH), is of course also neutral and can be regarded as a tautomer of the zwitterion. Although only two dissociation constants Kfldic and Kbasic (macrodissociation constants) can be determined experimentally, each of these is composed of individual microdissociation constants because of simultaneous ionisation of the two groups (see section 3.5.5). These microdissociation constants represent equilibria between the cation and zwitterion, the anion and the zwitterion, the cation and the unionised form, and the anion and the unionised form. At pHi, the unionised form and the zwitterion always coexist, but the ratio of the concentrations of each will vary depending on the relative magnitude of the microdissociation constants. The distribution of the ionic species for labetalol which has pKfidic = 7.4 and Kbasic = 9.4 is shown in Fig. 3.8.

Figure 3.8 Distribution of ionic species for the zwitterionic ampholyte labetalol.

Redrawn from A. Pagliara, P.-A. Carrupt, G. Caron, P. Gaillard and B. Testa, Chem. Rev., 97, 3385 (1997).

Examples of zwitterionic drugs with both large and small ApKa values are given in Box 3. 9; others can be noted in Table 3.6.

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