Percentage Ionization Of Indomethacin And Ephedrine

A plot of percent ionization versus pH illustrates how the degree of ionization can be shifted significantly with small changes in pH. The curves for an HA acid (indomethacin) and BH_ (protonated ephedrine, Table 2.1, reaction m) are shown in Figure 2.4. First, note that when pH = pKa, the compound is 50% ionized (or 50% un-ionized). In other words, when the pKa is equal to the pH, the molar concentration of the acid equals the molar concentration of its conjugate base. In the Henderson-Hasselbalch equation, pKa = pH when log [conjugate base]/[acid] = 1. An increase of 1 pH unit from the pKa (increase in alkalinity) causes an HA acid (indomethacin) to become 90.9% in the

Figure 2.4 • Percent ionized versus pH for indomethacin (pKa 4.5) and ephedrine (pKa 9.6).

ionized conjugate base form but results in a BH_ acid (ephedrine HCl) decreasing its percent ionization to only 9.1%. An increase of 2 pH units essentially shifts an HA acid to complete ionization (99%) and a BH_ acid to the nonionic conjugate base form (0.99%).

Just the opposite is seen when the medium is made more acidic relative to the drug's pKa value. Increasing the hydrogen ion concentration (decreasing the pH) will shift the equilibrium to the left, thereby increasing the concentration of the acid and decreasing the concentration of conjugate base. In the case of indomethacin, a decrease of 1 pH unit below the pKa will increase the concentration of un-ionized (protonated) indomethacin to 9.1%. Similarly, a decrease of 2 pH units results in only 0.99% of the indomethacin being present in the ionized conjugate base form. The opposite is seen for the BH_ acids. The percentage of ephedrine present as the ionized (protonated) acid is 90.9% at 1 pH unit below the pKa and is 99.0% at 2 pH units below the pKa. These results are summarized in Table 2.4.

With this knowledge in mind, return to the drawing of amoxicillin. At physiological pH, the carboxylic acid (HA acid; pKa1 2.4) will be in the ionized carboxylate form, the primary amine (BH_ acid; pKa2 7.4) will be 50% protonated and 50% in the free amine form, and the phenol (HA acid; pKa3 9.6) will be in the un-ionized protonated form. Knowledge of percent ionization makes it easier to explain and predict why the use of some preparations can cause

Indomethacin

TABLE 2.4 Percentage Ionization Relative to the pKa

Ionization (%)

HA Acids

BH Acids

TABLE 2.4 Percentage Ionization Relative to the pKa

Ionization (%)

HA Acids

BH Acids

pKa

- 2 pH units

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