Constant Ionic Medium Reference State

The ionization reactions for acids, bases, and ampholytes (diprotic) may be represented by the generic forms

Listed after the reactions are the corresponding equilibrium quotients. The law of mass action sets the concentration relations of the reactants and products in a reversible chemical reaction. The negative log (logarithm, base 10) of the quotients in Eqs. (3.1)-(3.4) yields the familiar Henderson-Hasselbalch equations, where "p" represents the operator "-log:"

pKa = pH + log pKa = pH + log pKai = pH + log pKa2 = pH + log

Equations (3.5)-(3.8) indicate that when the concentration of the free acid, HA (or conjugate acid, BH+), equals that of the conjugate base, A- (or free base, B), the pH has the special designation, pKa. If the pH is two units lower than the pKa for an acid, Eq. (3.5), [HA]/[A-] = 100, and the uncharged species accounts for 100/101

(99%) of the total substance in solution. If the pH is two units higher than the pKa, then it is the anion that accounts for 99% of the total.

Ibuprofen (HA) has a pKa 4.45 ± 0.04 [149] determined at 25°C and ionic strength I 0.15 M (fixed by KCl). Chlorpromazine (B) has a pKa 9.24 ± 0.01 at 25°C, I 0.15 M (NaCl) [150]. Morphine (XH) has pKa1 8.17 ± 0.01 and pKa2 9.26 ± 0.01 at 25°C, 10.15 M (NaCl) [151].

All equilibrium constants in the present discussion are based on the concentration (not activity) scale. This is a perfectly fine thermodynamic scale, provided the ionic strength of the solvent medium is kept fixed at a "reference" level ( and therefore sufficiently higher than the concentration of the species assayed). This is known as the ''constant ionic medium" thermodynamic state. Most of the results reported these days are determined in 0.15 M KCl or NaCl, the physiological level, because of standardization in the available commercial instruments. If the ionic strength is changed, the ionization constant may be affected. For example, at ionic strength of 0.001 M, morphine pKa values were determined to be 8.13 ± 0.01 and 9.46 ± 0.01 [151]. The change in the second constant illustrates the need to report the ionic strength (and the temperature, since constants are also temperature-dependent) [34,35].

The ionic strength dependence of ionization constants can be predicted by the Debye-Hiickel theory [34,35]. In the older literature, values were reported most often at ''zero sample and ionic strength" and were called the "thermodynamic" constants. The constants reported at 0.15 M ionic medium are no less thermo-dynamic. Nevertheless, a result determined at 0.15 M KCl background, can be corrected to another background salt concentration, provided the ionic strength is within the limitations of the theory (<0.3 M for the Davies [152] variant of the Debye-Huckel expression). It is sometimes convenient to convert constants to ''zero ionic strength'' to compare values to those reported in older literature. A general ionic strength correction equation is described in the literature [112,118,153].

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