Charge State

Weak acids and bases ionize in solutions to varying extent, depending on pH. This, in turn, affects the distribution of the chemicals in solution and affects their availability to enter biological reactions. The characteristic thermodynamic parameter relating the pH to the charge state of a molecule is the ionization constant, pKa [34,35]. Knowledge of the pKa of a substance is widely useful. It can predict the absorption, distribution, and excretion of medicinal substances. For example, urine pH (normally 5.7-5.8) can be altered (with oral doses of NH4Cl or NaHCO3) to satisfy reabsorption of uncharged species for therapeutic reasons, or to ease excretion of ionized species in toxicological emergencies [111]. Weak acids may be excreted in alkaline urine and weak bases may be eliminated in acidic urine, a principle that may be lifesaving with overdoses of barbiturates, amphetamines, and narcotics, for example. Knowledge of the pKa of a substance can be used in maximizing chemical reaction or synthesis yields. For example, solvent extraction can be best applied in a pH region where the synthesized molecule is uncharged. Interpretations of kinetic measurements can depend on the pKa of a reactant.

The method of choice for the measurement of ionization constants is potentio-metry [35,112-119]. Special circumstances warrant the determination of the pKa by UV spectrophotometry [120-143], capillary electrophoresis (CE) [144-147], and a chromatographic technique [148]. In principle, UV and CE methods are more sensitive and less sample-demanding than is the pH-metric method. That not withstanding, the latter method is preferred because it is so much better developed,

Absorption and Drug Development: Solubility, Permeability, and Charge State. By Alex Avdeef ISBN 0-471-423653. Copyright © 2003 John Wiley & Sons, Inc.

and is very strongly supported commercially [Sirius]. Currently, the UV method is under vigorous development, and is also supported commercially [131-143]. The CE method is in the orphan stage, with apparently little interest shown by the manufacturers of CE equipment, although that may soon change. A small and enthusiastic user base exists, however. Many other techniques have been used, but the methods described above are best suited for pharmaceutical applications.

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