Ionization of acids and bases

It is not surprising that many drugs are either weak acids or weak bases. They are able to cross membranes in their neutral forms and they are soluble in aqueous phases in their ionized forms. Due to this dual character they are readily absorbed and distributed in the different compartments of a biological system. 

The concentrations of A and in the organic pha may be neglected for compounds which are not too lipophilic much simpler equations than eqs. 105 and 106 can be used to estimate the log Papp values of most acids (eq. 107) and bases (eq. 108) at pH values which are not too far from the pKa values. 

Scherrer [469 — 471] calculated log D (= logPapp) values by eqs. 107 and 108, respectively, and used them instead of the most often inappropriate (pK, — pH) terms. The (pK — pH) approximation [472] only holds true for pH ranges where the compounds predominantly exist in their ionized forms. Eq. 109 (% ABS = % colonic absorption at pH = 6.8) [472] is incorrect in two respects first, percentage values are used instead of rate constants, and second, the (pK — pH) term produces wrong values (corresponding to more than 100% neutral form of the molecules) for compounds with pK values larger than 6.8 (Table 15) [175, 469]. 

A better and more consistent result is obtained if log k bs values are calculated from % ABS values by appropriate transformation and if log Papp values and the parabolic [469] or the bilinear model are used, e.g. eq. 110 [442]. 

Ill [345] correlates the buccal absorption rate constants of an acid (p-hexylphenylacetic acid, pK = 4.36) and a base (propranolol, pK = 9.45) at different pH values with log Papp values (Table 16) [345, 470]. 

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The same calculations may be applied to calculate the degree of ionization of acids and bases under alkaline conditions. It can be easily seen that weak acids will be mainly nonionized and will therefore, if lipid soluble, be absorbed from an acidic environment, whereas bases will not, being mainly ionized under acidic conditions. Conversely, under alkaline conditions, acids will be mainly ionized, whereas bases will be mainly nonionized and will therefore be absorbed. 

M. F. Hopgood, Nomogram for calculating percentage ionization of acids and bases, J. Chromatogr., 47A5 (1970). 

As a result of the ionization of acids and bases in water, the essential reaction in each case can be shown as... 

The most, comprehensive review of quantitative structure-pharmacokinetics relationships [452] tabulates about 100 equations, including absorption, distribution, protein binding, elimination, and metabolism of drugs. Since many of these equations and those included in other reviews e.g. [472, 761]) have been derived before appropriate mathematical models for nonlinear lipophilicity-activity relationships (chapter 4.4) and for the correct consideration of the dissociation and ionization of acids and bases (chapter 4.5, especially eqs. 107—110) were available, some of the older results should be recalculated by using the theoretical models (chapters 4.4 and 4.5) instead of the empirical ones. 

If the world were made of pure substances, our development of the thermodynamic model would now be complete. We have developed a method, based on measurements of heat flow, that enables predictions to be made about which way reactions will go in given circumstances. But one of the reasons that the world is so complex is that pure substances are relatively rare, and strictly speaking they are nonexistent (even pure substances contain impurities in trace quantities). Most natural substances are composed of several components, and the result is called a solution. Therefore, we need to develop a way to deal with components in solution in the same way that we can now deal with pure substances - we have to be able to get numerical values for the Gibbs energies, enthalpies, and entropies of components in solutions. We will then be able to predict the outcome of reactions that take place entirely in solution, such as the ionization of acids and bases, and reactions that involve soUds and gases as well as dissolved components, such as whether minerals will dissolve or precipitate. Our thermodynamic model will then be complete. 

Excited state ionization (ionization of acids and bases in the excited state at p// ranges where unexcited molecules do not ionize) has been studied for cations of 3-pyridinols, pyridoxine, pyridox-amine Pyndoxal, 2-pyridone, and yV-methyl-2-pyri-... 

The law of chemical equilibrium may be applied to virtually all reversible reactions and systems including the ionization of acids and bases. 

LEARNING GOAL Write equations for the ionization of acids and bases. 

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