Summary Of Chargedspecies Partitioning In Octanolwater

Excluding effects not in the scope of this book, such as interfacial transport of charged species driven by electrical potentials, the main lesson of the partitioning studies of charged drugs is that the charged molecule needs to be accompanied by a counterion in order for the ion pair to enter a lipid phase such as octanol. Later, it will become apparent that it must not be taken for granted that charged species enter other lipid phases as they do octanol. The peculiar structure of octanol (Fig. 2.8) may facilitate the entry of ion pairs in a way that may be impossible in a phospholipid bilayer, for example (covered below).

Scherrer observed [280,281], as have others [161,162,275], that for a large number of ordinary charged species partitioning into octanol in the presence of aqueous solutions containing 0.15 M KCl or NaCl, weak-acid salts have values of diff(log PN~') equal to ~4, and that weak-base salts have diff values equal to ~3. These are helpful numbers to keep in mind when predicting the values of log P1 when log PN is known.

Scherrer identified the conditions where diff 3-4 may be transgressed: (1) if the drug has several polar groups or a large polar surface over which charge can be delocalized, then smaller values of diff are observed; (2) hydroxyl groups adjacent to amines or carboxylic groups stabilize ion pairs, leading to lower diff values; and (3) steric hindrance to solvation leads to higher values of diff, as seen with tertiary amines, compared to primary ones [280,281].


A review article with this title appeared in 1983 [369]. It's an old question, one not fully resolved: What does the charged-species partitioning seen in octanol-water systems have to do with biological systems? If getting to the receptor site involves passing through many lipid membranes, and if the pH partition hypothesis is to hold, the answer to the question is a resounding ''Nothing.'' If the active site is in the outer leaflet of the apical membrane and the drug is orally introduced, or if ocular or skin absorption is considered [372,373], the answer is ''Maybe something." We will return to this question in several instances in the next sections, for its answer warrants serious consideration.

4.9 MICRO-log P

We considered micro-pKa values in Section 3.6. A parallel concept applies to partition coefficients (of multiprotic molecules); namely, if an ionizable substance of a particular stoichiometric composition can exist in different structural forms, then it is possible for each form to have a different micro-log P [224,243,273,275]. When log P is determined by the potentiometric method (below), the constant determined is the macro-log P. Other log P methods may also determine only the macroscopic constant.

Niflumic acid, which has two pKa values, was studied both pH-metrically and spectroscopically using the shake-flask method [224]. The monoprotonated species can exist in two forms: (1) zwitterion, XH± and (2) ordinary (uncharged) ampholyte, XH0. The ratio between the two forms (tautomeric ratio) was measured spectroscopically to be 17.4. On assuming that a negligible amount of zwitterion XH± partitions into octanol, the calculated micro-logP for XH0 was 5.1, quite a bit higher than the macro-logP 3.9 determined pH-metrically in 0.15 M NaCl. It is noteworthy that the distribution coefficient D is the same regardless of whether the species are described with microconstants or macroconstants [275].

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