PARTITIONING INTO OCTANOL

In all other sections of this book, we use the term Kp to represent the partition coefficient and Kd, the apparent partition coefficient. These terms were chosen to avoid symbol conflict when discussing permeability and diffusivity. Since this chapter and Chapter 5 are devoted primarily to partition coefficients, we will use the most common terminology P for partition coefficients and D for apparent (pH-dependent) partition coefficients. [Other symbols for these parameters have been used in the literature, including Pow (oil-water partition), Kqw, PC, and APC.] 

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

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On the subject of applications of such experimental parameters, the questions of whether an ionized molecule may or may not partition into octanol and whether bulk-phase partitioning is in turn adequate to describe bilayer partitioning are important and pertinent ones, and are addressed in Section 16.3. 

The danger of calculating logP from logD determinations Hes primarily in the assumption that only the neutral form of the drug could partition into octanol and we have briefly illustrated, and we will discuss in Section 16.3, that this is not necessarily true and, in fact, may often be an incorrect assumption. 

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 KC1 or NaCl, weak-acid salts have values of diff(k)g PN ) equal to 4, and that weak-base salts have cliff values equal to 3. These are helpful numbers to keep in mind when predicting the values of log P1 when log PN is known. 

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 1 and (2) ordinary (uncharged) ampholyte, XH°. 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-log/1 for XH° was 5.1, quite a bit higher than the macro-log/1 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]. 

Passive diffusion through the lipid bilayer of the epithelium can be described using the partition coefficient between octanol/water (log P) and A log P (the difference between the partition into octanol/water and heptane/ethylene glycol or heptane/ octanol) [157, 158], The lipophilicity of the drug (log P) (or rather log D at a certain pH) can easily be either measured or calculated, and is therefore generally used as a predictor of drug permeability. Recently, a method using artificial membrane permeation (PAMPA) has also been found to describe the passive diffusion in a similar manner to the Caco-2 cell monolayers [159]. 

For the neutral form of 13 bases, again a very poor correlation between partitioning into octanol and liposomes was observed. The range found for the partition coefficients was 2.0 to 6.0 in octanol and +1.0 to < 5.0 in the liposomal system (-2 is the observable minimum according to the authors). Poor correlations were also found for the cationic forms of the bases (r2 = 0.49). Generally, the differences (log Poct.-log Psuv) for the neutral forms are smaller than the differences observed for the charged species. 

The larger partition coefficient into lipids is because only the neutral form can efficiently partition into octanol. Ordered phospholipid bilayers can, however, take up both forms neutral and charged. The influence of anionic and cationic charge on the ability of amphiphilic drugs to partition and bind to DPPC liposomes was investigat-... 

It needs to be emphasized that the results from calcium channel antagonists cannot be generalized with respect to the relative order and degree of partitioning into octanol, liposomes, and native membranes. The partition coefficients, JCM, and Doct of dopamine antagonists in brain membranes and liposomes formed by the extracted lipids were also found to vary. In the case of these drugs, Doct was larger... 

This method is particularly well suited for ionizable compounds for which lipophilidty varies with pH (see Rgure 15.7).The pH-metric technique basically consists of two linked titrations, one without 1-octanol and one in the presence of a given volume of the partition solvent. When the substance partitions into octanol, the aqueous pKa is shifted, and logP values can be derived from this difference. " The method covers an exceptional dynamic range of about 8 log units, from -1 to +7. In addition the lipophilicity pH... 

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