f ^

/ h3C^\HT

^ CH3


Figure 4.6 Hypothetical lipophilicity profiles: (a) fixed extraction constant with differing salt concentrations; (b) fixed salt concentration with differing extraction constants. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]

The next example, shown in Fig. 4.6a, is the amusing consequence of continually increasing the concentration of background salt (beyond its aqueous solubility—just to make the point) to the shape of log D/pH profile for acebutolol (whose normal 0.15 M salt curve [362] is indicated by the thick line in Fig. 4.6a). The base-like (cf. Fig. 4.3a) lipophilicity curve shape at low levels of salt can become an acid-like shape (cf. Fig. 4.2a) at high levels of salt! An actual example of a dramatic reversal of character is the ionophore monensin, which has a log PI (in a background of Na+) 0.5 greater than log PN [276,281].

To cap off the topic of salt dependence, is the following example (also using acebutolol), which will indeed surprise most readers, at first. It is possible to have a peak in a log D/pH profile of a monoprotic molecule! In Fig. 4.6b, we simulated the case by assuming that the level of salt was kept constant and equal to the concentration of the sample, and proceeded to explore what should happen if the log of the extraction constant Ke [162,225,275,277]

were raised from the value 0.32 [362] to higher values. The logD profile eventually develops a peak at pH = pKa and the series of curves in Fig. 4.6b all have the same pKaoct, whose value is equal to pKa — log PN, namely, 7.5 [Eq. (4.10) is inadequate to explain the phenomenon]. Similarly shaped curves were reported by Kramer et al. [368], who considered the partitioning of propranolol into liposomes (containing free fatty acids) that had surface charge that was pH-dependent. In the present case of salt-induced extraction, the maximum point in Fig. 4.6b is not sustainable as pH increases past the pKa, because the concentration of the charged sample component diminishes, in accordance with the pKa.

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