D of Multiprotic Drugs and the Common-Ion Effect

When the log /J/pH measurement of a peptide is performed by the shake-flask or the partition chromatography method (using hydrophilic buffers to control pH), usually the shape of the curve is that of a parabola (see Ref. 371 and Fig. 1 in Ref. 282), where the maximum log I) value corresponds to the pH at the isoelectric point (near pH 5-6). Surprisingly, when the potentiometric method is used to characterize the same peptide [275], the curve produced is a step function, as indicated by the thick line in Fig. 4.5 for dipeptide Trp-Phe. 

EXTRACTION INTO OCTANOL EXTRACTION INTO OCTANOL 

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 /J/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 P (in a background of Na+) 0.5 greater than logP [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 logD/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] 

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