Ampholytes ordinary

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]. 

The widely used term log P refers to the logarithm of the partition coefficient P of the unionized species, which is P° for a base with no acidic functions, and P1 for a monoprotic acid or an ordinary ampholyte. Log P is equal to log D at any pH remote from the pKa where the molecule exists entirely in its unionized form. Log D at any pH is equal to log P for a non-ionizable molecule. 

Ampholytes (amphoteric electrolytes) can function as either weak acids or weak bases in aqueous solution and have plC values corresponding to the ionisation of each group. They may be conveniently divided into two categories - ordinary ampholytes and zwitterionic ampholytes - depending on the relative acidity of the two ionisable groups. 

Figure 3.7 Distribution of ionic species for the ordinary ampholyte m-aminophenol.

Isoelectric focusing is a well documented technique that uses carrier ampholytes (Rilbe, 1973 Fawcett, 1975). A pH gradient can also be created using a thermal gradient in ordinary buffers (Luner and... 

Ordinary ampholytes have an acidic and a basic ionizable group with pKa (acidic) > pKa (basic). Proteolysis and partitioning of ordinary ampholytes are straightforward when the difference between pKa (acidic) and pKa (basic) is greater than 3. In this case the substance is fully neutral in the pH region between the two pKa values. If, however, ApKa is lower than 3, an overlap between the two protonation equilibria takes place, allowing for the existence of a small proportion of the zwitterionic species as discussed next. 

In order to analyze the distribution of simple ampholytes (i.e. single acid and base) they were first classified as either ordinary or zwitterionic ampholytes and the isoelectric points were calculated. Figure 6 illustrates the range of isoelectric points for both the ordinary and zwitterionic ampholytes. While no clear pattern emerges this may be a reflection of the limited number of compounds (65) available for this analysis. The larger number of ordinary ampholytes at the high end of the scale represent simple phenols with alkylamine side chains (e.g. phenylephrine). If these compounds are left aside, those that remain tend to have isoelectric points between 3.5 and 7-5. 

When the CNS and non-CNS drugs were compared interesting differences were observed. For the CNS class there were 13 simple ampholytes which made up only 7.5% of the 174 CNS compound subset. Of these 13 compounds there were six opioids and six benzodiazepines all of which were ordinary ampholytes. In contrast, the non-CNS subset contained 52 ampholytes comprising 20 zwit-terions and 32 ordinary ampholytes. No doubt the predominance of ordinary ampholytes in the CNS class reflects the neutral character of these compounds at their isoelectric point where neutrality would favour CNS penetration. 

Figure 6. Histogram comparing the isoelectric points of both ordinary and zwitterionic ampholytes. In this case the frequencies of the distributions were shown to reflect the differing number of ordinary ampholytes (44 compounds) and zwitterionic ampholytes (21 compounds). Compounds were binned into 1 log unit ranges as per Figure 3.

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