Partition coefficients charged-species partitioning

However, recent studies on the variation of the distribution coefficient of ionizable drugs as a function of pH (pH-lipophilicity profiles) shows that the partitioning of charged species cannot be neglected [143]. In other words, the general relationship between distribution and partition coefficients [Eq. (15)] cannot be simplified. 

Principal differences between bulk media water and membrane water partition coefficients are listed in Table 2. These differences are essentially based on the several orders of magnitude difference in surface-to-volume ratio. In the liposomal system, charges built up due to sorption of charged species can be electrically neutralised by counter-ions from the electrolyte (diffuse double... 

Note that no ion pair is assumed in the aqueous phase. The overall distribution ratio of the charged species is then a combination of the partition coefficient of the charged species and the distribution ratio of the ion pair. 

Thus, on measuring a partition coefficient of HA, it is imperative to know which species is being measured, i.e., neutral (undissociated, HA) or charged species (A ). Mathematical procedures can be used to take into account the complicating equilibria, and partition coefficients can be calculated for both the nonionized and ionized species of organic acids. The difference in partition coefficient between the two species is approximately... 

Our final task in this chapter is to demonstrate how partition constants/coefficients can be used to calculate the equilibrium distribution of a compound i in a given multiphase system. As already pointed out earlier, for simplicity, we consider only neutral species. As we will see in Chapter 8, the equilibrium partitioning of ionogenic compounds (i.e., compounds that are or may also be present as charged species, as, for example, acids or bases) is somewhat more complicated to describe. However, the general approach discussed here is the same. 

If a solute is an acid or base, its charge changes as the pH is changed. Usually, a neutral species is more soluble in an organic solvent and a charged species is more soluble in aqueous solution. Consider a basic amine whose neutral form, B, has partition coefficient A" between aqueous phase 1 and organic phase 2. Suppose that the conjugate acid, BH+, is soluble only in aqueous phase I. Let s denote its acid dissociation constant as Kir The distribution coefficient, D, is defined as... 

These values are, in some sense derived from corrosion theory, "mean" or "mixed" potentials because they are determined by exchange of two charged species. When activity coefficients are ignored equation 13 reduces to 10. By the same analysis, a single salt MY partitioned gives a constant potential in equation 9. 

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. 

A partition coefficient measurement involves the equilibration of a solute between an aqueous and an organic phase. A compound that is ionizable will be present a combination of ionic and neutral species, determined by its pifa values(s) and the pH of the aqueous phase. Hence, the equilibrium of a solute between the aqueous and organic phases will depend on pH in a manner that is dependent on the structure (and hence properties) of the solute. The measurement of such an equilibrium results in a distribution coefficient, which is defined as the ratio of the total concentrations of all species of the compound in the non-polar to the polar phase. The log of this is the logZ) value. Because it is usually assumed that charged species do not partition to the non-aqueous phase, logZ) values are lower than logP values for the same compound. This is depicted in Figure 3.6. 

These two parameters are intimately involved with each other particularly in the charged state. Hydrophobicity, as measured by log P, refers to the partitioning of a solute that remains neutral over the pH range in question, while log D (distribution coefficient or apparent log P) constitutes a measure of the partitioning of both the neutral and charged species of a compound at a particular pH. Thus log D is related to log P via the ionization constant, pKa. 

When both the neutral and the n different charged forms of a compound partition into the organic phase, a minimum of n + 1) titrations with different phase volume ratios is necessary to determine the partition coefficient of each species. For a monoprotic substance, for instance, can be related to pK by an empirical equation [119] ... 

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