Ionisable species partitioning

Figure 5.14 summarises the physicochemical problems in the use of preservative molecules in formulations. Solubility and partition coefficients of ionised species are determined, as we have seen, by the pH and ionic strength of the system. In this example, partitioning may occur from the aqueous phase to the oily... 

In case this sounds too much like an advert for the partition coefficient, in reality the simple relationship above only applies if the solute in question does not ionise at the pH of measurement. If the solute is a weak acid or weak base (and a huge number of drugs are), then ionisation to form an anion or a cation will considerably alter the solubility profile of the drug. A fully ionised species will be much more soluble in water than the unionised acid or base, and so the above ratio will vary depending on the pH at which the measurement was carried out. 

In the RP CEC of neutral species selectivity is provided primarily by differences in the partition of the analytes between the hydrophobic stationary phase and the more polar mobile phase. There are also contributions from interactions with the silica support, the major one being polar interactions with ionised silanol groups. This is identical to the process in LC, albeit with the advantages of higher efficiencies in CEC resulting from the plug-flow profile. Additional selectivity is introduced in the case of charged species in CEC due to differences in the analytes electromobilities. 

The term partitioning constant or coefficient refers to one chemical species in each phase (for example, ionisable chemicals present in water may exist in both neutral and dissociated forms and therefore each would have a separate partitioning coefficient). For well-defined phases, such as pure water or the pure liquid state of the chemical, then partitioning with another equally well-defined phase such as air results in the use of the term partitioning constant. The Henry s Law constant describing chemical partitioning between pure air and water is one example. Distribution ratios on the other hand, such as the soil-water... 

Similar to the log D-pH profile, the distribution of the compounds in a chromatographic partition system is also influenced by the pH. Charged species have much shorter retention times than their uncharged parent compounds. Horvath et al. [105 described first the effect of solute ionisation on the retention of weak acids, bases and ampholytes on octadecyl silica, both theoretically and experimentally. They have found a similar equation to Eqs. (12.11) and (12.12) that describes the pH dependence of the isocratic retention factor (A) for weak acids as shown in Eq. (12.1.3) ... 

In many systems the ionisation of the solute in one or both phases or the association of the solute in one of the solvents complicates the calculation of partition coefficient. As early as 1891, Nemst stressed the fact that the partition coefficient as a function of concentration would be constant only if a single molecular species was involved. If the solute forms aggregates or otherwise self-associates, the following equilibrium between the two phases 1 and 2 occurs when dimerisation occurs in phase 2 ... 

If, in the first instance, the plasma membrane is considered to be a strip of lipoidal material, homogeneous in nature and with a defined thickness, one must assume that only lipid-soluble agents will pass across this barrier. As most dmgs are weak electrolytes it is to be expected that the unionised form (U) of either acids or bases, the lipid-soluble species, will diffuse across the membrane, while the ionised forms (1) will be rejected. This is the basis of the pH-partition hypothesis in which the pH dependence of drug absorption and solute transport across membranes is considered. The equations of Chapters 3 and 5 are relevant here. 

Some ionised drug molecules can traverse the lipophilic gut membrane by combining with an ion of opposite charge (a counter ion) to form an ion pair. The ion pair, although composed of two ionic species, behaves as a neutral molecule with a high partition coefficient and can cross biomembranes effectively Quaternary ammonium compounds, which are charged at all values of pH, may be absorbed into the body in this way ... 

The temperature of the plasma must be precisely known and controlled for the calculation of the degree of ionisation, as the partition functions and Zj for the atom and ion species, respectively are strongly temperature dependent. The accuracy of the values of gA determines the accuracy of the calculation of the degree of ionisation. The line pairs Mg(II) 279.6 nm/Mg(I) 278.0 run and Mg(II) 279.6 nm/ Mg(I) 285.2 nm are very often used to calculate the degree of ionisation of an element in a plasma. When the degree of ionisation a is known, the electron pressure in the plasma can be determined. Starting from... 

The pH of solutions will therefore influence the partitioning and solubility properties of acidic or basic dmgs. The pH of the gastrointestinal tract varies considerably, and will therefore affect significantly the equilibrium between the ionised and un-ionised forms of the species in question, which has important implications for dmg absorption. 

---