Solvation of Ionizable Drug Molecules

The hydrophilicity/hydrophobicity balance of the counter-ion present or added affects the affinity of the compound of interest to the two phases. Examples for such general statements can be provided by partition into a solvent of low polarity and low solvating ability, such as chloroform. When Bu N is the counter-ion, the order of the extractability of aromatic anions is phenoIate benzoate toluene-4-suIfonate salicylate l-phenylpropyl sulfate. When the counter-ion is chloride, the extractability of amines with one long chain R, RNMe Hj follows the sequence quaternary (n = 3) primary (n = 0) secondary (n = 1) tertiary ( = 2). When a solvent with much better donor properties than chloroform is used, such as methyl isobutyl ketone, tertiary amines are no longer extracted preferentially as reported by Marcus [52]. 

The summation in the last tenn is lirom y=0 to =2 and pertains to specific interactions of the solute with itself and with the solvent components and those among these components themselves in the absence of the solute. This term increases the predictive accuracy on the average threefold over a similar expression without this term, the log-linear expression (8.17). 

These expressions are applicable to drugs and drug-related ionizable substances, such as asparagine, aspartic add, caffeine, leucine, nalidixic acid, paracetamol, salicylic acid, and sulfanilamide. However, the log-linear expression (8.17) or the first two terms on the right-hand side of Equation 8.18 and even its modificafion in terms of the complete Equation 8.18 cannot model cases where the solubility curve exhibits a maximum as is observed in many cases, a problem solved when fluctuation theory is employed in the calculations as pointed out by Ruckenstein and Shulgin, [57]. If the solute is rather poorly soluble in the solvents and their mixtures, then solute-solute interactions can be ignored and the mutual interactions of the solvent components can then be treated either as ideal or as non-ideal. The molar volume of the binary solvent mixture is expressed as VJ +s) = where c is an empirical parameter that in 

The role of ion solvation in nonaqueous and mixed aqueous-organic solvents in ion separations by ion exchange resins has been summarized in detail in the earlier edition of this book [26] and need not to be repeated here, no new insight having been obtained since then. 

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