Dissolution and partitioning behavior of hydrophobic ion-paired compounds

Purpose. This study was conducted to determine the effects of counterion hydrophobicity on organic/aqueous partition coefficients for hydrophobic ion paired (HIP) complexes. Furthermore, the coupled dissolution and reverse ion-exchange kinetics for dissolution of HIP complexes into aqueous electrolyte solutions were measured and mathematically modeled.Methods. HIP complexes of model drugs tacrine and l-phenylephrine were formed using linear sodium alkylsulfates and bis (2-ethylhexyl sodium sulfosuccinate). Equilibrium partition coefficients between chloroform and aqueous solutions for the complexes and the kinetics of dissolution of the complexes in buffered aqueous solutions were measured.Results. The chloroform/aqueous partition coefficients for l-phenylephrine/bis (2-ethylhexyl sodium sulfosuccinate) complexes decrease with increasing molar surface tension increment of salts added to the aqueous solution. The logarithm of the partition coefficient for a homologous series of alkyl sulfate complexes decreases as the hydrophilic-lipophilic balance number increases. Dissolution of HIP complexes in deionized water shows first order kinetics, whereas dissolution in aqueous electrolyte solutions shows biphasic kinetics. A kinetic model explains these dissolution rates.Conclusions. Solubility and dissolution rates for HIP complexes depend on the hydrophobic-lipophilic balance number of the organic counter ion as well as on the electrolyte composition of aqueous solutions. Reverse ion-exchange kinetics are sufficiently slow to allow HIP complexes to be considered simple prodrugs.