Influence of ionization and ion-pair formation on lipophilicity of some 4-hydroxycoumarin derivatives in the octanol-water system

Abstract

SummaryThe pH-dependent distribution of weak acids in the octanol-water system was investigated. For a series of six 4-hydroxycoumarins, substituted at position 3, the apparent partition coefficient or the distribution coefficient, Per,,,, was measured in the pH range 1-i 1. The log Parr, -pH profiles obtained are in complete agreement with the theory. At high pH the value of Pap,, is independent of pH, but dependent on the concentration of counterions (Na+ in this study) in the aqueous phase; in other words ion-pair extraction occurs. The pNa (-log [Na+ ])-dependent distribution is analogous to the pH-dependent distribution, except in the case of 4-hydroxycoumarin. Evidence was found. that the sodium ion-pair of 4-hydroxycoumarin dissociates considerably in the octanol phase. A large discrepancy was noted between the experimentally obtained log P values and the theoretical values calculated using the hydrophobic fragmental constant system. Log Parr, values obtained under conditions where the compounds are ionized in the aqueous phase depend on both the partition coefficient and the dissociation constant of the acid or salt. Partition coefficients of the sodium ion-pairs obtained by extrapolation are just slightly lower than the partition coefficients of the undissociated acids.

Hydrazinyldiene-chroman-2,4-diones in inducing growth arrest and apoptosis in breast cancer cells: Synergism with doxorubicin and correlation with physicochemical properties

“…The solubility, pK a and log D 7.4 values determined experimentally for monobasic acid 4-HC were in accord with the literature data (28). In the pH region where pH >> pK a (or pH > pK a + 1.5), the equation log D = log P -pH + pK a holds and can be used to estimate the partition coefficient of the undissociated monobasic acid (log P) when the pK a value is al-ready known.…”

“…In the pH region where pH >> pK a (or pH > pK a + 1.5), the equation log D = log P -pH + pK a holds and can be used to estimate the partition coefficient of the undissociated monobasic acid (log P) when the pK a value is al-ready known. Log P of 4-HC thus obtained was 2.63, which is fairly close to the value of 2.37 determined by van der Giessen and Janssen (28). Experimentally determined distribution coefficients (log D 7.4exp ) of the synthesized compounds ranged between -0.096 (1c) and 0.602 (1e).…”

A quantitative approach to the determination of drug release from reverse-phase evaporation lipid vesicles. The influence of sodium ion-pair formation on warfarin partitioning and permeability

“…In a previous communication from our laboratory (van der Giesen and Janssen, 1982) it was reported that the apparent partition coefficient of warfarin at pH 10.0 (warfarin has a pK of 5.0 and is completely dissociated under those conditions) was increased by the presence of Nat ions. A linear relationship between the logarithm of the apparent partition coefficient Kapp and the negative logarithm of the sodium ion concentration pNa was observed.…”