IONIZATION AND SOLUBILIZATION OF 4 ALKYL BENZOIC-ACIDS AND 4 ALKYL ANILINES IN SODIUM TAURODEOXYCHOLATE SOLUTIONS

Purpose. The aqueous solubility and the extent of solubilization and i onization constant in sodium taurodeoxycholate (NaTDC) solutions of a series of benzoic acid and aniline derivatives were measured as a basi s to characterize and thereby help predict the nature of the interacti on of drugs with bile aggregates. Methods, The aqueous solubility and the solubilization of two series of compounds, 4-alkyl benzoic acids a nd 4-alkyl anilines, was measured as a function of NaTDC in 0 and 150 mM NaCl. The ionization constants were determined in water and in 50 m M NaTDC at sodium chloride concentrations of 0, 75 and 150 mM by spect rophotometric titration. The diffusion coefficients of NaTDC and the s olutes were measured by pulsed-field gradient spin echo NMR spectrosco py. Results, The aqueous solubilities decreased with increasing alkyl chain length in both series, and the aniline derivatives had larger so lubilities than the benzoic acid derivatives. The number of moles of s olute solubilized per mole of bile salt ranged from 0.17 to 0.31 for t he benzoic acid derivatives and from 1.3 to 3.0 for the aniline deriva tives. The pKa values of the benzoic acid derivatives in the presence of NaTDC were higher relative to the controls, and the difference in t he pKa (Delta pKa,obs) increased with increasing chain length. With th e aniline derivatives, the pKa values were also shifted to higher valu es in NaTDC relative to the control but only in the absence of salt. T he presence of the solute caused a decrease in the diffusion coefficie nt of NaTDC, and the diffusion coefficients of the solutes decreased w ith increasing alkyl chain length. With the hexyl derivatives, the dif fusion coefficient of the solute was smaller than the diffusion coeffi cient of the bile salt. The chemical shift of the protons attached to carbon 18 and 19 of the bile salt were decreased to a greater extent i n the presence of the solutes than the protons attached to carbon 26. Conclusions, Both the solubilization and ionization behavior of solute s were affected by the presence of bile salt aggregates. The surface p otential and effective polarity of NaTDC aggregates were found to be d ependent on the alkyl chain length for these two homologous series of solutes. The solubilization ratio was largely independent of alkyl cha in length, but the unitary partition coefficient was dependent on both the alkyl chain length as well as ionization State. The derivatives r educed the diffusivity of the micelles suggesting the formation of lar ger sized aggregates and the solutes (hexyl derivatives) appear to fav or association with the larger sized aggregates. The phenyl ring of th e solutes appears to be oriented parallel to the plane of the steroid frame with preferential positioning near the hydrophobic rings.