DETERMINATION OF PROTONATION MACROCONSTANTS AND MICROCONSTANTS AND OCTANOL WATER PARTITION-COEFFICIENT OF THE ANTIINFLAMMATORY DRUG NIFLUMIC ACID

The drug niflumic acid is an amphoteric substance with overlapping pK( a) values. The acid-base chemistry of the molecule has been characteri zed in terms of protonation macroconstants (with reference to stoichio metric ionizations) and microconstants (with reference to ionizations of individual species). The proton-binding sites were assigned using H -1 and C-13 NMR spectroscopy. Due to the very poor water solubility of niflumic acid, the aqueous pK(a) values were determined from the appa rent ionization constants in methanol-water solutions of various propo rtions by extrapolation to zero co-solvent using the Yasuda-Shedlovsky procedure. The k(z) tautomerization microconstant of the equilibrium unionized form reversible arrow zwitterionic form was determined from mixtures of organic solvent (dioxane or methanol) with aqueous buffer (at the pH of isoelectric point) by UV spectroscopy, and used for calc ulation of the other protonation microconstants. The zwitterionic form of the molecule predominates over the uncharged form, the concentrati on being maximal at the isoelectric pH. The apparent partition coeffic ients (P-app) of niflumic acid were measured in octanol/water solution by the shake-flask method over a wide pH range. The lipophilicity pro file (logP(app) vs pH) shows a parabolic shape near its maximum at the isoelectric point. A relationship derived between P-app, P-XH.(microp artition coefficient of the uncharged microspecies) and P-X-(partition coefficient of the anion) is valid for amphoteric drugs, in cases whe re the partition of the unionized form and the ion-pair partition of a nion can be confirmed. The logP values of microspecies indicate the hi gh lipophilicity of niflumic acid, which is consistent with its good s kin penetration and absorption.