Determination of protonation macro- and microconstants and octanol/water partition coefficient of the antiinflammatory drug niflumic acid

Krisztina Takács-Novák, Alex Avdeef, Karl J. Box, Benjamin Podányi, György Szász

Research output: Contribution to journalArticle

70 Citations (Scopus)


The drug niflumic acid is an amphoteric substance with overlapping pKa values. The acid-base chemistry of the molecule has been characterized in terms of protonation macroconstants (with reference to stoichiometric ionizations) and microconstants (with reference to ionizations of individual species). The proton-binding sites were assigned using 1H and 13C NMR spectroscopy. Due to the very poor water solubility of niflumic acid, the aqueous pKa values were determined from the apparent ionization constants in methanol-water solutions of various proportions by extrapolation to zero co-solvent using the Yasuda-Shedlovsky procedure. The kz tautomerization microconstant of the equilibrium unionized form 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 calculation of the other protonation microconstants. The zwitterionic form of the molecule predominates over the uncharged form, the concentration being maximal at the isoelectric pH. The apparent partition coefficients (Papp) of niflumic acid were measured in octanol/water solution by the shake-flask method over a wide pH range. The lipophilicity profile (logPapp vs pH) shows a parabolic shape near its maximum at the isoelectric point. A relationship derived between Papp, pXH0(micropartition coefficient of the uncharged microspecies) and PX-(partition coefficient of the anion) is valid for amphoteric drugs, in cases where the partition of the unionized form and the ion-pair partition of anion can be confirmed. The logP values of microspecies indicate the high lipophilicity of niflumic acid, which is consistent with its good skin penetration and absorption.

Original languageEnglish
Pages (from-to)1369-1377
Number of pages9
JournalJournal of Pharmaceutical and Biomedical Analysis
Issue number11
Publication statusPublished - Nov 1994



  • Niflumic acid
  • macro-logP
  • micro-logP.
  • pH profile of lipophilicity
  • protonation macro- and microconstants

ASJC Scopus subject areas

  • Analytical Chemistry
  • Pharmaceutical Science
  • Drug Discovery
  • Spectroscopy
  • Clinical Biochemistry

Cite this