Gradient HPLC in the determination of drug lipophilicity and acidity*
Roman Kaliszan, Piotr Haber, Tomasz Baczek, and Danuta Siluk
Department of Biopharmaceutics and Pharmacodynamics,
Medical University of Gdansk, Gen. J. Hallera 107, 80-416 Gdansk, Poland
Abstract: The linear-solvent strength (LSS) model of gradient
elution in high-performance liquid chromatography (HPLC) has been demonstrated
to provide parameters of lipophilicity and acidity of analytes. pKa
and log kw values are determined in three gradient runs. The first two
experiments use an aqueous buffered eluent with a wide-range organic
modifier gradient at pH of buffer, providing suppression of ionization
of the analyte. That experiment allows an estimate of contents of the
organic modifier in the mobile phase (%B), producing requested retention
coefficient, k, for the nonionized form of the analyte. The next experiment
is carried out with the latter %B and a pH-gradient of the aqueous component
of the eluent that is sufficient to overlap possible pKa value of the
analyte. The initial pH of the buffer used to make the mobile phase
is selected to insure that the analyte is in nonionized form. The resulting
retention time allows an estimate of pKa in a solvent of the given %B.
The log kw parameter obtained correlated well with the corresponding
value obtained by the standard procedure of extrapolation of retention
data determined in a series of isocratic measurements. The correlation
between log kw and the reference parameter of lipophilicity, log P,
was very good for a series of test analytes. The values of pKa were
found to correlate with the literature pKa data determined in water
for a set of aniline derivatives studied.
*Plenary lecture presented at the Hungarian-German-Italian-Polish
Joint Meeting on Medicinal Chemistry, Budapest, Hungary, 2 –6 September
2001. Other presentations are published in this issue, pp.
1387-1509.
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