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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. April 2005, Volume 4, Number 4, 256-263 |
Chromatographic Estimation of Apparent Acid Dissociation Constants (pKa)
in Physiological Resembling Conditions. A Case Study: Ionisable
Non-Steroidal Anti-Inflammatory Drugs
Juan José Martínez-Pla, Laura Escuder-Gilabert, Salvador Sagrado, Rosa María Villanueva-Camañas, and María José Medina-Hernández
Internet Electron. J. Mol. Des. 2005, 4, 256-263
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Abstract:
Biopartitioning micellar chromatography (BMC) is a mode of
reversed phase micellar liquid chromatography that has proved to
be useful in the description and prediction of several
pharmacological properties of xenobiotics including oral drug
absorption, ocular and skin drug permeability. The present paper
deals with the application of BMC to modelling the acid
dissociation constant (pKa values), consistent to physiological
conditions, of eleven ionisable non-steroidal anti-inflammatory
drugs (NSAIDs). The logarithm of the retention factor using 0.04
M Brij35 as mobile phase (logk4), of the set of compounds at two
pH values, 5.5 and 7.4 and 36.5 °C, was measured. The difference
between logk4 values at these pHs,
dif_logk4 = logk4(pH=5.5) - logk4(pH=7.4),
can be used to differentiate between ionisable
(dif_logk4 > 0) and neutral (dif_logk4 = 0) NSAIDs. A
quantitative retention-pKa relationship, can be used to estimate the
pKa values of future ionisable NSAIDs. The BMC based model in
the form pKa = b0 + b1 dif_logk4
(n = 11, r2 = 0.85, F = 52.7, SE = 0.26,
q2 = 0.78) is made up of one descriptor. A leave-one-out test
procedure shows that the predictive ability of the model for
NSAIDs is good. The estimated values should be more reliable for
drug discovery studies than the currently used estimated pKa (BMC)
values in water at 25°C.
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