Talanta 49 (1999) 539–546
Multiwavelength spectrophotometric determination of acid
dissociation constants
Part IV. Water-insoluble pyridine derivatives
K.Y. Tam
a,
*, M. Hadley
b
, W. Patterson
b
a
Sirius Analytical Instruments Ltd., Rierside, Forest Row Business Park, Forest Row, East Sussex, RH18 5DW, UK
b
SmithKline Beecham Pharmaceuticals, Old Powder Mills, Near Leigh, Tonbridge, Kent TN11 9AN, UK
Received 3 November 1998; received in revised form 29 December 1998; accepted 6 January 1999
Abstract
A multiwavelength spectrophotometric (WApH) titration method for determination of acid dissociation constants
(pK
a
values) of ionizable compounds developed previously was applied in the case of pyridine derivatives of
pharmaceutical interest. Specifically, UV absorption spectra of the drug solution are acquired in the course of a
pH-metric titration using an optical device based on a fibre optics dip probe, a light source and a diode array
detector. Target factor analysis was applied to deduce the pK
a
values from the spectral data recorded at different pH.
Using this technique, the pK
a
values of six pyridine derivatives were determined successfully. It was demonstrated that
the WApH technique in this case outperforms conventional pH-metric methods with respect to the measurement of
pK
a
values of the sparingly water soluble samples reported in this study. © 1999 Elsevier Science B.V. All rights
reserved.
Keywords: Acid dissociation constants; Spectrophotometric titration; Target factor analysis; Pyridine
1. Introduction
Acid dissociation constants (pK
a
values) are
important parameters to denote the extent of
ionization of molecules in solution at different pH
values. In the context of pharmaceutical drug
discovery and development, the aqueous solubility
of compounds may not be high enough for precise
pK
a
determination using conventional pH-metric
titration. If the sample is sufficiently soluble in a
water-miscible organic solvent, it is possible to
determine pH-metrically the apparent pK
a
(p
s
K
a
)
in co-solvent mixtures [1]. Aqueous pK
a
values
can be determined by extrapolation of the p
s
K
a
values, using the Yasuda – Shedlovsky method, to
zero organic solvent content (a plot of p
s
K
a
+
log[H
2
O] vs. A / +B, where [H
2
O], , A and B
represent, respectively, the molar concentration of
water, the dielectric constant of the co-solvent
mixture, the slope and the intercept of the plot)
* Corresponding author. Tel.: +44-1324-820-720; fax: +
44-1324-820-725.
E-mail address: sirius@cix.compulink.co.uk (K.Y. Tam)
0039-9140/99/$ - see front matter © 1999 Elsevier Science B.V. All rights reserved.
PII:S0039-9140(99)00010-7