PH-metric log P 11. pK_a determination of water-insoluble drugs in organic solvent–water mixtures

Abstract

The apparent acid dissociation constants (p_sK_a) of two water-insoluble drugs, ibuprofen and quinine, were determined pH-metrically in acetonitrile–water, dimethylformamide–water, dimethylsulfoxide–water, 1,4-dioxane–water, ethanol–water, ethylene glycol–water, methanol–water and tetrahydrofuran–water mixtures. A glass electrode calibration procedure based on a four-parameter equation (pH=α+Sp_cH+j_H[H⁺]+j_OH[OH⁻]) was used to obtain pH readings based on the concentration scale (p_cH). We have called this four-parameter method the Four-Plus™ technique. The Yasuda–Shedlovsky extrapolation (p_sK_a+log [H₂O]=A/ε+B) was used to derive acid dissociation constants in aqueous solution (pK_a). It has been demonstrated that the pK_a values extrapolated from such solvent–water mixtures are consistent with each other and with previously reported measurements. The suggested method has also been applied with success to determine the pK_a values of two pyridine derivatives of pharmaceutical interest.

Introduction

Acid dissociation constants (pK_a values) are useful physico-chemical measurements describing the extent of ionization of functional groups with respect to pH. These parameters are important in research areas such as pharmaceutical drug discovery and development, where knowledge of the ionization state of a particular functional group is often vital in order to understand the pharmacokinetic and pharmacodynamic properties of new drug substances [1]. Traditionally, pH-metric titration was employed to determine the pK_a’s of ionizable groups in aqueous solution. However, the success of this approach is sometimes hampered by poor aqueous solubility (<10⁻⁴ M). Spectrophotometric pK_a determination is an attractive alternative provided that the compound is water soluble to the extent of 10⁻⁶ M and it contains chromophore(s) in proximity to the ionization centre(s) such that the protonated and deprotonated forms exhibit sufficient spectral dissimilarities [2], [3]. If the compound is sufficiently soluble in a water-miscible organic solvent, it is possible to determine pH-metrically the apparent pK_a (p_sK_a) in co-solvent mixtures. Aqueous pK_a values can be determined by extrapolation of the p_sK_a values to zero organic solvent content [2].

Knowledge of p_sK_a values as a function of solvent composition is also useful in the application of reversed-phase HPLC for the separation of ionizable compounds [4]. Retention in such systems is influenced by the ionization state of functional groups present on the analytes [5]. Typically, acetonitrile or methanol are employed as co-solvents with water, often in the presence of buffers or other modifiers. In order to obtain satisfactory chromatographic resolution for individual components, the p_sK_a values of the samples and the pH values of the eluents are useful parameters for consideration [5].

Methanol is widely accepted as a co-solvent in semi-aqueous work and its effect on pK_a has been investigated extensively [1], [2]. In a previous study (part 3 of this series) [6], we presented a glass electrode calibration protocol based on a four-parameter equation which enabled reliable pH measurement and hence accurate p_sK_a determination of water-insoluble samples in methanol–water mixtures. This approach, in conjunction with the Yasuda–Shedlovsky extrapolation method [7], [8], was successfully applied to determine aqueous pK_a values from co-solvent measurements [6]. It has been demonstrated that the Yasuda–Shedlovsky extrapolation procedure for aqueous pK_a determinations using co-solvent data is generally more accurate than conventional method (p_sK_a vs weight% organic solvent) as the latter often exhibits marked non-linearity [1], [2], [6]. Recently, this method was validated using a broad range of drug compounds [9].

In this report, we extend our investigations to include other commonly used solvents, namely acetonitrile, dimethylformamide, dimethylsulfoxide, 1,4-dioxane, ethanol, ethylene glycol and tetrahydrofuran. The four-parameter approach is referred to as the Four-Plus™ technique. The main aim of the investigation was to establish an accurate procedure to relate the operational pH scale to the concentration pH scale based on the Four-Plus™ technique, thus forming the basis for reliable p_sK_a determinations in a variety of co-solvent systems. In the following discussion, we detail experimental procedures employed for such measurements. The accuracy of the technique is then illustrated by determination of pK_a values for several water-insoluble drug compounds in co-solvent solution by Yasuda–Shedlovsky extrapolations to zero percent organic content.