The Solubility Problem and Cosolvent Methods

Since many new substances of interest are very poorly soluble in water, the assessment of the pKa in aqueous solution can be difficult and problematic. Potentiometry can be a quick technique for such assessment, provided the solubility of the substance is at least 100 pM. (Solutions as dilute as 10 pM can still be analyzed, but special attention must be given to electrode calibration, and ambient carbon dioxide must be excluded.) If the substance is soluble to only 1-10 pM and possesses a pH-sensitive UV chromophore, then spectrophotometry can be applied. CE methods may also be useful since very small sample quantities are required, and detection methods are generally quite sensitive. 

If the compound is virtually insoluble ( 1 pM), then a pH-metric mixed-solvent approach can be tried [112]. For example, the pKa of the antiarrhythmic amiodar-one, 9.06 0.14, was estimated from water-methanol mixtures, though the intrinsic solubility of the molecule is --0.008 pM (6 ng/mL) / ION.  

The most frequently explored solvent systems are based on water-alcohol mixtures [119,164,166,181-210]. DMSO-water [211-215], dioxane-water [216-220], and other systems [221,222] have been explored. Where possible, methanol is the solvent of choice, because its general effect on pKa values has been studied so extensively. It is thought to be the least error-prone of the common solvents. 

Mixed-solvent solutions of various cosolvent-water proportions are titrated and psKa (the apparent pKa) is measured in each mixture. The aqueous pKa is deduced by extrapolation of the psKa values to zero cosolvent. This technique was first used by Mizutani in 1925 [181-183]. Many examples may be cited of pKa estimated by extrapolation in mixtures of methanol [119,161,162,191,192,196,200], ethanol [184,188-190,193], propanol [209], DMSO [212,215], dimethylformamide [222], acetone [221], and dioxane [216]. Plots of psKa versus weight percent organic solvent, Rw = 0 — 60 wt%, at times show either a hockey-stick or a bow shape [119]. For Rw 60 wt%, S-shaped curves are sometimes observed. (Generally, psKa values from titrations with Rw 60 wt% are not suitable for extrapolation to zero cosolvent because KC1 and other ion pairing interferes significantly in the reduced dielectric medium [223].) 

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