Yasuda-Shedlovsky plot

If a compound is poorly soluble in water, the pKa may be difficult to measure. One way around this problem is to measure the apparent pKa of the compound in solvent and water mixtures and then extrapolate the data back to a purely aqueous medium using a Yasuda-Shedlovsky plot. The organic solvents most frequently used are methanol, ethanol, propanol, dimethylsulphoxide (DMSO), dimethyl formamide (DMFA), acetone and tetrahydrofuran (THF). However, methanol is by far the most popular because its properties are closest to water. A validation study in water-methanol mixtures has been reported by Takacs-Novdk et al. (1997) and the determination of the pfCas of ibuprofen and quinine in a range of organic solvent-water mixtures has been reported by Avdeef et al. (1999). 

M KCl were performed on the PCA 101 titrator. .. at 25 °C for amiodarone, metoprolol and ramipril and at 37 °C for atenolol. The pKa values of metoprolol, atenolol, and ramipril were determined in 0.15M KCl. For die extrapolation of the aqueous pKa of amiodarone, we used the Yasuda-Shedlovsky plot (4). Apparent pKa values (+ log [H2O]) in the medianol/O.lSM KCl mixtures at ratios between 47 and 71%(w/w) methanol were plotted against the inverse dielectric constant... and the pKa of the molecule in 100% aqueous solution was extrapolated by linear regression." surface H2O Ferreira J, Brasseur R, Chatelain P and Ruysschaest J, Properties of... 

A plot of the Yasuda-Shedlovsky equation generally is a straight line. The fitted coefficients A and B are then used to estimate the pK value in a 100% aqueous solution, for which [H2O] = 55.5 molal and e = 78.3. Successful use of this approach in cosolvent mixtures requires a complex pH electrode calibration procedure [20]. 

NB As is well-known, this method of extrapolation often leads to errors due to the non-linearity of these plots, especially for amines at low alcohol percentages. It is a pity that the raw data (apparent pXa vs alcohol-water composition) was not available, so diat more recent procedures, such as the Yasuda-Shedlovsky equation, could be used in an attempt to extract more reliable pKa values. 

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