Dissolution and Ionization of Warfarin

Warfarin: history, tautomerism and activity

“…Stella et al reported the pK a determination for warfarin using solubility vs. pH measurements and found pK a = 5.06. They also reported pK a = 5.03 ± 0.01 for warfarin and pK a = 3.77 ± 0.01 for phenprocoumon, both of which were determined spectrophotometrically in aqueous buffers maintained at 0.1 M ionic strength [109]; these workers then argued that, because of the similarity in structure between the 4-hydroxy enol tautomeric form of warfarin and phenprocoumon, the difference in ionization constants must reflect the presence of the cyclic hemiketal tautomers of warfarin in solution. They estimated the ratio of cyclic tautomers to the open chain form equal to * 20:1.…”

“…Even a careful study of analogs cannot shed much light on the influence of tautomerism on the physical properties of warfarin. As noted previously, Stella et al [109] argued that the increased acidity of phenprocoumon compared to warfarin could be used to estimate the fraction of warfarin existing in solution as ring tautomeric forms J and K (Fig. 22) but their argument is based on an assumption that all of the difference in acidity could be accounted for entirely by ring-chain tautomerism.…”

“…Box plot of experimentally measured[106][107][108][109][110][111][112][113][114][115][116] and computationally predicted[105] values for the pK a of warfarin. Box plots are a simplified way of depicting statistical distributions that aid in the identification of suspect values.…”

Quantitative Liquid Chromatography/Mass Spectrometry/Mass Spectrometry Warfarin Assay for in Vitro Cytochrome P450 Studies

“…The resolution of these metabolites was strictly mobile phase pH dependent, especially if the pH is close to the pK a of warfarin (approx. 5.0) (28). The resolution of 6-, 7-, and 8-hydroxywarfarin was evaluated by varying the pH of the mobile phase (A) from 6.0 to 4.6, and the best resolution was obtained at pH 4.6, as shown in Fig.…”

Coupling of acetonitrile deproteinization and salting-out extraction with acetonitrile stacking in chiral capillary electrophoresis for the determination of warfarin enantiomers

“…These observations are consistent with the pK a values reported for warfarin, which has a value of ca. 5.0 in aqueous solutions [35], i.e., warfarin is unionized (neutral) at pH ≤4.0, partly ionized (anionic) at pH 5.0, and completely ionized at pH >7.0. Thus, for the efficient extraction of warfarin enantiomers into the smaller volume organic solvent (acetonitrile) phase in subsequent experiments, the sample solution was adjusted to a pH value of 4.0 to achieve optimal E% for the salting-out extraction of the warfarin enantiomers in their neutral, unionized forms.…”