Dissolution and Ionization of Warfarin

It has been shown in recent studies that warfarin exists in the solid state and in some nonaqueous solvents as a cyclic hemiketal. The present study was undertaken to investigate the ionization and ionization kinetics of warfarin, to confirm the probable existence of the cyclic hemiketal in aqueous solution, and to determine the possible consequences of the cyclic hemiketal to acyclic enol equilibrium and ionization kinetics on the dissolution rate of warfarin. The equilibrium aqueous solubility of un-ionized warfarin acid at 25°C and ionic strength 0.5 (with potassium chloride) was found to be 1.28 × 10−5 M, and its observed macroscopic pKa was 5.03–5.06, depending on the method of determination. By comparing the aqueous pKa of warfarin to phenprocoumin, a hydroxycoumarin that cannot exist in the cyclic hemiketal form, the hemiketal-acyclic enol ratio was estimated to be ~20:1. By stop-flow spectrophotometry, the ionization rate of warfarin (pH 3.5 jumped to pH 6.5) was found to have a t1/2