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 degrees C and ionic strength 0.5 (with potassium chloride) was found to be 1.28 X 10(-5) M, and its observed macroscopic pK alpha was 5.03-5.06, depending on the method of determination. By comparing the aqueous pK alpha of warfarin to phenprocoumin, a hydroxycoumarin that cannot exist in the cyclic hemiketal form, the hemiketal-acyclic enol ratio was estimated to be approximately 20:1. By stop-flow spectrophotometry, the ionization rate of warfarin (pH 3.5 jumped to pH 6.5) was found to have t1/2 less than 1-2 X 10(-3) s. The dissolution rate of warfarin from a rotating disk (600 rpm), as a function of pH, was measured under nonbuffered but pH-stat conditions (mu = 0.5 with potassium chloride). The pH-dissolution rate profile for warfarin agreed with that calculated from an equation derived previously to describe the dissolution of instantaneous ionizing acids, i.e., the profile was not perturbed from that expected from an acid of aqueous solubility 1.28 X 10(-5) M (un-ionized form) and pK alpha 5.06.