pKa of 4MP and Chemical Equivalence in Formulations of Free Base and Salts of 4MP

Abstract

Fomepizole (4-Methylpyrazole, 4MP) is used as an antidote for ethylene glycol and methanol poisoning. In France it is administered intravenously as the sulfate or hydrochloride salt formulation and in the United States, as the free base formulation. Since its pKa was unknown, it was unknown if the free base, hydrochloride and sulfate salt formulations of 4MP are chemically equivalent, and if 4MP is in chemically equivalent forms in blood when these base and salt formulations are administered intravenously. Using UV spectrophotometry, the pKa of 4MP was determined to be 2.91 ± 0.05 (n = 7) at a low concentration of 0.006M in formate buffers of various pH, and 3.00 ± 0.16 (n = 7) when high concentration of 4MP (0.06M) was titrated with HCl at 25°C. The hydrochloride salt formulation (pH 6.64) was ionically and hence chemically equivalent to the free base formulation (pH 7.02), while the sulfate salt formulation, due to its lower pH of 2.33, showed presence of some ionized 4MP indicating chemical inequivalence. In order to determine chemical equivalence upon intravenous administration, these formulations were diluted with phosphate buffer (pH 7.4) with identical ionic strength and buffer capacity as blood. In spite of chemical inequivalence of the sulfate salt formulation, 4MP free base was observed from all three formulations when diluted with physiological buffer suggesting chemical equivalence under physiological conditions due to the strong buffering action of blood.