Thermal and photolytic decomposition of methotrexate in aqueous solutions

The chemical kinetics of thermal and photolytic degradation of methotrexate in aqueous solutions were studied. At above pH 7 and 85 degrees, methotrexate hydrolyzed to yield mainly N10-Methylpteroylglutamic acid. The hydrolysis rate followed first-order kinetics with respect to methotrexate concentration and increases rapidly above pH 9. When methotrexate solutions were kept under laboratory fluorescent light, the major degradation products were 2,4-diamino-6-pteridinecarbaldehyde, 2,4-diamino-6-pteridinecarboxylic acid, and p-aminobenzoylglutamic acid. The photolytic reaction followed zero-order kinetics with respect to methotrexate concentration and was catalyzed by bicarbonate ion. Evidence is presented for a proposed sequential cleavage of methotrexate by a free radical mechanism for the photolysis. Commercial parenteral methotrexate was found to be quite stable as marked when stored in the original vial at room temperature.