AUTOXIDATION OF TETRAZEPAM IN TABLETS - PREDICTION OF DEGRADATION IMPURITIES FROM THE OXIDATIVE BEHAVIOR IN SOLUTION

The major route of degradation of tetrazepam (1) is oxidation to 7-chloro-5-(3-keto-cyclohexen-1-yl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (3) via the stable 7-chloro-5-(3-hydroperoxycyclohexen-1-yl)-1,3-dihydro-1-methyl-2H-1,4 benzodiazepin-2-one (2). Minor degradation products are 7-chloro-5-(1,2-epoxycyclohexan-1-yl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (5) and 7-chloro-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin,2,5-dione (4), resulting from cleavage of the C-C bond between the cyclohexene ring and the benzodiazepine ring. After 48 h, AIBN (2,2'-azobis[2-methylpropanenitrile]) in acetonitrile at 40-degrees-C produced qualitatively the same impurities as those observed in the stability study of tablets of 1. Other stress tests (thermal stress at 80-degrees-C, heavy metal oxidation, hydrogen peroxide, acid-catalyzed oxidation) caused qualitatively different profiles of degradation.