Isolation, identification, and synthesis of two oxidative degradation products of olanzapine (LY170053) in solid oral formulations.
Two impurities found in both stressed and aged solid-state formulations of olanzapine have been identified as (Z)-1,3-dihydro-4-(4-methyl-1-piperazinyl)-2-(2-oxopropylidene)-2H-1,5-benzodiazepin-2-one (1) and (Z)-1-[1,2-dihydro-4-(4-methyl-1-piperazinyl)-2-thioxo-3H-1,5-benzodiazepin-3-ylidene]propan-2-one (2). The structures indicate that the two impurities are degradation products resulting from oxidation of the thiophene ring of olanzapine. The impurities were isolated by preparative HPLC from a thermally stressed formulation, and characterized by UV, IR, MS, and NMR. A synthetic preparation of compounds 1 and 2 by reaction of olanzapine with the singlet oxygen mimic 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) is presented. The structure of 2 was also determined by single-crystal X-ray diffraction analysis. A degradation pathway for the formation of 1 and 2 is proposed.
Baertschi
Steven W
SW
Eli Lilly and Company, Analytical Sciences Research and Development, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Brunner
Heiko
H
Bunnell
Charles A
CA
Cooke
Gary G
GG
Diseroad
Benjamin
B
Dorman
Douglas E
DE
Jansen
Patrick J
PJ
Kemp
Craig A J
CA
Maple
Steven R
SR
McCune
Karen A
KA
Speakman
Jeffrey L
JL
D000284:Administration, Oral; D001569:Benzodiazepines / Q000008:administration & dosage / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004340:Drug Contamination; D009682:Magnetic Resonance Spectroscopy; D000077152:Olanzapine; D010084:Oxidation-Reduction; D014961:X-Ray Diffraction
D001569:Benzodiazepines; D000077152:Olanzapine