Potential impurities of anxiolytic drug, clobazam: Identification, synthesis and characterization using HPLC, LC-ESI/MSnand NMR.
During the optimization of process, eight impurities (CLB Imp-A to CLB Imp-H) were detected in few of the laboratory batches of clobazam, used as anxiolytic agent, in the range of 0.02-0.12% using gradient HPLC method with UV detection. On the basis of co-spiking analysis, six impurities (CLB Imp-A to -F) enumerated by European Pharmacopoeia, however, not reported in the earlier literature, have been harmonized and found to be two impurities are completely unknown (CLB Imp-G and -H). These two new impurities structures were presumed based on LC-ESI/MSnstudy as 8-chloro-1-methyl-5-phenyl-1,5-dihydro-3H-1,5-benzodiazepine-2,4-dione (CLB Imp-G) and 5-chloro-1-methyl-3-phenyl-1H-benzo[d]imidazol-2(3H)-one (CLB Imp-H). The presumed impurities structures were confirmed by their synthesis followed by the complete spectral analysis such as ESI-MS, 1D NMR (1H,13C and DEPT), 2D NMR (HSQC, HMBC and COSY) and IR, and chromatographic retention time profile. Identification, synthesis, structural characterization, prospects to the formation and controlling of these new impurities were described in detail and reported first in this paper.
Micro Labs Ltd., Chemical Research Department, API R&D Centre, Bommasandra-Jigani Link Road, KIADB INDL Area, Bommasandra, Bangalore 560105, Karnataka, India. Electronic address: neerajkumar@microlabs.in.
Neeraj
N
Kumar
Micro Labs Ltd., Chemical Research Department, API R&D Centre, Bommasandra-Jigani Link Road, KIADB INDL Area, Bommasandra, Bangalore 560105, Karnataka, India.
Subba Rao
SR
Devineni
Micro Labs Ltd., Chemical Research Department, API R&D Centre, Bommasandra-Jigani Link Road, KIADB INDL Area, Bommasandra, Bangalore 560105, Karnataka, India. Electronic address: shailendradubey@microlabs.in.
Shailendra Kumar
SK
Dubey
Micro Labs Ltd., Chemical Research Department, API R&D Centre, Bommasandra-Jigani Link Road, KIADB INDL Area, Bommasandra, Bangalore 560105, Karnataka, India. Electronic address: pramodkumar@microlabs.in.
Pramod
P
Kumar
D014151:Anti-Anxiety Agents / Q000032:analysis* / Q000737:chemistry*; D001569:Benzodiazepines / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D000078306:Clobazam; D004340:Drug Contamination / Q000517:prevention & control*; D007093:Imidazoles / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods
D014151:Anti-Anxiety Agents; D007093:Imidazoles; D001569:Benzodiazepines; D000078306:Clobazam; C029899:imidazole
Clobazam; Identification; Impurities; LC-ESI/MS(n); NMR; Synthesis