title: Identification, isolation, synthesis and characterization of impurities of quetiapine fumarate.
abstract: In the process for the preparation of quetiapine fumarate (1), six unknown impurities and one known impurity (intermediate) were identified ranging from 0.05-0.15% by reverse-phase HPLC. These impurities were isolated from crude samples using reverse-phase preparative HPLC. Based on the spectral data, the impurities were characterized as 2-[4-dibenzo[b,f][1,4]thiazepine-11-yl-1 -piperazinyl]1 -2-ethanol (impurity I, desethanol quetiapine), 11-[(N-formyl)-1-piperazinyl]-dibenzo[b,f][1,4]thiazepine (impurity II, N-formyl piperazinyl thiazepine), 2-(2-hydroxy ethoxy)ethyl-2-[2-[4-dibenzo[b,f][1,4]thiazepine-11- piperazinyl-1-carboxylate (impurity III, quetiapine carboxylate), 11-[4-ethyl-1-piperazinyl]dibenzo [b,f][1,4] thiazepine (impurity IV, ethylpiperazinyl thiazepine), 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]1-ethyl ethanol [impurity V, ethyl quetiapine), 1,4-bis[dibenzo[b,f][1,4]thiazepine-11-yl] piperazine [impurity VI, bis(dibenzo)piperazine]. The known impurity was an intermediate, 11-piperazinyldibenzo [b,f][1,4]thiazepine (piperazinyl thiazepine). The structures were established unambiguously by independent synthesis and co-injection in HPLC to confirm the retention times. To the best of our knowledge, these impurities have not been reported before. Structural elucidation of all impurities by spectral data (1H NMR, 13C NMR, MS and IR), synthesis and formation of these impurities are discussed in detail.
authors.affiliation: Aurobindo Pharma Ltd. Research Centre, Hyderabad, India.
authors.forename: Ch
authors.initials: Ch
authors.lastname: Bharathi
authors.forename: K J
authors.initials: KJ
authors.lastname: Prabahar
authors.forename: Ch S
authors.initials: ChS
authors.lastname: Prasad
authors.forename: M
authors.initials: M
authors.lastname: Srinivasa Rao
authors.forename: G N
authors.initials: GN
authors.lastname: Trinadhachary
authors.forename: V K
authors.initials: VK
authors.lastname: Handa
authors.forename: R
authors.initials: R
authors.lastname: Dandala
authors.forename: A
authors.initials: A
authors.lastname: Naidu
mesh_terms: D002851:Chromatography, High Pressure Liquid; D003987:Dibenzothiazepines / Q000737:chemistry*; D004340:Drug Contamination; D009682:Magnetic Resonance Spectroscopy; D000069348:Quetiapine Fumarate; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate