Identification, isolation, synthesis and characterization of impurities of quetiapine fumarate

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 1, desethanol quetiapine), 11-[(N-formyl)-1-piperazinyl]-dibenzo[b,f][1,4]thiazepine (impurity 11, N-formyl piperazinyl thiazepine), 2-(2-hydroxy ethoxy)ethyl-2-[2-[4-dibenzo[b,f][1,4]thiazepine-11-piperazinyl-1-carboxylate (impurity 111, 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]l -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-piperazinyl-dibenzo [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 (H-1 NMR, C-13 NMR, MS and IR), synthesis and formation of these impurities are discussed in detail.