title: HILIC-MS Determination of Genotoxic Impurity of 2-Chloro-N-(2-Chloroethyl)Ethanamine in the Vortioxetine Manufacturing Process.
abstract: In the last decade, pharmaceutical regulatory agencies are focused on monitoring and evaluation of trace-level genotoxic impurities (GTIs) in drug substances, which requires manufacturers to deliver innovative approaches for their analysis and control. GTIs in the low p.p.m. level rising from the process of drug production have to be positively identified and quantified. Therefore, sensitive and selective analytical methods are necessary for required quantification level of these GTIs. Unfortunately, general guidance on how to develop strategy of the analysis and control of GTIs is currently missing in the pharmaceutical industry. Therefore, practical example of the analytical control of 2-chloro-N-(2-chloroethyl)ethanamine GTI in the vortioxetine (VOR) manufacturing process was demonstrated in this work. QDa mass detection with electrospray ionization in selected-ion recording mode was utilized for quantitation of GTIs. The method of hydrophilic interaction liquid chromatography coupled with mass spectrometry detection (HILIC-MS) was validated as per International Conference on Harmonization guidelines and was able to quantitate GTIs at 75 p.p.m. with respect to VOR. The HILIC-MS method was achieved using a Primesep B column (150 × 4.6 mm, 5.0 µm; Sielc, USA) using mobile phase consisting of 10 mM ammonium formate buffer pH 3.0 and acetonitrile (5 : 95, v/v) at 0.8 mL/min flow rate. The QDa mass detector was operated in the positive ion mode. Quadrupole mass analyzer was employed in selected-ion monitoring mode using target ion at m/z 142 as [M+H](+).
authors.affiliation: Zentiva, k.s. Praha, a Sanofi Company, U Kabelovny 130, 102 37 Prague 10, Czech Republic michal.dousa@seznam.cz.
authors.forename: Michal
authors.initials: M
authors.lastname: Douša
authors.affiliation: Zentiva, k.s. Praha, a Sanofi Company, U Kabelovny 130, 102 37 Prague 10, Czech Republic.
authors.forename: Robert
authors.initials: R
authors.lastname: Klvaňa
authors.affiliation: Zentiva, k.s. Praha, a Sanofi Company, U Kabelovny 130, 102 37 Prague 10, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Doubský
authors.affiliation: Zentiva, k.s. Praha, a Sanofi Company, U Kabelovny 130, 102 37 Prague 10, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Srbek
authors.affiliation: Zentiva, k.s. Praha, a Sanofi Company, U Kabelovny 130, 102 37 Prague 10, Czech Republic.
authors.forename: Jindřich
authors.initials: J
authors.lastname: Richter
authors.affiliation: Waters Gesellschaft m.b.H, Psohlavců 43, 147 00 Prague 4, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Exner
authors.affiliation: Zentiva, k.s. Praha, a Sanofi Company, U Kabelovny 130, 102 37 Prague 10, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Gibala
mesh_terms: D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004340:Drug Contamination; D013058:Mass Spectrometry / Q000379:methods*; D009153:Mutagens / Q000032:analysis*; D010879:Piperazines / Q000032:analysis*; D013440:Sulfides / Q000032:analysis*; D000078784:Vortioxetine
chemical_list: D009153:Mutagens; D010879:Piperazines; D013440:Sulfides; D000078784:Vortioxetine