title: Assay at low ppm level of dimethyl sulfate in starting materials for API synthesis using derivatization in ionic liquid media and LC-MS.
abstract: Dimethyl sulfate (DMS) is frequently used in pharmaceutical manufacturing processes as an alkylating agent. Trace levels of DMS in drug substances should be carefully monitored since the compound can become an impurity which is genotoxic in nature. Derivatization of DMS with dibenzazepine leads to formation of the N-methyl derivative, which can be retained on a reversed phase column and subsequently separated from other potential impurities. Such derivatization occurs relatively slowly. However, it can be substantially speed up if ionic liquids are used as reaction media. In this paper we report the use of 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide (IL1) and 1-butyl-4-methylpyridinium tetrafluoroborate (IL2) as reaction media for the derivatization of DMS with dibenzazepine. It was determined that the stoichiometry between the substrate and DMS may be 1:1 or 2:1, in relation with the nature of the reaction media. An (+)ESI-MS/MS approach was used for quantitation of the derivatized product. Alternatively, DMS derivatization may be carried out with pyridine in acetonitrile (ACN). The N-methylpyridinium derivative was separated by hydrophilic interaction liquid chromatography (HILIC) and detected through (+)ESI-MS (in the SIM mode). In both cases, a limit of quantitation (LOQ) of 0.05 μg/ml DMS was achievable, with a linearity range up to 10 μg/ml. Both analytical alternatives were applied to assay DMS in 4-(2-methoxyethyl)phenol, which is used as a starting material in the synthesis of metoprolol.
authors: Chemical Development Department, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd., Ridgefield, CT 06877-0368, USA.
authors: Nelu
authors: N
authors: Grinberg
authors: Florin
authors: F
authors: Albu
authors: Keith
authors: K
authors: Fandrick
authors: Elena
authors: E
authors: Iorgulescu
authors: Andrei
authors: A
authors: Medvedovici
mesh_terms: D000097:Acetonitriles / Q000737:chemistry; D000477:Alkylating Agents / Q000032:analysis* / Q000737:chemistry; D053000:Analytic Sample Preparation Methods; D001881:Borates / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D003984:Dibenzazepines / Q000737:chemistry; D004340:Drug Contamination / Q000517:prevention & control; D057927:Hydrophobic and Hydrophilic Interactions; D007094:Imides / Q000737:chemistry; D007202:Indicators and Reagents / Q000737:chemistry; D052578:Ionic Liquids / Q000737:chemistry; D007700:Kinetics; D057230:Limit of Detection; D009153:Mutagens / Q000032:analysis* / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D011726:Pyridinium Compounds / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D013463:Sulfuric Acid Esters / Q000032:analysis* / Q000737:chemistry; D053719:Tandem Mass Spectrometry
chemical_list: C581933:1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide; C581935:1-butyl-4-methylpyridinium tetrafluoroborate; D000097:Acetonitriles; D000477:Alkylating Agents; D001881:Borates; D003984:Dibenzazepines; D007094:Imides; D007202:Indicators and Reagents; D052578:Ionic Liquids; D009153:Mutagens; D011725:Pyridines; D011726:Pyridinium Compounds; D011759:Pyrrolidines; D013463:Sulfuric Acid Esters; C527817:dibenzazepine; C007482:dimethyl sulfate; C023666:pyridine; C032159:acetonitrile