title: Detection of the principal synthetic route indicative impurity in lamotrigine.
abstract: An analytical method has been developed for the detection of trace amounts of the principal synthetic route indicative impurity in lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine). A sample extract was preconcentrated by normal-phase high-performance liquid chromatography (HPLC) and analysed by subsequent on-line reversed-phase HPLC-thermospray mass spectrometry (TSP-MS). During the sample extraction and concentration step, carried out by semipreparative normal-phase chromatography, the preliminary separation of the impurity from the lamotrigine takes place. The organic solvent (dichloroethane-methanol, 90:10, v/v) is evaporated from the collected fraction and the material is redissolved in a smaller volume of the reversed-phase mobile phase. The collected fraction is then subjected to reversed-phase HPLC-TSP-MS. The influence of an ultrasonic extraction step has been examined. When the method was applied to lamotrigine tablets, a shake flask partitioning step using 1 mg/ml EDTA in water-dichloroethane was used instead of the ultrasonic extraction. Detection limit and recovery measurements showed that the route indicative impurity formed during the synthesis could be detected in the 50-100 ppb (w/w) range.
authors.affiliation: School of Pharmacy, University of London, 29-39 Brunswick Square, London, UK.
authors.forename: D S
authors.initials: DS
authors.lastname: Ashton
authors.forename: A D
authors.initials: AD
authors.lastname: Ray
authors.forename: K
authors.initials: K
authors.lastname: Valko
mesh_terms: D000097:Acetonitriles / Q000032:analysis; D000927:Anticonvulsants / Q000032:analysis* / Q000138:chemical synthesis; D002851:Chromatography, High Pressure Liquid; D004340:Drug Contamination / Q000517:prevention & control; D004492:Edetic Acid; D000077213:Lamotrigine; D013058:Mass Spectrometry / Q000379:methods; D011208:Powders / Q000032:analysis; D014227:Triazines / Q000032:analysis* / Q000138:chemical synthesis
chemical_list: D000097:Acetonitriles; D000927:Anticonvulsants; D011208:Powders; D014227:Triazines; C402746:14W80; D004492:Edetic Acid; D000077213:Lamotrigine; C402745:13W80