title: "In-source" fragmentation of an isobaric impurity of lamotrigine for its measurement by liquid chromatography tandem mass spectrometry after pre-concentration using solid phase extraction.
abstract: An analytical method has been developed for trace analysis (i.e. sub-ppm levels) of a key synthetic impurity, 14W80 ((Z)-2-(2,3-dichlorophenyl)-2-(guanidinylimino)acetonitrile) in lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine). 14W80 is isobaric with lamotrigine, which gives an extra layer of complexity to its determination and the various problems associated with development of an appropriate methodology are discussed in this work. Ultimately, a liquid chromatography tandem mass spectrometry (LC-MS/MS) method using in-source fragmentation with Atmospheric Pressure Chemical Ionisation (APCI) followed by multiple reaction monitoring (MRM) has been found to provide adequate sensitivity and specificity. A detection limit of 25 ppb mass fraction relative to lamotrigine was achieved for 14W80. The use of solid phase extraction (SPE) enhanced the detection limit to 2 ppb mass fraction relative to lamotrigine.
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK. dan.j.carrier@gsk.com
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Carrier
authors.forename: Christine
authors.initials: C
authors.lastname: Eckers
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Wolff
mesh_terms: D000097:Acetonitriles / Q000032:analysis / Q000737:chemistry; D000927:Anticonvulsants / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry; D002853:Chromatography, Liquid / Q000379:methods*; D004340:Drug Contamination / Q000517:prevention & control; D000077213:Lamotrigine; D015394:Molecular Structure; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D052616:Solid Phase Extraction / Q000379:methods*; D013607:Tablets / Q000737:chemistry; D053719:Tandem Mass Spectrometry / Q000379:methods*; D014227:Triazines / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000097:Acetonitriles; D000927:Anticonvulsants; D013607:Tablets; D014227:Triazines; C402746:14W80; D000077213:Lamotrigine