title: A multi-technique approach using LC-NMR, LC-MS, semi-preparative HPLC, HR-NMR and HR-MS for the isolation and characterization of low-level unknown impurities in GW876008, a novel corticotropin-release factor 1 antagonist.
abstract: A multi-technique approach was applied in order to fully characterize four low-level unknown impurities of GW876008, a novel CRF(1) receptor antagonist. Liquid chromatography (LC)-NMR spectroscopy was used in combination with LC-MS to obtain detailed information regarding the structure of the two major impurities present in batches of GW876008 and observed in the first synthetic scale-up for preclinical use. Two additional impurities were unexpectedly found at greater levels in a large scale synthesis for clinical use and their structure was elucidated by means of high resolution (HR)-MS and HR-NMR, after a small scale preparative HPLC purification step. This structural information was useful in terms of shedding light on the typical impurity profile of this new chemical entity with the aim to support the early development package for Phase I clinical studies.
authors.affiliation: Analytical Chemistry, GlaxoSmithKline Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy. ste.provera@gmail.com
authors.forename: Stefano
authors.initials: S
authors.lastname: Provera
authors.forename: Luca
authors.initials: L
authors.lastname: Rovatti
authors.forename: Lucilla
authors.initials: L
authors.lastname: Turco
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Mozzo
authors.forename: Alberto
authors.initials: A
authors.lastname: Spezzaferri
authors.forename: Sergio
authors.initials: S
authors.lastname: Bacchi
authors.forename: Arianna
authors.initials: A
authors.lastname: Ribecai
authors.forename: Simone
authors.initials: S
authors.lastname: Guelfi
authors.forename: Anna
authors.initials: A
authors.lastname: Mingardi
authors.forename: Carla
authors.initials: C
authors.lastname: Marchioro
authors.forename: Damiano
authors.initials: D
authors.lastname: Papini
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000032:analysis* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004340:Drug Contamination; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D011720:Pyrazoles / Q000032:analysis* / Q000737:chemistry; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D000099052:CRF Receptor, Type 1
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C552097:GW 876008; D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1