Detection, identification and quantification of a new de-fluorinated impurity in casopitant mesylate drug substance during late phase development: an analytical challenge involving a multidisciplinary approach.

During late phase development of the selective NK1 receptor antagonist casopitant mesylate, a de-fluorinated impurity was discovered and quantified by an orthogonal analytical approach, using NMR and LC-MS. A dedicated (19)F NMR method was initially developed for first line identification and semi-quantification of the impurity. Subsequently, a more accurate quantification was achieved by means of a selective normal-phase LC-MS method, which was fully validated.

NMR spectroscopy and surface tension measurements applied to the study of self-association of casopitant mesylate, a novel NK1 antagonist.

The aggregation behaviour of casopitant mesylate, a new NK1 antagonist drug, was investigated by means of NMR spectroscopy and surface tension measurements. The critical micelle concentration (CMC) in glycine buffer at pH 3.5 was determined by analyzing the (1)H NMR chemical shifts variation and the surface tension in function of the concentration in a series of solutions.

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.

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.

Application of LC-NMR to the identification of bulk drug impurities in NK1 antagonist GW597599 (vestipitant).

Liquid chromatography-NMR (LC-NMR) spectroscopy was used to obtain detailed information regarding the structure of the major bulk drug impurities present in GW597599 (vestipitant). The one-dimensional (1)H LC-NMR experiments were performed in both continuous and stop-flow modes on a sample of GW597599 (vestipitant) enriched with mother liquor impurities. The information derived from both LC-NMR and LC-MS data provided the structural information of all major impurities.

Application of LC-NMR and HR-NMR to the characterization of biphenyl impurities in the synthetic route development for vestipitant, a novel NK1 antagonist.

Vestipitant (1) is a novel NK1 antagonist currently under investigation for the treatment of CNS disorders and emesis. The first synthetic step comprised a Grignard synthesis. An impurity was identified and initially expected to be a symmetric biphenyl.