ABSTRACT
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. The temperature dependence of the CMC was also evaluated by NMR spectroscopy as well as the thermodynamic parameters contributing to the aggregation discussed. Surface tension measurements were conducted as well in the formulation conditions, e.g. in the presence of sodium chloride.
Subject(s)
Chemistry, Pharmaceutical/methods , Magnetic Resonance Spectroscopy/methods , Neurokinin-1 Receptor Antagonists , Piperazines/pharmacology , Piperidines/pharmacology , Drug Design , Humans , Hydrogen-Ion Concentration , Micelles , Models, Chemical , Piperazine , Piperazines/chemistry , Surface Properties , Technology, Pharmaceutical/methods , Temperature , ThermodynamicsABSTRACT
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. The results obtained on the development batches of the drug substance were used by the project team to set up a suitable control strategy and ultimately to ensure patient safety and the progression of the project.
Subject(s)
Chemistry, Pharmaceutical/methods , Drug Contamination , Fluorine/chemistry , Piperazines/analysis , Piperidines/analysis , Chemistry Techniques, Analytical , Chromatography, Liquid/methods , Halogenation , Magnetic Resonance Spectroscopy/methods , Mass Spectrometry/methods , Models, Chemical , Pharmaceutical Preparations/chemistry , Quality Control , Reproducibility of ResultsABSTRACT
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.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/analysis , Chromatography, High Pressure Liquid/methods , Drug Contamination , Magnetic Resonance Spectroscopy/methods , Pyrazoles/analysis , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Spectrometry, Mass, Electrospray Ionization/methods , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Pyrazoles/chemistryABSTRACT
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. The full characterisation of the impurities by high-resolution NMR spectroscopy was ultimately performed on appropriately synthesised compounds.
Subject(s)
Chromatography, High Pressure Liquid/methods , Drug Contamination , Drug Industry/methods , Magnetic Resonance Spectroscopy/methods , Neurokinin-1 Receptor Antagonists , Piperidines/analysis , Fluorobenzenes , Mass Spectrometry/methods , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , SolutionsABSTRACT
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. This paper reports the work to synthesise the supposed structure and the spectroscopic analyses (LC-NMR and HR-NMR) to correctly identify the real structure and understand the chemical pathway of the impurity.