RESUMEN
Edivoxetine (LY2216684 HCl), although a chemically stable drug substance, has shown the tendency to degrade in the presence of carbohydrates that are commonly used tablet excipients, especially at high excipient:drug ratios. The major degradation product has been identified as N-formyl edivoxetine. Experimental evidence including solution and solid-state investigations, is consistent with the N-formylation degradation pathway resulting from a direct reaction of edivoxetine with (1) formic acid (generated from decomposition of microcrystalline cellulose or residual glucose) and (2) the reducing sugar ends (aldehydic carbons) of either residual glucose or the microcrystalline cellulose polymer. Results of labeling experiments indicate that the primary source of the formyl group is the C1 position from reducing sugars. Presence of water or moisture accelerates this degradation pathway. Investigations in solid and solution states support that the glucose Amadori Rearrangement Product does not appear to be a direct intermediate leading to N-formyl degradation of edivoxetine, and oxygen does not appear to play a significant role. Solution-phase studies, developed to rapidly assess propensity of amines toward Maillard reactivity and formylation, were extended to show comparative behavior with example systems. The cyclic amine systems, such as edivoxetine, showed the highest propensity toward these side reactions.
Asunto(s)
Composición de Medicamentos/métodos , Morfolinas/administración & dosificación , Morfolinas/química , Alcohol Feniletílico/análogos & derivados , Administración Oral , Inhibidores de Captación Adrenérgica/administración & dosificación , Inhibidores de Captación Adrenérgica/química , Formas de Dosificación , Alcohol Feniletílico/administración & dosificación , Alcohol Feniletílico/químicaRESUMEN
The fragmentation pathways of different conformations of three charge states of ubiquitin ions are examined using ion mobility/collisional activation/time-of-flight techniques. Mass spectra for fragments for different conformers of a single charge state appear to be identical (within the experimental reproducibility). These results are consistent with a mechanism in which different conformers of each charge state rearrange to similar dissociation transition states prior to fragment formation.
Asunto(s)
Ubiquitina/química , Cromatografía de Gases y Espectrometría de Masas , Conformación Molecular , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
An ion trap/ion mobility/quadrupole/collision cell/time-of-flight mass spectrometer that incorporates a differentially pumped orifice-skimmer cone region at the back of the drift tube has been developed for the analysis of peptide mixtures. The combined approach allows a variety of strategies to be employed for collisionally activating ions, and fragments can be monitored by subsequent stages of mass spectrometry in a parallel fashion, as described previously (Anal. Chem. 2000, 72, 2737). Here, we describe the overall experimental approach in detail. Applications involving different aspects of the initial mobility separation and various collisional activation and parallel sequencing strategies are illustrated by examining several simple peptide mixtures and a mixture of tryptic peptides from beta-casein. Detection limits associated with various experimental configurations and the utility for analysis of complex systems are discussed.