Tuesday, 24 May 2005 - 3:45 PM

This presentation is part of: Applications of LC-MS in Drug Discovery/Development

LC/MS Degradation Studies in Pharmaceutical Development

Charles Pan, Frances Liu, and Richard Vivilecchia. Novartis, East Hanover, NJ

Liquid chromatography mass spectrometry (LC/MS) has been widely used in pharmaceutical development over the past decade. It has become a powerful tool for identification of degradation products to support method development/ validation and elucidation of degradation pathways to support excipient selection.

Drug degradation is very critical in pharmaceutical development as it has significant impacts on drug efficacy, safety profile and storage conditions. As a result, identification of degradation compounds has become very important to formulation development. The LC/MS studies in pharmaceutical development are faced with some unique challenges. The content levels of degradation compounds are normally as low as 0.1%. The presence of excipient could cause source contamination or chromatographic interferences. The stability conditions may result in multiple chemical reactions, such as oxidation, hydrolysis, thermal decomposition, or light-induced free radical reactions. These reactions can sometimes occur in a combined manner, which makes identification more complicated and less predictable. In addition, isolation and enrichment are normally required to confirm the proposed structures for late phase projects.

This presentation will focus on the use of mass spectrometry to identify unknowns resulting from drug substance degradation, drug-excipient interaction, and excipient degradation. Using combined GC/MS and LC/NMR techniques, a degradation compound that was not detectable in LC/MS has been identified. Thermal desorption GC/MS was developed and used to understand chemical reactions responsible to weight loss in thermogravimetric analyses of salts of drug substance. In addition, the use of Ion trap LC/MS to support peptide mapping for protein analysis will be discussed.

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