Process-related impurities case studies

Actual case studies using these isolation and syntheses as well as mass spectral and NMR approaches are outlined in the remainder of this chapter. This collaborative multidisciplinary strategy is applied to the structure elucidation of all the impurity and degradant case studies presented. The successful elucidation of these structures was essential to predict potential toxicity, set threshold limits, and identify ways to prevent or greatly reduce their formation. The case studies have been organized into degradation and process-related impurities examples. 

A bulk lot sample of drug substance contained an unknown process-related impurity at 0.4% in case study B.7. To meet project time lines, it was necessary to identify the impurity. Mass spectral data indicated that the impurity had a molecular weight of M+12 (compared to the parent). LC/MS/ MS data indicated that the change was located in the sugar portion of the molecule. Isolation and NMR analysis was required to provide more structural information on the impurity. This again was a process-related impurity not observed in forced degradation studies therefore, effort was placed on finding an enriched mother liquor sample. 

A bulk lot sample of drug substance in case study B.8 contained an unknown impurity at the 0.3% level. This unknown process-related impurity was less polar than the parent in the chromatographic assay. Based on mass spectral data, the impurity had a molecular weight of M+4, suggesting over-reduction of the benzene ring. Attempts to obtain mass spectral... 

Chapter 14 provides practical guidance with case studies on isolating and characterizing process-related impurities and degradation products for pharmaceutical drug candidates. The case studies utilize isolation or synthesis in conjunction with mass spectral and NMR characterizations. A collaborative multiple disciplinary strategy has been found to be the most efficient way to solve impurity/degradation product problems. 

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