Manufacturing Development and Genotoxic Impurity Control Strategy of the Hedgehog Pathway Inhibitor Vismodegib
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- 作者：Remy Angelaud ; Mark Reynolds ; Cadapakam Venkatramani ; Scott Savage ; Huldreich Trafelet ; Thomas Landmesser ; Peter Demel ; Michael Levis ; Olivier Ruha ; Baerbel Rueckert ; Heinz Jaeggi
- 刊名：Organic Process Research & Development
- 出版年：2016
- 出版时间：August 19, 2016
- 年：2016
- 卷：20
- 期：8
- 页码：1509-1519
- 全文大小：436K
- 年卷期：0
- ISSN：1520-586X
文摘
The development work toward the robust and efficient manufacturing process to vismodegib, the active pharmaceutical ingredient (API) in Erivedge, is described. The optimization of the four-stage manufacturing process was designed to produce the API with the required critical quality attributes: (1) the selective catalytic hydrogenation reduction of the nitro compound 3 to the corresponding aniline 4 while minimizing the formation of potential genotoxic (mutagenic) impurities; (2) the control of the polymorphic phase and multipoint specification for particle size distribution.