368151 Kinetics Model for Designing Grignard Reactions in Batch or Flow Operations

Thursday, November 20, 2014: 10:10 AM
203 (Hilton Atlanta)
Shujauddin M. Changi and Sze Wing (Candice) Wong, Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, IN

Grignard reactions are one of the oldest, yet quite complicated to understand and design for, at different scales of operation. The heterogeneity of the solid-liquid reaction means that there is an interplay of mass transfer and reaction kinetics rates. In designing a Grignard reaction for scales ranging from laboratory to manufacturing, using either batch or continuous operation, a key component of process design development is to obtain an understanding of kinetics that are relatively free of mass-transfer. A fit-for-use reaction kinetics model was developed to parameterize the reaction and mass transfer rates of the Grignard reaction across different scales from 250mL to 500 gallon and for different grades of magnesium. The model includes three parameters, one (kSLa) representing the mass-transfer component and two (k and Ea) representing the Arrhenius dependent rate constant. The reaction kinetics model was then applied to design the magnesium recharge frequency by taking operational variability into account. Furthermore, the model is coupled with equipment heat transfer characteristic to understand the process dynamic of the CSTR in the presence of process disturbances. Based on the kinetics model and energy balance, reactor temperature was determined to be suitable to detect process failure to ensure process safety at manufacturing.  The resulting process understanding enabled the team to define the final operation strategy to ensure a safe and robust process to be scaled up to commercial scale production.  This exercise can be extended as a platform for other similar Grignard reactions in the future.

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