Investigation of Variable Impurity Profile from a Mitsunobu Reaction Using Insights from Kinetic Modeling, Multi-Phase Interactions, and Computational Fluid Dynamics

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• 作者：Samrat Mukherjee ; Shailendra Bordawekar ; Nandkishor Nere
• 刊名：Industrial & Engineering Chemistry Research
• 出版年：2016
• 出版时间：May 4, 2016
• 年：2016
• 卷：55
• 期：17
• 页码：4867-4877
• 全文大小：569K
• 年卷期：0
• ISSN：1520-5045

文摘

A drug substance intermediate synthesis involving a Mitsunobu coupling reaction using triphenylphosphine and diisopropyl azodicarboxylate was investigated to understand the variable levels of an impurity. One of the precursors for the impurity, 1,2-isopropylhydrazine dicarboxylate (a reaction byproduct), crystallizes out of the reaction medium and also forms a cocrystal with triphenylphosphine oxide (TPPO), another reaction byproduct. The dynamic byproduct concentrations as a result of these phenomena were taken into account in a reaction kinetics model. The variability in impurity formation was linked to the concentration of 1,2-isopropylhydrazine dicarboxylate, which is dependent on reaction progress and 1,2-isopropylhydrazine dicarboxylate–TPPO cocrystal formation. The cocrystal formation is in turn affected by the mixing characteristics in the reactor. Computational fluid dynamics simulation of the mixing patterns and a series of proof-of-concept experiments were performed to establish the influence of mixing intensity and cocrystal formation on the level of impurity formed.