Development and Scale-up of Acrylamide Formation Using an Impinging Jet

In a synthetic step of a pre-clinical drug candidate, a problematic dimer impurity was observed. Early work identified the origin of this dimer impurity as reaction between the starting material and product, indicating that efficient mixing was critical to achieving low levels of this impurity. A fit-for-purpose flow chemistry solution using an impinging jet was developed and implemented for this process. Kinetics work performed on this reaction also led to mechanistic understanding for the formation of additional impurities, including a chloro impurity that was identified as a GTI (genotoxic impurity). Reaction kinetics and response surface simulations were used to reduce the chloro impurity to acceptable levels. Using these insights, this process was successfully scaled to 12 kg in a cGMP manufacturing environment.

The work presented here was sponsored by AbbVie. AbbVie contributed to the design, research, and interpretation of data, writing, reviewing, and approving the presentation.  Daniel Caspi, Benoit Cardinal-David and Alex Huters are employees of AbbVie.