How to Optimize a Reaction using in-situ IR

The Problem

A filed process was experiencing poor impurity control, causing 25% of batches to fail release specification. The reaction in question was a low-temperature lithiation reaction, operating at -70 °C.

The Breakthrough

An assessment of the standard process for factors influencing the impurity concentration during manufacturing was completed with in-situ IR tracking reaction products. The process was studied through engineering first principles which enabled design space mapping.

The Impact

Reduction in impurity 1 levels by greater than 40% as a result of first principle understanding of the link between heat of reaction, turbulent diffusion / meso-mixing and impurity generation.

Impurity control is one of the most important tasks in process scale-up. Where the underlying kinetics and thermodynamics driving the process are not fully understood, it can result in significant levels of impurities generated on scale. However, this can be easily avoided by going back to engineering first principles and developing models to help make predictions to design strategies to improve the process. This blog highlights the need to incorporate an engineering perspective into process development at all stages to avoid failures at later stages.

APC scientists recognised the need for a greater understanding of the parameters that affected the process and impurity generation. An assessment of the standard process was completed with in-situ monitoring to measure the real-time effect of a parameter change. The study highlighted the reaction sensitivity to heat transfer, mixing and the addition profile. The mixing profile was studied with respect to macro, meso and micro mixing. Due to the temperature differential between the addition stream and the bulk (T_diff = 90 °C) localized exotherms were identified to be responsible for higher than predicted impurity levels. Although the bulk was well-mixed (macro-mixing), each drop entering from the feed pipe was not amalgamated into the system fast enough to limit the effects of the localized reactions and exotherms.

This approach led to an optimized control strategy. This was enabled through a greater understanding of the individual factors which contribute to the generation of process impurities. As this was a registered process, there were only limited changes that could be made within the bounds of the filing. However, the impurity control was gained through an in-depth understanding of how small tweaks to the controls on the plant reactors – (particularly those pertaining to reaction temperature, jacket temperature and flow rate through the jacket), in addition to how small changes to the addition time, for a specific selection of agitation conditions could reliably deliver the required material. The ability to identify all of these subtle changes resulted in a reduction of 40% of the key impurity.