In situ Monitoring of a Heterogeneous Etherification Reaction Using Quantitative Raman Spectroscopy

Abstract

The development and use of an in situ Raman spectroscopic method for the end-point detection of an etherification reaction, during a pilot plant scale manufacturing campaign, is described. Monitoring the reaction progress and minimising the level remaining of a chloropyrazine starting material at the reaction end-point were important, as the latter impacted a drug substance critical quality attribute (CQA). Furthermore, the etherification reaction required the use of a heterogeneous base (K2CO3), and therefore the time to reach reaction completion could be scale dependent, owing to differences in reactor geometry and mixing characteristics. To provide valuable process understanding about the rate and extent of reaction during scale-up, a quantitative method utilising in situ Raman spectroscopy was developed. A series of laboratory scale reactions were performed to provide the spectroscopic and off-line reference measurements (HPLC) required for calibration model development. A quantitative multivariate ca...