Derivatization and determination of residual N,N-Carbonyldiimidazole by LC for an in-process control test

For the robust analysis of N,N-Carbonyldiimidazole (CDI), its derivatization into a more stable compound may be needed. Herein, the reaction of CDI with N-benzylmethylamine followed by LC-UV quantitative analysis was explored. Reaction conditions as well as LC method feasibility were demonstrated by qualification of selectivity from other impurities and reagents, linearity across a range of 0.05-0.15%w/w, spike and recovery across a range of 0.05-0.15%w/w, reaction reproducibility with various samples, reagents and analytical chemists, and sample stability of over 24 h. Rapid and quantitative derivatization of residual CDI was achieved at 0.1% w/w relative to the synthetic product under consideration. A fit-for-purpose limit test using a RPLC-UV method as an in-process control for the reaction completion of product, at scale, was successfully implemented and executed.