Optimising reaction performance in the pharmaceutical industry by monitoring with NMR

Abstract

Quality assurance and process understanding are assuming increasing importance in the production of Active Pharmaceutical Ingredients (APIs). NMR has the potential to report on physical processes, quantities, structures, and speciation as chemical reactions progress. Following the progression of chemical reactions by placing the sample in an NMR tube, one can perform a large number of useful studies that provide chemical and mechanistic insight. But this simple approach can have limitations, and we have therefore constructed an apparatus comprising a laboratory reactor coupled with an NMR flow cell. The reactor duplicates the exact reaction conditions that will apply with large-scale production. This reaction mixture is sampled and pumped to a high-resolution NMR flow cell where the spectrum is recorded through the course of the reaction. We demonstrate the utility of reaction monitoring using NMR both for simple cases where tubes can be used, and describe the design of the on-flow apparatus and highlight its utility with an example.

Trends in Spectroscopic Techniques for Process Control

“…Various applications of chemical as well as pharmaceutical reaction and process monitoring of reactions and processes are described in the recent literature [14][15][16].…”

Process NMR Spectroscopy: Technology and On‐Line Applications

“…The smaller coil is wrapped around a sealed capillary of LiCl containing a paramagnetic relaxation agent. 7 Li is a high receptivity, quadrupolar nucleus that yields a strong signal with a very short relaxation delay requirement between NMR pulses. The spectrometer can work in several modes to ' lock ' the NMR spectrometer in order to produce high -resolution spectra that are immune to the effects of magnetic fi eld drift during the NMR acquisition.…”

Modelling chemical kinetics of a complex reaction network of active pharmaceutical ingredient (API) synthesis with process optimization for benzazepine heterocyclic compound

“…These include process optimization, process safety evaluation, scale-sensitivity understanding, and robustness testing [1]. Reaction kinetics and model-based reactor engineering are seldom adopted for the production of pharmaceutical ingredients, even though they can be quite advantageous for process design and engineering [2][3][4][5][6][7][8][9][10][11][12]. Let alone their economical favourability, which is even more valid for complex reaction networks [2].…”