NMR Detective Agency: Uncovering the Truth for Process Chemists

Abstract

NMR plays a “detective role” that through observation and data analysis acts as a “magnifying lens” facilitating the visualization of chemical problems in detail to provide solutions; therefore, NMR is an essential part of analytical control strategies during scaling up drug development stages in preparation of commercial regulatory approval. NMR is a critical analytical technique for the structure characterization of organic impurities during drug development, supporting the work of process chemists for analytical control strategies. During the past decade, NMR has played an important role in investigating reaction mechanisms for process understanding and improvement on scale-up drug processes to support clinical trials in the pharmaceutical industry. Those mechanistic investigation studies are key to improving the quality, efficiency, and yield of materials in the APIs syntheses, providing mitigation pathways that directly impact the performance of scale-up processes and their analytical control strategies. Structure elucidation of drug impurities and investigations of reaction mechanisms during scale-up chemical reactions have become the principal “detective roles” of NMR, providing better control strategies for drugs during process development. In addition, other existing NMR methodologies and technologies may provide impact expanding the “detective role” of NMR as part of the analytical control strategies for process chemists. Those methodologies are NMR anisotropy for the determination of relative configuration of stereoisomers of chiral drugs, quantitation by low field time-domain (TD) NMR of fluorinated drug substances in their formulated drug products, low field TD-NMR for the water content of lyophilized materials in sealed vials as a nondestructive and not invasive technique, and the application of low field benchtop NMR and high field cryogen-free NMR as PAT tools in real-time reaction monitoring of chemical processes in the manufacturing plant. The “detective role” of NMR in drug development provides solutions based on knowledge of process understanding for improvement, which plays a critical role in implementing appropriate analytical control strategies for process chemists.