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On-Line Application of Near-Infrared Spectroscopy for Monitoring Water Levels in Parts per Million in a Manufacturing-Scale Distillation Process

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An on-line analytical method based on transmission near-infrared spectroscopy (NIRS) for the quantitative determination of water concentrations (in parts per million) was developed and applied to the manufacture of a pharmaceutical intermediate. Calibration models for water analysis, built at the development site and applied at the manufacturing site, were successfully demonstrated during six manufacturing runs at a 250-gallon scale. The water measurements will be used as a forward-processing control point following distillation of a toluene product solution prior to use in a Grignard reaction. The most significant impact of using this NIRS-based process analytical technology (PAT) to replace off-line measurements is the significant reduction in the risk of operator exposure through the elimination of sampling of a severely lachrymatory and mutagenic compound. The work described in this report illustrates the development effort from proof-of-concept phase to manufacturing implementation.

Keywords: Distillation; Method development; Near-infrared spectroscopy; Process analytical technology; Technical transfer; Trace water

Document Type: Research Article


Affiliations: Eli Lilly and Company, SMDD, Indianapolis, IN 46285 USA

Publication date: April 1, 2014

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