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On-Line Determination of Reaction Completion in a Closed-Loop Hydrogenator Using NIR Spectroscopy

Volume 52, Number 1 (Jan. 1998) Page 17-21

Ward, Howard W.; Sekulic, S. Sonja; Wheeler, Michael J.; Taber, Geraldine; Urbanski, Frank J.; Sistare, Frank E.; Norris, Timothy; Aldridge, Paul K.


An on-line near-infrared (NIR) spectroscopic method has been developed to determine in situ the endpoint of a bulk pharmaceutical hydrogenation reaction in a loop hydrogenator. This hydrogenation employs a 5% palladium-on-carbon catalyst with tetrahydrofuran (THF) as the reaction solvent. The traditional test for monitoring the endpoint of the hydrogenation is a gas chromatographic procedure that requires an estimated 60 min from the time a sample is taken to the point where the analysis results become available. The use of NIR spectroscopy in an on-line mode of operation allows spectra to be collected every 2 min and thereby significantly improves response time and result availability. The need for obtaining results in ''real time'' stems from the creation of undesired side products if the reaction is allowed to continue past the optimal endpoint. If the reaction is not stopped before these side products reach a level of approximately 0.8% (wt/wt), the batch requires additional purification at considerable time and cost. A partial least-squares model was constructed, validated, and successfully used to determine the endpoint of subsequent batches.