Fiber-optic UV/visible composition monitoring for process control of batch reactions

In this paper, a method for characterizing an industrially significant reaction using chemometrics, fiber-optic UV/visible spectroscopy and a single fiber transmission probe is reported. Aliquots of the reaction mixture were also taken at constant intervals for off-line HPLC analysis. HPLC peak areas were used to develop multivariate calibrations for the real-time determination of product and consumption of reactants. Composition profiles and pure component spectra of the reactant mixture, intermediate, and product were estimated using automatic window factor analysis (WFA), a type of self-modeling curve resolution (SMCR), without the aid of referee methods of analysis or standards. Window edges were automatically refined by a new iterative process that uses a robust adaptive noise threshold in the stopping criterion. Strong evidence for the formation of a reactive intermediate was detected and characterized by SMCR that could not be detected by HPLC. Eight replicate runs over a period of 3 months demonstrated that the SMCR results were reproducible. Robust smoothing of the SMCR profiles with locally weighted scatter plot smoothing (LOWESS) was used to construct control charts for detecting upsets in the batch reaction caused by the introduction of small amounts of water. Residuals (smooth–unsmoothed) outside control limits (3×MAD, median absolute deviation of residuals from pre-run batches) were used to detect small, sudden process upsets.