Considerations in Raman Spectroscopy for Real-Time API Concentration Measurement at Tablet Press Feed Frame

Raman spectroscopy is one of the important process analytical technology tools available for implementation in the continuous manufacturing of oral solid dosages. The aim of this study was to investigate several practical considerations in generating real-time measurements using Raman spectrometer at a tablet press feed frame, including the effects of fluorescence interference, photobleaching, feed-frame rpm, and material particle size. Fluorescence, in particular, is a significant drawback of Raman spectroscopy, compared to the use of near-infrared spectroscopy. Potential material sparing strategies were also investigated, including using stationary powders for calibration and isolation of feed-frame materials. Acetaminophen was used as the main active pharmaceutical ingredient (API), and microcrystalline cellulose (MCC) and lactose were used as excipients. The fluorescent behavior of MCC at 785 nm laser wavelength was reported and discussed. Raman spectra of a blend of MCC and acetaminophen and lactose and acetaminophen were collected at the feed frame of the tablet press. A series of preprocessing steps applied to remove the fluorescence interference was found to be effective, including the use of standard normal variate, subtraction of spectra of fluorescent material, baseline correction, and smoothing. Three different PLS models were prepared for different scenarios and their performances were compared. The models were able to predict the concentration of acetaminophen with root mean squared error prediction (RMSEP) of 0.29% w/w when there was no fluorescence interference and 0.57% w/w when there was fluorescence interference in background spectra. The study demonstrated the feasibility of using Raman spectroscopy for API concentration prediction even in the case of fluorescent interference and showed that Raman measurements were robust; that is, they were not much affected by feed-frame rpm and excipient particle size.