Complemental hard modeling in Raman spectroscopy: A case study on titanium dioxide-free coating in-line monitoring.

Tablets are coated for taste or odor modification, for modified release profiles or as a protective layer to increase the stability. Here, titanium dioxide is frequently added as a coating component due to its opaque properties. Furthermore, its Raman activity makes it an integral part of in-line monitoring models. However, due to the carcinogenic potential of titanium dioxide, calcium carbonate is utilized as a substitute, exhibiting similar opaque properties. Calcium carbonate tends to exhibit overlapped peaks with carbon hydrates in the Raman spectrum. Consequently, new models based on e.g. hard modeling are required instead of peak integration. In this study, tablets were coated with a coating including calcium carbonate. Partial Least Squares Regression (PLS) and Complemental Hard Modeling (CHM) were examined as feasible in-line monitoring approaches. Furthermore, two different measurement positions in the coater were compared, orthogonal and tangential with respect to the moving tablet bed. Cross-validation exhibited improved CHM performance with reduced RMSECV values of about 5 %. The prediction of the coating mass growth occurred comparable with RMSEP values in a similar range of 2-5 %. Despite this, the CHM´s achieved improved performance with reduced training data quantity and quality. The different measurement positions indicated no process-relevant differences.