Linking Process, Product and Performance by Raman Imaging Analysis

Abstract

This work aims at exploring two applications of Raman spectroscopy in the development and manufacturing of pharmaceutical tablets made from amorphous solid dispersions (ASDs), in terms of both physical and chemical properties. The first application consisted on applying Raman spectroscopy to predict the tablets’ hard-ness. In contrast to typical destructive hardness testing, this strategy can be implemented as at-line and real-time process control via process analytical technology and thus provide real-time release during continuous manufacturing. This is investigated here for the first time for tablets composed of ASDs rather than crystalline-based formulations using a Confocal Raman Micro-scope. The generated data show an apparent relationship between the measured hardness and the Raman spectra baseline, consistent with previous findings in the literature. However, a more stringent analysis leads to the conclusion that the trend line is not strictly monotonic and with a slope across the measured range comparable to the variability of the Raman imaging analysis. The second application consisted on exploring the potential of confocal Raman microscopy to provide spatially resolved chemical images of the tablets’ surface, which allows to characterize the components spatial distribution. The goal was to evaluate the impact of two process param-eters: blending shear rate and sieving mesh size. These parameters were investigated using a structured 2-level design of experiments where Confocal Raman microscopy allowed the evalu-ation of the spatial distribution and the detection of API agglomerates and its relationship with the process parameters. However, the analysis was hindered by a lack of a perfectly flat surface of the tablets and to correct the influence of the change in focus on the Raman spectra, post-pro-cessing scripts were implemented. It is shown that there is an impact of both process parameters on the heterogeneity of tablets’ surface and, consequentially, a significant impact in disintegration of the tablets.