SEM/EDX and Raman chemical imaging of pharmaceutical tablets: A comparison of tablet surface preparation and analysis methods

[Display omitted] •SEM/EDX and Raman chemical imaging (RCI) of commercial zinc sulfate tablets.•Microstructural analyses based on common tablet surface preparation methods.•Results depend on surface preparation, CI tool, and correct problem formulation.•Comparison of general advantages, disadvantages, and errors with SEM/EDX and RCI. A better understanding of a pharmaceutical tablet’s microstructure has the potential to unlock the black box between material attributes, process parameters and the critical quality attributes. Microstructure determination requires measuring the spatial-, particle size-distributions (absolute and relative) of the ingredients, and the void space, which is the overt goal of chemical Imaging (CI). Reliable quantitative results can be obtained by imaging multiple layers per tablet, with each layer having a minimal surface roughness. This study utilized scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDX) and Raman chemical imaging (RCI) to provide a comparative discussion of results obtained when determining the microstructure of commercial zinc sulfate tablets, using three methods of tablet surface preparation: scoring & hand-fracturing, microtoming, and grating. A description of the working principles of the measurement and surface preparation methods is followed by a comparison of microstructure (particle size distribution and homogeneity of distribution) using chemical images. A comparison of the general advantages and disadvantages of SEM/EDX and RCI and the common errors in analyzing microstructure are also discussed. The results indicate that in addition to selecting the correct tablet surface preparation method, chemical imaging method, and the subsequent microstructural analyses method, correct problem formulation is also critical.