BackgroundPhysical characteristics of packed samples, such as packing density, influence subsequent near-infrared (NIR) and Raman spectral features. This potential decrease in accuracy is a concerning issue in practical applications, such as the analysis of pharmaceutical tablets using vibrational spectroscopy. Thus, we compared the accuracy tolerances of both methods under varying packing densities. For evaluation, diffuse reflectance NIR and two different Raman measurements with laser illumination diameters of 1 and 6 mm (referred to as the WAI-1 and WAI-6 schemes, respectively) were used to analyze paracetamol tablets with packing densities of 1.1, 1.17, 1.24, and 1.29 g/cm³. ResultsIn all three measurements, increased packing density resulted in an increase in band intensity and an upward-moving baseline due to the variation in void volume (equivalent to porosity) in the tablets. The Raman spectra acquired using the WAI-6 scheme were less sensitive to packing density variations by averaging out different photon propagations over a large area during spectral acquisition. The accuracies for determining paracetamol concentration using the WAI-6 scheme did not significantly deteriorate when the packing density difference was not large, such as between 1.17 and 1.24 g/cm³ (absolute difference of 0.07 g/cm³). The WAI-6 scheme enabled more robust compositional analysis of the tablets with different packing densities. SignificanceThe WAI-6 Raman scheme provides a more robust compositional analysis of tablets under variations in packing density, making it a preferable choice for practical applications. Using the WAI-6 scheme, an additional effective strategy to minimize accuracy deterioration is further beneficial.