Internal Multiple-Scattering Hole-Enhanced Raman Spectroscopy: Improved Backscattering Fourier Transform Raman Sampling in Pharmaceutical Tablets Utilizing Cylindrical–Conical Holes

The benefits of Raman signal enhancement and improved measurement precision are demonstrated using 180° backscattering Fourier transform Raman (FT-Raman) spectroscopy from drilled cylindrical–conical holes within pharmaceutical tablet cores. Multiple scattering of the incident laser light within the holes results in an increased Raman signal due to the larger Raman sampling volume. This is important for overcoming typical sub-sampling issues encountered when employing FT-Raman backscattering of heterogeneous pharmaceutical tablets. Hole depth and diameter were found to be important experimental parameters and were optimized to yield the greatest signal enhancement. The FT-Raman spectra collected using backscattering from cylindrical–conical holes is compared to typical 180° backscattering from flat surfaces using tablet cores of Excedrin® and Vivarin®. Raman chemical images are used to establish a representative sampling area. We observe a three- to five-fold increase in the Raman intensity and a two-fold improvement in the measurement precision when sampling from cylindrical–conical holes rather than classic backscattering from flat tablet cores. Self-absorption effects on analyte band ratios are negligible in the fingerprint region but are more significant at the higher near-infrared (NIR) absorbances found in the C–H/O–H/–N–H stretching region. The sampling technique will facilitate developing quantitative FT-Raman methods for application to pharmaceutical tablets using fingerprint spectral region.