Use of low-frequency Raman spectroscopy and chemometrics for the quantification of crystallinity in amorphous griseofulvin tablets

Abstract

Low-frequency Raman spectroscopy, which directly probes phonon lattice modes of crystal structures, has much unexplored potential for sensitive qualitative and quantitative analysis of crystallinity in drugs and excipients. In this study, the level of crystallinity in tablets containing amorphous drug is quantified using low-frequency Raman spectroscopy in concert with chemometrics for the first time. Importantly, these data are directly compared to simultaneously obtained mid-frequency Raman spectra, as well as to FT-Raman data, which is commonly used for such quantification. Griseofulvin was used as a model drug. The PLS model using FT-Raman spectroscopy gave a root mean squared error of prediction (RMSEP) of 0.65%. The PLS models of the low- and mid-frequency regions using a charge coupled device (CCD) based Raman system with 785nm excitation gave an RMSEP=1.2% when using the low-frequency region (5–120cm−1) and RMSEP=1.4% for the mid-range frequencies (520–1740cm−1). The recrystallization profiles determined using the various Raman techniques and their associated models were similar. The FT-Raman and the low frequency Raman systems were able to detect and quantify crystallinity in stored amorphous samples earlier than the mid-frequency 785nm Raman system. Overall, this study suggests that low-frequency Raman spectroscopy has at least equally good performance compared to mid-frequency Raman for quantitative analysis of crystallinity in the pharmaceutical setting. More generally, the much stronger Raman scattering in the low-frequency region combined with the intrinsic spectral differences between amorphous and crystalline materials may prove advantageous for some analyses.