Surface-Enhanced, Low-Frequency Raman Spectroscopy:\nA Sensitive Screening Tool for Structural Characterization of Pharmaceuticals

Surface-enhanced,\nlow-frequency Raman spectroscopy (SELFRS) was\nexplored for its potential as a structural screening tool within pharmaceutical\napplications, including facile small-scale multicomponent analysis.\nParacetamol was used as the model drug, and its crystallization behavior\nwith or without the presence of a templating agent (benzoic acid)\nwas investigated using commercial silver-based SERS substrates. The\nRaman imaging was carried out using two different LFR-enabled instruments\nemploying 532 and 785 nm incident lasers, where each of the setups\nshowed certain affinity for differentiating lattice vibrations of\nthe polymorphic forms of interest: form I and form II. A comparison\nof SELFRS, SERS, and their combination using chemometrics showed the\npotential for the LFR spectral range to improve surface-enhanced measurements\neither individually or in combination with the typically-used fingerprint\nregion without the need to alter the experimental configuration. Additionally,\nthe use of crystallization additives that helped to drive the formation\nof metastable form II was shown using SELFRS to provide additional\nmechanistic understanding of the template-assisted crystallization\nprocesses.