Raman, surface‐enhanced Raman and density functional theory analyses of poorly soluble pharmaceuticals in water

Pharmacologically active compounds can be dispersed in nature during their manufacture, consumption, and disposal. In this study three pharmaceutical ingredients (acetaminophen, indomethacin and acetazolamide), commonly found in wastewaters, were studied in aqueous environment by Raman spectroscopy. Their spectroscopic properties were computed using density functional theory methods, and a combined atomistic/continuum description of the aqueous solution. The theoretical study allowed to explore the potential energy surface, to identify stable structures, and to accurately predict their Raman response in solution. Given the relevance of the determination of these compounds, their spectral information were related to their concentration level in water and synthetic wastewater by Raman multivariate regression models (partial least squares and Gaussian process regression), reaching limit of detection down to millimolar (investigated range 2.5 – 40 mM, 1.25 – 5 mM, and 0.25 – 5 mM for acetaminophen, indomethacin and acetazolamide, respectively). However, since in real samples pharmaceutical ingredients are usually found at trace level, the suitability of a more performing techniques such as surface-enhanced Raman spectroscopy was evaluated, which enabled us to lower the detection limit of one order on magnitude at least. The quality of the obtained surface-enhanced Raman spectra for the selected molecules should also be highlighted respect to those currently available in the literature. Surface-enhanced Raman analysis of acetazolamide, especially, shows promising features for the development of a sensitive (down to nanomolar) and highly specific analytical method.