Vibrational circular dichroism (VCD) spectroscopy appears as a useful method for characterizing optically active substances in the solid state. This is particularly important for active pharmaceutical ingredients. However, measurement and interpretation of the spectra bring about many difficulties. To assess the experimental and computational methodologies, we explore an anti-inflammatory drug, naproxen. Infrared (IR) and VCD spectra of the pure compound and its cocrystals with alanine and proline were recorded, and the data were interpreted by quantum chemical simulations based on a cluster model and density functional theory. Although unpolarized IR spectroscopy can already distinguish pure ingredients from cocrystals or a mixture, the VCD technique is much more sensitive. For example, the naproxen carboxyl group strongly interacts with the zwitterionic alanine in the cocrystal via two strong hydrogen bonds, which results in a rather rigid structure crystallizing in the chiral P212121 Sohncke group and its VCD is relatively strong. In contrast, the d-proline and (S)-naproxen cocrystal (P21 group) involves a single hydrogen bond between the subunits, which together with a limited motion of the proline ring gives a weaker signal. Solid-state VCD spectroscopy thus appears useful for exploring composite crystal structures and interactions within them, including studies of pharmaceutical compounds.

Department of Analytical Chemistry University of Chemistry and Technology Prague 6 Czech Republic

Institut des Sciences Moléculaires d'Orsay CNRS Université Paris Saclay Orsay France

Institute of Organic Chemistry and Biochemistry Academy of Sciences Prague Czech Republic

Institute of Physics Academy of Sciences Prague Czech Republic

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