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.

• Keywords
• alanine, cocrystals, density functional theory, naproxen, proline, solid state, spectra modeling, vibrational circular dichroism,
• MeSH
• Alanine chemistry   MeSH
• Anti-Inflammatory Agents, Non-Steroidal chemistry   MeSH
• Circular Dichroism * methods   MeSH
• Crystallization MeSH
• Models, Molecular MeSH
• Naproxen * chemistry   MeSH
• Proline chemistry   MeSH
• Spectrophotometry, Infrared MeSH
• Stereoisomerism MeSH
• Vibration MeSH
• Hydrogen Bonding MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Alanine MeSH
• Anti-Inflammatory Agents, Non-Steroidal MeSH
• Naproxen * MeSH
• Proline MeSH

Most currently marketed pharmaceuticals are manufactured in the solid state, where the bioavailability of the active pharmaceutical ingredient (API) can be optimized through different polymorphs, cocrystals, solvates, or salts. Efficient techniques are needed to monitor the structure of pharmaceuticals during production. Here, we explore the potential of linearly and circularly polarized Raman microscopy for distinguishing three polymorphs of sofosbuvir, an antiviral drug used to treat hepatitis C. Raman spectra were recorded on a Raman microscope for a polycrystalline API diluted in a KBr matrix. To understand spectral features including the low-frequency region, we simulated band frequencies and intensities using quantum-chemical computational strategies based on cluster and transfer approaches. Very good agreement was achieved between simulated and experimental intensities. The 20 to 200 cm-1 wavenumber region appeared particularly useful for polymorph discrimination already based on unpolarized measurements. The depolarization ratios obtained from linearly polarized Raman spectra made the distinction even more reliable. Moreover, circularly polarized Raman spectra and normalized degrees of circularity provided useful additional information and revealed several tentative markers of the different polymorphs of sofosbuvir. Although in some spectral regions the differences were less obvious, the results indicate that polarized Raman microscopy is a handy tool for discriminating between polymorphs of APIs and other compounds.

• Publication type
• Journal Article MeSH