Resolution of chiral drug cocrystals: complementary roles of NMR, low-frequency Raman and vibrational circular...

Reliable discrimination of diastereomeric pharmaceutical cocrystals remains a significant analytical challenge, particularly when structural differences are subtle or when monocrystals suitable for X-ray diffraction are not available or difficult to prepare. Here, we compare the performance of four spectroscopic techniques, solid-state nuclear magnetic resonance (ssNMR), Raman spectroscopy, infrared (IR) absorption, and solid-state vibrational circular dichroism (ssVCD), in terms of the resolution of model diastereomeric cocrystals. The first pair of diastereomeric cocrystals, (S)-naproxen with (R)- and (S)-alanine, represents an example of systems with pronounced packing differences, whereas the cocrystals of (R)-ivabradine hydrochloride with (R)- and (S)-mandelic acid are nearly isostructural diastereomers. The NMR and vibrational spectra were interpreted based on density functional theory (DFT) simulations, allowing for a detailed spectra-structure assignment and analysis. Although all techniques detected cocrystal formation, their practical discriminatory power toward diastereomers varied. VCD spectroscopy provided reliable differentiation, even for nearly isostructural systems, although the data were hampered by the experimental noise. Raman spectroscopy, especially in the low-frequency region, was effective for a rapid detection of distinct packing motifs but less sensitive for the closely related structures. ssNMR provides a complementary localized insight. The results indicate the advantages and drawbacks of using Raman spectroscopy, ssNMR, and VCD for screening, structural studies, and chiral identification of pharmaceutical cocrystals and other chiral complex solid-state systems.