X-ray diffraction is a commonly used technique in the pharmaceutical industry for the determination of the atomic and molecular structure of crystals. However, it is costly, sometimes time-consuming, and it requires a considerable degree of expertise. Vibrational circular dichroism (VCD) spectroscopy resolves these limitations, while also exhibiting substantial sensitivity to subtle modifications in the conformation and molecular packaging in the solid state. This study showcases VCD's ability to differentiate between various crystal structures of the same molecule (polymorphs, cocrystals). We examined the most effective approach for producing high-quality spectra and unveiled the intricate link between structure and spectrum via quantum-chemical computations. We rigorously assessed, using alanine as a model compound, multiple experimental conditions on the resulting VCD spectra, with the aim of proposing an optimal and efficient procedure. The proposed approach, which yields reliable, reproducible, and artifact-free results with maximal signal-to-noise ratio, was then validated using a set comprising of three amino acids (serine, alanine, tyrosine), one hydroxy acid (tartaric acid), and a monosaccharide (ribose) to mimic active pharmaceutical components. Finally, the optimized approach was applied to distinguish three polymorphs of the antiviral drug sofosbuvir and its cocrystal with piperazine. Our results indicate that solid-state VCD is a prompt, cost-effective, and easy-to-use technique to identify crystal structures, demonstrating potential for application in pharmaceuticals. We also adapted the cluster and transfer approach to calculate the spectral properties of molecules in a periodic crystal environment. Our findings demonstrate that this approach reliably produces solid-state VCD spectra of model compounds. Although for large molecules with many atoms per unit cell, such as sofosbuvir, this approach has to be simplified and provides only a qualitative match, spectral calculations, and energy analysis helped us to decipher the observed differences in the experimental spectra of sofosbuvir.

Institute of Organic Chemistry and Biochemistry of the CAS Flemingovo nám 2 Prague 166 10 Czech Republic

Institute of Organic Chemistry and Biochemistry of the CAS Flemingovo nám 2 Prague 166 10 Czech Republic; Imperial College London Department of Life Sciences South Kensington Campus London SW7 2AZ UK

Institute of Organic Chemistry and Biochemistry of the CAS Flemingovo nám 2 Prague 166 10 Czech Republic; University of Chemistry and Technology Prague Technická 5 Prague 166 28 Czech Republic

University of Chemistry and Technology Prague Technická 5 Prague 166 28 Czech Republic

University of Chemistry and Technology Prague Technická 5 Prague 166 28 Czech Republic; Institute of Physics of the CAS Na Slovance 1999 2 Prague 182 21 Czech Republic

Citace poskytuje Crossref.org

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