Solid-state vibrational circular dichroism for pharmaceutical applications: Polymorphs and cocrystal of sofosbuvir

Area of Science:

• Solid-state chemistry
• Spectroscopy
• Crystallography

Background:

• X-ray diffraction (XRD) is standard for crystal structure determination in pharmaceuticals but is expensive and time-consuming.
• Vibrational circular dichroism (VCD) spectroscopy offers a sensitive, cost-effective alternative, capable of detecting subtle structural changes.

Purpose of the Study:

• To establish an optimal and efficient method for solid-state VCD spectroscopy.
• To demonstrate VCD's capability in differentiating polymorphs and cocrystals.
• To validate VCD for pharmaceutical crystal structure analysis.

Main Methods:

• Rigorous assessment of experimental conditions using alanine as a model compound.
• Validation of the optimized VCD approach with diverse compounds (amino acids, hydroxy acid, monosaccharide).
• Application of VCD to identify polymorphs and cocrystals of the antiviral drug sofosbuvir.
• Adaptation of cluster and transfer approach for calculating spectral properties in periodic crystal environments.

Main Results:

• An optimized VCD protocol yielding reliable, reproducible, artifact-free spectra with high signal-to-noise ratio was developed.
• VCD successfully differentiated various crystal forms, including polymorphs and cocrystals of sofosbuvir.
• Computational methods (cluster and transfer approach) aided in interpreting spectral differences, particularly for complex molecules like sofosbuvir.

Conclusions:

• Solid-state VCD is a prompt, cost-effective, and user-friendly technique for identifying pharmaceutical crystal structures.
• The optimized VCD method shows significant potential for routine application in the pharmaceutical industry.
• Computational spectral analysis enhances the interpretation of VCD data for solid-state materials.