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.

Institute of Organic Chemistry and Biochemistry of the Academy of Sciences Flemingovo Nám 2 Prague 16610 Czech Republic

Palacký University Olomouc 17 Listopadu 12 Olomouc 77146 Czech Republic

University of Chemistry and Technology Prague Technická 5 Prague 16628 Czech Republic

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