Sofosbuvir\nPolymorphs Distinguished by Linearly and\nCircularly Polarized Raman Microscopy

Most currently marketed pharmaceuticals are manufactured\nin the\nsolid state, where the bioavailability of the active pharmaceutical\ningredient (API) can be optimized through different polymorphs, cocrystals,\nsolvates, or salts. Efficient techniques are needed to monitor the\nstructure of pharmaceuticals during production. Here, we explore the\npotential of linearly and circularly polarized Raman microscopy for\ndistinguishing three polymorphs of sofosbuvir, an antiviral drug used\nto treat hepatitis C. Raman spectra were recorded on a Raman microscope\nfor a polycrystalline API diluted in a KBr matrix. To understand spectral\nfeatures including the low-frequency region, we simulated band frequencies\nand intensities using quantum-chemical computational strategies based\non cluster and transfer approaches. Very good agreement was achieved\nbetween simulated and experimental intensities. The 20 to 200 cm<sup>–1</sup> wavenumber region appeared particularly useful for\npolymorph discrimination already based on unpolarized measurements.\nThe depolarization ratios obtained from linearly polarized Raman spectra\nmade the distinction even more reliable. Moreover, circularly polarized\nRaman spectra and normalized degrees of circularity provided useful\nadditional information and revealed several tentative markers of the\ndifferent polymorphs of sofosbuvir. Although in some spectral regions\nthe differences were less obvious, the results indicate that polarized\nRaman microscopy is a handy tool for discriminating between polymorphs\nof APIs and other compounds.