Formation mechanisms of sub-micron pharmaceutical composite particles derived from far-and near-field Raman microscopy

Surface enhanced Raman spectroscopy(SERS) and confocal Raman microscopy are applied to investigate the structure and the molecular arrangement of sub-micron furosemide and polyvinylpyrrolidone(furosemide/PVP) particles produced by spray flash evaporation(SFE). Morphology, size and crystallinity of furosemide/PVP particles are analyzed by scanning electron microscopy(SEM) and X-ray powder diffraction(XRPD). Far-field Raman spectra and confocal far-field Raman maps of furosemide/PVP particles are interpreted based on the far-field Raman spectra of pure furosemide and PVP precursors.Confocal far-field Raman microscopy shows that furosemide/PVP particles feature an intermixture of furosemide and PVP molecules at the sub-micron scale. SERS and surface-enhanced confocal Raman microscopy(SECo RM) are performed on furosemide, PVP and furosemide/PVP composite particles sputtered with silver(40 nm). SERS and SECo RM maps reveal that furosemide/PVP particle surfaces mainly consist of PVP molecules. The combination of surface and bulk sensitive analyses reveal that furosemide/PVP sub-micron particles are formed by the agglomeration of primary furosemide nanocrystals embedded in a thin PVP matrix. Interestingly, both far-field Raman microscopy and SECo RM provide molecular information on a statistically-relevant amount of sub-micron particles in a single microscopic map;this combination is thus an effective and time-saving tool for investigating organic sub-micron composites.