Formation Mechanism 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 a sub-micron pharmaceutical organic composite. As a model system, sub-micron Furosemide and polyvinylpyrrolidone (Furosemide/PVP) particles produced by spray flash evaporation (SFE) from a single solution are investigated. The morphology, size and crystallinity of Furosemide/PVP composites are first analyzed by scanning electron microscopy (SEM) and X-ray powder diffraction (XRPD). Afterwards, reference 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 pure 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. In order to have a better insight on the molecular arrangement of PVP and Furosemide in composite particles, SERS and surface-enhanced confocal Raman microscopy (SECoRM) are performed on Furosemide, PVP and Furosemide/PVP composites particles sputtered with silver (40 nm). Surface-sensitive SERS and SECoRM maps reveal that Furosemide/PVP particle surfaces mainly consist of PVP molecules coating Furosemide domains. Overall, the combination surface and bulk sensitive analyses allows drawing a clear picture of the particle morphology and the molecular arrangement in Furosemide/PVP sub-micron particles. Namely, SFE-produced Furosemide/PVP sub-micron particles are formed by the agglomeration of primary particles consisting of Furosemide nano-crystals embedded in a thin PVP matrix. Interestingly, both far-field (bulk-sensitive) and surface-enhanced (surface-sensitive) confocal Raman microscopies 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 and tool for investigating organic and inorganic sub-micron composites.