The aim of this study was to evaluate the effect of three coformers and five disintegrants in the granulation formulation on the dissociation of cocrystal during the granulation process by monitoring wet granulation with probe-type low-frequency Raman (LF-Raman) spectroscopy. As model cocrystals, paracetamol (APAP)-oxalic acid (OXA), APAP-maleic acid (MLA), and APAP-trimethylglycine (TMG) were used. The monitoring of the granulation recipe containing cocrystals during wet granulation was performed over time with high-performance LF-Raman spectrometry and the dissociation rate was calculated from the results of multivariate analysis of LF-Raman spectra. The dissociation rate decreased in the order of APAP-TMG, APAP-OXA, and APAP-MLA, showing the same order as observed in Powder X-ray diffraction measurements. Furthermore, to compare the effect of disintegrants on the dissociation rate of APAP-OXA, LF-Raman monitoring was performed for the granulation recipes containing five typical disintegrants (two lowsubstitution hydroxypropyl cellulose (HPC), cornstarch (CSW), carmellose sodium (CMC), and crospovidone (CRP)). The dissociation rate of APAP-OXA decreased in the order of CSW, HPCs, CMC, and CRP. This difference in the dissociation rate of APAP-OXA was thought to be due to the disintegration mechanism of the disintegrants and the water absorption ratio, which was expected to affect the water behavior on the disintegrant surface during wet granulation. These results suggested that probe-type LF-Raman spectroscopy is useful to monitor the dissociation behavior of cocrystals during wet granulation and can compare the relative stability of cocrystal during wet granulation between different formulations.

The mechanochemical milling was utilized to control the nanostructures of plate-like graphite (Gp) microparticles in an argon atmosphere and at room temperature. The aggregated Gp nanoparticles were prepared by the simple solid-state process without organic solvent. Electron microscope observations, X-ray diffraction patterns and Raman spectra revealed the fractured plate-like Gp microparticles as well as the Gp microparticles agglomerated to each other through the dissociative edge surfaces by the milling process to finally generate the Gp nanoparticle aggregates. In the process, the ratio of the edge plane surfaces with the dangling bondings to layered internal surfaces clearly increased with the milling. Therefore, the low environmental burden process for preparing the Gp nanoparticle aggregation was achieved.

No abstract