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Abstract:

Purpose: Mechanical stresses such as milling and compression are known to destabilize pure amorphous systems. However, study of compression effects on binary solid dispersions (SD) are scarce and a research lacuna exists. Few studies available points toward compressive stress induced mixing or demixing in SD. These compression induced changes are mediated through alteration of the stabilization mechanism of SD i.e. intermolecular interactions (Naproxen-PVPVA64, Naproxen-PVPVK25) and enhanced local viscosity (Miconazole-PVPVA64). In this study we investigated the Itraconazole-Soluplus system to extend our know-how and pin-point the source of changes causing alterations in SD phase-behaviour upon compression. Materials and methods: Itraconazole-Soluplus SD’s were prepared using the Xplore DSM twin screw hot-melt extrusion equipment (Geleen, The Netherlands) with 50% (w/w) drug loading. Compression was performed at dwell times of 0.1, 30 and 60 seconds and pressures of 60, 230 and 400 MPa. The powder and compressed tablets were analysed using modulated differential scanning calorimetry (MDSC), powder X-ray diffractometry (PXRD), small/wide angle X-ray scattering (SWAXS), Fourier transform infra-red spectroscopy (FTIR), broadband dielectric spectroscopy (BDS), high-performance liquid chromatography (HPLC) and thermogravimetric analysis (TGA). Results: The uncompressed Itraconazole-Soluplus SD’s were phase-separated with the presence of a very minute crystalline fraction (ΔHf= 0.2 ± 0.0 J/g). The amorphous fraction showed the presence of a single Tg at 55.8 ± 1°C with Tg width of 13.7 ± 1.5°C. Compression destabilized the systems which was evident by an increase in Tg width, AUC of the derivative reversing heat flow and net heat of fusion in compressed samples. These changes were more pronounced at a combination of high compression pressure and dwell times. Interestingly, only in tablets an endothermic peak was observed around 80°C in the non rev. heat flow signal (Figure 1), which could have originated either due to itraconazole liquid crystals or phase-separation of the SD. SAXS and BDS (Figure 2) investigations proved that the endothermic peak in the non rev. heat flow originated due to enthalpy recovery of the phase separated domains and not because of liquid crystals. BDS analysis proved that compression lead to phase-separation as indicated by the presence of a relaxation process similar in dielectric strength and temperature dependence to bulk Soluplus. Also, a decrease in fragility value of SD upon compression was found suggesting an alteration of hydrogen bonding between components. Finally, FTIR analysis proved that upon compression the ratio of carbonyl stretch of Soluplus (1735cm-1) and itraconazole (1698cm-1) decreased indicating free carbonyl attributable to itraconazole which was phase-separated upon compression. A number of other compression induced FTIR spectrum changes corresponding to stretching and bending of the itraconazole molecule were detected. Conclusion: Compression causes increased heterogeneity of solid dispersions at various compression pressures and dwell times. The destabilization is caused by alteration of H-bonding between itraconazole and Soluplus which enhances phase-separation. This finding can have significant impact on the downstream processing decisions of solid dispersions and warrants further research.