期刊
MOLECULAR PHARMACEUTICS
卷 14, 期 5, 页码 1691-1705出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.6b01151
关键词
amorphous solid dispersions; miscibility; water; microstructure; AFM; TEM
资金
- National Institutes of Health [R41 GM1006.57-01A1, R42 GM100657-03]
Miscibility is critical for amorphous solid dispersions (ASDs). Phase-separated ASDs are more prone to crystallization and thus can lose their solubility advantage leading to product failure. Additionally; dissolution performance can be diminished as a result of phase separation in the ASD matrix. Water is, known to induce phase separation during storage for some :ASDs. However, the impact of water introduced,during preparation has not been as thoroughly investigated to date. The purpose of this study was to develop a mechanistic understanding of the effect of water on the phase behavior and microstructure of ASDs. Evacetrapib and two polymers were selected as the model system. Atomic force microscopy coupled With Lorentz contact resonance, and transmission electron microscopy with energy dispersive X-ray spectroscopy were employed to evaluate the microstructure and composition-of phase-separated ASDs. It was found that phase separation could be induced via two routes; solution-state phase separation during ASD formation caused by water absorption during film formation by a hydrophilic solvent, or solid-phase separation following exposure to high RH during storage. Water contents of as low as 2% in the organic solvent system used to dissolve,the drug and polymer were found to result in phase separation in the resultant ASD filth. These findings have profound implications on lab-scale ASD preparation and potentially also for industrial production. Additionally, these high resolution imaging techniques combined with orthogonal analyses are powerful tools to visualize structural changes in ASDs, which in turn will enable better links to be made between ASD structure And performance.
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