Weili Heng1, Yuanfeng Wei2, Yifan Xue1, Hao Cheng2, Linghe Zhang3, Jianjun Zhang1, Yuan Gao4, Shuai Qian5. 1. School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. 2. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. 3. Department of Chemistry, Smith College, Northampton, MA, 01063, USA. 4. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. newgaoyuan@163.com. 5. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. silence_qs@163.com.
Abstract
PURPOSE: Amorphous indomethacin (IMC) forms gel with a decreased dissolution behavior compared to crystalline IMC during dissolution. The current study aims to explore gelation mechanism and attempt to eliminate gelling effect by formulation development. METHODS: Amorphous IMC was prepared by melt-quenching method. Dissolution tests of amorphous IMC were performed at various temperatures under sink condition. The formed gels were characterized by PLM, SEM, DSC and XRPD. RESULTS: Amorphous IMC exhibited an initial higher dissolution followed by a decreased dissolution lower than its crystalline counterpart at 32 and 37°C, and even a much lower dissolution during the whole dissolution period at 45°C. Meanwhile, a viscous soft mass ("gel") was observed to adhere upon the paddle or wall of the vessel. The formed gel could be characterized as a three-dimensional dense micro-fiber structure under SEM. The gel formation was proposed to be related to the decreased Tg of amorphous IMC when contacting aqueous medium, resulting in entering into supercooled liquid state with high viscosity. The addition of hydrophilic silica accelerated gel formation, while mixing with hydrophobic silica was able to weaken and even eliminate the gelation, and hence significantly enhancing dissolution. CONCLUSIONS: The present study recommends that gel formation should be included in the investigation of amorphous materials in order to find ways for resolving defects of amorphous materials while keeping their advantages in pharmaceutics.
PURPOSE: Amorphous indomethacin (IMC) forms gel with a decreased dissolution behavior compared to crystalline IMC during dissolution. The current study aims to explore gelation mechanism and attempt to eliminate gelling effect by formulation development. METHODS: Amorphous IMC was prepared by melt-quenching method. Dissolution tests of amorphous IMC were performed at various temperatures under sink condition. The formed gels were characterized by PLM, SEM, DSC and XRPD. RESULTS: Amorphous IMC exhibited an initial higher dissolution followed by a decreased dissolution lower than its crystalline counterpart at 32 and 37°C, and even a much lower dissolution during the whole dissolution period at 45°C. Meanwhile, a viscous soft mass ("gel") was observed to adhere upon the paddle or wall of the vessel. The formed gel could be characterized as a three-dimensional dense micro-fiber structure under SEM. The gel formation was proposed to be related to the decreased Tg of amorphous IMC when contacting aqueous medium, resulting in entering into supercooled liquid state with high viscosity. The addition of hydrophilic silica accelerated gel formation, while mixing with hydrophobic silica was able to weaken and even eliminate the gelation, and hence significantly enhancing dissolution. CONCLUSIONS: The present study recommends that gel formation should be included in the investigation of amorphous materials in order to find ways for resolving defects of amorphous materials while keeping their advantages in pharmaceutics.
Entities:
Keywords:
amorphous; degelation; dissolution; gel formation; indomethacin