The formation and physical stability of two-phase solid dispersion systems of indomethacin in supercooled molten mixtures with different matrix formers

详细信息    查看全文

• 作者：Kristian Semjonov^a ; ^{kristian.semjonov@ut.ee} ; Karin Kogermann^a ; ^{karin.kogerman@ut.ee} ; Ivo Laidmä ; e^a ; ^{ivo.laidmae@ut.ee} ; Osmo Antikainen^b ; ^{osmo.antikainen@helsinki.fi} ; Clare J Strachan^b ; ^{clare.strachan@helsinki.fi} ; Henrik Ehlers^b ; ^{henrik.ehlers@helsinki.fi} ; Jouko Yliruusi^b ; ^{jouko.yliruusi@helsinki.fi} ; Jyrki Heinä ; mä ; ki^a ; ^{jyrki.heinamaki@ut.ee}
• 关键词：Solid dispersion ; Two-phase systems ; Supercooled molten mixture ; Indomethacin ; Soluplus® ; Xylitol ; Solid-state stability
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：97
• 期：Complete
• 页码：237-246
• 全文大小：2085 K
• 卷排序：97

文摘

Amorphous solid dispersions (SDs) are a promising approach to improve the dissolution rate of and oral bioavailability of poorly water-soluble drugs. In some cases multi-phase, instead of single-phase, SD systems with amorphous drug are obtained. While it is widely assumed that one-phase amorphous systems are desirable, two-phase systems may still potentially exhibit enhanced stability and dissolution advantages over undispersed systems. The objective of the present study was to understand the solid-state properties of two-phase SDs with amorphous drug and their relation to physical stability. Two different types of excipients for SD formation were used, one being a polymer and the other a small molecule excipient. The supercooled molten SDs of a poorly water-soluble indomethacin (IND) with a graft copolymer, Soluplus® (SOL) and sugar alcohol, xylitol (XYL) were prepared. Supercooled molten SDs of IND with SOL were two-phase glassy suspension in which the amorphous drug was dispersed in an amorphous polymer matrix. A short-term aging of the SDs led to the formation of glassy suspensions where the crystalline drug was dispersed in an amorphous polymer matrix. These were physically stable at room temperature for the time period studied (RT, 23 ± 2 °C), but aging at high-humidity conditions (75% RH) recrystallization to metastable α-IND occurred. Interestingly, the SDs with XYL were two-phase amorphous precipitation systems in which the drug was in an amorphous form in the crystalline sugar alcohol matrix. The SDs of IND and XYL exhibited fast drug recrystallization. In conclusion, the preparation method of two-phase systems via co-melting in association with the rapid quench cooling is a feasible method for the formulation of poorly water-soluble drugs. The physical stability of these two-phase systems, however, is dependent on the carrier material and storage conditions.