Small Molecule Pharmaceutical Sciences, Genentech, South San Francisco, California 94080.
Small Molecule Pharmaceutical Sciences, Genentech, South San Francisco, California 94080.
J Pharm Sci. 2019 Feb;108(2):870-879. doi: 10.1016/j.xphs.2018.09.008. Epub 2018 Sep 19.
Usage of the amorphous phase of compounds has become the method of choice to overcome oral bioavailability problems related to poor solubility. Due to the unstable nature of glasses, it is clear that the method of preparation of the amorphous glass will have an impact on physical/chemical stability and in turn in vivo performance. The method of preparation can also have a profound impact on the mechanical properties of the amorphous phase. We have explored the impact of preparation method on the mechanical properties of an amorphous solid dispersion using a development compound, GDC-0810. Three methods were used to generate amorphous solid dispersions (ASDs) of 50% GDC-0810 with hydroxypropyl methylcellulose acetate succinate: (1) spray drying, (2) coprecipitation using overhead mixing, and (3) coprecipitation using resonant acoustic mixing. All 3 methods were found to generate ASDs with good phase mixing and similar glass transition temperatures. Coprecipitated ASD powders (overhead mixing and resonant acoustic mixing) demonstrated superior tabletability and flow properties when compared to the spray drying powder. Careful choice of manufacturing process can be used to tune material properties of ASDs to make them more amenable for downstream operations like tableting. Acoustic mixing has been demonstrated as a scalable new method to make ASDs through coprecipitation.
使用化合物的无定形相已成为克服与低溶解度相关的口服生物利用度问题的首选方法。由于玻璃的不稳定性，显然制备无定形玻璃的方法将对物理/化学稳定性产生影响，并进而影响体内性能。制备方法还可以对非晶相的力学性能产生深远影响。我们使用开发化合物 GDC-0810 探索了制备方法对无定形固体分散体（ASD）力学性能的影响。使用三种方法（1）喷雾干燥、（2）使用顶置混合的共沉淀和（3）使用谐振声混合来生成 50% GDC-0810 的无定形固体分散体（ASD）。所有 3 种方法都发现可以生成具有良好相混合和相似玻璃化转变温度的 ASD。与喷雾干燥粉末相比，共沉淀 ASD 粉末（顶置混合和谐振声混合）表现出更好的可压性和流动性能。仔细选择制造工艺可以用于调整 ASD 的材料性能，使其更适合下游操作，如压片。声混合已被证明是通过共沉淀来制造 ASD 的一种可扩展的新方法。
