Baxter Global Science and Technology, 927 S. Curry Pike, Bloomington, Indiana 47403.
Baxter Global Science and Technology, 927 S. Curry Pike, Bloomington, Indiana 47403.
J Pharm Sci. 2017 Dec;106(12):3583-3590. doi: 10.1016/j.xphs.2017.08.018. Epub 2017 Sep 1.
The objective of this research was to study the atypical secondary drying dynamics observed during the freeze-drying of a formulation consisting of mannitol, disaccharide, and sodium chloride, where "bursts" of water vapor release were observed during secondary drying as detected by comparative pressure measurement. "Thief" samples were removed at the end of primary drying and during secondary drying as the shelf temperature was increased in a stepwise fashion. These samples were examined by X-ray powder diffraction and thermal analysis. From the X-ray powder diffraction data, we determined that mannitol crystallized predominantly as its hemihydrate. The physical state of mannitol changed from the hemihydrate form to anhydrous forms during secondary drying. Investigation of the effect of excipients on mannitol crystallization demonstrated that sodium chloride (at 225 mM, 1.3% w/v) had the greatest influence on hemihydrate crystallization, followed by trehalose and sucrose. However, only negligible hemihydrate formation was observed when mannitol was freeze-dried either by itself or in the presence of 150 mM sodium chloride and no hemihydrate in the presence of 75 mM sodium chloride. In general, a combination of a disaccharide and sodium chloride promoted the hemihydrate formation to a greater extent than the individual components. Comparative pressure measurement was demonstrated to be an effective tool to monitor mannitol hemihydrate dehydration during secondary drying.
本研究的目的是研究在由甘露醇、二糖和氯化钠组成的制剂的冷冻干燥过程中观察到的非典型二次干燥动力学，在二次干燥过程中，通过比较压力测量观察到水蒸气释放的“爆发”。在逐步升高搁板温度的过程中，在一次干燥结束时和二次干燥期间取出“小偷”样品。这些样品通过 X 射线粉末衍射和热分析进行了检查。从 X 射线粉末衍射数据中，我们确定甘露醇主要结晶为半水合物。在二次干燥过程中，甘露醇的物理状态从半水合物形式转变为无水形式。考察赋形剂对甘露醇结晶的影响表明，氯化钠（225mM，1.3%w/v）对半水合物结晶的影响最大，其次是海藻糖和蔗糖。然而，当甘露醇单独冷冻干燥或在 150mM 氯化钠存在下或在 75mM 氯化钠存在下时，几乎没有观察到半水合物形成。一般来说，二糖和氯化钠的组合比单独的成分更能促进半水合物的形成。比较压力测量被证明是监测二次干燥过程中甘露醇半水合物脱水的有效工具。
