Jena Sampreeti, Suryanarayanan Raj, Aksan Alptekin
Biostabilization Laboratory, Department of Mechanical Engineering, University of Minnesota, Minneapolis, Minnesota, 55455, USA.
Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, 55455, USA.
Pharm Res. 2016 Jun;33(6):1413-25. doi: 10.1007/s11095-016-1883-7. Epub 2016 Feb 23.
Phase separation of trehalose during freeze-drying could render it ineffective as a lyoprotectant. The bulking agent, mannitol, on the other hand, should crystallize readily upon freezing. It is therefore imperative to understand the mutual interaction of these sugars during freezing to ensure preservation of the API during freeze-drying.
We investigated the effect of mannitol to trehalose ratio (R) on the crystallization behavior of both solutes using Differential Scanning Calorimetry, X-Ray Crystallography and FTIR Spectrosopy during controlled freezing and annealing.
When R = 1, crystallization of both mannitol (as hemihydrate) and trehalose (as α-anhydrate) were observed. When R ≥ 1, extent of mannitol crystallization was directly proportional to the value of R. When R < 1, trehalose completely suppressed mannitol crystallization. At R > 1, the freeze concentrate was heterogeneous and characterized by two glass transitions - the lower temperature transition (Tg") attributed to systems containing "extra" unfrozen water. When heated above Tg", crystallization of mannitol and the associated unfrozen water resulted in Tg' (glass transition temperature of the freeze-concentrate).
R and not the total solute concentration, dictates the composition of the freeze concentrate as well as the physical stability of the excipients.
冻干过程中海藻糖的相分离可能使其作为冻干保护剂失效。另一方面，填充剂甘露醇在冷冻时应易于结晶。因此，了解这些糖类在冷冻过程中的相互作用对于确保冻干过程中活性药物成分的保存至关重要。
我们使用差示扫描量热法、X射线晶体学和傅里叶变换红外光谱法，在控制冷冻和退火过程中，研究了甘露醇与海藻糖的比例（R）对两种溶质结晶行为的影响。
当R = 1时，观察到甘露醇（半水合物形式）和海藻糖（α-无水物形式）均结晶。当R≥1时，甘露醇的结晶程度与R值成正比。当R < 1时，海藻糖完全抑制甘露醇结晶。当R> 1时，冷冻浓缩物是不均匀的，其特征是有两个玻璃化转变——较低温度的转变（Tg"）归因于含有“额外”未冻水的体系。当加热到Tg"以上时，甘露醇的结晶和相关的未冻水导致了Tg'（冷冻浓缩物的玻璃化转变温度）。
决定冷冻浓缩物组成以及辅料物理稳定性的是R，而非溶质的总浓度。
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