Kim A I, Akers M J, Nail S L
Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, USA.
J Pharm Sci. 1998 Aug;87(8):931-5. doi: 10.1021/js980001d.
The objectives of this study were to (1) measure the effects of freezing rate and mannitol concentration on the physical state of freeze-dried mannitol when mannitol is present as a single component, (2) determine the relative concentration threshold above which crystalline mannitol can be observed by X-ray powder diffraction in the freeze-dried solid when a variety of noncrystallizing solutes are included in the formulation, and (3) measure the glass transition temperature of amorphous mannitol and to determine the degree to which the glass transition temperature of freeze-dried solids consisting of mannitol and a disaccharide is predicted by the Gordon-Taylor equation. Both freezing rate and mannitol concentration influence the crystal form of mannitol in the freeze-dried solid when mannitol is present as a single component. Slow freezing of 10% (w/v) mannitol produces a mixture of the alpha and beta polymorphs, whereas fast freezing of the same solution produces the delta form. Fast freezing of 5% (w/v) mannitol results primarily in the beta form. The threshold concentration above which crystalline mannitol is detected in the freeze-dried solid by X-ray diffraction is consistently about 30% (w/w) when a second, noncrystallizing solute is present, regardless of the nature of the second component. The glass transition temperature of amorphous mannitol measured from the quench-cooled melt is approximately 13 degreesC. Accordingly, mannitol is an effective plasticizer of freeze-dried solids when the mannitol remains amorphous. Glass transition temperatures of mixtures of mannitol and the disaccharides sucrose, maltose, trehalose, and lactose are well predicted by the Gordon-Taylor equation with values of k in the range of 3 to 4.
（1）当甘露醇作为单一成分存在时，测量冷冻速率和甘露醇浓度对冻干甘露醇物理状态的影响；（2）当制剂中包含多种非结晶溶质时，确定在冻干固体中通过X射线粉末衍射可观察到结晶甘露醇的相对浓度阈值；（3）测量无定形甘露醇的玻璃化转变温度，并确定由甘露醇和二糖组成的冻干固体的玻璃化转变温度由戈登-泰勒方程预测的程度。当甘露醇作为单一成分存在时，冷冻速率和甘露醇浓度均会影响冻干固体中甘露醇的晶型。10%（w/v）甘露醇缓慢冷冻会产生α和β多晶型的混合物，而相同溶液快速冷冻则产生δ晶型。5%（w/v）甘露醇快速冷冻主要产生β晶型。当存在第二种非结晶溶质时，无论第二种成分的性质如何，通过X射线衍射在冻干固体中检测到结晶甘露醇的阈值浓度始终约为30%（w/w）。从骤冷熔体测量的无定形甘露醇的玻璃化转变温度约为13℃。因此，当甘露醇保持无定形时，它是冻干固体的有效增塑剂。甘露醇与二糖蔗糖、麦芽糖、海藻糖和乳糖混合物的玻璃化转变温度通过戈登-泰勒方程得到了很好的预测，k值在3到4范围内。
