Physical Stability and Protein Stability of Freeze-Dried Cakes During Storage at Elevated Temperatures

The relationship between physical stability of freeze-dried cakes and protein stability during storage was studied using -galactosidase as a model protein and inositol as an excipient. Amorphous samples freeze-dried from solutions containing the enzyme and various concentrations of inositol in sodium phosphate buffer (50 mM, pH 7.4) were stored for 7 days over P₂O₅ at 40 to 70°C. Structural collapse and inositol crystallization were observed in some of the samples, depending on the formulation and storage temperature. The physical stability of freeze-dried samples was also studied by differential scanning calorimeter (DSC). Inositol showed a protein-stabilizing effect when its amorphous form was retained during storage, regardless of structural collapse. However, crystallization of inositol during storage removed its stabilizing effect. Addition of water-soluble polymers such as dextran, Ficoll and carboxymethyl cellulose sodium salt (CMC-Na) preserved activity of the enzyme by preventing inositol crystallization.     

Measurement of Glass Transition Temperatures of Freeze-Concentrated Solutes by Differential Scanning Calorimetry

Thermal analysis of aqueous solutions in which the solute does not crystallize immediately upon freezing was carried out to define the effects of experimental parameters on thermograms in the glass transition region. The intensity of enthalpy relaxations in the glass transition region is related to both the rate of cooling and the rate of heating through the glass transition region—slow cooling or slow heating increases the extent of structural relaxation in the glassy state and increases the intensity of the endotherm. Plots of the logarithm of heating rate versus l /Tg are linear, and activation enthalpies for structural relaxation are in the range of 210–350 kJ/mol. For polymeric solutes, both the activation enthalpies for structural relaxation and the heat capacity change accompanying the glass transition increase with increasing molecular weight of the solute. Molecular weight dependence of the observed midpoint of the glass transition agrees with the Fox–Flory relationship. Results are compared and contrasted with glass transitions in solid polymers and with the glass transition of hyperquenched water. Practical implications for characterization of formulations intended for freeze-drying are discussed.     

地龙冻干粉针对家兔血液流变学的作用

急性缺血性心脑血管病是临床死亡率、致残率很高的常见病,疗法以溶栓为主,而从天然药物中研发新型溶栓药始终是研究热点.近年发现中药地龙提取物有良好溶栓性,并开发出口服制剂如蚓激酶胶囊(主要成分是纤维蛋白水解酶)用于临床[1,2].地龙冻干粉针(DFDP)是在此基础上研发的新型制剂,以鲜地龙为原料,含有纤维蛋白溶解酶和纤溶酶原激活物,酶活性比蚓激酶活性多两倍以上.该制剂对血液流变学的作用目前尚未见报道,本文主要研究DFDP对家兔血液流变学的作用.     

冷冻干燥法制备阿糖胞苷冻干脂质体粉针研究

本文采用冷冻干燥法制备阿糖胞苷冻干脂质体粉针，并建立了质量控制标准。在扫描电镜和透射电镜观察下，将此脂质体冻干品加注射用水溶解后，能很快重新形成脂质体。算术平均粒径为０．４７５６±０．０８３３μｍ，包封率约３０％。     

乳液冷冻干燥法制备明胶多孔支架及其性能研究

目的 采用乳液冷冻干燥法制备用于组织修复的明胶多孔支架材料,考察主要制备参数对支架材料性能的影响,为进一步制备满足细胞培养和临床应用的支架材料提供依据.方法 采用乳液冷冻干燥法,将明胶溶液与有机醇混合制成乳液,预冻,冷冻干燥得到支架材料,考察其性能.结果 制备过程中,乳液的固含量,预冻温度对支架材料的微观结构、表观密度、含水量和孔隙率有较大影响.结论 采用乳液冷冻干燥法可以成功的制备明胶多孔支架材料,通过控制反应条件和参数可以调整支架孔隙结构和性能,从而得到满足需要的支架材料.     

人红细胞冻干程序优化的实验研究

目的 探讨冻干程序中几种参数设置对红细胞冻干复水后回收率的影响.方法 将红细胞装入细管分别用四种模式对其进行降温,降温完成后将细管取投入25℃水浴中,对其外形变化进行比较判断玻璃化的程度;将冻好的样品放入冻干机搁板上,温度分别设置为-40、-50、-60、-70和-80℃,对样品进行冻干;对干燥开始不同温度、升温速率、红细胞样品在每一温度干燥的时间等多因素加以比较;最后测定了红细胞残余含水量.结果 直接将样品投入液氮中降温,保护液在冷冻或溶化过程中形成玻璃化而未出现冰晶.搁板温度为-70℃和-80℃时红细胞回收率没有显著性差异(P>0.05),这两组与其他各温度下的回收率均有显著性差异(P<0.01).E程序下的红细胞和血红蛋白回收率最高,分别为83.14%±9.55%和85.33%±11.42%.与其他各程序间存在显著差异(与A、B、C相比P<0.01;与D相比P<0.05).随着残余含水量的增多,细胞回收率呈正相关的增加趋势.结论 冻干中采用液氮快速降温,搁板温度预冷至-70℃,开始干燥时的温度越接近样品最初在搁板的平衡温度,红细胞升华干燥阶段升温速率越均匀缓和,红细胞的冻干效果越好.     

生产工艺对氨苄西林钠质量的影响

 目的 考察溶媒结晶和冷冻干燥两种工艺生产的氨苄西林钠的杂质水平和稳定性情况,判断两种工艺产品的质量优劣。方法 通过6个月的加速稳定性实验[实验温度（40±2）℃;相对湿度（75±5）％]和6个月的长期稳定性实验[实验温度（30±2）℃;相对湿度（65±5）％],考察两种工艺产品的含量、有关物质、水分、晶形特征等。结果 采用溶媒结晶法生产的氨苄西林钠比冷冻干燥法的产品杂质水平低,稳定性高;同为溶媒结晶法的产品,稳定性与其水分活度的关系密切。结论 采用溶媒结晶法生产的氨苄西林钠的质量优于冷冻干燥法的产品;生产过程中严格控制水分活度有利于得到高稳定性的产品。     

冻干物料共晶点、共熔点测定仪的设计

目的：设计一种可以检测冻干物料共晶点、共熔点的装置。方法：根据冻干物料的电阻随温度变化的变化率,结合物料电阻值来判定物料的共晶点、共熔点。结果：对几种物料进行了测定,获得了它们的共晶点、共熔点。结论：可使用电阻测定法来判定冻干物料共晶点、共熔点,物料的温度、电阻变化曲线反映了物料内部冻结过程。     

Effect of Preparation Method on Physical Properties of Amorphous Trehalose

PURPOSE: To determine the effect of preparation method on the physical properties of amorphous trehalose. METHODS: Amorphous anhydrous trehalose was prepared by four different methods. viz., freeze-drying, spray-drying, dehydration, and melt quenching. The glass transition temperature (Tg), enthalpic relaxation behavior, and crystallization were studied by differential scanning calorimetry, whereas X-ray diffractometry was used for phase identification. The rate and extent of water uptake at different relative humidity values were also obtained. RESULTS: Though the enthalpic relaxation and crystallization behaviors were influenced by the method of preparation of amorphous trehalose, the Tg and fragility were not. The phase prepared by dehydration showed the highest enthalpic recovery at Tg, indicating that aging may have occurred during preparation. Among the four methods used, trehalose prepared by dehydration had the highest tendency to crystallize, whereas there was no crystallization in melt-quenched amorphous trehalose. The method of preparation influenced not only the rate and extent of water sorption but also the phase crystallized. Water vapor sorption removed the effects of structural history in the amorphous phase formed by dehydration. CONCLUSIONS: The method of preparation strongly influenced the pharmaceutically relevant properties of amorphous trehalose. The resistance to crystallization can be rank ordered as trehalose prepared by dehydration < freeze-dried approximately spray-dried < melt-quenched. The rate of water sorption can be rank ordered as trehalose prepared by dehydration < freeze-dried < spray-dried.