Chatterjee Koustuv, Shalaev Evgenyi Y, Suryanarayanan Raj
College of Pharmacy, 308, Harvard St. S.E., University of Minnesota, Minneapolis, Minnesota 55455, USA.
J Pharm Sci. 2005 Apr;94(4):798-808. doi: 10.1002/jps.20303.
Two model ternary systems: water-glycine-raffinose and water-glycine-trehalose were investigated to determine the extent of glycine crystallization in frozen solutions. The use of such partially crystalline systems allows primary drying to be carried out substantially above the collapse temperature. Differential scanning calorimetry (DSC) and variable temperature X-ray diffractometry (XRD) were used to monitor phase transitions in frozen systems as well as to determine the T'g. Aqueous solutions containing different glycine to carbohydrate weight ratios were first cooled to -60 degrees C and then warmed to room temperature. In both raffinose and trehalose systems, when the initial glycine to sugar (raffinose pentahydrate or trehalose dihydrate) ratio was <1, glycine crystallization was not detected. When the ratio was >or=1, partial glycine crystallization was observed during warming. The presence of amorphous glycine caused the T'g to be substantially lower than that of the solution containing only the carbohydrate. To determine the extent of glycine crystallization, the solutions were annealed for 5 h just above the temperature of glycine crystallization. The T'g observed in the second warming curve was very close to that of the carbohydrate solution alone, indicating almost complete glycine crystallization. These studies enabled the construction of the water-rich sections of the raffinose-glycine-water and trehalose-glycine-water state diagrams. These diagrams consist of a kinetically stable freeze-concentrated solution and a doubly unstable glassy region, which readily crystallizes during cooling or subsequent warming. In addition, there is an intermediate region, where during the experimental timescale, there appears to be hindered glycine nucleation but unhindered crystal growth. To obtain substantially crystalline glycine in the frozen solutions, the glycine to carbohydrate ratios should be >or=1.
水-甘氨酸-棉子糖和水-甘氨酸-海藻糖，以确定冷冻溶液中甘氨酸的结晶程度。使用这种部分结晶体系可使一次干燥在显著高于塌陷温度的条件下进行。采用差示扫描量热法（DSC）和变温X射线衍射法（XRD）监测冷冻体系中的相变以及测定玻璃化转变温度（T'g）。首先将含有不同甘氨酸与碳水化合物重量比的水溶液冷却至-60℃，然后升温至室温。在棉子糖和海藻糖体系中，当初始甘氨酸与糖（棉子糖五水合物或海藻糖二水合物）的比例<1时，未检测到甘氨酸结晶。当比例≥1时，升温过程中观察到部分甘氨酸结晶。无定形甘氨酸的存在导致T'g显著低于仅含碳水化合物的溶液的T'g。为了确定甘氨酸的结晶程度，将溶液在略高于甘氨酸结晶温度的条件下退火5小时。在第二次升温曲线中观察到的T'g与单独的碳水化合物溶液的T'g非常接近，表明甘氨酸几乎完全结晶。这些研究使得能够构建棉子糖-甘氨酸-水和海藻糖-甘氨酸-水状态图的富水部分。这些图由动力学稳定的冷冻浓缩溶液和双不稳定的玻璃态区域组成，后者在冷却或随后升温过程中容易结晶。此外，存在一个中间区域，在实验时间尺度内，似乎甘氨酸成核受阻但晶体生长不受阻。为了在冷冻溶液中获得基本上结晶的甘氨酸，甘氨酸与碳水化合物的比例应≥1。
