Akers M J, Milton N, Byrn S R, Nail S L
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Pharm Res. 1995 Oct;12(10):1457-61. doi: 10.1023/a:1016223101872.
The purpose of the study is to characterize glycine crystallization during freezing of aqueous solutions as a function of the glycine salt form (i.e., neutral glycine, glycine hydrochloride, and sodium glycinate), pH, and ionic strength.
Crystallization was studied by thermal analysis, microscopy, x-ray diffraction, and pulsed Fourier transform nmr spectroscopy.
A solution of neutral glycine with no additives undergoes rapid secondary crystallization during freezing, forming the beta polymorph, with a eutectic melting temperature of -3.4 degrees C. Glycine hydrochloride solutions undergo secondary crystallization relatively slowly, and the eutectic melting temperature is -28 degrees C. Sodium glycinate crystallizes from frozen solution at an intermediate rate, forming a eutectic mixture with a melting temperature of -17.8 degrees C. Where secondary crystallization does not occur rapidly, a complex glass transition is observed in the -70 degrees to -85 degrees C temperature range in the DSC thermograms of all systems studied. Rates of secondary crystallization and the type of crystal formed are influenced by solution pH relative the the pKs of glycine, and also by the change in ionic strength caused by adjustment of pH. Increased ionic strength significantly slows the crystallization of neutral glycine and promotes formation of the gamma polymorph. Thermal treatment or extended holding times during the freezing process may be necessary in order to promote secondary crystallization and prevent collapse during freeze drying.
The results underscore the importance of recognizing that seemingly minor changes in formulation conditions can have profound effects on the physical chemistry of freezing and freeze drying.
本研究的目的是表征水溶液冷冻过程中甘氨酸结晶情况，作为甘氨酸盐形式（即中性甘氨酸、甘氨酸盐酸盐和甘氨酸钠）、pH值和离子强度的函数。
通过热分析、显微镜、X射线衍射和脉冲傅里叶变换核磁共振光谱研究结晶情况。
无添加剂的中性甘氨酸溶液在冷冻过程中经历快速二次结晶，形成β多晶型物，共晶熔化温度为-3.4℃。甘氨酸盐酸盐溶液的二次结晶相对较慢，共晶熔化温度为-28℃。甘氨酸钠从冷冻溶液中以中等速率结晶，形成熔化温度为-17.8℃的共晶混合物。在二次结晶不快速发生的情况下，在所研究的所有体系的DSC热谱图中，在-70℃至-85℃温度范围内观察到复杂的玻璃化转变。二次结晶速率和形成的晶体类型受相对于甘氨酸pK值的溶液pH值影响，也受pH值调节引起的离子强度变化影响。离子强度增加显著减慢中性甘氨酸的结晶速率并促进γ多晶型物的形成。为了促进二次结晶并防止冷冻干燥过程中的塌陷，可能需要在冷冻过程中进行热处理或延长保持时间。
结果强调了认识到配方条件看似微小的变化可能对冷冻和冷冻干燥的物理化学产生深远影响的重要性。
