Chongprasert S, Griesser U J, Bottorff A T, Williams N A, Byrn S R, Nail S L
Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, USA.
J Pharm Sci. 1998 Sep;87(9):1155-60. doi: 10.1021/js970342b.
The results of this study show that pentamidine isethionate (PI) can exist in at least four crystalline forms-three anhydrates designated as forms A, B, and C, and a trihydrate. Form C is the high-temperature modification, produced by heating forms A, B, and the trihydrate above 130 degrees C and cannot be produced under actual lyophilization conditions. The crystal forms of PI present after freeze-drying depend on the initial solution concentration and the thermal history of freezing. At low concentrations of PI (4% and less), form A is observed regardless of freezing method. At a higher concentration (10%), the crystal forms observed are a function of the freezing method. Three freezing methods were used to effect different cooling rates: (1) cooling on the shelf to 2 degrees C and holding for 3 h prior to decreasing the temperature to -45 degrees C, (2) directly cooling on the shelf from room temperature to -45 degrees C, and (3) dipping the vials in liquid nitrogen. The results show that form A, form B, or a mixture of both forms are present in the freeze-dried solid depending upon whether the trihydrate crystallizes during freezing or not. Since form B can only be produced by dehydration of the trihydrate at low temperature, the presence of this form in the freeze-dried powders depends on the nucleation and growth of the trihydrate during freezing. Photostability studies have demonstrated marked differences between freeze-dried solids frozen under different conditions. The results underscore the importance of recognizing that seemingly subtle differences in processing conditions can have a significant impact on critical quality attributes of freeze-dried products.
本研究结果表明，乙磺半脒（PI）至少可以以四种晶型存在——三种无水物，分别指定为A、B和C型，以及一种三水合物。C型是高温变体，通过将A、B型和三水合物加热到130℃以上产生，在实际冻干条件下无法产生。冻干后PI的晶型取决于初始溶液浓度和冷冻的热历史。在低浓度的PI（4%及以下）时，无论冷冻方法如何，均观察到A型。在较高浓度（10%）时，观察到的晶型是冷冻方法的函数。使用三种冷冻方法来实现不同的冷却速率：（1）在搁板上冷却至2℃并保持3小时，然后将温度降至-45℃；（2）直接在搁板上从室温冷却至-45℃；（3）将小瓶浸入液氮中。结果表明，冻干固体中存在A型、B型或两种晶型的混合物，这取决于三水合物在冷冻过程中是否结晶。由于B型只能通过三水合物在低温下脱水产生，冻干粉末中这种晶型的存在取决于三水合物在冷冻过程中的成核和生长。光稳定性研究表明，在不同条件下冷冻的冻干固体之间存在显著差异。结果强调了认识到加工条件中看似细微的差异可能对冻干产品的关键质量属性产生重大影响的重要性。
