Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
J Pharm Sci. 2012 May;101(5):1732-43. doi: 10.1002/jps.23055. Epub 2012 Jan 23.
The purpose of this study was to perform physical characterization of pentamidine isethionate (PI) in frozen and freeze-dried systems and to monitor the phase behavior during all the stages of freeze-drying. Frozen aqueous PI solutions as well as the final lyophiles were characterized by differential scanning calorimetry and X-ray diffractometry. The effect of cosolutes, cosolvents, and processing conditions on the PI crystallization behavior during freeze-drying was evaluated. In frozen aqueous solutions, irrespective of the cooling rate and the initial solute concentration, PI readily crystallized as a trihydrate (C(19) H(24) N(4) O(2) ·3H(2) O). It dehydrated to a poorly crystalline anhydrate upon drying at 100 mTorr. The presence of a readily crystallizing cosolute or an organic cosolvent did not influence the physical form of PI in the final lyophile. On the contrary, even in the absence of cosolutes and cosolvents, the crystalline trihydrate was retained when the chamber pressure was increased to 500 mTorr. By altering the drying conditions, it was possible to obtain either a crystalline trihydrate or a poorly crystalline anhydrate. The stability of PI is dependent on its physical form and only the amorphous PI undergoes discoloration. The PI stability can be enhanced by retaining it in a crystalline state in the lyophile.
本研究的目的是对戊二脒碘化物（PI）在冷冻和冻干系统中的物理特性进行表征，并监测冻干过程中的各阶段的相行为。通过差示扫描量热法和 X 射线衍射法对冷冻的 PI 水溶液以及最终的冻干粉末进行了表征。评估了共溶质、共溶剂和加工条件对冻干过程中 PI 结晶行为的影响。在冷冻的水溶液中，无论冷却速率和初始溶质浓度如何，PI 都容易结晶为三水合物（C(19)H(24)N(4)O(2)·3H(2)O）。在 100 mTorr 的干燥条件下，它会脱水形成无定形的无水物。存在易于结晶的共溶质或有机溶剂并不会影响最终冻干粉末中 PI 的物理形态。相反，即使没有共溶质和共溶剂，当腔室压力增加到 500 mTorr 时，结晶三水合物也会保留。通过改变干燥条件，可以得到结晶三水合物或无定形无水物。PI 的稳定性取决于其物理形态，只有无定形 PI 会发生变色。通过将 PI 保留在冻干粉末的结晶状态，可以增强其稳定性。
