Effects of Freeze-Dry Processing Conditions on the Crystallization of Pentamidine Isethionate

Abstract

□ 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°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°C and holding for 3h prior to decreasing the temperature to −45°C, (2) directly cooling on the shelf from room temperature to −45°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.