EFFECTS OF FREEZE DRY PROCESSING CONDITIONS ON THE CRYSTALLIZATION OFPENTAMIDINE ISETHIONATE

The results of this study show that pentamidine isethionate (PI) can e xist in at least four crystalline forms-three anhydrates designated as forms A, B, and C, and a trihydrate. Form C is the high-temperature m odification, produced by heating forms A, B, and the trihydrate above 130 degrees C and cannot be produced under actual lyophilization condi tions. The crystal forms of PI present after freeze-drying depend on t he initial solution concentration and the thermal history of freezing. At low concentrations of PI (4% and less), form A is observed regardl ess of freezing method. At a higher concentration (10%), the crystal f orms observed are a function of the freezing method. Three freezing me thods 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 tempe rature to -45 degrees C, (2) directly cooling on the shelf from room t emperature to -45 degrees C, and (3) dipping the vials in liquid nitro gen. 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 trihy drate crystallizes during freezing or not. Since form B can only be pr oduced by dehydration of the trihydrate at low temperature, the presen ce of this form in the freeze-dried powders depends on the nucleation and growth of the trihydrate during freezing. Photostability studies h ave 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 freez e-dried products.