STABILITY OF COMMERCIAL FORMULATIONS AND AQUEOUS-SOLUTIONS OF IFOSFAMIDE - A REPLY

This study is a reply to a paper in this journal reporting on the chem ical instability of ifosfamide (IF) (Drug Metab. Dispos. 23, 433-437, 1995), The authors describe chloroethylamine as a major degradation pr oduct of IF in both the powder and aqueous solutions, In the present s tudy, we show that: i) IF powder remains pure up to 3-5 years after it s expiration date; ii) solutions of IF at pH 7 are stable for at least 12 hr at 40 degrees C; and iii) solutions of IF at pH 4 or pH 10 are only slightly degraded (approximate to 1%) after standing for 6 hr at 37 degrees C. We also demonstrate that the reported IF instability dep ends on the analytical procedure used, The trifluoroacetylation proced ure used by the authors, which is conducted in dichloromethane, led to low derivatization yields and to the formation of several degradation compounds of IF, among them chloroethylamine. In contrast, when the t rifluoroacetylation reaction is conducted in ethyl acetate, there is h igh yield of trifluoroacetylated IF, and degradation compounds are min or, In conclusion, we believe that the large amounts of chloroethylami ne reported by the authors in both powder and aqueous solutions of IF stemmed from degradation linked to the method of derivatization, Becau se IF is not readily derivatized by trifluoroacetic anhydride in dichl oromethane, the combination of heating with possible uncontrolled evap oration of solvent and the presence of trifluoroacetic acid in the med ium lead to degradation of IF and formation of chloroethylamine.