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 chemical instability of ifosfamide (IF) (Drug Metab. Dispos. 23, 433-437, 1995). The authors describe chloroethylamine as a major degradation product of IF in both the powder and aqueous solutions. In the present study, we show that: i) IF powder remains pure up to 3-5 years after its 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 (approximately 1%) after standing for 6 hr at 37 degrees C. We also demonstrate that the reported IF instability depends on the analytical procedure used. The trifluoroacetylation procedure 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 trifluoroacetylation reaction is conducted in ethyl acetate, there is high yield of trifluoroacetylated IF, and degradation compounds are minor. In conclusion, we believe that the large amounts of chloroethylamine reported by the authors in both powder and aqueous solutions of IF stemmed from degradation linked to the method of derivatization. Because IF is not readily derivatized by trifluoroacetic anhydride in dichloromethane, the combination of heating with possible uncontrolled evaporation of solvent and the presence of trifluoroacetic acid in the medium lead to degradation of IF and formation of chloroethylamine.