AN HPLC AND SPECTROPHOTOMETRIC STUDY OF THE HYDROLYSIS OF ICRF-187 (DEXRAZOXANE, (+)-1,2-BIS(3,5-DIOXOPIPERAZINYL-1-YL)PROPANE) AND ITS ONE-RING OPENED INTERMEDIATES

The hydrolysis of the cardioprotective agent dexrazoxane ICRF-187 ((+)-1,2-bis(3,5-dioxopiperazinyr-1-yl)propane) and its one-ring open intermediates has been examined over a wide pH range using both HPLC and spectrophotometric methods. The isolation of these one-ring open intermediates by HPLC allowed a study of their hydrolysis reactions to be carried out spectrophotometrically without interference from other competing hydrolysis reactions. In 40 mM NaOH (25 degrees C) the half-life for the hydrolysis of ICRF-187 is 0.3 h, at pH 7.4 (37 degrees C) 9.3 h and in 1.0 M HCl (25 degrees C) 560 h. However, at pH 7.4 (37 degrees C) the half-time for the production of the fully ring-opened hydrolysis product, which is presumably the active metal ion binding form of the drug, is 28 h. A full kinetic analysis was carried out within a reaction scheme that included both parallel and consecutive reaction steps and allowed the determination of the individual ring-opening reaction rate constants.