Acid-Catalyzed Hydrolysis of BMS-582664: Degradation Product Identification and Mechanism Elucidation

ABSTRACT:BMS-582664 is an investigational drug intended for cancer treatment through oral administration. The preformulation studies revealed two unexpected degradation products under acidic conditions by reversed-phase high-performance liquid chromatography with ultraviolet detection. Additional liquid chromatography–mass spectrometry results suggested that these were cleavage (hydrolysis) products of a diaryl ether. To further understand the degradation mechanism, the reaction was carried out in 18O-labeled water. The 18O was found to be incorporated in only one of the two hydrolysis products. The results suggest that the corresponding α carbon in the heterocycle was unusually eletrophilic in acidic conditions probably because of the protonation of the neighboring nitrogen. This led to the selective attack by water and the consequent hydrolysis products. The study provides a new example of hydrolytic degradation of pharmaceutical compounds, and the reaction center is an aromatic heterocyclic carbon with an aryloxy substitution. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3526–3530, 2012