Liquid chromatography/mass spectrometry (LC/MS) identification of photooxidative degradates of crystalline and amorphous MK-912

How and why the chemical stability of amorphous solid is different from cry stalline solid is an important problem. In this study, this problem is addr essed by evaluation of the photodegradation of both crystalline and amorpho us MK-912 (an alpha -2 adrenoceptor antagonist) according to the photostabi lity tests of the ICH (International. Conference on Harmonization) guidelin es, Under the ICH conditions, the photodegradation rate of the amorphous MK -912 was similar to 40 times faster than that of the crystalline MK-912, Th e photodegradation yielded isomeric, oxidative degradates. Three keto-degra dates (molecular weight of 14 Da over MK-912) were observed for both forms. But, whereas five alcohol and one N-oxide degradates (molecular weight of 16 Da over MK-912) were observed for the amorphous form, only one alcohol d egradate was observed for the crystalline form. Liquid chromatography/mass spectrometry (LC/MS) and LC/MS/MS were applied to identify these low-level photodegradates. A thorough analysis of the MS/MS data of protonated MK-912 was the key to the identification, and the special MS/MS features of the d egradates due to the structural modifications from degradations were also i mportant. Following this strategy, the structures of all the photodegradate s were proposed. The structural identification of the photodegradates of MK -912 shed light on the different photostabilities between the crystalline a nd amorphous MK-912. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceuti cal Association J Pharm Sci 90:833-844, 2001.