Direct Chromatographic Resolution of Racemic Aminoglutethimide and its Acetylated Metabolite Using Different Cellulose Based Chiral Stationary Phases H. Y. Aboul-Enein* / M. R. Islam Drug Development Laboratory, Radionuclide & Cyclotron Operations Department, King Faisal Specialist Hospital & Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia Key Words Chiral chromatography Chiral stationary phases Aminoglutethimide Enantiomeric separation Summary Two improved methods for the enantiomeric separa- tion of racemic aminoglutethimide (+AG) and its acetylated metabolite (+AAG) have been developed. Direct liquid chromatographic resolution of the enantiomers of aminoglutethimide and its acetylated metabolite was accomplished using Chiralcel OD and Chiralcel OJ columns without any derivatization. Maximum resolution of 8.87 and 2.23 was obtained for the enantiomers of aminoglutethimide and its acetyl- ated metabolite using a Chiralcel OD column, while maximum resolution of 10.34 and 7.01 was obtained for the enantiomers using a Chiralcel OJ column. Optimization of separation was obtained using different concentration of 2-propanol in hexane as a mobile phase. Introduction Aminoglutethimide (_+AG), (_+)-3-(4-aminophenyl)-3- ethyl-2,6 piperidinedione, (Figure 1) was initially developed as an anticonvulsant for the treatment of epilepsy, but was subsequently withdrawn because of its inhibitory effects on adrenal function. Persons receiving large doses of racemic aminoglutethimide developed clinical manifestations and serum elec- trolyte changes because of adrenal insufficiency [1]. Aminoglutethimide is currently used clinically as a drug of choice in the treatment of hormone-dependent metastatic breast cancer [2, 3]. It has also been used in the treatment of adrenocortical tumors and Cushing, syndrome [4]. Aminoglutethimide inhibits ovarian secretion of progesterone and the potential abort- ifacient properties of aminoglutethimide have been investigated [5, 6]. It inhibits the conversion of andro- stenedione to estrone [7, 8]. Because aminoglutethimide is used clinically as a racemic mixture, it is of interest to know whether the steroid synthesis inhibiting properties reside in one antipode or in the racemate. It was reported that the (+)-R-isomer had the greatest steroidogenesis inhibit- ory activity (two to three times more potent than the racemate), while the (-)-S-isomer (Figure 1) had very little activity at dose levels 10-fold higher [9]. The major mammalian metabolite of aminoglutethimide reported [10] is the N-acetylaminoglutethimide; 4 to 25 % of the administered dose appears in the urine as this compound which is devoid of any pharmacolog- ical activity [11, 12]. Resolution of racemic aminoglutethimide by chemical methods has been reported in earlier work [9]. A direct resolution of racemic aminoglutethimide and its acetylated metabolite (AAG) was also obtained using NH2 CH3CH2 I. II I ~ ' ~ CH 2CH3 O O H H (-)-S- aminoglutethimide (+)-R- aminoglutethimide Figure 1 The absolute configuration of (-)-S and (+)-R aminoglutethimide. Chromatographia Vol. 30, No. 3/4, August 1990 Short Communications 223 0009-5893/90/8 0233-05 $ 03.00/0 9 1990 Friedr. Vieweg & Sohn Verlagsgescllschaft mbH