Chemical stability study of diuretics in a concomitant simple suspension with magnesium oxide

BACKGROUND: A simple suspension method has been widely used in Japan, however, chemical interactions among drugs in co-suspensions have not been fully clarified. Magnesium oxide (MgO), which is frequently prescribed as a laxative, can interact with various drugs. Eplerenone and spironolactone, potassium-sparing diuretics, are sometimes co-prescribed with MgO to older patients. In this study, we investigated the chemical stability of eplerenone and spironolactone in a co-suspension with MgO and characterized the structures of the degradation products that were formed under the conditions. METHODS: An eplerenone or spironolactone tablet was soaked with or without an MgO tablet in warm water in a tube according to a standard simple suspension method. The contents in the tube were mixed by inversion after 10 min, 1 h or 5 h to prepare a simple suspension. In separate experiments, the suspension prepared after 10 min soaking was allowed to stand for 50 min or 4.8 h at room temperature. The suspensions were immediately analyzed by high-performance liquid chromatography. The recovery rates of the diuretics from the suspensions were calculated relative to the labeled amounts. The degradation products were isolated and the structures analyzed by high-resolution mass spectrometry. RESULTS: The high-performance liquid chromatographic analysis showed that the diuretics were stable in their simple suspensions without MgO under any of the conditions. When co-suspended with MgO, a slight degradation was observed for eplerenone after just 10 min soaking and the degradation was statistically significant after 5 h soaking, whereas spironolactone was stable even after 5 h soaking. On the other hand, when the co-suspensions with MgO were left alone after mixing, eplerenone significantly degraded in 50 min, and spironolactone slightly degraded in the same period. Based on the mass spectra from the degradation products, hydrolysis of the lactone ring was shown to have occurred in both diuretics co-suspended with MgO. For spironolactone, hydrolysis and elimination of the thioester were also shown to have occurred in the co-suspensions. CONCLUSIONS: Eplerenone is more unstable than spironolactone in the simple co-suspension with MgO. As such, the simple co-suspensions of eplerenone are preferably prepared immediately before administration.