Degradation Products of Mycophenolate Mofetil in Aqueous Solution

Abstract

The thermal and peroxide-catalyzed degradation products of mycophenolate mofetil (1) were studied in aqueous solution at pH 2.0, 3.5, 6.0, and 8.2. The major thermal degradation product observed was mycophenolic acid (2). At pH 6.0 and 8.2, 2 was the only product observed in the absence of peroxide, while at pH 2.0 and 3.5, the lactone analogue of mycophenolic acid (5), a hydroxylactone due to oxygenation of the double bond (6), and an unidentified product were formed. Compound 6 degraded to 4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-carbaldehyde (9) on prolonged storage and was present in the sample stressed at pH 2. Mycophenolic acid (2), the N-oxide of mycophenolate mofetil (3), the hydroxylactone of mycophenolic acid (6), and the erythro form of 4-methoxy-5-methyl- 2-(2-methyl-5-oxo-tetrahydro-furan-2-yl)-3,6-dihydro-2H-1,7-dioxa-as-indacen-8- one (8) were observed in the presence of hydrogen peroxide at pH 3.5, 6.0, and 8.2. In addition, at pH 8.2, 4-hydroxy-4-(4-methoxy-5-methyl-8-oxo-2,3,6,8-tetrahydro-1,7-dioxa-as-indacen-2-yl)-pentanoic acid (7) was seen. Peroxide-stressed samples at pH 2.0 gave no major degradation peaks, but a small amount of the hydroxylactone of mycophenolic acid (6) was formed.