title: Stabilization of 5-azacytidine by nucleophilic addition of bisulfite ion.
abstract: 5-Azacytidine (I) stability was increased approximately 10-fold over its stability in water or lactated Ringer injection by the addition of excess sodium bisulfite and the maintenance of pH approximately 2.5. The increased stability in the presence of bisulfite at pH 2.5 was attributed to the addition of bisulfite across the 5-6 protonated imine bond of I, which prevented the hydrolytic attack on this labile double bond. However, above pH 4, bisulfite increased I degradation. At higher pH, the compound was no longer protonated and bisulfite did not form the stable addition product. The addition compound quickly decomposed above pH 6 to give back the parent compound and, thus, acted as a I prodrug. The intact drug remaining was assayed by high-pressure liquid chromatography (HPLC), and the reversibility of the bisulfite-I addition product above pH 6 was demonstrated by UV spectrophotometry and HPLC. The potential utility of the bisulfite-I addition product as a I prodrug in parenteral and possible oral dosage forms is discussed.
mesh_terms: D001374:Azacitidine / Q000032:analysis*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D013447:Sulfites
chemical_list: D013447:Sulfites; D001374:Azacitidine