Development of an intravenous formulation for the unstable investigational cytotoxic nucleosides 5-azacytosine arabinoside (NSC 281272) and 5-azacytidine (NSC 102816)

Abstract

In aqueous solutions 5-azacytosine arabinoside (aza-A) (NSC 281272) exhibits complex and rapid degradation of a type analogous to 5-azacytidine (aza-C) (NSC 102816). Consequently, it is not amenable for use as slow i.v. infusions. This study has determined that both compounds are relatively stable in dry dimethylsulfoxide (DMSO) or dimethylacetamide (DMA). In mixed aqueous-organic solvents, as the water content is reduced the rate of degradation is descreased. Based on these findings, aza-A may be dissolved in DMSO at 100 mg ml−1, sterile filtered, and sealed in ampoules. The contents appear to be adequately stable at 4 °C, and may at the time of use be diluted with water to yield a 70% DMSO solution which retains >90% potency for 24 h at 25 °C and is compatible with commercially available i.v. infusion tubing. The diluted solution may be added in-line to a flowing i.v. vehicle, resulting in a physiologically acceptable solution in which the drug is unstable (t90 2 h). Its short residence time before reaching the bloodstream precludes any significant loss.