Physicochemical Stability of Reconstituted Decitabine (Dacogen®) Solutions and Ready-to-Administer Infusion Bags when Stored Refrigerated or Frozen

Abstract

Abstract Background Profound knowledge about the physicochemical stability is necessary in order to determine the “beyond-use-dates” of ready-to-administer preparations after reconstitution and dilution. This is especially true for unstable azanucleoside drugs like decitabine. The aim of this study was to determine the physicochemical stability of decitabine after reconstitution and dilution of Dacogen® 50 mg lyophilized powder. Decitabine concentration of Dacogen® powder reconstituted with cold water for injections (5 mg/mL) has been determined after storage in the original vials under refrigeration for 48 hours and in single use syringes in a freezer at –25 °C for 28 days. Concentration of diluted decitabine infusion solutions (0.5 mg/mL) prepared in prefilled 0.9 % NaCl polyolefine (PO) infusion bags has been determined after storage under refrigeration (2–8 °C) for 48 hours. Methods To determine the stability of frozen Dacogen® solutions the powder was reconstituted with 10 mL of cold (2–8 °C) sterile water for injections, transferred into 1 mL plastic polycarbonate (PC)/polypropylene (PP) syringes and stored at –25 °C. Decitabine concentrations were determined on day 0, 22 and 28 after thawing at room temperature immediately before assaying. In parallel, pH-values were determined. To determine the stability of reconstituted Dacogen® 50 mg powder in the original glass vials, three Dacogen® 50 mg vials were aseptically reconstituted with 10 mL of cold sterile water. The reconstituted solutions were stored under refrigeration and decitabine concentrations were determined at 0, 3, 7, 12 and 24 hours after reconstitution. The pH-values were determined at 0, 7 and 24 hours. Diluted Dacogen® test solutions were aseptically prepared by adding 2 mL of the reconstituted Dacogen® solution from each of the three vials to 18 mL cold (2–8 °C) 0.9 % NaCl solution in prefilled multi-layer PO infusion bags of the nominal value 50 mL. Test solutions of the nominal concentration 0.5 mg/mL were stored under refrigeration. Decitabine concentrations were determined at 0, 5, 8, 12, 24 and 48 hours after preparation. The pH-values were determined at 0, 8, 24 and 48 hours. Each sample was assayed by a validated stability-indicating reversed-phase high-performance liquid chromatography (RP-HPLC) assay with photodiode array detection. Results When test solutions of reconstituted Dacogen® solution were stored frozen at −25 °C, decitabine concentrations decreased less than 2 % and no degradation products were detected in the HPLC chromatograms over the storage period of 28 days. In reconstituted test solutions in glass vials and in diluted test solutions in infusion bags stored under refrigeration decitabine concentrations remained above 90 % of the initial concentration for 12 hours and 24 hours, respectively. Several peaks of degradation products were observed which explicitly increased over time. In all test solutions the pH-values amounted to pH 7 and remained unchanged. No particulate matter and no colour changes were observed over the test period. Conclusions Reconstituted decitabine solution (Dacogen® 50 mg powder) stored in 1 mL PC/PP syringes and frozen at −25 °C is physicochemically stable for at least 28 days. Decitabine solution in glass vials after reconstitution with cold sterile water for injections and in PO infusion bags after dilution with cold 0.9 % NaCl solution and stored under refrigeration is physicochemically stable for approximately 12 hours and 24 hours, respectively. The results of our study facilitate the preparation of Dacogen® powder in pharmacy based centralized preparation units.