Impact of temperature on the physico-chemical stability of Azacitidine Zentiva 25 mg/ml suspensions packaged in polypropylene syringes

V.Vieillard, W. Saeed, G. Le Guyader, M.Paul
Pharmacy Department, CHU Henri Mondor, 51 Avenue du Maréchal De Lattre de Tassigny 94000 Créteil, France

Context
The sensitivity of Azacitidine (5-AZA) suspension is well known since it has already been studied with the originator. Previous studies have established a maximum stability of 5 days at 4°C and up to 30 days at -20°C. The arrival of generics on the market makes it necessary to confirm the applicability of these stability data.

Objective
The objective of this study was therefore to evaluate the impact of temperature on the physicochemical stability time of Azacitidine Zentiva suspensions contained in polypropylene syringes.

Materials and methods
Suspensions were reconstituted at D0 with 4 ml of previously cold (4°C) water (SWFI). The syringes were then placed in a refrigerator (protocol 1) or in a freezer (protocol 2). For syringes placed in the freezer, they were removed after 30 days and then stored in the refrigerator. Other suspensions were reconstituted at D0 with 4 ml of water at room temperature and then placed in the refrigerator (Protocol 3).

Results
For each analysis time (at D0 and every 24 hours), the analyses performed were visual inspection, optical microscopy analysis, turbidity measurement by UV-visible spectroscopy (500 nm), and HPLC determination using a validated, stability-indicating method.
When refrigerated water was used for reconstitution, the physical parameters of the suspension (turbidity, appearance of the suspension and crystals) remained unchanged during 96 hours of storage at 4°C. Moreover, the concentration of Azacitidine remained within 95% of the initial value during this same period (T96h: 98.6% ± 2.4%). However, when the suspension was reconstituted with water at room temperature, the stability of the 5-AZA syringes was no longer assured beyond 48h at 4°C. Finally, after freezing, the stability of the suspension is maintained during the 30 days of storage and can be extended for another 72 hours at 4°C (T72h: 96.0% ± 0.8%).

Discussion/ Conclusion
These new stability data allow to maintain the current organization of the Pharmaceutical Technology Unit Hospital for the preparation of Azacitidine syringes with the Zentiva generic, i.e. the advance preparation. In addition, the study carried out with water at room temperature for reconstitution provides an answer to the pharmacy having difficulties to respect this parameter.

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