DI-004 BUSULFAN stability determination by UHPLC-MS

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Abstract

Background

Busulfan is an alkylating antineoplastic drug extensively used in myeloablative regimens prior to haematopoietic stem cell transplantation. Administration every 6 hours for 4 consecutive days and the low stability of this product induces organisational problems for cytotoxic preparation units in hospital pharmacies. A few studies have already been conducted to investigate the stability of diluted busulfan solutions but published results showed important variability.

Purpose

The purpose of this study was to evaluate the stability of busulfan solutions diluted to 0.54 mg/mL with 0.9% sodium chloride and stored in polypropylene (PP) syringes or PP infusion bags with a highly sensitive, specific and rapid (<2 min) method.

Material and methods

Busulfan solutions (0.54 mg/mL) were prepared from three Busilvex batch numbers and transferred into 50 mL PP syringes (n=12), or 100 mL (n=12) or 500 mL (n=4) PP infusion bags (stored at 2–8°C or 23–27°C). The chemical stability of busulfan was assessed by measuring in each container the percentage of the initial concentration remaining at each time point of analysis (max 100 hours) with an ultra high performance liquid chromatography coupled to mass spectrometry (UHPLC-MS) method. Busulfan and [2H8]-busulfan (internal standard) were detected in selected ion recording mode as ammonium adducts at m/z: 264.1 and 272.1, respectively. Stability was defined as retention of at least 90% of the initial busulfan concentration. Physical stability was assessed by visual inspection.

Results

Busulfan in PP syringes proved to be stable for 30 hours at 2–8°C and 12 hours at 23–27°C. A reduced stability of 12 hours and 9 hours were obtained at 2–8°C for 100 mL and 500 mL PP bags, respectively. At 23–27°C, all PP bags presented stability for 3 hours. The main effects observed were hydrolysis at 23–27°C and precipitation at 2–8°C.

Conclusion

This study demonstrated that the stability of busulfan diluted solutions depends on the container type and storage temperature. Stability for 30 hours in PP syringes stored at 2–8°C is a considerable improvement compared with the manufacturer’s recommendations (12 hours). The extended shelf life of busulfan infusion in syringes allows better organisation of the chemotherapy preparation unit by reducing the number of busulfan production to once a day.

Conclusion

No conflict of interest

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