Stability study of 10 mg/mL cyclophosphamide solution

Context
Cyclophosphamide is used in oral paediatric patients in the maintenance treatment of cancers such as Ewing’s sarcoma and rhabdomyosarcoma. Only tablets are marketed which is hardly compatible with the management of paediatric patients. Thus, hospital pharmacies resort to the manufacture of oral liquid magistral preparations for which few stability data are available. The commonly used form is a syrup containing excipients with known effects (EKE)

Objective
The objective of this study was to formulate a 10 mg/mL oral solution of cyclophosphamide without EKE and to conduct a stability study in order to establish a shelf life.

Method
Three batches of oral cyclophosphamide solutions were prepared with Endoxan^® 1000 mg (powder for injectable solution), sterile water and Inorpha^®. These preparations were packaged in amber glass bottles and stored at 2-8°C.
A stability-indicating assay method was developed and validated using an UHPLC chromatographic system with UV detection. Forced degradation of cyclophosphamide was carried out under different conditions (acid and alkaline hydrolysis, oxidative, and thermal stress).
The physicochemical stability (pH, osmolality, concentration and visual examination) of the preparation was evaluated over 93 days at D0, D4, D7, D28, D42, D57 and D93.

Results
The chromatographic method provides good separation between cyclophosphamide and its degradation products. The method has been validated in terms of linearity (R2 > 0.99), accuracy (maximum bias: 1.63%), precision (relative standard deviation: 0.57%) and specificity in accordance with the International Council for Harmonisation (ICH) guidelines. No matrix effects were observed.
Cyclophosphamide concentration remained above 95% of the initial concentration for up to 57 days (97.7% at D57; 93.2% at D93).
pH (4.8 at D0; 4.5 at D93) and osmolality (124 mOsm/kg at D0; 121 mOsm/kg at D93) remained stable until D93. Visual examination showed no macroscopic changes during the study.

Conclusion
An EKE-free oral solution of cyclophosphamide 10 mg/mL has been developed using the neutral formulation of Inorpha®. In addition to flavouring, this vehicle contains a bitterness-masking agent of particular interest for this active ingredient. The physicochemical properties of this preparation appear to be stable for at least 57 days when stored in amber glass bottles in the refrigerator.

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