Influence of ultrasonic dissolution on the stability of cyclophosphamide powder for injection

Aim. Cyclophosphamide is widely employed as cytotoxic agent both for conventional (2) and high dose (up to 7 g/m²) anticancer therapies. In Italy cyclophosphamide is available in vials containing 500 mg and 1 g of drug generally reconstituted with 25 ml and 50 ml of solvent, respectively (20 mg/ml). Both formulations are inconvenient for routine preparation due to the prolonged handling-time and the high amounts of solvent required for dissolution. Materials and methods. We evaluated the effects of ultrasonic treatment of cyclophosphamide to short the dissolution time and to reduce the amounts of solvent required in comparison with the traditional manual shaking. Commercially available formulations of cyclophosphamide (Endoxan® 500 mg, 1 g vials) were resuspended at 50 mg/ml in sterile water, 0.9% sodium chloride or 5% dextrose and treated for 5 min at 50°C in an ultrasonic bath. The solvent volumes were 10 ml for 500 mg vials and 20 ml for 1 g vials. After complete dissolution (visual inspection), the chemical stability of two concentrations (10 and 50 μg/ml) was determined using the high performance liquid chromatography method with UV detection and nuclear proton magnetic resonance. Results. No significant differences in chemical stability between the solutions obtained from the two different methods were found. Conclusion. Ultrasonic treatment allows the reduction of the amount of solvent to be dissolved and a significant shortening of dissolution time.