Chemical Stability of Two Sterile, Parenteral Formulations of Cyclophosphamide (Endoxan^®) after Reconstitution and Dilution in Commonly used Infusion Fluids

Abstract

The commercially available parenteral dosage forms of cyclophosphamide (Endoxan^®, Cycloblastine^®) are manufactured by an aseptic dry-filling technique and exhibit a slow dissolution rate. A novel dosage form has been developed by one of the manufacturers based on the technique of freeze drying. Dissolution rates of both types of formulations were determined and it was shown that the freeze-dried formulation dissolves more rapidly, within 20 seconds, while it takes at least three minutes to dissolve the dry-filled formulation. The chemical stabilities of the cyclophosphamide solutions, obtained after reconstitution and/or dilution of both formulations. have been investigated and tested as a function of drug concentration (20 and 1 mg/mL). solvent (water. 0.9% sodium chloride, 5% dextrose), container material (glass and polyvinyl chloride (pvc)), light conditions (normal room fluorescent light/dark) and temperature (4°, 20,22° and 37°C). The test solutions were analyzed by a stability-indicating reverse phase high performance liquid chromatographic method with ultraviolet detection at 214 nm. Cyclophosphamide solutions (solvent: water; drug concentration: 20 mg/mL) are stable when stored for seven days at 4°C in the dark. At higher temperatures degradation occurred during the test period with 10% loss after seven days at 37°C ambient temperature and 50% loss after seven days storage at 37?C. Similar data were found in admixtures with 5% dextrose and 0.9% sodium chloride and initial drug concentration of 1mg/mL. There are no significant differences in chemical stability between the solutions obtained from reconstitution and dilution of the dry-filled and lyophilized formulations. The type of container materials tested (glass and PVC) HAVE NO INFLUENCE ON the overall chemical stability of cyclophosphamide (concentration: 20 mg/mL) in the dark On the other hand, in diluted solutions (drug concentration: 1 mglmL in 0.9% sodium chloride) exposed to normal room fluorescent light in a day-night cycle at ambient temperature, cyclophosphamide is stable in PVC (less than 5% degradation after seven days storage) but shows 10% degradation in glass. In pvc minibags containing 0.9% sodium chloride. cyclophosphamide (1 mg/mL) shows > 5% degradation when stored for seven days at ambient temperature in the dark. When exposed to normal fluorescent light at ambient temperature the drug (1 mg/mL) degrades for approximate 5% in both glass and PVC containers.