Stability and compatibility of fluorouracil with morphine sulfate and hydromorphone hydrochloride

OBJECTIVE: To study the physical compatibility and chemical stability of fluorouracil 1 and 16 mg/mL with morphine sulfate 1 mg/mL and with hydromorphone hydrochloride 0.5 mg/mL in dextrose 5% injection and in NaCl 0.9% injection. DESIGN: Test solutions of the drugs in dextrose 5% and in NaCl 0.9% were prepared in triplicate and stored at -20, 4, 23, and 32 °C. Samples were removed immediately and at various time points over 35 days and stored at -70 °C until analyzed. Physical compatibility was assessed visually and by measuring turbidity with a color-correcting turbidimeter and particle content with a light-obscuration particle sizer and counter. Chemical stability was determined by measuring the concentration of each drug in the test solutions in duplicate with stability-indicating HPLC. RESULTS: The morphine test solutions all rapidly developed crystalline precipitation when admixed with fluorouracil. Further, substantial loss of morphine content, usually around 60-80%, occurred in all samples within 24 hours at all temperatures. There were no visual or subvisual changes in turbidity or particle content in any of the fluorouracil with hydromorphone test solutions at any of the time points. Further, there was no loss of fluorouracil over 7 days at 32 °C and 35 days at 23.4, and -20 °C. Hydromorphone also was stable for 7 days at 32 °C and for 35 days at the other temperatures when combined with fluorouracil 1 mg/mL and at -20 and 4 °C with fluorouracil 16 mg/mL. However, with fluorouracil 16 mg/mL, hydromorphone was stable only for 3 days at 32 °C and for 7 days at 23 °C, exhibiting approximately 10% loss after those times. CONCLUSIONS: When admixed in dextrose 5% injection and NaCl 0.9% injection, fluorouracil 1 and 16 mg/mL and morphine 0.5 mg/mL were immediately physically incompatible in all samples resulting in substantial loss of morphine content as precipitated crystals. Fluorouracil 1 mg/mL plus hydromorphone 0.5 mg/mL were compatible and stable for at least 7 days at 32 °C and for at least 35 days at 23, 4, and -20 °C. Admixed with fluorouracil 16 mg/mL, hydromorphone was stable for 3 days at 32 °C, 7 days at 23 °C, and 35 days at 4 and -20 °C.