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 sulphate 1 mg/ml and with hydromorphone hydrochloride 0.5 mg/mL in dextrose 5% injection and in NaCl 0.9% injection.


METHODS
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 degrees C. Samples were removed immediately and at various time points over 35 days and stored at -70 degrees 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 degrees C and 35 days at 23, 4, and -20 degrees C. Hydromorphone also was stable for 7 days at 32 degrees C and for 35 days at the other temperatures when combined with fluorouracil 1 mg/mL and at -20 and 4 degrees C with fluorouracil 16 mg/mL. However, with fluorouracil 16 mg/mL, hydromorphone was stable only for 3 days at 32 degrees C and for 7 days at 23 degrees 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 degrees C and for at least 35 days at 23, 4 and -20 degrees C. Admixed with fluorouracil 16 mg/mL, hydromorphone was stable for 3 days at 32 degrees C, 7 days at 23 degrees C, and 35 days at 4 and -20 degrees C.
Xu
Q A
QA
Division of Pharmacy, University of Texas, MD Anderson Cancer Center, Houston 77030, USA.
Trissel
L A
LA
Martinez
J F
JF
D000701:Analgesics, Opioid / Q000737:chemistry*; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry*; D004338:Drug Combinations; D004355:Drug Stability; D005472:Fluorouracil / Q000737:chemistry*; D004091:Hydromorphone / Q000737:chemistry*; D007166:Immunosuppressive Agents / Q000737:chemistry*; D007275:Injections, Intravenous; D009020:Morphine / Q000737:chemistry*; D012996:Solutions; D013696:Temperature; D013997:Time Factors
D000701:Analgesics, Opioid; D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D012996:Solutions; D009020:Morphine; D004091:Hydromorphone; D005472:Fluorouracil