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Published on 29 April 2009

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Stability of 5-fluorouracil and sodium folinate admixture

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This study demonstrated that an admixture of 5-fluorouracil and sodium folinate remained stable in two different ambulatory infusion systems over a two-week period

Julie Cadrobbi
Pharmacist, Medical Laboratory

Jean-Daniel Hecq
PhD
Pharmacist, Hospital Pharmacy

Danielle Vanbeckbergen
Biologist
Medical Laboratory

Jacques Jamart
MD
Centre of Biostatistics and Medical Documentation

Laurence Galanti
MD PhD
Medical Laboratory, Cliniques Universitaires
UCL, Yvoir, Belgium

The aim of this study was to evaluate the chemical stability of an admixture of 5-fluorouracil (5-FU) and sodium folinate in two ambulatory infusion systems placed in simulated clinical conditions. Concentrations were measured by high-performance liquid chromatography (HPLC). The solution concentrations remained stable in the infusion systems for at least two weeks, the lower confidence limits of the results value for each drug remaining superior to 90% of the initial concentration. This has practical importance for both the patient and medical staff because it determines the suitability of administration at home.

Introduction
The simultaneous administration of 5-FU and sodium folinate, used to treat a wide variety of malignancies, [1-12] in one infusion system rather than via separate infusion lines, would be more convenient and less expensive, especially for home care and ambulatory patients.[13] Little is known about the stability of this ready-to-use injectable solution.[14,15] The aim of the study was to evaluate the stability of this admixture in two type of reservoir stored at 32°C, temperature reached by the solution when the containers are carried close to the body.

Main discussion
The Easypump® (Braun, Boulogne, France) and the Infusor® (Baxter, Lessines, Belgium) were filled in a vertical laminar-airflow hood with 250 ml of a 5% dextrose solution containing 24 mg/ml 5-FU and 3.2 mg/ml sodium folinate prepared from commercially available vials of 5-FU (FLURACEDYL® 5000 mg/100 ml) and sodium folinate (VORINA® 500 mg/20 ml) (Teva Pharma, Wilrijk, Belgium). A standard solution containing 25 mg/ml 5-FU and 3.12 mg/ml sodium folinate was extemporaneously diluted in sterile water for injection each day. Concentrations were measured by HPLC (Alliance system, DAD detector, Empower 2 software, Waters Association, Milford, MA, USA) using a reversed-phase column (Hypersil ODS column C18, Waters Association). The flow rate of the 5% methanol (v/v) in KH2PO4 buffer 0.01 M mobile phase was 1 ml/min, the column temperature was set at 35°C and the wavelength at 300 nm. Solutions were visually inspected and pH was measured with a pH-meter (Radiometer PHM82, Copenhagen, Denmark). The within-day variation calculated from three concentrations of 5-FU (10, 25 and 35 mg/ml) and sodium folinate (1, 3.12 and 5 mg/ml) remained below 1.1%, the between-day variation below 3.3%. The method was linear (r2 > 0.99) from 1 mg/ml to 35 mg/ml for 5-FU and 0.1 mg/ml to 7.5 mg/ml for sodium folinate. After alkaline (pH = 12.0) and acidic (pH = 1.2) treatment and heating at 100°C for 60 min, the degradation products remained separate from each parent molecule.

Five Easypump and five Infusor reservoirs were stored at 32°C for two weeks. At day 0, 1, 2, 3, 4, 7, 9 and 11, 2 ml aliquots from each reservoir were placed in glass containers to be visually inspected. pH and concentration were measured in triplicate. After injection (10 Microlitres) of standard and samples, the concentrations were automatically calculated by interpolation of a single-level calibration curve (linear trough zero) using peak areas versus standard concentrations. Data were expressed as mean ± standard deviation.

Statistical analysis demonstrated that the pH remained stable, varying from 8.86 to 8.94. No significant change was observed in the concentrations of the admixture in the two infusion pumps, the slope of the regression line was not statistically different from 0 and, as recommended by the US Food and Drug Administration,[16,17] the lower 95% confidence limit of the estimated common regression line for the two systems remained above 90% of the initial concentration during the two-week period (see Tables 1 and 2).

Conclusion
In treating various types of carcinoma, 5-FU may be combined with folinate salts justifying the investigation of the stability of the mixture to find out whether their prolonged administration in the same infusion system is feasible. We demonstrated that 5-FU and sodium folinate concentrations when mixed together in the same ambulatory infusion system remained stable in two types of currently used reservoirs when used for at least two weeks at 32°C. This has practical importance for both patient and medical staff because it determines the suitability of administration of this admixture in the same infusion device.

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References
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