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Assistant Professor of Pharmaceutics, Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, 847 Monroe Avenue, Memphis, Tennessee 38163, fax 901/448-3446, halmoaze{at}uthsc.edu
Research Assistant Professor, Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee
Research Assistant, Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee
Manager, Outpatient Pharmaceutical Services, Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee
Published Online, December 22, 2009. www.theannals.com, DOI 10.1345/aph.1M390
Methods. Infusion devices and control vials were prepared from commercialized 100 mg/mL mesna (Bedford Laboratories, Bedford, OH) that had 0.25 mg/mL of EDTA, a chelating agent, All solutions were diluted with dextrose 5% solution (Baxter International Inc., Deerfield, IL) to reduce the mesna concentration to 10 mg/mL. All devices and control vials were stored in a refrigerator and a temperature-controlled stability chamber at 5 °C and 25 °C. Samples were collected at 0, 2, 7, 14, and 28 days and were transferred to test tubes in order to react with Ellman's reagent2 (Sigma-Aldrich, St. Louis, MO). Each analytical sample consisted of 50 µL of mesna solution, 800 µL of water, 100 µL of 1.0 M TRIS buffer, and 50 µL of 10 mM Ellman's reagent.
Each sample was then allowed to react for 45 minutes in the absence of light. The analytical technique used with Ellman's reagent was performed according to Interchim (Interchim, Inc., San Pedro, CA) recommendations.3 All samples were then analyzed using an ultraviolet-visible spectrophotometer (Shimadzu UV-2401PC; Shimadzu, Columbia, MD) at a wavelength of 412 nm.
Results and Discussion. Results indicated that mesna concentrations in the ReadyMed infusion devices were maintained within acceptable limits (110-90%), relative to their original concentrations, over a period of 28 days when stored at 5 °C and 14 days when stored at 25 °C (Figure 1). Our results were consistent with those of Goren et al.,4 who reported on the stability of mesna in polypropylene syringes at 5 °C, 24 °C, and 35 °C and those of Menard et al.,5 who studied the stability of cyclophosphamide and mesna mixtures in polyethylene infusion bags of 5% dextrose.
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In order to elucidate the effect of EDTA on the stability of mesna, a separate study was conducted in which a fresh mesna solution was prepared by weighing pure mesna (Fluka, St. Louis, MO) and mixing it with water to make a solution at 100 mg/mL. Then this solution was further diluted with 5% dextrose solution to lower the mesna concentration to 10 mg/mL. The solution was stored in a vial at 25 °C and was analyzed as described in the Methods section. The stability profile of this mesna solution followed a first-order degradation pattern (data fitted to first-order function; Figure 1). The rate constant of degradation was 0.023 h-1, which corresponds to a shelf life (t90) of 4.56 hours. This study explained why the presence of EDTA has a positive influence on the stability of mesna.
Mesna solutions in ReadyMed devices were stable for 14 days at 25 °C and for 28 days at 5 °C when a commercialized product of mesna stabilized with EDTA (0.25 mg/mL) was mixed at a ratio of 1:10 with 5% dextrose solution. Our second stability study of mesna indicated that the shelf life could be significantly shortened with the absence of EDTA.
References
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