The objective of this study was to evaluate the physical and chemical stability of amikacin 25 mg/100 mL and 500 mg/100 mL as the sulfate salt admixed in 0.9% sodium chloride injection and packaged in AutoDose Infusion System bags.
Triplicate test samples of each concentration were prepared by admixing the necessary amounts of the amikacin sulfate with a portion of 0.9% sodium chloride injection. The admixtures were brought to a final volume of 100 mL with additional 0.9% sodium chloride injection. The test solutions were packaged in AutoDose bags, which are ethylene vinyl acetate plastic containers designed for use in the AutoDose Infusion System. Samples were stored protected from light and evaluated at appropriate intervals for up to 7 days at 23 deg C and up to 30 days at 4 deg C.
Physical stability was assessed by means of a multistep evaluation procedure that included both turbidimetric and particulate measurement, as well as visual inspection. Chemical stability was assessed by stability-indicating high-performance liquid chromatographic analytical techniques based on the determination of initial drug concentrations and drug concentrations at appropriate intervals over the study periods.
The amikacin sulfate admixtures were clear and colorless when viewed in normal fluorescent room light and when viewed with a Tyndall beam. Measured turbidity and particulate content were low and exhibited little change. High-performance liquid chromatographic analysis indicated that the amikacin sulfate remained stable for 30 days at 4 deg C and for 7 days at 23 deg C.
At both concentrations, amikacin sulfate exhibited physical and chemical stability consistent with previous studies of this drug. The AutoDose Infusion System bags did not adversely affect the physical and chemical stability of the amikacin sulfate.
The AutoDose Infusion System (Tandem Medical, Inc., San Diego, California) is a new, simplified infusion system for the administration of antibiotics that is suitable for patient or caregiver operation and for use by healthcare providers. In the AutoDose Infusion System, specially designed multichamber drug-solution reservoirs (AutoDose bags, Tandem Medical, Inc.) composed primarily of ethylene vinyl acetate (EVA) are used. In a simple automated process, the system provides an infusion line flush, antibiotic administration, second infusion line flush, and reinstallation of heparin sodium lock solution. Although studies1 of the physical and chemical stability of many antibiotics in glass and polyvinyl chloride (PVC) containers have been reported, no published information is available on the stability of aminoglycoside antibiotics in EVA containers. Consequently, studies must be conducted to determine the physical and chemical stability of the antibiotic solutions in EVA reservoirs before they are used in the clinical setting.
The purpose of this study was to evaluate the physical and chemical stability of amikacin sulfate admixtures that were packaged in AutoDose Infusion System bags and stored and evaluated at appropriate intervals for up to 7 days at 23 deg C and up to 30 days at 4 deg C.
Materials and Methods
Empty AutoDose Infusion System bags that had been sterilized by gamma irradiation were supplied by the manufacturer. The following materials were obtained commercially: amikacin sulfate injection (Lot 0G26873, Apothecon, Princeton, New Jersey) and its reference standard (Lot I, United States Pharmacopeia, Rockville, Maryland). The mobile-phase components were all of a grade suitable for high-performance liquid chromatographic (HPLC) analysis. The water used was also HPLC grade and was prepared immediately before use.
Preparation and Sampling of Solutions. The appropriate amounts of the amikacin sulfate injection were brought to a final volume of 100 mL with 0.9% sodium chloride injection (Lot C510289, Baxter Healthcare Corporation, Deerfield, Illinois). The test solutions were packaged in AutoDose Infusion System bags for testing. All manipulations were performed in a biological safety cabinet. The nominal concentrations used in this study were amikacin 25 mg/100 mL and 500 mg/ 100 mL as the sulfate salt. Triplicate test solutions of each antibiotic admixture were prepared. The test solutions were stored at 4 deg C and 23 deg C and were protected from light. Aliquots were removed from each bag at the beginning of the study and at appropriate time intervals up to 7 days at 23 deg C and up to 30 days at 4 deg C.
Physical Stability. The physical stability of the admixtures was assessed by visual examination and by measurement of turbidity, particle size and content.2-4 Five milliliters of each sample solution was transferred to 15-mL borosilicate glass culture tubes (Kimble, Division of Owens-Illinois, Toledo, Ohio) with polypropylene screw caps (Kimble). The tubes had been previously triple-washed in HPLC-grade water and dried. To minimize the effects of scratches and imperfections in the glass, a thin layer of silicone oil was applied to the tube exteriors. Visual examinations were performed in normal, diffuse fluorescent room light with the unaided eye, and also with the use of a high-intensity monodirectional light (Tyndall beam, Dolan-- Jenner Industries, Woburn, Massachusetts).3
The turbidity of each sample was measured by means of a color-correcting turbidimeter (Ratio X/R, Hach Company, Loveland, Colorado). Triplicate determinations were made on each of the samples. The particle content of the samples was quantified using a light obscuration particle sizer/counter (Model 8003, Hiac-Royco, Division of Pacific Scientific Company, Silver Spring, Maryland) to determine particle content in the size range of 1.04 to 112 (mu)m (the validated detection limits of the particle sizer/counter). Triplicate determinations were made on those samples. Physical instability was defined as visible particulate matter, haze, color change, or a change (increase or decrease) in measured turbidity of 0.5 nephelometric turbidity unit (NTU) or more.2-4
Analysis by High-Performance Liquid Chromatography. The amikacin concentrations were determined using stability-- indicating HPLC assay methods. The analytical method used in this study was adapted from a published method.5 A highperformance liquid chromatograph (LC Module 1 Plus, Waters Corporation, Milford, Massachusetts) was used for analysis of the drugs. The chromatograph consisted of a multi-- solvent delivery pump, an autosampler, and an ultraviolet light detector. The system was controlled and peak areas were integrated by a personal computer with chromatography management software (Millennium 32 Chromatography Manager, Waters Corporation).
The samples were derivatized by means of 2,4,6-trinitrobenzenesulfonic acid (Lot 1K5006, Sigma Chemical Company, St. Louis, Missouri) 10 mg/mL in water as the derivatizing reagent. For analysis, the high-concentration samples were diluted with water to a concentration of 0.25 mg/mL. Aliquots of 0.4 mL of the amikacin 0.25-mg/mL sample solutions were transferred to sample tubes that contained 1 mL of the derivatizing reagent. Pyridine 1.6 ml (Lot 96H0491, Sigma Chemical Company) was added and vortex mixed for 30 seconds. The sample tubes were placed in a 70 +/- 1 deg C water bath for 45 minutes, and then the sample tubes were removed and allowed to cool to room temperature. The samples were then passed through 0.45-(mu)m filters (Nylon Acrodisc 13, 13 turn, Gelman Sciences, Ann Arbor, Michigan) prior to HPLC analysis.
Duplicate HPLC determinations were performed on triplicate samples of each test admixture solution. Separation was performed by means of a Cps reverse-phase column (Vydac C^sub 18^, 5 (mu)m, 250 x 4.6 mm, Separation Group, Hesperia, California) with a guard column of the same material. The mobile phase consisted of 27.5% 0.02 M KH^sub 2^PO^sub 4^ with the pH adjusted to 6.5 with sodium hydroxide and 72.5% methanol. It was delivered isocratically at a flow rate of 1.3 mL/minute. Ultraviolet light detection was performed at 340 nm and 0.5 absorbance units full scale. Injection volume was 10 (mu)L. Under these conditions, the intact amikacin derivatized peak eluted at 9.2 minutes.
For a nominal amikacin quantity of 100 (mu)g (400 (mu)L of a 250-(mu)g/mL solution), the precision of the assay (mean +/- standard deviation), which was determined from 10 replicate injections, was 100.5 +/- 1.3 (mu)g/mL. The precision expressed as percent relative standard deviation was 1.3 %. The calibration curve was linear within the range of 50 to 150 (mu)g/mL. The correlation coefficient was greater than 0.9997. Duplicate HPLC determinations were performed on triplicate samples of each test concentration at each time point. The intraday and interday coefficients of variations were 2.3 % and 2.1%, respectively.
The analytical methods for each of the drugs were demonstrated to be stability indicating by accelerated degradation. The amikacin sulfate sample solutions were mixed with each of the following: 0.1 N sodium hydroxide, 0.1 N hydrochloric acid, and 3% hydrogen peroxide. The sample solutions were also subjected to heating. Loss of the intact drugs was observed, and there was no interference by the degradation product peaks or other drug peaks with the peak of the intact subject drug. The major decomposition peaks after derivatization eluted at 4.9, 5.7, 6.2, and 6.8 minutes.
The initial concentrations of amikacin were defined as 100%, and subsequent sample concentrations were expressed as a percentage of initial concentration. The stability of the drug was defined as not less than 90% of the initial drug concentration remaining in the admixtures.
Results and Discussion
All admixtures were initially clear and colorless when viewed in normal fluorescent room light and when viewed with a Tyndall beam. The admixtures were essentially without haze, having measured turbidities of less than 0.14 NTU. Changes in turbidity for the samples were minor throughout the study and did not exceed 0.11 NTU in any sample. Measured particulates of 10 (mu)m or larger were found to be few in number in all samples and remained so throughout the observation periods at both storage temperatures. The admixtures remained colorless throughout the study.
The results of the HPLC analysis for each of the test drugs are shown in Table 1. Amikacin sulfate remained stable for 30 days at 4 deg C, exhibiting amikacin concentrations of 97% or greater of the initial concentrations. At 23 deg C, the concentrations were 98% or greater of the initial concentrations after 7 days.
The stability of amikacin sulfate in the AutoDose Infusion System bags is consistent with previously published results6-9 of the stability of this drug in infusion solutions in glass and PVC containers but extends the observed stability period beyond those of earlier studies. The stability of amikacin sulfate is similar to the stabilities of gentamicin sulfate and tobramycin sulfate in the AutoDose Infusion System bags.10
Amikacin sulfate exhibited physical and chemical stability consistent with the results of other studies. As with gentamicin sulfate and tobramycin sulfate, the EVA bags used in the Auto-- Dose Infusion System did not adversely affect the physical and chemical stability of amikacin sulfate.
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10. Xu CIA, Trissel LA, Saenz CA, et al. Stability of gentamicin sulfate and tobramycin sulfate in AutoDose infusion bags. IJPC2003;7:149-151.
Yanping Zhang, BS
Lawrence A. Trissel, BS, RPh, FASHP
Clinical Pharmaceutics Research
Division of Pharmacy
The University of Texas
M. D. Anderson Cancer Center
This study was supported by a grant (LS01-160-1) from Tandem Medical, Inc., San Diego, California.
Address correspondence to: Lawrence A. Trissel, BS, RPh, FASHP, Division of Pharmacy, Box 90, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030.
Copyright International Journal of Pharmaceutical Compounding May/Jun 2003
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