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Research Investigator, Pharmacy Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX
at time of writing, Director, Clinical Pharmaceutics Research, The University of Texas MD Anderson Cancer Center; now, Consultant, TriPharma Research, Cashiers, NC
Reprints: Mr. Trissel, TriPharma Research, PO Box 265, Cashiers, NC 28717-0265, fax 828/743-1752, tripharma{at}mail.com
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Abstract |
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OBJECTIVE: To evaluate the stability of pemetrexed admixtures in common infusion solutions frozen at -20 °C to determine the drug stability period up to 90 days.
METHODS: Triplicate samples of pemetrexed were prepared in concentrations of 2, 10, and 20 mg/mL in dextrose 5% and NaCl 0.9% injection in polyvinyl chloride (PVC) bags. Evaluations for physical and chemical stability were performed initially and over 90 days of frozen storage. Physical stability was assessed using turbidimetric and particulate measurement as well as visual observation. Chemical stability was evaluated by HPLC.
RESULTS: All pemetrexed solutions remained chemically stable throughout the 90 day study period, with little or no loss of pemetrexed. However, the pemetrexed admixtures in PVC bags developed large numbers of microparticulates during long-term frozen storage.
CONCLUSIONS: Although pemetrexed is chemically stable for 90 days frozen at -20 °C, substantial numbers of microparticulates formed in pemetrexed diluted in the infusion solutions in PVC bags upon long-term frozen storage. The avoidance of freezing pemetrexed solutions in PVC bags is therefore warranted.
Key Words: admixture, Alimta, freezing, particulates, pemetrexed, stability
Published Online, July 5, 2006. www.theannals.com, DOI 10.1345/aph.1G558
The purpose of this study was to evaluate the physical and chemical stability of pemetrexed solutions over periods up to 90 days frozen at -20 °C in concentrations of 2, 10, and 20 mg/mL in dextrose 5% injection and in NaCl 0.9% injection in 100 mL polyvinyl chloride (PVC) bags.
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Methods |
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Pemetrexed vials were reconstituted with NaCl 0.9% injection to yield a pemetrexed concentration of 25 mg/mL.1 The intravenous admixtures were prepared at concentrations of 2, 10, and 20 mg/mL by aseptically transferring the required amount of reconstituted pemetrexed to PVC bags of dextrose 5% injection and NaCl 0.9% injection. All preparation manipulations were conducted in a biological safety cabinet providing an International Organization for Standardization Class 5 environment. Triplicate test solutions of each of the concentrations were prepared and stored at -20 °C. Physical and chemical stability evaluations were performed initially after preparation and after 7, 14, 30, 60, and 90 days of frozen storage.
PHYSICAL STABILITY
The physical stability of the pemetrexed solutions was assessed by visual
examination and by measurement of turbidity and particle size and
content.3-5
After thawing, samples of each of the pemetrexed solutions were transferred
into 15 mL borosilicate glass culture
tubesf with
polypropylene screw
caps.f The
tubes had been previously triple-washed in HPLC grade water, dried, and
sterilized by autoclaving.
To minimize the effects of scratches and imperfections in the glass, a thin layer of silicone oil was applied to the exteriors of the tubes. Visual examinations were performed at each of the time points in normal diffuse fluorescent room light with the unaided eye and using a high-intensity monodirectional lightg (Tyndall beam).5 The turbidity of each sample was measured using a formazin-calibrated color-correcting turbidimeter.h Triplicate determinations were made on each of the samples. Particle size and content were also assessed electronically.i
Physical instability was defined as visible particulate matter, haze, or color change or a change (increase or decrease) in measured turbidity of 0.5 nephelometric turbidity unit (NTU) or more.3-5
CHEMICAL STABILITY
The HPLC analytical method was adapted for use in this study from an
analytical method provided by the manufacturer
(Table
1).6
Pemetrexed concentrations in the sample solutions were determined using this
stability-indicating HPLC assay method. The high-pressure liquid
chromatographj
consisted of a multisolvent delivery pump, ultraviolet light detector, and
autosampler in one unit with a C8 reverse-phase analytical
columnk and a
guard column of the same packing material. The system was controlled and
integrated by a personal computer with chromatography management
software.l All
samples were diluted for analysis with water to a nominal pemetrexed
concentration of 0.1 mg/mL. Triplicate HPLC determinations were performed on
each of the triplicate samples for a total of 9 assays of each pemetrexed
solution at each time point. Analysis was performed on the aliquots
immediately after being removed from the samples.
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The HPLC analytical method was validated to be stability-indicating by accelerated degradation. Using this HPLC method, intact pemetrexed eluted at about 6.9 minutes. Pemetrexed 0.1 mg/mL sample solution was exposed to heat, acid, base, and hydrogen peroxide. The intact pemetrexed peak decreased and formation of new peaks was observed at about 2.7, 3.3, and 5.1 minutes. There was no interference of degradation product peaks with the peak of the intact pemetrexed.
The initial pemetrexed concentrations were determined individually for the test samples. The initial concentrations in the samples were defined as 100%, and subsequent sample concentrations were expressed as percentage of initial concentration. Stability of the pemetrexed was defined as not less than 90% of the initial drug concentration remaining in the solutions.
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Results and Discussion |
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Pemetrexed admixtures in PVC minibags prior to freezing were initially
clear and very light yellow to colorless in normal fluorescent room light and
when viewed with a Tyndall beam. Measured turbidities were initially in the
range of about 0.15-0.3 NTU. The solutions were free of visually observable
particulates, and particulates of 10 mm or larger were determined by
electronic evaluation to be few in number at the outset of the testing.
However, upon thawing, previously frozen pemetrexed admixtures in PVC
containers demonstrated large increases in both measured turbidity (
4 NTU)
and in total measured particulates at all time points evaluated. Particulates
in the tens of thousands per milliliter—ranging up to 30
000/mL—were found, including particulates of 10 µm or larger in
amounts of hundreds per milliliter. These larger microparticulates are of
greater clinical concern and pharmaceutically unacceptable. Repeating the
study of the pemetrexed frozen samples in glass containers resulted in few
total particulates and few or no particulates of 10 mm or larger.
Although we are unable to determine the source of the microparticulates that formed, it appears to be related to the PVC containers. Determination of whether pemetrexed interacts with the plastic or if some other process is occurring would require additional study. The manufacturer does not recommend frozen storage of pemetrexed admixtures.1 Although chemically stable, avoidance of freezing of pemetrexed admixtures in PVC bags is warranted due to the large number of microparticulates that form.
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Footnotes |
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a Eli Lilly, Indianapolis, lot 8726-113, exp. 12/1/04. 
b Baxter Healthcare, Deerfield, IL, lot PS134866.
c Baxter Healthcare, lot P141192.
e Milli-Q Plus, Millipore Corporation, Bedford, MA.
f Kimble, Division of Owens-Illinois, Toledo, OH.
g Dolan-Jenner Industries, Woburn, MA.
h Model 2100AN, Hach Company, Loveland, CO.
i Model 9703, Hiac-Royco, Division of Pacific Scientific Company, Grants
Pass, OR.
j LC Module-1 Plus, Waters Corporation, Milford, MA.
k Zorbax SB-C8, 250 x 4.6 mm id, 5 µm, SNUSSE008678,
Agilent, Palo Alto, CA.
l Millennium 32, Chromatography Manager, Waters Corporation.
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