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` Study of the Interaction of Selected Drugs and Plastic Syringes
`ully J. Speaker, Salvatore J. Turco, David A. Nardone, et al.
`
`(cid:160)A
`
`(cid:160)T
`
`
`
` PDA J Pharm Sci and Tech
`
`1991
`
`45,
`
` 212-217
`
`Hospira, Exh. 2011, p. 1
`
`(cid:160)(cid:160)
`

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`RESEARCH ARTICLE
`
`A Study of the Interaction of Selected Drugs and Plastic Syringes
`
`TULLY J. SPEAK~R, SALVATORE J. TURCO", DAVID A. NARDONE, and JEFFREY E. MIRIPOL
`
`School of Pharmacy, Ti!lnple University, Philadelphia, Pennsylvania and Ternmo Medical Corporation, Elkton, MD
`
`ABSTRACT: It is common hospital pharmacy practice to preload syringes with selected drugs and store them
`ready for use. Because the several components of syringes, (such as ba1rels, gasket seals, etc.) may vary among
`manufacturers, there exists the possibility that syringe components of differing provenance might interact e.g., by
`sorption, with stored drugs to differing degrees. To examine possible interactions, three brands of commercially
`available syringes w.ere compared to determine what influence, if any, shon term storage of injectable solutions
`might exen on the solutions or the syringes. Four drugs; dexamethasone sodium phosphate, diazepam, diatrizoate
`meglumine and nitroglycerin USP were individually loaded into 3 mL syringes and stored at temperatures between
`- 20"C and + 25°C for periods from 6 hours to 30 days. The syringes were examined for any gross changes. Drug
`solutions were analyzed after storage to determine the presence of organic leachates from the syringes and any
`change from original drug concentration values. No syringes showed gross physical changes after storage with drug
`solution nor were any drug solutions found to contain leachates on gas chromatographic-mass spectroscopic
`analysis. Drug concentrations were seen to change following storage, the greatest changes occurring with the highly
`lipophilic drugs dexamethasone and diazepam. In most instances loss of drug concentration was most rapid at
`room temperature. Although there were clear differences among the three brands of syringe, no overall pattern
`emerged which might allow the selection or rejection of one syringe over another for the extemporaneous
`preloading of the drugs examined.
`
`Background
`
`Hospital services frequently have need for a range of
`drug solutions in quickly available injectable dosage
`forms. Certain drugs, for example, narcotics or aminogly(cid:173)
`cosides, for which there is frequent need, are available
`packaged in syringes as sterile unit doses by their
`manufacturers. Other Jess frequently used or less stable
`drugs, such as some antibiotics or amines are transferred
`or reconstituted to syringes from single or multiple dose
`containers by hospital personnel at the time of use. In
`instances in which drugs are not available prepackaged
`in syringes in the sizes or doses wanted, hospital pharma(cid:173)
`cies meet the need by aseptically preloading sterile drug
`solutions into sterile syringes and storing the resultant
`unit dose form for short periods at room, refrigerator or
`freezer temperatures.
`Because the several components of syringes, e.g.,
`plastic barrels, seals, vary among manufacturers there
`exists the possibility that syringe components might
`interact with stored drugs to differing degrees.
`To examine the possible interactions of drugs and
`syringe component materials, three brands of commer(cid:173)
`cially available syringes were compared to determine
`what influence, if any, short term storage of injectable
`solutions might exert on the solutions or the syringes.
`
`Received October 12, 1990. Accepted for publication
`February 14, 1991.
`.:.. Author to whom correspondence should be addressed:
`School of Pharmacy, Temple University, 3307 North Broad Street.
`Philadelphia. PA 19140.
`
`The drugs examined included dexamethasone sodium
`phosphate, diazepam, diatrizoate meglumine and nitro(cid:173)
`glycerin USP. The selected drug solutions were loaded
`into 3 mL plastic syringes sealed with commercially
`available syringe caps and stored in the dark at tempera(cid:173)
`tures between - 20 and + 25 °C for periods ranging from
`6 hours to 30 days. The syringes were examined for gross
`physical changes; drug solutions were analyzed to deter(cid:173)
`mine the presence of organic leachates from the syringes
`and for changes in drug concentration.
`
`Experimental Section
`
`Materials
`
`Three brands of 3 mL plastic syringe, each from a
`single manufacturer's lot, were utilized in the study:
`Becton-Dickinson lot No. 90233, Sherwood Monoject
`lot No. 221873 and Terumo lot LE248MIX1. Four drugs,
`each from a single lot, were employed: dexamethasone
`sodium phosphate injection, USP, 4 mg/mL, (Quad
`Pharmaceuticals lot No. 405H51 ), diazepam injection,
`USP, 5 mg/mL (Warner Chilcott Labs lot No. 053D7)
`diatrizoate meglumine/diatrizoate sodium (Squibb Diag(cid:173)
`nostics) lot No. 9A47196) and nitroglycerin injection
`USP (Dupont Pharmaceuticals Tridil brand lot No.
`8CA202). Syringe seals (Sherwood Medical Corp. Tip
`Cap brand, lot No. 67965) were used to close each
`syringe after filling .
`All samples were coded and blinded and this informa(cid:173)
`tion was not available to the analysts.
`
`212
`
`Joumal of Parenten:il RdAnr.i:> R. T~hnntnn11
`
`Hospira, Exh. 2011, p. 2
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`Sample Preparation
`
`Syringes from each brand/lot were randomly divided
`into four groups of 18, numbered and assembled into
`four sets of 54, each set containing an equal number of
`syringes of each brand/lot, At appropriate times three
`syringes of each brand/lot were loaded with approxi(cid:173)
`mately 2.5 mL of one drug solution, capped, weighed to
`the nearest 10 mg, and exposed to thermal stress for one
`of the time at temperature periods listed below:
`
`temperature 'C
`-20
`-20
`4
`4
`25
`25
`
`time in days
`30
`1
`7
`
`1
`0.25
`
`At the end of a time period at temperature the weight of
`each syringe and contents was checked to determine
`whether any appreciable loss had occurred. The two
`samples which changed weight by more than 5 mg were
`removed from the study. From all drug solution/syringe
`combinations which were unchanged in weight after
`storage, an aliquot of drug solution was taken for assay
`of drug content and the remainder was transferred and
`sealed into clean dry 2 mL prescored glass ampuls
`(Fisher Scientific Company No. 01-215B) for determina(cid:173)
`tion of leachants. In the instance nitroglycerin, in which
`it was not practical to conduct the assay for drug content
`immediately after a storage at temperature period, the
`contents of all syringes and an aliquot from a previously
`unbroached vial of drug to serve as control were promptly
`transferred to and sealed in clean dry 2 mL prescored
`glass ampuls for storage overnight at 4'C until the assay
`could be performed.
`General Description of Assays for Leachants: Hexane
`extractions were performed on all samples and exam(cid:173)
`ined by gas chromatography /mass spectroscopy (GC/
`MS) for specific compounds previously identified as
`additives and reaction products of some of the syringe
`plunger gaskets (diethylhexyl phthalate (DEHP), acri(cid:173)
`dine, hydrazine).
`Specific Assay for Volatile Extractables: A 1.5 mL aliquot
`of the sample drug solution which had been in contact
`with a test syringe was added to a clean, dry test tube
`along with 1.0 mL hexane and 0.5 mL saline. The tube
`was vortexted for 30 seconds and the upper organic layer
`was aspirated into GC sample vials and crimped closed.
`One microliter samples were injected on-column and
`evaluated isothermally at 280' with a gas chromatograph
`(Hewlett Packard 5890) and mass selective detector
`(Hewlett Packard 5970) in the mass range between 50
`and 600 atomic mass units ( amu ).
`Extracts of blanks (drugs that were not stored in
`syringes), as well as blanks with 10 ng of carbon-13-
`labeled and unlabeled DEHP added, were prepared and
`analyzed. In addition, scans for specific ions which are
`characteristic of particular compounds were performed.
`
`For example, 149 amu is characteristic of phthalates
`extracted from the elastomeric silicone seal component
`of some syringes, while 169 amu and 194 amu are
`characteristic of hydrazine and acridine degradation
`products of some rubber seals.
`General Description of Assays for Drug Concentration:
`For the assay of dexamethasone sodium phosphate.
`diatrizoate and diazepam, aliquots of the same commer(cid:173)
`cial formulation as used in the study were drawn from
`the original container and accurately diluted with dis(cid:173)
`tilled water or aqueous methanol, as appropriate. to
`provide concentrations with absorbance maxima in the
`range between 1 and 2 absorbance units (AU.) in the
`ultraviolet region between 230 and 350 nm. For nitroglyc(cid:173)
`erin, the solution was utilized in a diazotization reaction
`providing a chromophoric product which, suitably di(cid:173)
`luted, provided coupled product concentrations with
`absorbancesat about 455 nm in the range near 1.00 AU.
`These dilutions were scanned to determine the wave(cid:173)
`length of maximum absorbance for each drug.
`New samples were accurately diluted to provide
`triplicate dilutions from which a standard curve for each
`drug at its wavelength of maximum absorbance was
`prepared and the corresponding regression equation
`generated. Standard curves and regression equations
`were based either on measured absorbances or on ratios
`of areas under elution curves. In the instance of diaz(cid:173)
`epam, a constant amount of tolualdehyde was added to
`each of the dilutions to serve as internal standard in the
`high performance liquid chromatographic assay. For all
`drugs the average of triplicate determinations were
`employed to generate standard curves. Standard curve
`regression equations are presented below. The wave(cid:173)
`lengths of maximum absorbance and the standard dilu(cid:173)
`tions used in assays of the four drugs are shown below:
`Assay Wavelengths and Dilutions Employed in Assays
`
`Drug
`dexamethasone
`sodium phosphate
`diatriazoate meglumine
`diazepam
`nitroglycerin
`
`Wavelength
`(nm)
`
`Dilution
`
`242
`244
`254
`455
`
`1:200
`1:20000
`1:10
`1:100
`
`Specific Assays
`Dexamethasone sodium phosphate injection:
`The absorbance of an accurate distilled water dilution
`of 0.5 mL of sample to 100 mL was measured at 242 nm
`against a water blank. The remaining percent of original
`concentration was calculated using the regression equa(cid:173)
`tion:
`
`percent remaining= 0.0045(A) + 1.447
`where A is the absorbance measured at 242 nm; r =
`0.998.
`Diatrizoate meglumine injection: The absorbance of
`0.005% (V /VJ solution in distilled water was measured
`at 244 nm against a water blank and the remaining
`percent of original concentration was calculated using
`
`Vol. 45, No. 5 / September-October 1991
`
`213
`
`Hospira, Exh. 2011, p. 3
`
`

`
`
`
`journal.pda.orgDownloaded from
`
` on October 31, 2016
`
`6.UE+6
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`Figure 1-Gas chromatogram from hexane extract of nitroglycerin solution stored in a test syringe showing single peak for hexane extract·
`ant eluting at about 2.0 minutes.
`
`•••
`
`•••
`
`1e.e
`
`the regression equation:
`
`percent remaining = 0.0113(A) - 0.016
`
`where A is the absorbance measured at 244 nm; r
`0.999.
`Diazepam injection: A solution containing 20% tolual(cid:173)
`dehyde and 0.005% diazepam was passed over an
`octadecylsilyl (6 x 200 mm. 5 micron) HPLC column.
`The absorbances at 254 nm of diazepam and tolualde(cid:173)
`hyde were measured and integrated. The percent of
`original concentration was calculated using the regres-
`
`sion equation:
`percent remaining= 12.886(PAR) + 0754
`where PAR is diazepam to tolualdehyde peak area ratio.
`Nitroglycerin injection: In an automated analysis sys(cid:173)
`tem 0.23 mL of sample was hydrolyzed with 0.42 mL of
`1 % strontium hydroxide solution. This solution was
`diluted to 2.5 mL with distilled water and diazotized by
`mixing successively with 0. 73 mL of 3% procaine hydro(cid:173)
`chloride solution. 0. 73 mL of 2N hydrochloric acid and
`0. 73 mL of 0.1 % naphthalenediamine solution. The
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`Figure 2-Mass spectrograms of hexane extracts from (A) nitroglycerin, (B) dexarnethasone and (C) diatrizoate meglumine solutions stored
`in test syringes showing background noise but no characteristic peaks.
`
`214
`
`Journal of Parenteral Science & Technology
`
`Hospira, Exh. 2011, p. 4
`
`

`
`Downloaded from
`
`journal.pda.org
`
` on October 31, 2016
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`Figure 3--(A) Gas chromatogram from hexane extract of diazepam solution stored in a test syringe and (B) corresponding mass
`spectrogram of the diazapam peak eluting at about 4.4 minutes.
`
`absorbance of the resulting diazotizotion product was
`measured at 455 nm and the remaining percent of
`original concentration was calculated with the regres(cid:173)
`sion equation:
`
`percent remaining = Aul AR
`
`where A is the absorbance measured at 455 nm and
`subscripts U and R refer to the unknown and reference
`samples, respectively.
`
`Results
`
`Gas Chromatographic I Mass Spectrometric Study
`
`Chromatography of the nitroglycerin, diatrizoate
`meglumine and dexamethasone samples resulted in
`chromatograms similar to those shown in Figures I and
`2. (Note the abundance axis in each figure.) The jagged
`line is background noise and shows the detector at the
`limits of sensitivity with no compound present. The
`
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`lEf' and tl3l-C-DEll' IB ng
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`Figure 4-(A) Gas chromatogram from diethylhexyl phthalate spiked hexane extract of nitroglycerin solution stored in a test syringe and (8)
`mass spectrogram obtained from the diethyl hexyl phthalate peak at about 4.4 minutes.
`
`!Brill
`
`128
`
`148
`
`168
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`
`Vol. 45, No. 5 / September-October 1991
`
`215
`
`Hospira, Exh. 2011, p. 5
`
`

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`journal.pda.org
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` on October 31, 2016
`
`ton range 148.e to 150.0 from Heglu~ln~ 142
`
`Ion range 193.0 to 195.0 from Heglumlne 142
`
`Ion range 168.0 to 170.e from Meglumtne 142
`
`... )
`···1
`•••
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`···1
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`
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`
`Figure 5-(A-C)Gas chromatograms of hexane extracts from meglumine diatriazoate solution stored in a test syringe showing absence
`of peaks in total ion current in ion ranges from 148 to 195 a.m.u.
`
`diazepam samples extracted drug but no additional
`compounds were detected by our techniques as shown in
`Figure 3. Sensitivity of the method for one possible
`syringe contaminant, diethylhexyl phthalate (DEHP),
`was demonstrated by injecting a sample containing
`carbon-13-labeled DEHP and nitroglycerin. As shown in
`Figure 4, the method was sensitive to as little as 10
`ng/mL of plasticizer in the starting sample. Figure 5
`shows the ion chromatograph scans for three specific ion
`masses. The flat lines are indications that the particular
`masses scanned, e.g., phthalate, acridine or hydrazine
`derivatives, are not present.
`
`Drug Concentration Assays
`
`The average percents of original drug concentration
`remaining in drug solutions after storage in each of the
`three syringe types are separately tabulated below. One
`may see from these data the concentrations of relatively
`lipophilic drug solutions may be reduced during even
`short periods of storage in plastic syringes and, con-
`
`versely, that the concentration of a less Iipophilic drug
`such as nitroglycerin is only slightly changed even after
`extended periods of storage. It is reasonable to infer that
`such changes reflect partitioning or adsorption of Ii(cid:173)
`pophilic drug to the wetted surfaces and that physical
`differences among the three brands of syringe might give
`rise to the differences found.
`The barrels of all three syringe brands are made of
`polypropylene which, except for possible variations in
`polymer chain length, is essentially the same material in
`all syringes. However, the syringes do differ in composi(cid:173)
`tion of the elastomeric seals fitted to the plungers.
`Moreover, the loaded syringes were stored with barrel
`axis oriented vertically, needle hub upward, with the
`result that the solutions were in continuous contact with
`the faces of the elastomeric seal materials. This orienta(cid:173)
`tion provided maximal contact between drug solution
`and seal polymers. Thus, it is quite likely that differences
`in drug disappearance from solution after storage reflect
`the differing abilities of elastomeric seal material to
`
`TABLE I
`Average Percent of Original Dexamethasone Sodium
`Sulfate Injection Concentration Remaining after Storage in
`Three Types of Syringes at Three Temperatures
`
`TABLE II
`Average Percent of Original Diatrizoate Meglumine Injection
`Concentration Remaining after Storage in Three Types of
`Syringes at Three Temperatures
`
`Brand of Syringe
`
`Braud of Syringe
`
`Days at
`DegreeC
`
`30 days at - 20
`1 day at -20
`7 days at 4
`1 day at 4
`1 day at 25
`0.25 day at 25
`
`Becton
`Dickinson
`86.6 :t 2.2
`95.J :t 4.5
`77.7 :t 0.8
`95.5 :t 1.1
`80.5 :t 1.2
`85.9 :t 0.8
`
`Sherwood
`72.2 :t 1.1
`82.7 :t 0.4
`89.2 :t 1.1
`81.4 :t 1.3
`81.1 :t 1.4
`96.7 :t 1.4
`
`Terumo
`Medical
`
`74.4 :t 3.4
`86.5 :t 2.9
`73.3 :t 0.4
`87.7 :t 0.9
`87.7 :t 0.9
`91.8 :t 0.8
`
`Days at
`DegreeC
`
`30 days at - 20
`1 day at -20
`7 days at 4
`1 dayat4
`1 dayat25
`0.25 day at 25
`
`Becton
`Dickinson
`97.4 :t 0.4
`98.6 :t 0.9
`96.8 :t 0.6
`95.0 :t 0.5
`96.8 :t 0.6
`98.8 :t 0.4
`
`Sherwood
`97.1 :t 0.4
`98.3 :t 0.2
`94.2 :t 0.2
`97.1 :t 0.4
`96.5 :t 0.4
`97.4 :t 0.4
`
`Terumo
`Medical
`96.2 :t 0.5
`98.0 :t 0.4
`97.4 :t 0.5
`95.9 :t 0.3
`98.3 :t 0.2
`93.9 :t 0.5
`
`216
`
`Journal of Parenteral Science & Technology
`
`Hospira, Exh. 2011, p. 6
`
`

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`
`TABLE Ill
`Average Percent of Original Diazepam Injection
`Concentration Remaining after Storage in Three Types of
`Syringes at Three Temperatures
`
`TABLE IV
`Average Percent of Original Nitroglycerin Injection
`Concentration Remaining after Storage in Three Types of
`Syringes at Three Temperatures
`
`Brand of Syringe
`
`Brand of Syringe
`
`Days at
`Degree C
`30 days at -20
`I day at -20
`7 days at 4
`1 day at 4
`1 day at 25
`0.25 day at 25
`
`Becton
`Dickinson
`86.7 :!: 0.3
`102.3 :!: 0.5
`95.1 :!: 1.3
`97.5 :!: 3.8
`94.1 :!: 4.9
`94.7 :!: 0.8
`
`Sherwood
`89.3 :!: 3.4
`99.3 :!: 4.3
`92.3 :!: 0.9
`97.9 :!: 3.2
`94.1 :!: 1.8
`96.6 :!: 1.2
`
`Terumo
`Medical
`95.8 :!: 1.0
`98.6 :!: 1.1
`96.9 :!: 2.6
`98.3 :!: 0.7
`94.1 :!: 3.0
`97.8 :!: 0.9
`
`Days at
`Degree C
`30 days at - 20
`1 day at -20
`7 days at 4
`1 day at 4
`1 day at 25
`0.25 day at 25
`
`Becton
`Dickinson
`98.5 :!: 0.2
`99.4 :!: 0.9
`95.1 :!: 0.3
`97.7 :!: 0.3
`84.9 :!: 1.5
`97.4 :!: 0.3
`
`Sheraood
`99.5 :!: 1.0
`98.4 :!: 1.3
`93.2 :!: 0.4
`97.6 :!: 0.3
`86.2 :!: 5.8
`96.7 :!: 0.5
`
`Terumo
`Medical
`98.6 :!: 0.3
`100.0 :!: 0.4
`95.6 :!: 0.8
`98.5 :!: 0.6
`90.4 :!: 4.8
`98.4 :!: 0.7
`
`adsorb and partition lipophilic drug from aqueous vehi(cid:173)
`cles.
`Plots of percentage of original concentration of drug
`against reciprocal Kelvin temperatures are reasonably
`linear. However the dependency of drug loss to temper(cid:173)
`ature relations differ in slope and sometimes in sign
`among the three brands of syringe. These variations
`serve to demonstrate the sometimes substantial differ(cid:173)
`ences in the tendency of the syringe seals to adsorb or
`partition drug from aqueous solution.
`
`Conclusion
`
`In all cases, none of the expected extractable com(cid:173)
`pounds were detected by combined gas chromatographic I
`mass spectrometric analysis nor were compounds other
`than the studied drugs or their derivatives observed in
`the samples. It appears that the drugs used in this study,
`under the conditions of exposure defined in the study
`protocol, do not extract known syringe gasket or barrel
`additive agents, reaction products, or other possibly
`deleterious compounds.
`No across-the-board differences emerge from these
`data which might suggest the syringes differ substantially
`from one another in the extent to which their compo(cid:173)
`nents alter the concentrations of drugs stored in them
`for short periods of time. However, it must be noted,
`concentrations of Iipophilic drugs in aqueous solution,
`best exemplified by dexamethasone injection, suffer
`significant depletion when extemporaneously packaged
`in syringes of the types examined in this study. It is
`
`noteworthy too that in some instances the rate of drug
`loss appeared to be accelerated at lower temperatures,
`(e.g., dexamethasone packaged in Terumo syringes)
`while in others, the rate of drug loss was greater at
`higher temperatures (e.g., diazepam stored in Becton
`Dickinson syringes).
`In summary, three brands of syringes were evaluated
`to assess the extent to which the concentrations of four
`drugs packaged in them would undergo change when
`stored at freezer, refrigerator and room temperatures.
`The same drugs in their original multiple dose vials
`served as controls. In all instances changes in concentra(cid:173)
`tion attributable to either or both sorption and partition
`into elastomeric seals were observed. A generalization
`which emerges from this study is that highly lipophilic
`drugs are lost both more rapidly and more extensively
`than are more hydrophilic materials. The advisability of
`preloading highly lipophilic drugs into polymeric sy(cid:173)
`ringes may reasonably be called into question in in(cid:173)
`stances in which substantial fractions of a unit dose of
`drug may be inadvertently lost to syringe components.
`
`Acknowledgement
`
`This study was in part supported by a grant from
`Terumo Medical Corporation to Temple University
`School of Pharmacy.
`Gas Chromatography/Mass Spectroscopy performed
`by Terumo Medical Corporation (Reference: Final Re(cid:173)
`port H013-M89, Nardone and Miripol, Terumo Medi(cid:173)
`cal Corp. Sept. 26, 1989).
`
`Vol. 45. No. 5 / September-October 1991
`
`217
`
`Hospira, Exh. 2011, p. 7