Pharmacology & Pharmacy, 2011, 2, 189-193
doi:10.4236/pp.2011.23027 Published Online July 2011 (http://www.scirp.org/journal/pp)
189
Intravenous Suitability Studies of Commonly Used
Oxacillin Sodium Solutions in the Accufuser®
Infusion Device
Min-Jeong Kim1, Ga-Young Lee2, Yoo-Sin Park3, Shin-Hee Kim3, Sang-Yeon Kim3, Min-A. Kang4,
Min-Ji Kim5, Ju-Seop Kang3
1Korean Minjok Leadership Academy, Gangwon-do, South Korea; 2Gimpo Foreign Language High School, Gimpo, South Korea;
3Department of Pharmacology & Clinical Pharmacology Lab, College of Medicine and Division of Molecular Therapeutics
Development, Hanyang Biomedical Research Institute, Hanyang University, Seoul, South Korea; 4Department of Nursing, College of
Nursing, Yonsei University, Seoul, South Korea; 5Korean International School in Beijing, Beijing, China.
Received March 23rd, 2011; revised May 20th, 2011; accepted June 22nd, 2011.
ABSTRACT
Our study compares two common ly used solutions of oxacillin sodium, 5.0 mg /mL in either 0.9% sodium chloride (NS)
or 5% dextrose water (D5W), for their continued suitability for IV usage, and stability of active compound over time,
when stored at two different controlled temperatures for six weeks. Both solutions were stored in an intravenous infu-
sion device commercially available as Accufuser® and kept at a continuously maintained temperature of either 4 ±
2˚C (CT) or 25 ± 2˚C (RT). Suitability for IV administration was assessed by mea suring changes in macrographica l
transparency and pH over time, and drug stab ility was assessed by measuring changes in oxacillin concentration over
time using high-performance liquid chromatography (HPLC). After 6 weeks, concentrations of oxacillin were un-
changed in the CT solutions, while both RT solutions showed significant decreases in the concentration of oxacillin
after only two weeks. Final concentration compared to starting concentrations after 6 weeks at RT, were 36.57% in NS,
while virtually no oxacillin was detectab le in D5W. Also pH measurements showed a slight decrement at 2 weeks with
RT and at 6 weeks, there was a significant change in pH in both NS and D5W at RT. There was no significa nt cha nge in
color, transparency or appearance after 6 weeks in any of the oxacillin solutions stored in the Accufuser® infusion de-
vice. In summary, two commonly used IV solutions for o xacillin administration
(5 mg/mL in NS or D5W) stored in the
Accufuser® showed significan t changes over time when ma intained at RT, that would make the solutions inappropriate
for therapeutic use. Both solutions when maintained in CT were not significantly altered and continu ed to be appropri-
ate in pH and drug concentration for IV therapy. This suggests that ready-to-use solutions of oxacillin sodium in the
Accufuser® infusion device can be kept at CT for up to 6 weeks safely but should not be stored at RT due to loss of po-
tency and changes in pH.
Keywords: Intravenous Suitability, Oxacillin Sod ium, Accufuser® Infusion Device, HPLC
1. Introduction
The disposable silicon balloon infusion device, Accufu-
ser® is a well-established simplified silicon-based elas-
tomeric device for administration of antibiotics and other
drugs that is suitable for patients or caregiver operation,
as well as for use by healthcare providers. An increasing
number of patients are being treated as outpatients and in
these patients, drugs are often infused using portable
pumps or infusion devices. Therefore, it is necessary that
studies determine the physical and chemical stability of
its admixtures in this infusion system before they appear
in the clinical settings [1-6]. This paper will be to pro-
vide such information with commonly used antibiotics
solutions in Accufuser® elastomeric infusion device under
recommended storage conditions. The purpose of this
study was to evaluate the intravenous suitability and
physical and chemical stabili ty of oxacillin sodium (Fig-
ure 1, 5.0 mg/mL, normal saline, NS and 5% dextrose,
D5W) solutions packaged in sterile Accufuser® device
stored and evaluated at appropriate intervals up to 6
weeks at different storage conditions with room (RT, 25

190 Intravenous Suitability Studies of Commonly Used Oxacillin Sodium Solutions in the Accufuser® Infusion Device
Figure 1. Oxacillin sodium (C19H18N3NaO5S).
± 2˚C) and cold temperature (CT, 4 ± 2˚C). The study
was performed with oxacillin sodium solution that made
with NS and D5W because these are the most available
infusion solution for oxacillin administration in clinical
situations [2, 6- 10] .
2. Materials
Oxacillin sodium was purchased from Fluka Co., Mil-
waukee, MI, USA. Normal saline (NS, 0.9% sodium
chloride in water) and 5% dextrose (D5W, injectable 5%
dextrose water) were purchased from JW Pharmaceutical
Co., Seoul, Korea. Disposable Silicone Balloon Infuser
(Accufuser®) was obtained from Woo-Young Medical
Co., LTD, Seoul, Korea. Acetonitrile and potassium pho-
sphate were purchased from Sigma-Aldrich Co., St.
Louis, MO, USA. Milli-Q water from Millipore’s Milli-
Q system (MA, USA) was used throughout the analysis.
All chemicals for HPLC analysis were all HPLC-grade
and were prepared immediately before use.
3. Preparation and Sampling of Solutions
To prepare the test samples, the appropriate amounts of
oxacillin sodium were added to a portion of the infusion
solution and then were brought to a final volume of 100
mL with N S and D5W. Th e test solutio ns were pack aged
in sterile Accufuser® device for testing. All manipula-
tions were performed in a biological safety cabinet. The
nominal oxacillin sodium concentration for testing was
5.0 mg/mL and triplicate test solutions under each
storage test conditions were prepared. The test solutions
were stored at RT and CT conditions. Aliquots were
taken from each device initially and at the intervals of 48
h, 1, 2, 4, and 6 weeks at RT and CT conditions and
determined its concentration by the HPLC method
(Table 1).
4. Methods
4.1. Physical Stability
The physical stability of the oxacillin infusion solutions
test of oxacillin Na solutions in Accufuser® device.
Table 1. Study designs based on appointed time for stability
Conditions Time
Solution 0 h48 h 1 wk 2 wks 4 wks6 wks
O*O O O O O
O O O O O O
NS
O O O O O O
O O O O O O
O O O O O O
RT
(25 ± 2˚C)
D5W
NS
CT
(4 ± 2˚C)
D5W
O O O O O O
O O O O O O
O O O O O O
O O O O O O
O O O O O O
O O O O O O
O O O O O O
O*: processed sample, RT; roommpeture,T; cotempature,
normal saline, D5W; injectable 5% dext wa
Macrographical transparency was performed in normal
consisted of an isocratic sol-
515, Waters Scientific Co.,
(inter-
tera
rose C ter. ld er NS;
was assessed by visual examination and HPLC analysis.
diffuse fluorescent room light with naked eye and a high-
intensity mono-direction al light. Th e pH of solutions was
measured with a stainless electrode pH meter (Thermo
Scientific Co., MA, USA). The drug concentrations were
determined using a stability-indicating HPLC assay me-
thod based on several literatures [2,10-13].
4.2. HPLC Method
4.2.1. HPLC- UV System
The HPLC system [2,13]
vent delivery pump (Model
Milford, MA, USA) which pumped a mixture (v/v, 35/65,
pH 3.0) of acetonitrile (ACN) in 0.05 M potassium
phosphate through a Capcell Pak C18 UG80 (3.0 × 250
mm, 3 µm, Shiseido Co., Tokyo, Japan) column at infu-
sion rate of 0.8 mL/min. The ratio of ACN to 0.05 M
potassium phosphate was 35:65 (pH 3.0) and was held
constant during a chromatographic run. The sample
volume of 2.0 µL was injected into the HPLC system
using an autosampler (Nanospace SI-2, Shiseido Co.,
Tokyo, Japan). The column effluent was monitored with
a variable wavelength ultraviolet detector (Nanospace
SI-1, Shiseido Co., Tokyo, Japan) at 220 nm. The inte-
gration of chromatogram was performed by dsCHROM®
software (Do Nam Instrument Co., Seoul, Korea).
4.2.2. Vali da ti on of the HP L C Met hod
The method was validated for linearity, precision
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Intravenous Suitability Studies of Commonly Used Oxacillin Sodium Solutions in the Accufuser® Infusion Device 191
ivity [10].
nt changes in physical appearance or cla
tions were observed during the study
concentration range of 0.5 - 7.5 mg/mL (r =
day and intra-day), accuracy, and select The
0.9998, Figure 3(a)). Table 3 lists the relative standard
deviation (R.S.D.) data obtained on analysis of the sam-
ples (n = 3) on the same day and on consecutive days (n
Table 2. Validation studies for Intra-day (n = 3) and In-
ter-day (n = 5) precision.
standard plot was con structed for oxacillin sodium in the
range of 0.5 - 7.5 mg/mL. The experiment was repeated
3 times on the same day and additionally on 2 consecu-
tive weeks to determine intra- and inter-day precisions.
Assays of control solutions at oxacillin sodium solutions
(5.0 mg/mL) were undertaken to calculate the intra-day
and inter-day variations using external standard method.
Linearity was evaluated by serial dilutions of oxacillin
sodium solutions with NS and D5W for loading. Linear
regression analysis of peak area and drug concentration
yielded a correlation >0.99 (range 0.5 - 7.5 mg/mL). The
stability of oxacillin infusion solution is determined in
disposable silicone balloon infuser (Accufuser®) dur-
ing 6 weeks of storage under RT and CT. Solutions of
oxacillin sodium with con centrations 5.0 mg/mL are pre-
pared with NS and D5W. Two kinds of oxacillin sodium
solutions are filled with 10 mL of each in three Accufu-
ser® and stored at room and cold temperature cabinets.
Then, each Accufuser® containers are filled with the
same volume of different solutions (NS and D5W) and
different temperatures (RT and CT) [1,3]. All the sam-
ples are stored at RT and CT. Periodically; the samples
are evaluated for appearance, visible particles, pH and
chromatographic parameters. We analyzed the amount of
oxacillin sodium in each two solutions at 0, 48 h, 1, 2, 4,
and 6 weeks after making solutions by HPLC-UV system
[1,7,10]. On each analysis day, 1.0 mL of samples for
chromatographic analysis with a nominal concentration
of 5.0 mg was drawn from Accufuser® device and 2.0
µL were directly injected into HPLC system for analysis.
The three aliquots of each solution were processed. Sta-
tistical analysis was performed using one-way ANOVA
with the level of significance set at 0.05 (PCS, version
4.0, Springer-Verlag, New York, USA).
5. Results
1) No significa
ity of the solur- . The
n
colors of the samples were transparent with no changes
of color. The particles are not detected in any samples.
2) Slight decrement of NS and D5W solutions in pH
from 5.56 to 5.32 and from 5.55 to 5.45 was observed i
cold storage, respectively and shown similar pattern in
NS solutions in RT conditions. But it was shown differ-
ent pattern with significan t changes in D5W solution and
reached to 3.6 at 6 weeks in the RT conditions (Table 2,
Figure 2).
3) The linearity could be established for oxacillin so-
dium in the2
RT CT
NS D5W NS D5W
Accuracy
(%) 1 1 01.01100.74 00.69100.81
Intra-day
(n = 3)
1 1 1 1
Inter-day
(n = 5)
R.S.D (%)0.91 1.23 1.37 0.94
Accuracy
(%) 01.0100.74 00.69 00.81
R.S.D (%)2.88 2.71 2.87 2.93
R tCTemper NS; saliW;
injectable 5ater
T; roomemperature,
% dextrose w; cold t . ature,normalne, D5
Figure 2. The changing plots of pH of oxacillin 5.0 mg/mL
solutions over time of storage.
. values were <1.37% and
<2.93% for intra-day and inter-day results, respectively,
lor or clarity was
tions during the
= 5). As evident, the R.S.D
meaning that the method was sufficiently precise.
4) The retention time for oxacillin sodium in the chro-
matogram was about 12.8 min. The typical HPLC chro-
matogram of oxacillin sodium (5.0 mg/mL) was shown
in the Figure 3(b). The initial concentration and th e per-
centages of oxacillin sodium on each appointed analytic
point during the study period for each solutions and a
storage condition is listed in the Table 3 and Figure 4.
The HPLC analysis showed that the amount of oxacillin
sodium was remained about initial values at CT up to 6
weeks in NS and D5W solution s. But it was significantly
decreased to 36.57% in NS solution and disappeared in
D5W solution at 6 weeks at RT.
6. Discussion and Conclusions
No visible precipitation or ch ange in co
observed in any kinds of oxacillin solu
study. We observed that the intravenous suitability and
stability of oxacillin is affected by temperature of storag e
(more stable in CT than RT) and solution (stable in NS
than D5W). When oxacillin solution is made according
to the sponser’s opinion to achieve concentrations of 50

192 Intravenous Suitability Studies of Commonly Used Oxacillin Sodium Solutions in the Accufuser® Infusion Device
(a)
(b)
Figure 3. (a) Calibration curve for the determination o
oxacillin sodium concentrat (0.5 - 7.5 mg/mL), area =
5W and analyzed oxacilli n 5.0 mg/mL
solutions after 10 times dilution of each solution that
f
ions
peak area, E = 10x; (b) Chromatogram for study solution
(NS and D5W) containing oxacillin sodium (5.0 mg/mL) AU
(absorbance units).
mg/mL in NS and D
stored in an Accufu ser® and retained 36.57% and 0.00 %
at RT up to 6 weeks, respectively. Otherwise, when ox-
acillin solution is made according to the sponser’s opin-
ion to achieve concentrations of 50 mg/mL in NS and
D5W and analyzed 5.0 mL solutions after 10 times dilu-
tion of each solution that stored in an Accufuser® and
retained 104.95% and 102.14% at RT up to 6 weeks,
respectively. Therefore, 5.0 mg/mL of oxacillin sodium
solutions of NS and D5W were stored in CT and stable
and retained about their initial concentration into Ac-
cufuser® up to 6 weeks, but shown unstable and its con-
Table 3. The changes of concentrations (mean ±SD, %) of
oxacillin in various solutions (NS and D5W) according to
storage temperature (RT and CT) and periods.
RT1) oxacillin (25 ± 2˚C) CT2) o xacillin (4 ± 2˚C)
Group
Time NS3) D5W4) NS D5W
0 h 1 1900.00 ± 0.49*100.00 ± 1.2100.00 ± 0.32 100.00 ± 0.2
48 h 100..6010101.50 98.
1 wk
2 wks
4 wks 104.
6 wks 36. 104. 102.
40 ± 00.24 ± 1.17 30 ± 0.37 ± 1.78
92.81 ± 0.47
*
71.49 ± 0.60
*
96.91 ± 0.31 98.19 ± 1.73
72.64 ± 1.29
73.29 ± 1.27*
37.28 ± 1.76
2.42 ± 0.01*
98.32 ± 0.42
106.24 ± 0.19
98.85 ± 0.50
26 ± 0.96
57 ± 14.10*0.00 ± 0.00 95 ± 1.35 14 ± 2.07
1)R temal
inje %
T: roomperature, 2)CT: cold temperatu re, 3)NS: norm saline, 4)D5W:
ctable 5 dextrose water, *Mean ±SD ( % ) , *p < 0.05 vs. 0 h.
Figure 4. The changes of amount (mean ±SD, %) of oxacil-
lin in various solutions (NS, D5W) according to storage
temperature (RT and CT) and periods.
tions for oxacillin administration (5 mg/mL in NS or
yang University and
Seoul, South Korea.
, S.
Y. Kim and J. S. Kang, “Stability of Commonly Used
centrations significantly decreased after 1 week in RT
conditions. In conclusion, two commonly used IV solu-
D5W) stored ready to use in the Accufuser® showed
significant changes over time when maintained at RT,
that would make the solutions inappropriate for thera-
peutic use. Both solutions when maintained in CT were
not significantly altered and continued to be appropriate
in pH and drug concentration for IV therapy. This sug-
gests that ready-to-use solutions of oxacillin sodium in
the Accufuser® infu sion device can be kept at CT for up
to 6 weeks safely but should not be stored at RT due to
loss of potency and changes in pH.
7. Acknowledgements
This research was supported by Han
Woo Young Medical Co. LTD.,
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Intravenous Suitability Studies of Commonly Used Oxacillin Sodium Solutions in the Accufuser® Infusion Device
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