Practice Reports  Dexmedetomidine

Stability of dexmedetomidine in polyvinyl chloride

bags containing 0.9% sodium chloride injection
Candice R. Preslaski, Scott W. Mueller, Michael F. Wempe, and Robert MacLaren

D
exmedetomidine hydrochloride
is a selective a-2-adrenoceptor
agonist, a class of metabotropic
G-protein-coupled receptors, with
sedative properties. 1 Supplied in
0.9% sodium chloride injection, dex-
medetomidine comes in a clear glass
vial, with each milliliter containing
approximately 100 mg of dexme-
detomidine (equivalent to 118 mg
dexmedetomidine hydrochloride).
The material should be stored be-
tween 14 and 30 °C, and the recom-
mended maximum concentration
when administered as a continuous
infusion is 4.0 mg/mL in 0.9% sodi-
um chloride.1 At this concentration,
the volume required to administer
the maximum labeled dosage rate
of 0.7 mg/kg/hr to patients weigh-
ing more than 155 kg exceeds 30
mL every hour.2 In heavier patients,
proprietary dosing guidelines further
demonstrate that hourly volumes
exceed 40 mL when rates approach
1.0 mg/kg/hr.2 In clinical practice and
studies in critically ill patients, maxi-
mum dosage rates often approach
Purpose. The stability of dexmedeto-
midine in polyvinyl chloride (PVC) bags
containing 0.9% sodium chloride injection
was studied.
Methods. Dexmedetomidine solutions
(4, 8, 12, and 20 mg/mL; n = 6 for each)
were prepared by removing 2, 4, 6, and
10 mL of 0.9% sodium chloride injection,
respectively, from 50-mL PVC bags and
injecting 2, 4, 6, and 10 mL of dexmedeto-
midine 100 mg/mL, respectively. To ensure
a homogeneous mixture, the contents
of each bag was manually mixed initially
and before each sample was removed.
All compounding was conducted by a
single pharmacist using aseptic technique
in a horizontal-laminar-airflow hood at 25
°C. Forced-degradation studies were con-
ducted at 70 ± 1 °C. Stability samples were
analyzed using high-performance liquid
chromatography electrospray ionization–
tandem mass spectrometry (LC/MS-MS) and
high-performance liquid chromatography–
or exceed 1.5 mg/kg/hr.3-13 At these
dosage rates, hourly infusion vol-
umes of 40–70 mL may be required
to keep patients comfortable. These
volumes of fluid, and the associated
ultraviolet-light (HPLC/UV) absorbance.
Forced-degradation samples were moni-
tored using LC/MS-MS, HPLC/UV, and gas
chromatography–MS.
Results. Dexmedetomidine solutions
were very stable at 23 ± 2 °C at all four
concentrations over the 48-hour test-
ing period. As determined via LC/MS-MS
and HPLC/UV methods, over 97% of the
initial concentration of dexmedetomidine
remained after 48 hours. Extensive HPLC/UV
active degradation products could be
observed in basic conditions; only minor
UV active degradation products were
observed in acidic, oxidative, and photo-
chemical conditions.
Conclusion. Dexmedetomidine hydrochlo-
ride 4, 8, 12, and 20 mg/mL stored in PVC
bags at 23 ± 2 °C was stable for 48 hours,
despite a slight decrease in solution pH
seen with increasing dexmedetomidine
concentrations.
Am J Health-Syst Pharm. 2013; 70:1336-41
sodium chloride solution required to
dilute dexmedetomidine, become a
concern since critically ill patients are
commonly fluid restricted for vari-
ous reasons. Similar challenges exist

Candice R. Preslaski, Pharm.D., is Clinical Pharmacist Specialist,
Surgical Intensive Care Unit, Denver Health Medical Center, Denver,
CO. Scott W. Mueller, Pharm.D., is Assistant Professor, Depart-
ment of Clinical Pharmacy; Michael F. Wempe, Ph.D., is Associate
Research Professor, Department of Pharmaceutical Sciences, and
Director, Medicinal Chemistry Core Facility, Department of Phar-
maceutical Sciences; and Robert MacLaren, Pharm.D., is Associate
Professor, Department of Clinical Pharmacy, Skaggs School of Phar-
macy and Pharmaceutical Sciences, University of Colorado, Aurora.
Address correspondence to Dr. MacLaren at the Department of
Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical
Sciences, University of Colorado, 12850 East Montview Boulevard,
C238, Aurora, CO 80045 (rob.maclaren@ucdenver.edu).
Supported by an investigator-initiated research grant from Ho-
spira. Proprietary dexmedetomidine hydrochloride (Precedex) was
provided by Hospira. Research was conducted using services of the
Medicinal Chemistry Core (MCC) facility housed within the Depart-
ment of Pharmaceutical Sciences at the University of Colorado. The
MCC receives funding from Colorado Clinical and Translational
Sciences Institute grant 5UL1RR025780 from the National Center for
Research Resources at the National Institutes of Health.
The authors have declared no potential conflicts of interest.
Copyright © 2013, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/13/0801-1336$06.00.
DOI 10.2146/ajhp120390

1336 Am J Health-Syst Pharm—Vol 70 Aug 1, 2013


in the pediatric population, in which
the administration of volume and
sodium chloride solution requires
special attention.
The purpose of this study was to
assess the stability of dexmedetomi-
dine at room temperature when pre-
pared at 4, 8, 12, and 20 mg/mL with
0.9% sodium chloride in polyvinyl
chloride (PVC) bags.
Methods
Sample preparation. Dexmedeto-
midine solutions (4, 8, 12, and 20 mg/
mL; n = 6 for each) were prepared
by removing 2, 4, 6, and 10 mL of
0.9% sodium chloride injection, a
respectively, from 50-mL PVC bags
and injecting 2, 4, 6, and 10 mL of
dexmedetomidine 100 mg/mL,b re-
spectively. To ensure a homogeneous
mixture, the contents of each bag was
manually mixed initially and before
each sample was removed. All com-
pounding was conducted by a single
pharmacist using aseptic technique
in a horizontal-laminar-airflow hood
at 25 °C. The environmental condi-
tions met United States Pharmacopeia
chapter 797 criteria for compound-
ing sterile preparations.14 Two-milliliter
samples from each PVC bag were re-
moved initially and at 4, 8, 12, 24, and
48 hours after mixing. To avoid the
potential of nonspecific plastic bind-
ing, glass syringes were used to trans-
fer volumes and remove samples. All
samples were transferred into 4-dr
glass vialsc and stored at –20 ± 3 °C;
thereafter, samples were removed in
sets, warmed to room temperature,
mixed, sampled, and analyzed.
Analytic methodology. High-
performance liquid chromatograph-
ic methods. The study samples
were analyzed using two analytic
techniques: high-performance liq-
uid chromatographic (HPLC) elec-
trospray ionization–tandem mass
spectrometry (LC/MS-MS) d and
HPLC–ultraviolet-light (HPLC/UV)
detection.e The LC/MS-MS method
used an extended C18, 50 × 4.6-mm,
5-mm columnf at 40 °C with a flow
Practice reports  Dexmedetomidine
rate of 0.4 mL/min equipped with
a column guard. The chromatog-
raphy method used was as follows:
95% 10 mM ammonium acetateg
and 0.1% formic acid h in water i
for 1.0 minute, then to 95% 50:50
acetonitrilej:methanolk at 3.0 min-
utes and held for 1.5 minutes, and
then brought back to 95% 10 mM
ammonium acetate and 0.1% formic
acid in water at 5.5 minutes and held
for 1.0 minute (total run time, 6.5
minutes). Dexmedetomidine and
medetomidine- d 3 (internal stan-
dard)l were monitored via electro-
spray ionization positive-ion mode
using an ion-spray voltage of 5500
V and a temperature of 450 °C. Ni-
trogen was used as the curtain gas
and collision-activated dissociation
gas. Ion source gas 1 and 2 were set
at 30, the entrance potential was set
at 10.0 V, and quadruple 1 and 2 were
set on unit resolution with a dwell
time of 200 milliseconds. Stability
study samples (n = 36 per time point;
each sample was analyzed six times)
were analyzed using LC/MS-MS. The
HPLC/UV method used the same
column type as described for the
LC/MS-MS method, but the flow
rate was 0.6 mL/min. The mobile
phase was the same used in the
LC/MS-MS methods. Detection
was monitored using a wavelength
of 270 nm, and the gradient condi-
tions were as follows: 95% 10 mM
ammonium acetate and 0.1% formic
acid in water for 1 minute, then to
95% 50:50 acetonitrile:methanol at
6.0 minutes and held for 5.5 minutes,
and then brought back to 95% 10
mM ammonium acetate and 0.1%
formic acid in water at 13.5 minutes
and held for 2.0 minutes (total run
time, 15.5 minutes). Study samples
(n = 24 per time point; each sample
was analyzed four times) were
analyzed using HPLC/UV detec-
tion. Color change and precipitation
were visually evaluated against light
and dark backgrounds. A calibrated
pH meterm was used to determine
solution pH at room temperature
Am J Health-Syst Pharm—Vol 70 Aug 1, 2013
for each sample at the denoted time
intervals.15 In addition, the interday
analytic variability of the LC/MS-MS
and HPLC/UV methods was assessed.
In the case of LC/MS-MS, an
11-point linear standard curve
was prepared from stock dexme-
detomidine solutions using solid
dexmedetomidine standard; solu-
tions were subsequently and seri-
ally diluted with a 4:1 mixture of
methanol:acetonitrile, 1:1 mixture
with; water) spiked with the internal
standard to afford dexmedetomidine
concentrations ranging between 0.02
and 125.0 ng/mL. The standard curve
data were prepared in quadruplicate
from four vials of dexmedetomidine
and fitted to a 1/x2 weighted linear
regression (R2 = 0.9923) with a limit
of detection of 0.02 ng/mL.
The second quantitative analytic
method was HPLC/UV (wavelength,
270 nm). Fifteen-point standard
curves were prepared from stock
dexmedetomidine solutions using
solid dexmedetomidine standard.
The standard curve data displayed
a linear regression with a level of
detection of 5.0 mM (1001 ng/mL)
(R2 = 0.9997).
Forced-degradation studies.
Forced-degradation studies were
conducted used a reciprocal shaking
water bath,n UVP shortwave (254
nm) UV lampo (115 V, 60 Hz, 0.16
amps), and gas chromatograph–
m a s s s p e c t ro m e t e r. p T h e g a s
chromatograph–mass spectrom-
eter was equipped with an Rtx-5MS
column.q The column temperature
was initially set at 40 °C with an
injector temperature of 250 °C; the
temperature was held at 40 °C for
1.0 minute and then ramped at 10
°C/min to 200 °C and held for 20
minutes. The ion source temperature
was set at 200 °C and the interface at
275 °C. Mass was scanned from 100
to 500 m/z from 7.0 to 27.0 minutes
with the scan speed set at 2500 and
operated in the split mode (set at
10). High-grade helium was used as
the carrier gas with a pressure of 9.9
1337
 Practice Reports  Dexmedetomidine

psi, total flow rate of 13.0 mL/min, dative (hydrogen peroxideu 10–30%), to generate robust data to confirm
column flow rate of 1.0 mL/min, and photochemical conditions of and monitor dexmedetomidine
linear velocity of 36.1 cm/sec, and continuous short-wave (270 nm) en- concentrations (Figures 1–3). For
purge flow rate of 2.0 mL/min. The ergy exposure. Degradation samples LC / M S - M S , the retention times
proton-nuclear magnetic resonance were analyzed using LC/MS-MS, for dexmedetomidine and the inter-
NMR spectra were collected using a HPLC/UV, and gas chromatography– nal standard were almost identical
400 MHz NMR imager.r mass spectrometry (GC/MS). (3.7–3.9 minutes) (Figure 2). In
Forced degradation. Extensive the case of the LC/MS-MS method,
forced-degradation experiments Results and discussion 10-mL samples were injected onto
were also conducted. Samples of The purity of the provided solid the column. The study samples (4,
dexmedetomidine solutions were dexmedetomidine was confirmed as 8, 12, and 20 mg/mL) were serially
probed at room temperature and over 99% pure by NMR, GC/MS, and diluted to afford solutions—based
at 70 ± 1 °C under neutral, acidic HPLC/UV analyses. on the initial concentrations—to
(0.25–6.0M hydrochloric acids), basic LC/MS-MS versus HPLC/UV. hypothetically contain 12.5, 25, 50,
(0.25–6.0M sodium hydroxidet), oxi- Two analytic methods were used and 100 ng/mL, respectively. In the
HPLC/UV method, 100-mL samples
were injected into the column. The
retention time for dexmedetomidine
Figure 1. Representative dexmedetomidine standard curves using high-performance hydrochloride was 5.7–6.3 minutes.
liquid chromatography–electrospray ionization–tandem mass spectrometry (A) and
high-performance liquid chromatography–ultraviolet light (B). AUC = area under the
Extensive HPLC/UV (wavelength,
concentration–time curve. 270 nm) active degradation products
were observed via basic conditions
A at 2 and 48 hours, while only minor
1.2 × 107 UV-light active degradation products
Intensity (counts per second)

were observed via acidic, oxidative,

1.0 × 107 and photochemical conditions.
In addition, freeze–thaw (–80 ±
8.0 × 106 10 °C to room temperature) experi-
ments found that the dexmedetomi-
6.0 × 106
dine solutions were stable for at least
4.0 × 106 three freeze–thaw cycles.
The use of LC/MS-MS in this
2.0 × 106 study had advantages and disad-
vantages. The LC/MS-MS system
0 contained a cool stack (6 ± 1 °C)
0 20 40 60 80 100 120 and could house six 96-well plates.
Concentration (ng/mL) This format afforded a robust high-
throughput analytic technique. The
B disadvantage was that samples re-
1.3 × 106 quired dilution in order to be within
the linear range of the LC/MS-MS
standard curve.
Absorbance (Peak AUC)

1.0 × 106
The HPLC/UV system also had
advantages and disadvantages. The
7.5 × 105 system had a vial sample holder
(holding up to 105 vials) but was not
5.0 × 105 temperature controlled, which can be
a serious disadvantage when materi-
als are not stable at room tempera-
2.5 × 105
ture. Furthermore, medetomidine-d3
was not used as an internal standard,
0 as the retention time was analogous
50 125 200 275 350 425 500
to that of dexmedetomidine. One
Concentration (mM)
major advantage of this method was

1338 Am J Health-Syst Pharm—Vol 70 Aug 1, 2013

 Practice reports  Dexmedetomidine

that samples removed from the PVC between the protonated dexmedeto- tration used is dictated by the ac-
bags did not require serial dilution midine form dissolved in solution ceptable or desired i.v. solution pH.
before analysis. to a higher concentration of free For instance, different 0.9% sodium
Stability at room temperature. base to liberate a greater quantity chloride injections (e.g., different
Samples were analyzed by LC/MS- of protons. Regardless of the slight lots, vendors, or storage conditions)
MS and HPLC/UV methods, and pH change, all solutions remained resulted in different initial pH val-
both techniques illustrated that dex- clear, and no particulate matter ues (ranging from 4 to 7 as listed
medetomidine was stable in 0.9% was apparent via visual inspection. on the i.v. bags). For example, when
sodium chloride injection stored Dexmedetomidine possesses high the initial saline pH was 5.0, the pH
in PVC bags at 23 ± 2 °C at all four aqueous solubility, so the concen- values of the original solution were
concentrations over the 48-hour
study period (Table 1). Greater
than 97% of the initial dexmedeto-
midine concentrations remained. Table 1.
Chromatographic peaks observed Stability of Dexmedetomidine Hydrochloride
during forced-degradation studies in Forced-Degradation Studies
(Figure 3) were not detected in any
of the analyzed study samples. The Mean ± S.D. Initial Concentration Remaining, %
pH decreased slightly (i.e., solution Degradation Condition 2 Hr 10 Hr 24 Hr 36 Hr 48 Hr
became more acidic) over the 48- Water, 70 °C 97 ± 2 94 ± 1 89 ± 1 87 ± 2 86 ± 1
hour study period with increasing Hydrochloric acid, 70 °C 100 ± 1 98 ± 1 95 ± 2 92 ± 1 90 ± 1
dexmedetomidine concentrations. Sodium hydroxide, 70 °C 87 ± 3 80 ± 1 31 ± 2 23 ± 3 10 ± 2
The slight pH change was likely at- Hydrogen peroxide, 70 °C 92 ± 2 68 ± 3 25 ± 3 15 ± 2 11 ± 1
tributable to an equilibrium shift Water/hν, 38 ± 2 °C 87 ± 4 81 ± 2 65 ± 2 52 ± 3 48 ± 2

Figure 2. Dexmedetomidine and internal standard high-performance liquid chromatography electrospray ionization–tandem mass
spectrometry chromatogram.

231
5.0e6
4.8e6
Dexmedetomidine
4.6e6
4.4e6
4.2e6
4.0e6
3.8e6
Intensity (counts per second)

3.6e6
3.4e6
3.2e6
3.0e6
2.8e6
2.6e6
2.4e6
2.2e6
2.0e6
1.8e6
1.6e6
1.4e6
1.2e6
1.0e6
8.0e5
6.0e5
4.0e5
2.0e5 Medetomidine-d3
0.0
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6
Time (min)

Am J Health-Syst Pharm—Vol 70 Aug 1, 2013 1339

1340
Figure 3. Dexmedetomidine chromatograms prepared using 6.0 M sodium hydroxide and heated at 70 °C for 2 (A) and 48 (B) hours.

A
75

50

25

Absorbance (mAU)
0

Am J Health-Syst Pharm—Vol 70 Aug 1, 2013

Practice Reports  Dexmedetomidine

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time (min)
B

80

60

40

Absorbance (mAU)
20

0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time (min)

5.8, 6.2, 6.3, and 6.4 for the prepared
dexmedetomidine solutions (4, 8,
12, and 20 mg/mL, respectively). The
stock dexmedetomidine injection as
100-mg/mL standard solution had a
pH of 5.7 ± 0.1. As expected, the final
solution pH was dictated by the pH
and buffering capacity of the initial
i.v. solution.
Conclusion
Dexmedetomidine hydrochloride
4, 8, 12, and 20 mg/mL stored in PVC
bags at 23 ± 2 °C was stable for 48
hours, despite a slight decrease in
solution pH seen with increasing
dexmedetomidine concentrations.
a
0.9% sodium chloride injection in PVC
bags, Baxter. Deerfield, IL, lot P257063.
b
Dexmedetomidine injection, 100-mg/mL
standard solution, Hospira, Lake Forest, IL,
lots 09-199-DK and 03-187-DK.
c
Fisher Scientific, Pittsburgh, PA.
d
Sciex 4000, Applied Biosystems, Foster
City, CA (includes Shimadzu HPLC, Shimadzu
Scientific Instruments, Columbia, MD, and
LEAP autosampler, LEAP Technologies,
Carrboro, NC).
e
Analytic HPLC system (LC-20AB, DGU-
20A, CTO-20A, Sil-20A HT) and SPD-20A
ultraviolet–visible-light detector, Shimadzu.
f
Zorbax, Agilent Technologies, Santa Clara,
CA.
g
Ammonium acetate, Sigma-Aldrich
Chemical Company, St. Louis, MO.
h
Formic acid, Sigma-Aldrich.
i
HPLC-grade water, Fisher Scientific.
j
HPLC-grade acetonitrile, Fisher Scientific.
Practice reports  Dexmedetomidine
k
HPLC-grade methanol, Fisher Scientific.
l
Medetomidine-d3-hydrochloride, Toronto
Research Chemicals, Toronto, Ontario, Cana-
da, lot 2-GJR-98-2.
m
AR15, Fisher Scientific.
n
Model 25, Precision Scientific, Chicago, IL.
o
Model UVG-54, UVP, Upland, CA.
p
GC/MS-QP2010 gas chromatograph–
mass spectrometer, Shimadzu.
q
Restek Corporation, Bellefonte, PA.
r
400 MHz Bruker NMR, Avance III,
Fremont, CA.
s
HPLC-grade hydrochloric acid, Fisher
Scientific.
t
HPLC-grade sodium hydroxide, Fisher
Scientific.
u
HPLC-grade hydrogen peroxide, Fisher
Scientific.
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1. Precedex (dexmedetomidine hydro-
chloride injection) package insert.
www.precedex.com (accessed 2011 Feb
24).
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ICU sedation. www.precedex.com/dosing
(accessed 2011 Feb 24).
3. Dasta JF, Kane-Gill SL, Durtschi AJ.
Comparing dexmedetomidine prescrib-
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macother. 2004; 38:1130-5.
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updated focused review of dexmedetomi-
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5. Popat K, Purugganan R, Malik I. Off-label
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1341