Original Article

Microbiological and Physicochemical Stability

of Fentanyl and Sufentanil Solutions
for Patient-Controlled Delivery Systems
Sophie Chapalain-Pargade, PharmD, Isabelle Laville, PharmD,
Angelo Paci, PharmD, PhD, Elisabeth Chachaty, BiolD, Lionel Mercier,
and Philippe Bourget, PharmD, PhD
Departments of Clinical Pharmacy (S.C.-P., I.L., A.P., L.M., P.B.) and Medical Microbiology (E.C.),
Institut Gustave-Roussy, Villejuif, France
Abstract
The aim of this study was to assess the microbiological and physicochemical stability of opioid
solutions containing fentanyl or sufentanil and thereby determine the feasibility of extending
the expiration dates after mixing. Five systems containing fentanyl or sufentanil solutions at
50 mg/mL in portable patient-controlled analgesia (PCA) systems were lled and stored at
room temperature for 14 days. They were sampled immediately after preparation, at day 3,
and each day of the following weeks. Microbiological stability was assessed by performing
sterility tests. The physicochemical study was performed by determining aspect, pH, and
osmolality evolution. All samples were tested for appearance, change in color, and loss
of concentration using an analytical method. There was no signicant change in pH
and osmolality values of any solutions. No precipitation or change in color was observed in
any of the sample solutions. There was no signicant loss of fentanyl or sufentanil over
14 days (4.3% and 4.1%, respectively). This study indicates that both drug solutions in the
PCA systems are stable for a minimum of 14 days at room temperature. J Pain Symptom
Manage 2006;32:90--97. 2006 U.S. Cancer Pain Relief Committee. Published by
Elsevier Inc. All rights reserved.
Key Words
Analgesics, microbiological stability, physicochemical stability, patient-controlled delivery
system, quality assurance, clinical pharmacy
Introduction
The Gustave-Roussy Institute is one of the
largest European centers for cancer research
and therapy. This position has inspired the
launch of a novel program to improve the
management of patient pain syndromes. Ini-
tiatives and actions have been conducted since
1999 by a Strike Against Pain committee in
which the Department of Clinical Pharmacy
participates actively. The Department of Com-
plementary Care, created in 2002, determines
the methodologies and policies for dealing
with various cancers. For the management of
painful syndromes, our objective is to facilitate
Address correspondence to: Angelo Paci, PharmD, PhD,
Department of Clinical Pharmacy, Institut Gustave-
Roussy 39, rue Camille Desmoulins, 94805 Villejuif
Cedex, France. E-mail: apaci@igr.fr
Accepted for publication: January 18, 2006.
2006 U.S. Cancer Pain Relief Committee
Published by Elsevier Inc. All rights reserved.
0885-3924/06/$--see front matter
doi:10.1016/j.jpainsymman.2006.01.006
90 Journal of Pain and Symptom Management Vol. 32 No. 1 July 2006
access to major analgesics as often as
necessary.
The regular administration of oral analge-
sics, given according to the World Health
Organization guidelines, is the mainstay of
cancer pain treatment.
1,2
However, patients
suffering from malignancies that may be re-
fractory to treatment by conventional oral ther-
apy frequently require opioids administered
via the parenteral or epidural routes.
3
Pa-
tient-controlled analgesia (PCA), introduced
in 1970,
4
allows patients to self-administer bo-
lus doses or to maintain a continuous ow of
analgesics. External portable infusion pumps
offer exibility for patients, increase the possi-
bilities for treatment at home, and may in-
crease the comfort of the patient with regard
to drug administration in syringes. Portable
pumps for PCA administration deliver the
active drug contained in a plastic container
made of polyvinyl chloride (PVC).
Fentanyl and sufentanil are high-potency
opioid drugs widely used for anesthesia and
analgesia in both adults and children with can-
cer pain.
5--8
Fentanyl citrate and sufentanil cit-
rate injections are commonly used in portable
infusion pumps. To ensure that the intact
drug is delivered to the patient, it is important
to study the stability and the compatibility of
these drugs with the reservoir and tubing in
the delivery devices. These questions have
been widely studied for morphine hydrochlo-
ride,
9--14
but very fewstudies have beenreported
for fentanyl or sufentanil.
15--18
Most of the latter
studies have evaluated the compatibility of
sufentanil with either ropivacaine or levobupi-
vacaine.
19--22
Furthermore, only a few authors
have investigatedbacteriologic problems associ-
ated with long-duration infusions of opioids in
cancer patients treated at home.
23,24
The commercially available formulations,
which contain 50 mg/ml of active drug, are
placed without any dilution in the drug reser-
voirs. The drug concentration should not
drop below the ofcial compendial require-
ment of 90%
25
of the labeled amount of active
substances. Interactions between drugs and
plastic infusion bags or intravenous adminis-
tration sets have been well documented,
26
and it is possible that drug losses may lead to
decreased delivery of drug to the patient, and
hence to a potentially decreased therapeutic
response. It has been demonstrated that 5%
dextrose or 0.9% NaCl solutions of fentanyl
are stable for 48 h in PVC infusion bags,
15
and that fentanyl and sufentanil solutions at
low temperatures (20

C and 4

C) remain
stable for 30 days according to Allen et al.
17
and for 20 days according to Roos et al.
18
Based on these limited data and the lack of mi-
crobiological evaluation, we arbitrarily xed
a 7-day expiration period for PCA solutions
containing either of these drugs.
To guarantee the pharmaceutical quality
of the aforementioned preparations up until
their dispensation and to extend their expira-
tion periods to 14 days, we performed microbi-
ological and physicochemical stability studies
of fentanyl and sufentanil solutions stored in
PVC containers. The analytical technique al-
lows the routine quality control (QC) of man-
ufactured PCA drug delivery system units using
a drug retention factor and the measurement
of each active substances concentration.
Methods
Materials
The pharmaceutical solutions used were
Fentanyl Merck

(Merck, Fontenay-sous-Bois,
France) containing 500 mg of fentanyl base
(785 mg of fentanyl citrate) in 10 mL 0.9%
NaCl solution adjusted to pH 4.4 with sodium
hydroxide, and Sufenta

(Janssen-Cilag, Issy-
les Moulineaux, France) containing 250 mg of
sufentanil base (375 mg of fentanyl citrate) in
5 mL 0.9% NaCl solution adjusted to pH 5.6
with sodium hydroxide and hydrochloric
acid. Both pharmaceutical products do not
contain any preservatives.
The solutions were transferred to a 100-mL
medication cassette reservoir for CADD-1

and CADD-PRIZM

(Pharmacia-Deltec, St.
Paul, USA) pumps under aseptic conditions.
These cassettes consist of medical-grade PVC
infusion bags with an inner layer of phthalate
ester placed in a light-protecting polycarbonate
reservoir and a Luer-Lock

PVC tube with the

plasticizer di-(2-ethylhexyl)phthalate. Each vol-
ume of solution was taken by means of two
50 mL syringes and transferred without dilu-
tion for 50 mg/mL solutions. For the 30 mg/
mL fentanyl solutions, the volume of active sub-
stance was diluted after transfer in 0.9% NaCl.
After homogenization, the residual air was evac-
uated by the use of the same syringes.
Vol. 32 No. 1 July 2006 91 Stability of Fentanyl and Sufentanil PCA Solutions
Microbiological Study
Validation of the Absence of Antimicrobial Activity.
According to the General Methods of the
European Pharmacopoeia 5th edition,
27
a pre-
liminary microbial growing test is necessary to
determine the presence, or the absence, of an-
timicrobial activity of studied active substances.
This test was carried out for four microbial
strains: Staphylococcus aureus (ATCC 6538, CIP
4.83), Pseudomonas aeruginosa (ATCC 9027,
CIP 82.118), Clostridium sporogenes (ATCC
19404, CIP 79.3), and Candida albicans
(ATCC 10231, CIP 48.72). This test compares
the fertility of thioglycolate broth (TGB) and
trypticase soy broth (TSB) with or without
the studied active substance. These broths al-
low the growth of anaerobic and aerobic bacte-
ria as well as yeasts. S. aureus, P. aeruginosa, and
C. albicans were seeded in TSB, and Clostridium
sporogenes was seeded in TGB. Three series
were prepared: 1) 5 mL of a 50 mg/mL fentanyl
solution was added into each broth, 2) 5 mL
of a 50 mg/mL sufentanil solution was added
into each broth, and 3) no substance was
added in the third series, which acts as the
sterility control. Inoculated broth culture was
incubated at 35

C for 48 h.
Sterility Test. Eighteen infusion bags in PCA
delivery systems were manufactured under
aseptic conditions for this study. Investigators
wearing surgical masks, caps, overshoes,
gowns, and sterile gloves prepared cassettes
on a clean class-100 vertical laminar-airow
bench. Six bags were made from the 50 mg/
mL fentanyl solution, six from the 30 mg/mL
fentanyl solution, and six from the 50 mg/mL
sufentanil solution. The cassettes were stored
for a period of 28 days under three different
temperature conditions: two of each active
substance group (i.e., 6 cassettes) were placed
at 4

C, two of each at ambient temperature
(25

C), and two of each under warm condi-
tions (35

C). A 5 mL volume of each infu-
sion bag was aseptically sampled on days D0,
D14, and D28 and directly seeded into TGB
and TSB. Negative controls were performed
with distilled water to guarantee the absence
of interference caused by the handling condi-
tions. An incubation time of 14 days set be-
tween 20

C and 35

C is recommended
by the European Pharmacopoeia to allow the
development of bacteria and fungi.
Physicochemical Study
pH, Weight, and Osmolality Evolution. A physi-
cochemical study was conducted on the same
18 infusion bags (i.e., six cassettes for each stor-
age condition). Each bag was weighed before
and after each sampling day (D0, D14, and
D28) to indicate the possible loss of solvent. Ac-
cording to Stiles et al.,
12
this phenomenon is
a function of both time and temperature, par-
ticularly at 35

C. A visual control of each cas-
sette and each sample against light was
conducted to determine any change of aspect,
i.e., color, limpidity, or appearance of turbidity.
Osmolality measurements were performed on
an automatic osmometer (Roebling, Messtech-
nik, Germany), and pH measurements were
recorded on a pH-meter (Metrohm 713,
Courtaboeuf, France).
Analytical Validation. According tothe note for
guidance on validation of analytical methods
written by the International Conference of Har-
monization (ICH topic Q2A and Q2B),
28,29
the
validation of an analytical technique requires
demonstration of linearity, accuracy, precision,
measurement range limits (limit of quantica-
tionor LQandlimit of detectionor LD), robust-
ness, and system suitability. According to the
USP XXV,
30
for quantitation of the active sub-
stance in hospital chemotherapeutic infusion
bags, which is a nished pharmaceutical prod-
uct, the data elements required for assay valida-
tion and analytical performance are selectivity
(specicity), linearity and range, accuracy, and
precision.
Calibration function. The calibration func-
tion (relationship between peak area and the
amount of substance applied) was determined
by linear regression over a previously dened
range. Each calibration curve was validated us-
ing two QC: the low QC (QC
L
) corresponds to
the midpoint of the rst and the second stan-
dard, and the high one (QC
H
) corresponds
to the midpoint of the fourth and the last
standard.
Accuracy. The accuracy of the method, which
gives information about the recovery of the
92 Vol. 32 No. 1 July 2006 Chapalain-Pargade et al.
analyte from the sample, was conrmed by
analysis using in-system calibration of sample
solutions of known substance content. The so-
lutions were spiked with three different known
concentrations of each substance, which were
assigned low, medium, and high QC values
(QC
L
, QC
M
, and QC
H
). The analysis of each
QC sample was repeated six times.
Precision. Inaccordance withICHguidelines,
precision contains three components: repeat-
ability, intermediate precision, and reproduc-
ibility. Here, the last-named was not studied.
Repeatability. Repeatability expressed as the
relative standard deviation (RSD), or coef-
cient of variation of repeatability (CV
r
), consists
of multiple measurements of a homogenous
sample according to the same analytical proce-
dure with the same equipment and in the
same laboratory. The analysis of each QC
sample was repeated six times.
Intermediate Precision. Intermediate preci-
sion evaluates the reliability of the method in
an environment different than that used dur-
ing development of the method. Determina-
tion, expressed as the RSD, or coefcient of
variation of intermediate precision (CV
i
), con-
sists of multiple measurements (n 6) of each
recommended level studied, i.e., QC under
the same analytical conditions, but on multi-
ple days, by different analysts and different
equipment with the exception of the high-per-
formance liquid chromatography (HPLC)
system.
Concentration Evolution Study. Ten infusion
bags in PCA delivery system were aseptically
manufactured especially for this study. Five
were made of 50 mg/mL fentanyl solution
and ve of 50 mg/mL sufentanil solution.
The cassettes were stored for a period of 14
days at room temperature conditions
(25

C). A 2-mL volume of each infusion
bag was aseptically sampled by the use of a poly-
propylene syringe and collected into 5-mL
glass tubes on days D0, D3, and D7--D14. All
samples were diluted with the mobile phase
to reach the target concentration of 12.5 mg/
mL. Calibration curves consisting of six points
in the range of 0--25 mg/mL for both fentanyl
and sufentanil were constructed on each
sampling day for quantitation purposes. An an-
alytical runconsistedof 10 samples (ve for fen-
tanyl and ve for sufentanil) analyzed twice.
Two QC solutions were assayed before and af-
ter each run. Diluted sample, 200 mL, was in-
jected into a chromatographic system using
a xed loop of 100 mL. All samples were ana-
lyzed by HPLC coupled with ultraviolet absor-
bance detection. The HPLC system consisted
of an isocratic pump (Jasco

PU-980, Tokyo,
Japan), an automatic sampler (Perkin-Elmer

ISS 100, Uberingen, Germany), an integra-

tor--recorder (Shimadzu

C-R6A, Kyoto,
Japan), and a UV--visible detector (Jasco

UV-975, Tokyo, Japan) set at 225 nm and an

HPLC column (Lichrospher

100 RP18 5 mm
250 4 mm; Merck, Fontenay-sous-Bois,
France) with a precolumn (Lichrospher

100
RP18 5 mm 8 4 mm; Merck, Fontenay-sous-
Bois, France). The mobile phase was a mixture
of 36.4% methanol, 36.4% acetonitrile, and
27.2% demineralized water (v/v/v) containing
0.01 M of ammonium acetate. The ow rate
was set to 1.2 mL/min resulting in retention
times of 4.2 min for fentanyl and 6.3 min for
sufentanil.
Results
Microbiologic Study
Validation of the Absence of Antimicrobial Activity.
Culture broth supplemented with fentanyl or
sufentanil solution was found to allow growth
of each of the four reference strains tested
with the same delays and intensities as that ob-
served with free control broth. No difference
of cloud or tint appeared after incubation.
Sterility Test. Cultures of the 18 fentanyl and
sufentanil solutions from infusion bags were
negative for the period of the study (28 days),
except for the D14 sample of the fentanyl
citrate infusion bags.
Physicochemical Study
pH, Weight, and Evolution of Osmolality. As
shown in Table 1, a loss of vehicle (i.e., sol-
vent) was observed over 28 days, which in-
creased with increasing temperature. A loss
of up to 1% per month of drug substances
was observed in the fentanyl and sufentanil
Vol. 32 No. 1 July 2006 93 Stability of Fentanyl and Sufentanil PCA Solutions
solutions in portable infusion pumps when
stored at 4

C and at room temperature. Af-
ter one month, 3.7% and 4.6% losses were ob-
served at 35

C for fentanyl and sufentanil
citrate solutions, respectively. This phenome-
non of evaporation leads to an increase of
drug concentrations already described in pub-
lished data for morphine in portable reservoir
pumps.
13,14
No change in color or apparent
precipitation was observed during 28 days in
any of the samples whatever the storage
conditions.
The fentanyl and sufentanil solutions osmo-
lality values slightly decreased (always below
10%) for the solutions stored at 4

C and
25

C, as shown in Table 2. According to the
loss of vehicle observed at 35

C, the osmolal-
ity values were found above the initial measure-
ments (up to 11.5%) for those stored at 25

C.
As shown in Table 3, the pH values remained
stable, although there were some variations
that caused an acidication of solutions, par-
ticularly for sufentanil portable infusion
pumps stored at 35

C.
Analytical Validation
Calibration. The calibration function was de-
termined by linear regression over the range
0--25 mg/mL for both active substances with
a target concentration of 12.5 mg/mL. Mean
equation of the linear regression study
is y 48459 (x) 3269 for fentanyl with
a mean r
2
calculated at 0.9971 and
y 111112 (x) 24963 for sufentanil with
a mean r
2
calculated at 0.9985. These equa-
tions allow the determination of concentra-
tions for each sample of fentanyl and
sufentanil solutions.
Accuracy. The results show the accuracy of
the method according to the mean values,
close to the theoretical amount, and the RSD
values, below 1%, calculated from the six anal-
yses for each QC. In view of the calculated av-
erage concentrations, with regard to the
theoretical value and of their dispersal, the an-
alytical technique is considered exact.
Precision. The CV values for repeatability
(CV
r
) and for intermediate precision (CV
i
)
for each active substance, with the exception
of one value, i.e., the CV
i
of QC
L
found to be
8.1%, were below 5.0% for intermediate
precision and repeatability.
Limit of Detection--Limit of Quantication.
The limit of detection (LD) and the limit of
quantication (LQ) of the technique for
Table 1
Weight Values of Infusion Pumps
Mean Weight
Weight Loss
over 28 Days (%)
(g) RSD 4

C 25

C 35

C
Fentanyl 50 162.3 1.03 0.6 0.9 3.7
Fentanyl 30 163.5 1.10 0.3 1.2 4.5
Sufentanil 50 163.5 1.10 1.2 0.9 4.6
Table 2
Osmolality Values of Solutions
Mean Osmolality
Values RSD
Osmolality Variations
over 28 days (%)
4

C 25

C 35

C
Fentanyl 50 J0 299 301 301
J28 280 287 314
D (variation %) 19 (6.4%) 14 (4.6%) 16 (5.3%)
Fentanyl 30 J0 286 286 286
J28 277 289 319
D (variation %) 9 (3.1%) 3 (3.0%) 33 (11.5%)
Sufentanil 50 J0 287 286 287
J28 270 275 320
D (variation %) 17 (5.9%) 11 (3.8%) 33 (11.5%)
Table 3
pH Values of Solutions
Mean pH
Values RSD
pH Variations
over 28 Days (%)
4

C 25

C 35

C
Fentanyl 50 4.88 0.02 2.9 3.8 4.4
Fentanyl 30 4.96 0.06 1.1 1.1 1.5
Sufentanil 50 5.57 0.02 3.1 3.3 6.1
94 Vol. 32 No. 1 July 2006 Chapalain-Pargade et al.
each active substance were obtained by use of
the slope (b) and the standard deviation of the
intercept (S.D.a) from six calibration curves
determined by linear regression, as dened
by the ICH TOPIC Q2B. The limit of detection
(LD 3.3 S.D.a/b) was 0.9 mg/mL and the
limit of quantication (LQ 10 S.D.a/b)
2.8 mg/mL for both substances. The method
is then completely adapted to the quantitation
of the drug substances under study.
Concentration Evolution Study. Concentrations
of fentanyl and sufentanil were calculated
through the integration of the surface areas
of chromatographic peaks. Mean equation of
the six linear regressions used for the concen-
tration evolution study was y 46242(x)
5093 for fentanyl and y 109034(x) 33956
for sufentanil. The calculated values are sum-
marized in Table 4. The values show a slight
decrease in concentration values for both
drugs but these decreases remained lower
than 5%, i.e., 4.3% for fentanyl and 4.1% for
sufentanil.
Discussion
The microbiological results support the con-
clusion that neither fentanyl nor sufentanil
possesses signicant antimicrobial activity.
During the sterility test, we noticed that one
of the fentanyl citrate infusion bags, the D14-
sample stored at room temperature, was con-
taminated, whereas the D28-sample from the
same bag showed no sign of contamination
at all. Thus, it was assumed that this contami-
nation (of the sample and not of the infusion
bag) by Bacillus species, which is an environ-
mental bacteria, was probably due to handling
during the sampling procedure of the D14-
sample.
According to the physicochemical results,
the loss of vehicle was not concomitant with
an increase of the drug concentration. We
can postulate that the observed decrease in
drug concentration was probably due to an ad-
sorption phenomenon of the drugs on the
PVC bag. In fact, no degradation product was
found during the stability study using the LC-
UV analytical method. Furthermore, the de-
crease in drug concentration was always below
5%, which is lower than the ofcial compen-
dial requirement.
Despite the lack of standardization, the re-
cent advent of injectable opioids for PCA in
hospital environments has led to huge im-
provements in medical care practices in several
regions of the world. The development of
a quality assurance system to ensure good qual-
ity care is of utmost importance to render the
care chain even more reliable. In the present
case, the entire circuit is tracked from the
drafting of patient prescriptions to the dispen-
sation of the prescribed therapeutic agents.
This approach, regarded as a reliability pledge
beneting both the patients and all others im-
plicated in the health system, has been the
driving force of the present study. Although
fentanyl and sufentanil do not possess antimi-
crobial activities, microbiological tests have
established that PCA solutions of these thera-
peutic agents remain stable and sterile for at
least 14 days at ambient temperature under
normal operational conditions. The analytical
methodology developed herein was found to
be highly reliable for all criteria and items re-
tained. Furthermore, it is compatible with
obligatory postproduction analytical controls
before the delivery of therapeutic agents to
patients.
In practice, the Department of Clinical Phar-
macy is now able to produce qualied batches
Table 4
Concentration Evolution Study
Day
D0 D3 D7 D8 D9 D10 D11 D12 D13 D14
Fentanyl Mean 13.4 12.5 12.8 12.7 13.3 13.0 12.6 12.4 13.4 12.8
RSD 1.6 0.7 0.8 0.5 0.9 0.3 0.5 1.0 0.9 0.7
D to J0 (variation %) 6.7 4.5 5.2 0.8 3.0 6.0 7.5 0 4.5
Sufentanil Mean 11.8 11.2 11.4 11.4 11.5 11.6 11.3 11.0 11.4 11.4
RSD 0.5 0.3 0.5 0.3 0.4 0.4 0.7 0.5 0.5 0.4
D to J0 (variation %) 5.1 3.4 3.4 2.5 1.7 4.2 6.8 3.4 3.4
The mean and RSD values were calculated on six different measurements.
Vol. 32 No. 1 July 2006 95 Stability of Fentanyl and Sufentanil PCA Solutions
of fentanyl citrate or sufentanil citrate solution
in infusion bags with expiration dates of
14 days. The clinical benets of this work,
which have been validated by the Strike
Against Pain committee, have resulted in
net improvements in care chain reactivity rela-
tive to the needs of suffering patients, with or
without cancer, in the context of daily hospital
therapeutics.
Acknowledgments
The authors are grateful to Professor J.-C.
Darbord for supplying microbial strains.
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