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(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
PU-980, Tokyo,
Japan), an automatic sampler (Perkin-Elmer
C-R6A, Kyoto,
Japan), and a UV--visible detector (Jasco
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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