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PHARMA-366; No. of Pages 6 ARTICLE IN PRESS

Annales Pharmaceutiques Françaises (2014) xxx, xxx—xxx

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ORIGINAL ARTICLE

Formulation and stability study of a

pediatric 2% phenylephrine hydrochloride
eye drop solution
Formulation et étude de stabilité d’un collyre pédiatrique de
chlorhydrate de phényléphrine à 2 %

C. Dreno a, T. Gicquel b, M. Harry c, O. Tribut d,

F. Aubin c, N. Brandhonneur e, G. Dollo a,e,∗

a
Pôle pharmaceutique, CHU Pontchaillou, 2, rue Henri-Le-Guilloux, 35033 Rennes cedex 9,
France
b
Laboratoire de toxicologie biologique et médico-légale, CHU Pontchaillou, 2, rue
Henri-Le-Guilloux, 35033 Rennes cedex 9, France
c
Pôle pharmaceutique, hôpital Sud, CHU de Rennes, 16, boulevard de Bulgarie, 35203 Rennes
cedex 2, France
d
UF biomarqueurs, CHU Pontchaillou, 2, rue Henri-Le-Guilloux, 35033 Rennes cedex 9, France
e
Laboratoire de pharmacie galénique, biopharmacie et pharmacie clinique, faculté des
sciences pharmaceutiques et biologiques, université Rennes-1, 2, avenue du Pr-Léon-Bernard,
35043 Rennes cedex, France

Received 18 April 2014; accepted 18 June 2014

KEYWORDS Summary
Phenylephrine Introduction. — We present formulation and stability evaluation of a 2% (w/v) phenylephrine
hydrochloride; hydrochloride biocompatible eye drop solution, routinely prepared in hospital pharmacy under
Eye drop; aseptic conditions, for retinal examination of neonates and premature infants.
Premature infant; Materials and methods. — Eye drop solution was formulated by dissolution of phenylephrine
Biocompatibility; hydrochloride and disodium hydrogen phosphate as buffering agent in sterile water for injection
Stability study; and sodium chloride for injection as isotonic agent. The previous solution was sterile filtered
Mass spectrometry through under aseptic conditions, in an iso class 5 air quality clean room under horizontal
laminar airflow hood. Physical stability (visual inspection, osmolality measurements), chemical
stability (pH measurement, phenylephrine assay by liquid chromatography coupled with an

∗ Corresponding author.
E-mail addresses: gilles.dollo@univ-rennes1.fr, gilles.dollo@chu-rennes.fr (G. Dollo).

http://dx.doi.org/10.1016/j.pharma.2014.06.006
0003-4509/© 2014 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Dreno C, et al. Formulation and stability study of a pediatric 2% phenylephrine
hydrochloride eye drop solution. Ann Pharm Fr (2014), http://dx.doi.org/10.1016/j.pharma.2014.06.006
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PHARMA-366; No. of Pages 6 ARTICLE IN PRESS
2 C. Dreno et al.

ultra-high resolution and accurate mass) and sterility evaluation of phenylephrine eye drop
solution stored at ambient temperature were studied during 60 days.
Results and discussion. — The formulated eye drop solution had a pH of 6.90 ± 0.05 and an
osmolality of 285 ± 2 mOsm/kg. Throughout the 60 days study the solutions remained clear
without any precipitation or color modification, sterility was maintained, pH and osmolality
were not significantly modified and no significant loss of product was detected using liquid
chromatography coupled with an ultra-high resolution and accurate mass instrument suggesting
the lack of degradation.
Conclusion. — These results indicate that 2% phenylephrine hydrochloride eye drop solutions
were physically, chemically and microbiologically stable for at least 60 days when stored in
type I amber glass vials at room temperature, allowing the compounding of higher batch sizes.
© 2014 Elsevier Masson SAS. All rights reserved.

MOTS CLÉS Résumé

Chlorhydrate de
phényléphrine ;
Collyre ;
Enfant prématuré ;
Biocompatibilité ;
Étude de stabilité ;
Spectrométrie de
masse
Introduction. — Le but de l’étude est de mettre au point et d’évaluer la stabilité d’un collyre
de chlorhydrate de phényléphrine à 2 %, préparation hospitalière biocompatible pour l’examen
de la rétine des enfants nouveau-nés et prématurés.
Matériels et méthodes. — Les collyres sont préparés par dissolution de chlorhydrate de
phényléphrine et de phosphate disodique dans de l’eau pour préparation injectable et de
chlorure de sodium isotonique comme agent isotonisant, suivi d’une filtration stérilisante et
d’une répartition aseptique en zone à atmosphère contrôlée, sous hotte à flux laminaire horizon-
tal. L’étude de stabilité sur 60 jours a été réalisée par inspection visuelle et mesure d’osmolalité
(stabilité physique), mesure du pH et détermination des concentrations de phényléphrine par
chromatographie liquide couplée à la spectrométrie de masse à haute résolution (stabilité
chimique) et évaluation de la stérilité par ensemencement direct (stabilité microbiologique).
Résultats et discussion. — Le collyre retenu a un pH de 6,90 ± 0,05 et une osmolalité de
285 ± 2 mOsm/kg. Pendant les 60 jours de l’étude, les solutions restent limpides sans précip-
itation ni modification de couleur, la stérilité est maintenue, le pH et l’osmolalité ne sont
pas significativement modifiés et aucune perte significative de produit n’est détectée par la
méthode de dosage, suggérant l’absence de dégradation.
Conclusion. — Ces résultats montrent la stabilité physique, chimique et microbiologique du col-
lyre de chlorhydrate de phényléphrine à 2 % pendant au moins 60 jours lorsqu’il est conservé en
flacon en verre ambré de type I, à température ambiante, ce qui nous a permis d’augmenter
la taille des lots fabriqués.
© 2014 Elsevier Masson SAS. Tous droits réservés.

Phenylephrine hydrochloride (Fig. 1) is a sympathomimetic,
alpha-adrenergic agonist drug. Following instillation in the
eye, phenylephrine acts locally as a rapid and potent vaso-
constrictor and mydriatic agent, by constricting ophthalmic
blood vessels and radial muscle of the iris. Phenylephrine
hydrochloride is commonly used in association with anti-
cholinergic agents such as tropicamide or cyclopentolate to
Figure 1. Chemical structure of phenylephrine hydrochloride.
Structure chimique du chlorhydrate de phényléphrine.
produce maximal dilation of the pupil for examination of the
peripheral retina [1,2].
In Rennes University Hospital Department of Pediatrics,
10 to 15 dilations are performed weekly, for retinal exami-
nation of neonates and premature infants. Several systemic
side effects of topical phenylephrine have been reported
in neonates and children undergoing retinopathy of pre-
maturity screening, such as increased blood pressure [3],
pulmonary edema [4] and grand mal seizure [5].
Other side effects such as paralytic ileus, necrotiz-
ing enterocolitis and feeding intolerance were significantly
increased when anti-cholinergic drug tropicamide or
cyclopentolate was associated to phenylephrine [6].
As systemic side effects in children may be significantly
underreported, it is strongly recommended to adopt strate-
gies for reducing systemic absorption and toxicity of ocular
phenylephrine, for example to use the lowest available
concentration of topical drug, to occlude the nasolacrimal
passage after topical instillation by gently but firmly pressing
the tear duct against the nose immediately after instillation

Please cite this article in press as: Dreno C, et al. Formulation and stability study of a pediatric 2% phenylephrine
hydrochloride eye drop solution. Ann Pharm Fr (2014), http://dx.doi.org/10.1016/j.pharma.2014.06.006
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PHARMA-366; No. of Pages 6 ARTICLE IN PRESS
Formulation and stability of 2% phenylephrine hydrochloride eye drop solution 3

for at least one minute, to close the patient’s eyelid and to
remove excess solution with absorbent tissue after instilla-
tion to avoid cutaneous or oral absorption [6].
In France, phenylephrine hydrochloride eye drops are
only available at the concentration of 5 and 10% but these
strengths are not recommended for children because of the
higher risk of systemic side effects in comparison to the 2.5%
strength that is available in several countries. Due to the
lack of marketed pediatric dosage, nurses in pediatric units
often dilute in the ward the adult strength product with a
different solvent and this can lead to the drug inactivation
or to a bacterial contamination of the dosage form. Among
the optional missions of French Hospital Pharmacies, stan-
dardized preparation compounding allows to face the lack of
industrial products. Among the few pediatric phenylephrine
eye drops prepared by French Hospital Pharmacies, the bio-
compatibility is not optimum for instillation to premature
infant as seen with alkaline pH values around 9 (higher
than the stability pH of phenylephrine hydrochloride, thus
limiting the shelf life to 8 days) as seen with the presence of
preservatives such as sodium borate and boric acid (which
are not indicated in children under 3 years) and as seen
with hypertonic eye drop solutions [7]. The aim of this work
was to formulate a biocompatible and stable 2% phenyle-
phrine hydrochloride eye drop solution with a longer shelf
life than existing preparations, in order to provide value-
added hospital preparation of high pharmaceutical quality.
Physico-chemical stability of phenylephrine eye drop solu-
tion stored at ambient temperature in sterile amber glass
vials and sterility of the preparation were evaluated dur-
ing 60 days. An original and specific liquid chromatography
coupled with an ultra-high resolution and accurate mass
instrument was used for phenylephrine hydrochloride assay.
Methods
Materials and reagents
Phenylephrine hydrochloride and disodium hydrogen phos-
phate were supplied from Inresa Pharma (Barthen-
heim, France), sterile water for injection and sterile
sodium chloride 0.9% for injection were purchased from
Macopharma (Tourcoing, France). Cellulose acetate syringe
filter (Minisart® , diameter 28 mm, pore size 0.2 ␮m)
were purchased from Sartorius Stedim (Aubagne, France)
and 60 ml Luer lock syringes used for sterile filtration
were purchased from Becton-Dickinson (Le Pont-de-Claix,
France). Methanol, acetonitrile and water were obtained
from Fisher Scientific (Illkirch, France). Formic acid and
normetanephrine (internal standard) were purchased from
Sigma Aldrich (Saint-Quentin-Fallavier, France). All chemi-
cals, reagents and solvents were of LC/MS quality grade.
Formulation and preparation of phenylephrine
eye drops
The eye drops were formulated and prepared in Rennes
University Hospital Pharmacy. Firstly a 2% (w/v) phenyle-
phrine hydrochloride solution was formulated by dissolution
of phenylephrine hydrochloride (4 g) and disodium hydro-
gen phosphate as buffering agent (from 0 to 2000 mg) in
about 80 ml of sterile water for injection in a 200 ml ster-
ile graduated flask. Then sodium chloride 0.9% for injection
as isotonic agent was added (from 0 to 200 ml) and sterile
water for injection was used to make it up to the fixed vol-
ume (200 ml). After selection of the best solution by means
of biocompatibility (Table 1), phenylephrine hydrochloride
eye drops were prepared in accordance with French Good
Manufacturing Practice for Hospital Pharmacies [8].
In the initial step, the 2% phenylephrine hydrochloride
solution was obtained by mixing appropriate drug and excip-
ients quantities according to the previous paragraph. The
previous 2% (w/v) phenylephrine solution was then rapidly
sterile filtered through a 0.22-␮m pore size syringe filter, in
a 10-ml sterile amber borosilicate type I glass bottle under
aseptic conditions, in an iso class 5 air quality clean room
under horizontal laminar airflow hood. Eye drop bottles were
closed with a pharmaceutical grade butyl rubber stopper and
sealed with a crimped aluminium seal. A polyethylene plas-
tic dropper tip was connected just before administration by
the nurse.
To evaluate the stability of phenylephrine eye drops,
three batches consisting of 40 bottles each were prepared
and stored at room temperature (20—25 ◦ C) for up to 60
days. Six bottles were withdrawn from each batch on days
0, 2, 7, 14, 30, 45 and 60 to perform physical and chemical
stability as well as sterility evaluation at each time point
for each batch. All bottles withdrawn for phenylephrine
hydrochloride assay were kept at −80 ◦ C until analysis at the
end of the two months study period. No study was performed
with a prolonged contact of the eye drop solution with the
rubber stopper because rubber stopper is of pharmaceutical
grade, vials storage is controlled by pharmacy (all vials are

Table 1 Result of the biocompatible phenylephrine hydrochloride eye drop formulation screening.
Résultat de la recherche d’une formulation biocompatible de collyre de chlorhydrate de phényléphrine.
Phenylephrine HCl (g) 4 4 4 4 4 4 4 4 4 4 4
Water for injection (ml) 200 200 — 140 140 140 140 130 130 130 143
NaCl 0.9% (ml) — — 200 60 60 60 60 70 70 70 57
Na2 HPO4 (mg) 2000 1000 0 2000 1000 100 60 50 40 30 0
pH 7.86a 7.74a 5.59a 7.84a 7.68a 7.07a 7.05a 7.04a 6.90 6.81 5.62a
Osmolality (mOsm/kg) 340a 259 462a 424a 337a 272 267 286 285 282 260
Compatibility (yes/no) No No No No No No No No Yes Yes No
a Do not meet product requirement, i.e. 6.0 < pH < 7.0 and 250 < osmolality < 330 mOsmol/kg.

Please cite this article in press as: Dreno C, et al. Formulation and stability study of a pediatric 2% phenylephrine
hydrochloride eye drop solution. Ann Pharm Fr (2014), http://dx.doi.org/10.1016/j.pharma.2014.06.006
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stored vertically) and vials are dispensed to unit just before
administration to patient.
Physical stability
Physical stability was assessed by visual inspection (color
variation, apparition of precipitate. . .) and osmolality
measurements were performed using the freezing point
depression technique with an advanced instruments model
3250 (Advanced Instruments, Norwood, MA, USA).
Chemical stability
pH measurement was performed using a phenomenal pH
1000L meter (VWR international SAS, Pessac, France). The
pH meter was calibrated using standard buffer solutions
before measuring the pH of phenylephrine hydrochloride eye
drop solutions.
The phenylephrine contents of the solutions were
determined by liquid chromatography-high resolution-mass
spectrometry (LC-HR-MS). Analyses were performed on a
Thermo Scientific Q ExactiveTM (San Jose, USA) mass spec-
trometer including an Accela pump (Thermo Scientific, San
Jose, USA). An HESI-II ion source was used for the ioniza-
tion of target compounds. Data acquisition, peak integration
and calibration were performed using Xcalibur® 2.1 software
(ThermoScientific, San Jose, CA, USA).
LC separation was performed using a gradient on a HILIC
Nucleodur column (100 × 2 mm, 1.8 ␮m). The mobile phases
used were 10 mM ammonium acetate buffer containing 0.1%
(v/v) formic acid (solvent A) and acetonitrile with 0.1% (v/v)
formic acid (solvent B). The mobile phase was delivered at a
flow rate of 300 ␮l/min using the following stepwise gradient
elution program: initial conditions of 30:70 (A:B) run from
70:30 (A:B) at 2 minutes, run from 30:70 (A:B) at 2.2 minutes
and conditions 30:70 (A:B) maintained to 3 minutes at a flow
rate of 400 ␮l/min for equilibration. All prepared samples
were kept at 10 ◦ C in the autosampler until full loop injection
into the LC-HR-MS system in a thermostated column at 40 ◦ C.
The MS conditions were as follows: HESI in positive mode,
capillary temperature: 300 ◦ C; spray voltage: 4500 V; sheath
and auxiliary gas (nitrogen) flow rate: 40 and 10 psi (arbitrary
units), respectively.
Tuning parameters were optimized by direct infusion of
phenylephrine at the concentration of 1 mg/l in the mobile
phase into the ionization probe at a flow rate of 5 ␮l/min
in ESI positive mode. Data were acquired simultaneously in
full scan with high resolution acquisition and in targeted-
MS2 mode. For full scan acquisition, resolution was set at
35,000 FWHM. The C-trap capacity was set at 106 charges
and the maximum injection time at 200 ms. The mass range
was made from 60 to 240 m/z. For targeted-MS2 mode, res-
olution was set at 17,500 FWHM and the AGC target was
set at 5.105 charges and the maximum injection time was
50 ms and isolation width 2.0 m/z. The measured accurate
m/z values of the protonated species were 168.1017 and
166.0874 for phenylephrine and normetanephrine, respec-
tively, corresponding to a loss of H2 0. Quantitation was
performed by extracting the exact mass of each of the
protonated fragment using a 5 ppm extraction window. Frag-
ments accurate mass were 109.0650 and 134.0598 m/z for
phenylephrine and normetanephrine, respectively. In full
Please cite this article in press as: Dreno C, et al. Formulation and stability study of a pediatric 2% phenylephrine
hydrochloride eye drop solution. Ann Pharm Fr (2014), http://dx.doi.org/10.1016/j.pharma.2014.06.006
scan, m/z of compounds were targeted as qualifiers. Reten-
tion times were 1.72 and 1.84 min for phenylephrine and
normetanephrine, respectively. This LC-HR-MS method was
validated for selectivity, repeatability and reproducibility.
Samples were considered stable if drug concentration was
higher than 90% of the initial concentration which is the limit
set up by the U.S. Pharmacopeia [9].
Sterility evaluation
Eye drop sterility was tested on day 0, 30 and 60 using
Bactec® system, (Becton-Dickinson), i.e. direct inoculation
of the content of one vial of phenylephrine eye drops (5 ml)
into standard aerobic and 5 ml into anaerobic liquid media
and detection of bacterial growth based on CO2 fluorimet-
ric detection. Both liquid media were incubated for 14 days
and bacterial growth was checked daily. The requirements
for sterility were met only when no bacterial growth was
observed.
Statistical analysis
Analysis between different times was performed with a
non-parametric Friedman test with Dunns post hoc test for
comparisons. All analyses were performed using Prism soft-
ware (GraphPad Software, La Jolla, CA, USA). For each
analysis, two-sided P-value less than 0.05 were considered
statistically significant.
Results and discussion
Table 1 presents the results of the formulation screening. An
interesting formulation in the premature infant is an isotonic
eye drop solution, i.e. osmolality around 290 mOsmol/kg,
with a neutral pH close to the physiological pH of tears
around 7.4. Phenylephrine hydrochloride is reported to have
a pH stability interval ranging from 3.5 to 7.0 [10], for other
authors the drug is stable below pH 7.3 [11]. Above pH 7.0,
degradation occurs involving the side chain with loss of the
secondary amine function and the reaction is accelerated
by the presence of phenylephrine base [10]. For that reason
we did not compromise drug stability and chose a neutral pH
just below 7.0, e.g. 6.9, by using disodium hydrogen phos-
phate as buffering agent. The eye tolerates a wide range of
pH from 3.5 to 9. Although phenylephrine is a weak base that
is more ionized at a lower pH than 6.9, a neutral pH must be
preferred for the formulation because at this pH phenyle-
phrine is mainly present under its ionized form avoiding any
base transformation and degradation, and because of its bio-
compatibility in preterm infants. Table 2 shows the chosen
formula.
Table 2 Two percent phenylephrine hydrochloride eye
drop components.
Composition du collyre de chlorhydrate de phényléphrine à 2 %.
Phenylephrine hydrochloride 4g
Disodium hydrogen phosphate 40 mg
NaCl 0.9% 75 ml
Sterile water for injection qs 200 ml
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PHARMA-366; No. of Pages 6 ARTICLE IN PRESS
Formulation and stability of 2% phenylephrine hydrochloride eye drop solution
Figure 2. pH evolution as a function of time (each point is the
mean ± S.D. of 3 determinations).
Évolution du pH en fonction du temps (chaque point correspond à
la moyenne ± écart-type de 3 échantillons).
Freshly prepared solutions were clear and uncol-
ored, with a pH of 6.90 ± 0.05 and an osmolality of
285 ± 2 mOsm/kg (mean ± S.D., n = 3 determinations).
The stability of an eye drop solution is very important
for its efficacy. Phenylephrine hydrochloride is known to
degrade into epinephrine by photochemical oxidation lead-
ing to a modification of the solution color, changing from
white or almost white into a brownish color [12].
As this phenomenon is accelerated by light, eye drops
were packaged in amber glass bottles. All solutions remained
clear and no precipitation or color modification appeared
throughout the study. All vials tested were sterile after
preparation and sterility was maintained throughout the
60-day study period. Fig. 2 shows that pH mean ± S.D.
values were not significantly modified compared to initial
pH mean ± S.D. values, staying around neutrality during
the study for all batches. The lack of significant varia-
tion in pH from 6.90 ± 0.05 to 6.95 ± 0.01 (P = 0.1121) was
Figure 3. Osmolality evolution as a function of time (each point
is the mean ± S.D. of 3 determinations).
Évolution de l’osmolalité en fonction du temps (chaque point cor-
respond à la moyenne ± écart-type de 3 échantillons).
Please cite this article in press as: Dreno C, et al. Formulation and stability study of a pediatric 2% phenylephrine
hydrochloride eye drop solution. Ann Pharm Fr (2014), http://dx.doi.org/10.1016/j.pharma.2014.06.006
5
Figure 4. Percentage of initial concentration remaining as a func-
tion of time (each point is the mean ± S.D. of 6 determinations).
Pourcentage de la concentration initiale restant en fonction du
temps (chaque point correspond à la moyenne ± écart-type de 6
déterminations).
in accordance with the lack of phenylephrine hydrochlo-
ride degradation observed by LC-HR-MS. In the same way,
osmolality mean ± S.D. values were not significantly mod-
ified during the study, varying from 285 ± 2 to 284 ± 1
(P = 0.0719), as seen in Fig. 3. Concerning phenylephrine
hydrochloride concentrations (Fig. 4), no significant loss of
product was detected throughout the study using specific
liquid chromatography coupled with an ultra-high resolution
and accurate mass instrument (P = 0.3275), suggesting the
lack of degradation over a 60-day storage period. Indeed,
during the study period, no degradation product such as
epinephrine was found using our LC-HR-MS method and the
fraction of the initial concentration remaining from day 0 to
day 60 was always higher than 90% (Fig. 4), the limit set
by the United State Pharmacopeia [9] and used by Kiser
et al. in his phenylephrine hydrochloride stability study
[13].
Conclusion
These results indicate that 2% phenylephrine hydrochloride
eye drop solutions were physically, chemically and microbi-
ologically stable for at least 60 days when stored in amber
glass vials at room temperature. Compared with existing
extemporaneously compounded hospital preparations, the
shelf life was increased to 60 days allowing the compound-
ing of batch size of 40 or higher, and allowing to wait for the
result of the sterility test, respecting a quarantine period
before pharmaceutical releasing and dispensing of the prod-
uct.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
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Acknowledgments phenylephrine hydrochloride eye drops were instilled. Pedi-

atrics 2004;113:e499.
The authors thanks the Fond d’innovation pour la recherche [6] Gray C. Systemic toxicity with topical ophthalmic medications
in children. Paediatr Perinat Drug Ther 2006;7:23—9.
of the centre hospitalier universitaire of Rennes for its finan-
[7] Mazet R [thèse] Étude de faisabilité de préparations oph-
cial support.
talmiques au centre hospitalier universitaire de Grenoble.
Grenoble: université Joseph-Fourier; 2012. p. 1—161.
[8] Agence française de sécurité sanitaire des produits de santé.
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Please cite this article in press as: Dreno C, et al. Formulation and stability study of a pediatric 2% phenylephrine
hydrochloride eye drop solution. Ann Pharm Fr (2014), http://dx.doi.org/10.1016/j.pharma.2014.06.006