REPORTS Sildenafil citrate oral suspensions

Extemporaneous sildenafil citrate oral suspensions

for the treatment of pulmonary hypertension
in children
MILAP C. NAHATA, RICHARD S. MOROSCO, AND MICHAEL T. BRADY

P
ulmonary hypertension is a se-
vere illness associated with in-
creased pulmonary vascular
resistance and pulmonary artery
pressure, which may cause heart fail-
ure and death.1-3 Inhaled nitric oxide
or a continuous i.v. infusion of epo-
prostenol is commonly used to treat
pulmonary hypertension, but both
options are expensive and difficult to
use.
Several case reports and small
clinical studies have demonstrated
the effectiveness of sildenafil in in-
fants and children with pulmonary
hypertension.4-10 Sildenafil is a selec-
tive inhibitor of cyclic guanosine
monophosphate-specific phospho-
diesterase-5, which is present in the
pulmonary vasculature, thereby en-
hancing nitric oxide-mediated va-
sodilation and decreasing pulmonary
vascular resistance.11,12 A recent ran-
domized, double-blind, placebo-
controlled, crossover study in adults
with primary pulmonary hyperten-
sion found that patients taking
sildenafil had substantial improve-
ments in cardiac index, exercise tol-
Purpose. The stability of sildenafil citrate
2.5 mg/mL in two extemporaneously pre-
pared oral suspensions stored at 4 and 25
°C was studied.
Methods. Thirty 25-mg tablets of sildena-
fil citrate were ground to powder, and the
powder was combined with a 1:1 mixture
of Ora-Sweet and Ora-Plus or a 1:1 mixture
of methylcellulose 1% and Simple Syrup,
NF, to produce two 2.5-mg/mL suspen-
sions. Five plastic bottles of each suspen-
sion were stored in amber plastic prescrip-
tion bottles at 4 or 25 °C. Samples were
collected on days 0, 7, 14, 28, 42, 56, 70,
and 91 for analysis of sildenafil content by
high-performance liquid chromatogra-
phy; pH was also measured. Samples were
visually observed against black and white
backgrounds.
erance, and quality of life (dyspnea
and fatigue) versus the placebo
group.13
Sildenafil citrate is currently avail-
able as 25-, 50-, and 100-mg tablets;
no suspension is available for oral
administration. A liquid dosage form
would allow for the administration
of individual doses, based on body
Results. The mean concentration of
sildenafil citrate exceeded 98% of the initial
concentration in all samples at both tem-
peratures throughout the 91-day study pe-
riod. No changes in pH, odor, or physical
appearance were observed.
Conclusion. Sildenafil citrate 2.5 mg/mL in
two extemporaneously compounded oral
suspensions was stable for 91 days in plas-
tic prescription bottles at 4 and 25 °C.
Index terms: Compounding; Concentra-
tion; Hydrogen ion concentration; Hyper-
tension; Methylcellulose; Odors; Ora-Plus;
Ora-Sweet; Pediatrics; Sildenafil citrate; Sta-
bility; Storage; Sucrose; Suspending agents;
Suspensions; Temperature; Vasodilating
agents; Vehicles
Am J Health-Syst Pharm. 2006; 63:254-7
weight, to infants and young chil-
dren, who are unable to swallow tab-
lets. In the absence of a commercially
available liquid preparation, the tab-
let must be ground into a powder,
which should be mixed in an appro-
priate vehicle just before administra-
tion to patients by nurses or caregiv-
ers. This approach is tedious and

MILAP C. NAHATA, M.S., PHARM.D., is Professor and Division Chair,
College of Pharmacy, and Professor of Internal Medicine and Pediat-
rics, College of Medicine; RICHARD S. MOROSCO is Research Associ-
ate; and MICHAEL T. BRADY, M.D., is Professor of Pediatrics, College
of Medicine, The Ohio State University, Columbus.
Address correspondence to Dr. Nahata at the College of Pharma-
cy, The Ohio State University, 500 West 12th Avenue, Columbus,
OH 43210 (nahata.1@osu.edu).
Julie Zaucha, B.S.Pharm., is acknowledged for preparing the for-
mulations used in this study.
Supported in part by the Pediatric Pharmacology Research Unit,
National Institute of Child Health and Human Development,
Bethesda, MD.
Presented at the ASHP Midyear Meeting, New Orleans, LA,
December 9, 2003.
Copyright © 2006, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/06/0201-0254$06.00.
DOI 10.2146/ajhp050208

254 Am J Health-Syst Pharm—Vol 63 Feb 1, 2006


time-consuming and may be associ-
ated with the administration of in-
correct doses.
The purpose of this study was to
develop two stable oral suspensions
of sildenafil that are suitable for ad-
ministration to infants and children.
Since little is known about the stabil-
ity of sildenafil in a liquid dosage
form, we designed a study to deter-
mine the extended stability of
sildenafil citrate in two oral suspen-
sions stored in amber plastic pre-
scription bottles at 4 and 25 °C.
Methods
Preparation of solutions. Sil-
denafil citrate 25-mg tabletsa were
used to prepare the suspensions. The
tablets were ground to fine powder
using a mortar and pestle and com-
bined with a 1:1 mixture of methyl-
cellulose 1%b (Appendix A) and Sim-
ple Syrup, NF,c or a 1:1 mixture of
Ora-Plusd and Ora-Sweete (Appendix
B). The nominal concentration of
sildenafil citrate in each suspension
was 2.5 mg/mL.
Approximately 30 mL of each sus-
pension was transferred to 10 2-oz
amber plastic prescription bottles.f
Five plastic bottles of each suspen-
sion were stored at 4 ° C in a
refrigerator,g and five were stored at
25 °C in a temperature-controlled
water bath.h The samples were taken
after the bottles were shaken on a
wrist-action shaker for 10 minutes
and then allowed to stand for 2 min-
utes. The bottles were then gently in-
verted three times and the caps re-
moved; the samples were withdrawn
from the center of the bottles at
midlevel of liquid. Three 500-μ L
samples were collected from each
bottle on days 0, 7, 14, 28, 42, 56,
70, and 91 after preparation and
analyzed in duplicate by a high-
performance liquid chromatographic
(HPLC) method modified and vali-
dated in our laboratory.14
The pH of each solution was mea-
sured on each study day. All solu-
tions were observed for any changes
REPORTS Sildenafil citrate oral suspensions
in color and turbidity using black
and white backgrounds.
HPLC method. The HPLC instru-
mentation consisted of a pump,i an
autosampler,j a variable-wavelength
ultraviolet-light detector,k a chroma-
tography data system,l a C18 col-
umn,m a digital pH meter,n a wrist-
action shaker,o and a Vortex mixer.p
The chemicals and reagents, includ-
ing acetonitrile, q methanol, r and
buffer solutions pH 7.00,s 4.00,t and
10.00,u were American Chemical So-
ciety or analytical grade. The mobile
phase consisted of 50% 0.2 M am-
monium acetatev and 50% acetoni-
trile. Before use, the mobile phase
was passed through a 0.45-μm nylon
66 filterw and then degassed with heli-
um. The flow rate was 0.5 mL/min.
The detector was set at 245 nm, and
the injection volume was 10 μL. The
column was maintained at 25 °C.
A stock solution of sildenafil cit-
rate reference standardx was pre-
pared in methanol and then diluted
with mobile phase to yield concen-
trations of 3.0, 2.5, 2.0, 1.0, and 0.5
mg/mL. One hundred microliters of
each of these solutions was mixed
with 1.0 mL of mobile phase and
centrifuged; the supernatant was an-
alyzed in the same manner as the
samples.
Assay validation. To establish the
stability-indicating nature of the
method, sildenafil citrate 1.0 mg/mL
alone, the vehicles alone, and the
mixtures were forcibly degraded by
acid (2.0 M hydrochloric acid)y and
base (2.0 M sodium hydroxide)z hy-
drolysis, oxidation (0.3% hydrogen
peroxide),aa and heat (80 °C). The
samples were analyzed as described
earlier every 30 minutes until the
sildenafil citrate peak decreased by
approximately 25%. Each chromato-
graphic run required about 12 min-
utes. Sildenafil citrate eluted at about
7.1 minutes (Figure 1). Linearity of
the standard curve was determined
by linear regression analysis of
sildenafil citrate concentrations ver-
sus peak areas of sildenafil citrate
Am J Health-Syst Pharm—Vol 63 Feb 1, 2006
standards. The correlation coeffi-
cient was greater than 0.999, with in-
traday and interday coefficients of
variation of less than 1.9% and 3.2%,
respectively. Stability was defined as
retention of greater than 90% of the
drug’s initial concentration.
Results
The mean concentration of sildena-
fil citrate exceeded 98% of the initial
concentration in each formulation at 4
and 25 °C throughout the 91-day
study period (Table 1). No changes
in pH, color, odor, or turbidity were
detected in any of the samples during
the study. Both formulations ap-
peared uniformly suspended.
Discussion
The results of this study indicate
that sildenafil was chemically and
physically stable in two extempora-
neously prepared oral suspensions
over the 91-day study period. The
liquid preparations may improve the
ease and accuracy of drug adminis-
tration in infants and young chil-
dren. These formulations may be
considered for adults unable to swal-
low tablets.
Providers who prefer a ready-to-
use preparation may choose Ora-
Plus and Ora-Sweet as the vehicle for
this preparation. However, the meth-
ylcellulose 1% and Simple Syrup, NF,
vehicle will be most useful in many
countries, as most do not have access
to commercially available Ora-Plus
and Ora-Sweet.
Data from available case reports
and small studies suggest that
sildenafil may be useful in the treat-
ment of pulmonary hypertension
pending proof of its effectiveness and
safety in large studies.15 Systemic hy-
potension and impaired oxygenation
have been associated with i.v. sildenafil
in infants after cardiac surgery.16
Other agents used for the treat-
ment of pulmonary hypertension in
adults may not be appropriate or eas-
ily administered in infants and chil-
dren. Prostacyclin is associated with
255
 REPORTS Sildenafil citrate oral suspensions

complications such as sepsis.13 Ilo- suring the appropriate dose, and Nearly 80% of the drugs currently
prost, an inhaled synthetic analogue safely discarding unused medication bearing Food and Drug Administra-
of prostacyclin PGI2, was recently ap- after each use. Bosentan, an endothe- tion (FDA)-approved labeling for
proved for the treatment of pulmo- lin receptor antagonist, is available in adults are not fully labeled for the
nary arterial hypertension in adults. tablet dosage form for the treatment pediatric population. The current
However, patients must be trained in of pulmonary arterial hypertension prescribing information for sildenafil
the proper use of a special “adaptive in adults, but has been associated states “Safety and efficacy of sildena-
aerosol delivery” system.17 Caregivers with serious adverse effects.18 It is not fil in patients younger than 18 years
would have to learn about accurately available in a liquid dosage form and of age have not been established.”
transferring medication from the has not been approved for use in in- This is true for many old drugs (e.g.,
single-use vials to the inhaler, mea- fants or children. morphine for neonates) and many
new drugs (e.g., most drugs for hy-
pertension, congestive heart failure,
Figure 1. Typical chromatogram of (A) sildenafil citrate at time 0 and (B) stored at 80 °C for
or arrhythmias), despite the fact that
18 hours. these drugs must be used in infants
and children. When drugs are not
A 7.16
approved by FDA for use in infants
and young children, they are often
unavailable in liquid dosage forms.
FDA provides an incentive of six-
month patent exclusivity or exten-
sion for the new drugs still under
patents assigned to the manufactur-
er. However, this incentive has not
yet been utilized for most drugs. Ob-
viously, health care providers and
patients cannot wait for this problem
Time (min) to be fully resolved. Thus, our study
provides important information
about the use of sildenafil in a liquid
B 7.16 form in patients requiring weight-
based dosages and unable to swallow
tablets or powder.
The liquid preparation of sildena-
fil in Ora-Plus and Ora-Sweet has
been used at our institution since
January 2004. Although pharmaco-
kinetic studies were not performed
Time (min) due to lack of funding, drug absorp-
tion or bioavailability from a well-
suspended liquid is expected to be at

Table 1.
Stability of Sildenafil Citrate in Two Extemporaneously Prepared Oral Dosage Forms Stored at 4 and 25 ° C
% Initial Concentration Remaininga
Diluents and Storage Initial Conc. Day Day Day Day Day Day Day Day
Temperature (mg/mL) 0 7 14 28 42 56 70 91
Methylcellulose and
Simple Syrup, NF
4 °C 2.6 ± 0.1 100.1 ± 1.2 99.3 ± 1.7 99.6 ± 2.0 98.2 ± 1.7 98.6 ± 2.3 99.3 ± 2.4 98.6 ± 2.1 98.8 ± 2.6
25 °C 2.5 ± 0.3 100.3 ± 1.3 98.9 ± 2.0 99.4 ± 1.1 98.9 ± 1.6 99.4 ± 2.2 98.7 ± 2.2 98.4 ± 2.1 98.6 ± 2.8
Ora-Plus and Ora-Sweet
4 °C 2.5 ± 0.2 100.5 ± 1.6 99.6 ± 1.9 100.1 ± 1.1 98.6 ± 2.4 99.9 ± 2.1 99.6 ± 2.4 98.9 ± 1.1 98.7 ± 2.7
25 °C 2.5 ± 0.1 100.1 ± 1.3 99.2 ± 1.6 99.3 ± 2.1 99.8 ± 1.2 99.3 ± 2.3 99.7 ± 2.0 98.3 ± 2.1 98.5 ± 2.7
aMean ± S.D. (n = 15).

256 Am J Health-Syst Pharm—Vol 63 Feb 1, 2006


least as good as it is after administra-
tion of the same drug in a tablet. An
important exception is if the liquid is
prepared from a tablet containing an
extended-release drug matrix; this is
not the case for sildenafil. Efficacy
and safety studies of a liquid dosage
form of sildenafil are not available to
date.
Conclusion
Sildenafil citrate 2.5 mg/mL in
two extemporaneously compounded
oral suspensions was stable for 91
days in plastic prescription bottles at
4 and 25 °C.
a
Viagra, Pfizer Inc., New York, NY, lot
2074603.
b
Children’s Hospital, Columbus, OH, lot
CH109608MG.
c
Humco Laboratory, Texarkana, TX, lot
88284E.
d
Paddock Laboratories, Minneapolis, MN,
lot 4E6462.
e
Paddock, lot 7L6459.
f
Polyethylenephthalate bottles, Owens-
Illinois, Toledo, OH.
g
White-Westinghouse, White Consolidated
Inc., Columbus, OH.
h
Lauda RM20, Brinkman Instruments,
Inc., Westbury, NY.
i
HP 1050 pump, Analytical Products
Group, Palo Alto, CA.
j
HP 1050 autosampler, Analytical Products
Group.
k 9. Erickson S, Reyes J, Bohn D et al. Sildena-
HP 1050 variable-wavelength ultraviolet-
light detector, Analytical Products Group.
l
Atlas, Thermo Electron Corporation,
Altrincham, Cheshire, United Kingdom.
m
Zorbax C 18 column, 3.0 × 150 mm,
MAC-MOD Analytical, Inc., Chadds Ford, PA.
n
Model 701A, Orion Research Inc., Boston,
MA.
o
Burrell Corp., Pittsburgh, PA.
p 11. Beavo JA. Cyclic nucleotide phosphodi-
Fisher Scientific, Pittsburgh, PA.
q esterases: functional implications of mul-
Fisher Scientific, lot 91090-24.
r tiple isoforms. Physiol Rev. 1995; 75:725-
Fisher Scientific, lot 910043-23.
s
Fisher Scientific, lot 906524-24.
t
Sigma Chemical Co., St. Louis, MO, lot
79F5609.
u
Mallinckrodt, Paris, KY, lot 8817KETG.
v
Burdick & Jackson, Division of Baxter,
Muskegon, MI, lot BS908.
REPORTS Sildenafil citrate oral suspensions
w
Gelman Sciences, Ann Arbor, MI, lot
0082205.
x
Sigma Chemical, lot 49H4070.
y
Malinckrodt Specialty Chemical Co.,
Chesterfield, MO, lot AB12KBSV.
z
Sodium hydroxide, Aldrich Chemical Co.,
Milwaukee, WI, lot 0011ODY.
aa
Hydrogen peroxide, Aldrich Chemical, lot
05427TX.
References
1. Rich S, Dantzker DR, Ayres SM et al. Pri-
mary pulmonary hypertension: a nation-
al prospective study. Ann Intern Med.
1987; 107:216-23.
2. D’Alonzo GE, Barst RJ, Ayres SM et al.
Survival in patients with primary pulmo-
nary hypertension. Results from a nation-
al prospective registry. Ann Intern Med.
1991; 115:343-9.
3. Rubin LJ. Primary pulmonary hyperten-
sion. N Engl J Med. 1997; 336:111-7.
4. Atz AM, Wessel DL. Sildenafil amelio-
rates effects of inhaled nitric oxide with-
drawal. Anesthesiology. 1999; 91:307-10.
5. Abrams D, Schulze-Neick I, Magee AG.
Sildenafil as a selective pulmonary va-
sodilator in childhood primary pulmo-
nary hypertension. Heart. 2000; 84(2):E4.
6. Atz AM, Lefler AK, Fairbrother DL et al.
Sildenafil augments the effect of inhaled
nitric oxide for postoperative pulmonary
hypertensive crises. J Thorac Cardiovasc
Surg. 2002; 124:628-9.
7. Kothari SS, Duggal B. Chronic oral
sildenafil therapy in severe pulmonary ar-
tery hypertension. Indian Heart J. 2002;
54:404-9.
8. Carroll WD, Dhillon R. Sildenafil as a
treatment for pulmonary hypertension.
Arch Dis Child. 2003; 88:827-8.
fil (Viagra) in childhood and neonatal
pulmonary hypertension. J Am Coll Car-
diol. 2002; 39:402A. Abstract.
10. Schulze-Neick I, Hartenstein P, Li J et al.
Intravenous sildenafil is a potent pulmo-
nary vasodilator in children with congen-
ital heart disease. Circulation. 2003;
108(suppl 1):II167-73.
48.
12. Das S, Kumar KN. Nitric oxide: its identi-
ty and role in blood pressure control. Life
Sci. 1995; 57:1547-56.
13. Sastry BK, Narasimhan C, Reddy NK et
al. Clinical efficacy of sildenafil in prima-
Am J Health-Syst Pharm—Vol 63 Feb 1, 2006
ry pulmonary hypertension: a random-
ized, placebo-controlled, double-blind,
crossover study. J Am Coll Cardiol. 2004;
43:1149-53.
14. Daraghmeh N, Al-Omari M, Badwan AA
et al. Determination of sildenafil citrate
and related substances in commercial
products and tablet dosage form using
HPLC. J Pharm Biomed Anal. 2001; 25:
483-92.
15. Buck ML. Sildenafil for the treatment of
pulmonary hypertension in children. Pe-
diatr Pharm. 2004; 10:1-4.
16. Stocker C, Penny DJ, Brizard CP et al.
Intravenous sildenafil and inhaled nitric
oxide: a randomised trial in infants after
cardiac surgery. Intensive Care Med. 2003;
29:1996-2003.
17. Prescott LM. Inhaled iloprost therapy ef-
fective in pulmonary arterial hyperten-
sion. Pulmonary Reviews. 2005; 10:1-4.
www.pulmonaryreviews.com/aug05/
iloprostPAH.html.
18. Bosentan. AHFS Drug Information.
American Society of Health-System Phar-
macists, Bethesda, MD. 2005:1728-9.
Appendix A—Procedure for
compounding methylcellulose 1%
1. Heat 200 mL of purified water, USP, to
boiling.
2. Add 200 mg methylparaben and 200 mg
propylparaben to the boiling water and mix well.
3. Wet 10 g of 4000-centipoise methylcellu-
lose powder and add it to the paraben–water
mixture. Allow to stand for 15 minutes, then
remove from heat.
4. Adjust to volume with cold purified wa-
ter while mixing well with a magnetic stirrer.
Keep mixing until the solution is clear and
homogeneous.
Appendix B—Procedure for
compounding sildenafil citrate
2.5-mg/mL suspension.
1. Place 30 25-mg sildenafil citrate tablets
into a mortar and reduce to a fine powder.
2. Mix 150 mL of Ora-Sweet with 150 mL of
Ora-Plus, or mix 150 mL of Simple Syrup, NF,
with 150 mL of methylcellulose 1%.
3. Add a small amount of the mixture to the
fine powder and mix into a uniform paste. Add
geometric amounts of the vehicle to the almost
desired volume while mixing. Transfer to a grad-
uated cylinder and adjust to volume while mix-
ing. Place in amber plastic bottles. Shake well
before use.
257