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Physicochemical Properties of Sildenafil Citrate (Viagra)
and Sildenafil Base
PETR MELNIKOV,
1
PEDRO P. CORBI,
2
ALEXANDRE CUIN,
2
MAURICIO CAVICCHIOLI,
2
WELLINGTON R. GUIMARA
˜ES
1
1
CCET, Department of Physics, UFMS, Cidade Universita
´ria s/n, CEP 79070-900, Campo Grande, MS, Brazil
2
Department of General and Inorganic Chemistry, Institute of Chemistry, UNESP, Rua Prof. Francisco Degni s/n, CP 355,
CEP 14801-970, Araraquara, SP, Brazil
Received 3 December 2002; revised 28 March 2003; accepted 1 April 2003
ABSTRACT: Sildenafil citrate (Viagra) [I] and sildenafil base [II] are easily and un-
equivocally characterized by a set of physicochemical methods that include X-ray
diffractometry, infrared spectroscopy, and thermal analysis. Monoclinic lattice con-
stants: [I]: a¼26.98 A
˚;b¼11.95 A
˚;c¼16.68 A
˚;b¼106.978. [II]: a¼8.66 A
˚;b¼34.27 A
˚;
c¼8.93 A
˚;b¼96.638. Both compounds decompose at 189.48C [I] and 251.98C [II].
Densities and refractive indices are given. ß2003 Wiley-Liss, Inc. and the American
Pharmacists Association J Pharm Sci 92:2140– 2143, 2003
Keywords: Viagra; sildenafil citrate; sildenafil base; bioinorganic chemistry
INTRODUCTION
Curiously enough, a vast number of publications
on 5-[2-ethoxy-5-(4-methylpiperazine-1-sulfonil)-
phenyl]-1-methyl-3 propyl-1,6 dihydro-pyrazolo
[4.3d] pyrimidine-7-one citric acid, more com-
monly known as Viagra or sildenafil citrate and
its precursor—sildenafil base—mention only the
preparation methods of pyrazolopyrimidin-one
derivatives, their in vitro biotransformations,
and clinical treatment of male erectile dysfunc-
tion. Meanwhile, recent publications indicate that
the usage of sildenafil citrate extends beyond
urological applications: it was proposed for treat-
ing central nervous system disorders, especially
Tourette’s syndrome
1
and showing a remarkable
activity as plant growth regulator.
2
However,
basic chemical characteristics of sildenafil citrate
and its base, such as crystal system and lattice
parameters, infrared (IR) spectra, and thermal
behavior have so far not been reported. X-ray
structural diffraction data are available only for
iso-Viagra
3
which is not exactly the agent used for
treatments. The present study, planned strictly
as laboratory research, reports on the physico-
chemical characteristics of both sildenafil citrate
(Structure 1) and sildenafil base.
2140 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 10, OCTOBER 2003
Structure 1. Structural formula of sildenafil citrate.
Correspondence to: Petr Melnikov (Telephone/Fax: 55-67-
345-7487; E-mail: petrmelnikov@yahoo.com)
Journal of Pharmaceutical Sciences, Vol. 92, 2140 –2143 (2003)
ß2003 Wiley-Liss, Inc. and the American Pharmacists Association
EXPERIMENTAL
Elemental analyses of carbon, hydrogen, nitro-
gen, and sulfur were performed using a CHNS-O
EA 1110 Analyzer. X-ray diffraction study was
performed using a Kristalloflex-Siemens diffracto-
meter, CuKaradiation, Ni filter. IR spectra were
recorded on an FT-IR Spectrophotometer Spec-
trum 2000 (PerkinElmer). Thermogravimetric
analysis (TGA) was performed under synthetic
air atmosphere, with a heating rate of 58C/min. A
TGA/50H-Shimadzu instrument was used for this
experiment.
Sildenafil citrate was not extracted from the
tablets but drug substance provided directly by
PFIZER Inc. as citrate salt (single substance,
information reference: UK-92480-10, lot number
RINR58-300-OB). Sildenafil free base was pre-
pared by adding 0.05M solution of NaOH drop-
wise to 0.02M solution of sildenafil until pH 8 was
achieved. The compound precipitates as a fine
crystalline powder. After being washed by decan-
tation, the precipitate was filtered off and dried
at room temperature over P
4
O
10
. Its composition
was confirmed by elemental analysis. Calc. for
C
22
H
30
N
6
O
4
S (%): C 55.68; H 6.37; N 17.70; S 6.74.
Found: C 55.80; H 5.97; N 17.71; S 5.61.
RESULTS AND DISCUSSION
Sildenafil citrate and sildenafil base are white to
off-white crystalline solids; densities 1.59 and
1.17 g/cm
3
. Under the microscope (100), silde-
nafil citrate shows characteristic well-defined
rod-shaped crystals with sharp ends that some-
times are brought together forming irregular
flat aggregates. On the contrary, sildenafil base
crystallinity is very poor. Average refractive in-
dices are 1.53 and 1.38, respectively. No single
crystals suitable for the full X-ray study could
be grown.
Powder diffractograms of sildenafil citrate and
sildenafil base are given in Figure 1. Patterns
do not change after thermal treatments at 50
and 1008C for 2 h. The indexations were success-
fully done on monoclinic cells. Calculated lattice
parameters are: sildenafil citrate: a¼26.98 A
˚,
b¼11.95 A
˚,c¼16.68 A
˚, and b¼106.968; sildenafil
base: a¼8.66 A
˚,b¼34.27 A
˚,c¼8.93 A
˚, and
b¼96.638. Their values have been deposited in
JCPDS database files. Calculated densities are
1.57 and 1.18 g/cm
3
, respectively; the number of
formula weights Zin both cases is 4.
As follows from these data, sildenafil citrate and
sildenafil base X-ray patterns are totally different
and unrelated, the unit cell of the former being
much larger than that of the latter. Their elemen-
tary units resemble quasi rectangular long strips.
X-ray phase analysis makes practicable an imme-
diate identification of these compounds by stron-
gest reflections at 6.12 and 17.13 A
˚for sildenafil
citrate and sildenafil base, respectively. It also al-
lows the possibility of controls for detecting the
traces of initial components in the manufactured
drug as a measure of its purity.
IR spectra of sildenafil citrate and sildenafil
base are reported in Figure 2. As a whole, they
are very similar because of the presence of intact
nitrogen containing rings and sulfone groups.
These last have almost identical stretching fre-
quencies: SO
2
(symmetric) sildenafil citrate
1174 cm
1
; sildenafil base 1170 cm
1
;SO
2
(asym-
metric) sildenafil citrate 1360 cm
1
; sildenafil
base 1351 cm
1
. A strong band at 1577 cm
1
in
the spectrum of sildenafil citrate is attributed
to the symmetric stretching frequency of COOH
groups belonging to citrate-ion. Naturally enough,
it disappears in the spectrum of sildenafil base
giving rise to a weak band at 1578 cm
1
which may
correspond to the previously overlapped angular
stretching frequency of the NH group.
4
The band
at 3310 cm
1
in the spectrum of the sildenafil base
is attributed to the NH symmetric and asym-
metric stretching. In the sildenafil citrate, this
band appears at 3300 cm
1
. A similar situation
takes place at the region 1703 cm
1
where the
asymmetric stretching frequency of the COOH
group of sildenafil citrate may be overlapped by
the band related to the stretching vibrations of
the isolated carbonyl (C–
–O) group. That is why its
intensity in the spectrum of sildenafil base is only
slightly diminished, being shifted to 1690 cm
1
.
Figure 1. Powder X-ray diffractograms of sildenafil
citrate (a) and sildenafil base (b).
PROPERTIES OF SILDENAFIL CITRATE AND BASE 2141
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 10, OCTOBER 2003
As postulated elsewhere,
5,6
the enlargement of
the CH and NH stretching vibration bands in
the region 2700–3600 cm
1
is usually due to the
presence of hydrogen bonds which are numerous
in the citrate complex and practically absent in
sildenafil free base. It provides a better resolution
of the sildenafil spectrum bands at 3105 cm
1
(very
weak), 2950 cm
1
(medium), and 2869 cm
1
(weak),
which may be assigned, respectively to –
–CH
aromatic, CH
3
asymmetric, and CH
3
symmetric
vibrations.
The TGA curve of sildenafil citrate is given in
Figure 3. The compound decomposes at 189.48C
with almost simultaneous melting of the decom-
position product. Because this temperature prac-
tically coincides with that of the decomposition of
pure citric acid (Fig. 3, box), we may conclude that
initially the compound is broken up and later its
anionic part is decomposed. These suggestions are
corroborated by a sharp endothermic peak 189.78C
observed on additionally registered differential
thermal analysis curve. Further confirmation is
given by the first mass loss of sildenafil citrate
which is equal to 27.2%, matching the value 28.8%
calculated for elimination of the citrate ion from
the complex. In this case, the phase remaining
after heating at 1908C should be sildenafil base
alone. Actually, the comparison with the TGA
curve of pure sildenafil base clearly shows that
thermal behavior of sildenafil citrate after 1908C
and that of sildenafil base is one and the same:
decomposition at 251.98C, incineration at 306 –
3108C, and gradual elimination of carbon parti-
cles until a complete ignition over 6008C. So the
characteristic melting points accompanied by
thermal decomposition are 189.48C for sildenafil
citrate and 251.98C for sildenafil base. These may
be taken as points of reference for rapid and re-
liable qualitative assays. The mechanism seems to
be similar to that of a-hydroxyacid complexes, in
particular the complexes with tartaric acid, where
tartaric anion is evolved in the form of an unstable
radical.
6
It is worth noting that differential thermal
analysis curve shows no endothermic peaks in the
range 22–1898C nor do X-ray powder diffracto-
grams exhibit unaccountable reflections, e.g.,
those not matching the pattern given by calculated
parameters. It proves that both sildenafil citrate
and sildenafil base do not undergo any phase
transitions and therefore no polymorph varieties
exist in the above interval.
CONCLUSIONS
Sildenafil citrate (Viagra) and sildenafil base are
easily and unequivocally characterized by a set
of physical methods including X-ray diffracto-
metry, IR spectroscopy, and thermal analysis
permitting the determination of lattice constants
and basic thermal parameters. No polymorph
forms were detected. Both compounds melt with
decomposition.
ACKNOWLEDGMENTS
The authors are grateful to Pfizer Inc. for having
supplied sildenafil citrate.
Figure 2. IR spectra of sildenafil citrate (a) and
sildenafil base (b).
Figure 3. TGA curves of sildenafil citrate (main
curve) and citric acid (box).
2142 MELNIKOV ET AL.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 10, OCTOBER 2003
REFERENCES
1. Graham R. 2000 Jun 13. U.S. patent 6,075,028.
2. Yokuyama T, Handa H. 2001 Mar 6. Japanese
patent 20 01,058,910-A.
3. El-Abadelah MM, Sabri SS, Khanfar MA, Voelter W,
Maichle-Moessmer C. 1999. X-ray structure of iso-
sildenafil (iso-Viagra). Z Naturforsch Teil B 54:
1323– 1326.
4. Silverstein RM, Bassler GC, Morrill TC. 1981.
Spectrometric identification of organic compounds.
New York: John Wiley & Sons.
5. Nakamoto K. 1997. Infrared spectra of inorganic and
coordination compounds, 5th ed. New York: John
Wiley & Sons.
6. Wendland WW. 1986. Thermal analysis, Vol. 19, 3rd
ed. New York: John Wiley & Sons.
PROPERTIES OF SILDENAFIL CITRATE AND BASE 2143
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 10, OCTOBER 2003
