FT-IR SPECTROSCOPY OF INCLUSION COMPLEXES
OF β-CYCLODEXTRIN WITH FENBUFEN AND IBUPROFEN
I. BRATU1*, A. HERNANZ2, J. M. GAVIRA2, GH. BORA3
1
National Institute for Research and Development of Isotopic and Molecular Technologies,
Cluj-Napoca 5, P.O. Box 700, R-400293, ROMANIA
2 Universidad Nacional de Educación a Distancia,
Depto. de CC y TT Físicoquímicas, Madrid, E-28040, SPAIN
3 ICCF, Fabricii st. no.126, Cluj-Napoca, ROMANIA
* Corresponding author: ibratu@s3.itim-cj.ro
Received December 21, 2004
FT IR spectra for inclusion complexes of β-cyclodextrin with fenbufen and
ibuprofen reveal the complexation process. The C=O stretching spectral region is
used successfully to investigate this mechanism which implies strong restriction of
the C=O group inside cyclodextrin cavity. The breaking of the hydrogen bonds plays
an important role also.
Key words: infrared spectroscopy, inclusion complexes,
antiinflammatories, fenbufen, and ibuprofen.
cyclodextrins,
1. INTRODUCTION
Fenbufen (FEN, see Fig. 1) is an NSAID used in the treatment of rheumatic
diseases and represents a weak acidic molecule with low solubility in water.
Cyclodextrins (CDs), which are cyclic oligo saccharides and their hydrophilic
derivatives are used for improving the solubility and dissolution rate of poorly
water soluble NSAID.
Ph
C CH2 CH2 CO2H
Fig. 1. – Fenbufen molecule.
O

Paper presented at the 5th International Balkan Workshop on Applied Physics, 5–7 July
2004, Constanþa, Romania.
Rom. Journ. Phys., Vol. 50, Nos. 9– 1 0 , P. 1063–1069, Bucharest, 2005
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Few papers appeared as to be dedicated to the spectroscopic investigation
of the inclusion complex (IC) of FEN with β-CD [1–3] or their photophysical
and photochemical behaviour [4]. FEN is known to produce high incidence of
skin rashes so the photo physical properties and their correlation with toxicity
were recently investigated [5]. Due to its gastrointestinal irritation, FEN is
prepared as an inclusion complex with β-CD and the drug release was studied by
using it as suppository. In recent years the dermal route for drug administration
was intensely studied [3], but no detailed vibrational analysis of IC was done.
Ibuprofen (IBU, see Fig. 2) is also a NSAID, being very slightly soluble in
water, causing adverse reactions in oral administration [6].
Bu-i
Fig. 2. – Ibuprofen molecule.
HO 2 C
CH
Me
The present work is aimed at characterising, by means of infrared
spectroscopy, the structure of 1:1 β-cyclodextrin (β-CD) inclusion complexes
with the non-steroidal anti-inflammatory drugs (NSAID) FEN and IBU,
members of the propionic acid class. Two different methods of obtaining the
inclusion complexes of these drugs were used: the co-precipitation and the
freeze-drying (lyophylization) ones. The different solubility of these two drugs
in water at identical pH conditions was also taken into account.
2. EXPERIMENTAL
The following methods were used in order to prepare the mentioned IC: co
precipitation (co) and lyophylisation, i.e. freeze drying (fd) ones. Other method
of IC preparation that was recently used [7, 8] is consisting on the enhancement
of IBU dissolution via wet granulation with β-CD. Physical mixtures (pm) of
FEN or IBU and β-CD (1:1 molar ratio) were prepared also.
FT IR spectra were obtained using the KBr pellet technique; they were
collected with Bomem DA3 FT IR spectrometer, under vacuum in the 4000 to
400 cm–1 spectral range with a resolution of 2 cm–1. Good S/N ratios were obtained
by co adding 250 interferograms.
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FT-IR spectroscopy
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3. RESULTS AND DISCUSSION
The infrared spectra of the complexes, Figs. 3 and 4, were analysed and
compared with the spectra of the pure compounds and their physical mixtures,
respectively. The differences, which appear in the 1800–1600 cm–1 spectral
region, were analysed in terms of the implication of different molecular groups
of the guest and the host molecules in the inclusion process. A special attention
was paid to the 4000–2500 cm–1 region, where absorption bands of different
O-H groups present in these supramolecular assemblies appear.
Fig. 3. – FT IR spectra (4000–2500 cm–1) of FEN (_____), pm (------), co (.....),
fd (-.-.) and β-CD (-..-..).
4000–2500 cm–1
In this spectral region one identify, Figs 3 and 4, the ν(O-H) stretching
vibrational modes belonging to different OH groups, primary, secondary and
H-O-H ones, each giving typical absorption bands [9]. The effect of the guest
molecules on the position and intensities of these bands depends also [10] on both
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Fig. 4. – FT IR spectra (4000–2500 cm–1) of IBU (_____), pm (------),
co (.....), fd (-.-.) and β-CD (-..-..).
the size and the rearrangement of the guest within the host cavity. A frequency
increase can be due to the weakening of the hydrogen bond in the heptameric
host units. The hydrophobic molecules at the interface insert into the space
between the hydrophobic chains of the β-CD and enhance the amphiphilic
character of the CD [11]. In the 2800–3000 cm–1 one see the C-H stretching
bands, which are unchanged upon complexation.
1800–1600 cm–1
The most influenced bands of the FEN and IBU upon complexation are the
carbonyl group vibrations, see Figs. 5 and 6, respectively.
In the case of FEN two bands appear in this spectral region, one centred at
1711 cm–1 (peak 1, the carboxyl carbonyl) and another one, a doublet (peak 2),
centred on 1681 cm–1, assigned to ketone carbonyl. The intensity of the peaks 1
and 2 are reduced drastically (more for peak 1 than for peak 2) and broaden
considerably suggesting a stronger interaction between FEN and β-CD. One can
explain the frequency shift of the ν(C=O) band by the restriction of the C=O
group of FEN or IBU into the β-CD cavity. The drastic decrease of the intensity
of these two bands tends to explain the inclusion of these groups into the CDs
cavity. It has been recently established that FEN molecule is deeply included
into the β-CD cavity, the C=O group has to be located in a hydrophobic
microenvironment [1].
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Fig. 5. – FT IR spectra (1800–1600 cm–1) of FEN (_____), pm (------), co (.....),
fd (-.-.) and β-CD (-..-..); the right absorbance axis refers to FEN spectrum.
The assignment of the C=O stretching vibration of IBU was done by
comparison with the ketoprofen [12, 13]. The C=O stretching vibration appears
unchanged in IBU and pm (1723 cm–1) spectra but is shifted to a higher
frequency (1735.7 cm–1 with a shoulder at 1711.6 cm–1) in co-precipitated and in
lyophilised products and diminishes strongly in intensity as was recently
observed [13]. This frequency shift might be due to the breakdown of
intermolecular hydrogen bonding strengthened by ionic resonance, associated
with IBU dimers and the establishment of weaker forces, already reported [8, 14]
and the formation of a monomeric dispersion of drug as a interaction with the
hydrophobic cavity of CDs. Whereas for co spectrum these two bands appear
clearly, in the case of fd spectrum only a very broad band appears, suggesting an
increase of the amorphous state, typical for lyophilised products, as X-ray
diffraction [13] measurements demonstrate.
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Fig. 6. – FT IR spectra (1800–1600 cm–1) of IBU (_____), pm (------), co (.....),
fd (-.-.) and β-CD (-..-..); the right absorbance axis refers to IBU spectrum.
The complexation of IBU with β-CD leads to a considerably increase of
their solubility in water and has a stabilising effect [15] on the pharmacologically
active substance. In the case of FEN complexation with β-CD, the drug release
was considerably promoted when used together with some ointment bases [2, 3].
4. CONCLUSIONS
The fundamental changes which appear in the FT IR spectra of IC
complexes of FEN and IBU with β-CD are reflected mainly in the C=O stretching
spectral region. These changes suggest similar basic complexation mechanism
for both guest molecules included in the torus host cavity.
Acknowledgements. One of us (I.B.) is grateful to the NATO Science Committee for a Dc
type grant supporting his scientific stage in UNED, Madrid.
REFERENCES
1. S. Sortino, S. Giuffrida, S. Fazio, S. Monti, New J. of Chem., 25, 707–713, 2001.
2. H. Krasowska, L. Krówczynski, Pharmazie, 51, 353–358, 1996.
7
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
FT-IR spectroscopy
1069
H. Krasowska, D. Czechowska, I. Bura, Acta Pol. Pharm., 54, 25–30, 1997.
S. Sortino, L. J. Martinez, G. Marconi, New J. Chem., 25, 975–980, 2001.
S. Navaratnam, S. A. Jones, J. Photochem. Photobiol., A 132, 175–180, 2000.
G. M. Khan, J. Bi Zhu, J. Chinese Pharm. Sci., 7, 72–79, 1998.
M. Ghorab, M. Ch. Adeyeye, Pharm. Dev. Tech., 6, 305–314, 2001.
M. Ghorab, M. Ch. Adeyeye, Pharm. Dev. Tech., 6, 315–324, 2001.
O. Egyed, Vibr. Spectrosc., 1, 225–227, 1990.
J. E. D. Davies, V. A. Tabner, J. of Inclusion Phenom, and Macrocyclic Chem., 27, 177–190,
1997.
F. Witte, H. Hoffman, J. of Incl. Phenom. Macrocyclic Chem., 25, 25–28, 1996.
P,Mura, M. T. Faucci, P. L. Parrini, S. Furlanetto, S. Pinzauti, Int. J. Pharm., 179, 117–128, 1999.
P. Mura, G. P. Bettinetti, A. Manderioli, M. T. Faucci, G. Bramanti, M. Sorrenti, Int. J. Pharm.,
166, 189–203, 1998.
R. K. Janjikhel, C. M. Adeyeye, Pharm. Dev. Tech., 4(1), 9–17, 1999.
T. Hladon, J. Pawlaczyk, B. Szafran, J. Incl. Phenom. and Macrocyclic Chem., 36, 1–8, 2000.