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Contents lists available at SciVerse ScienceDirect

Vibrational Spectroscopy
journal homepage: www.elsevier.com/locate/vibspec

Water soluble complexes of curcumin with cyclodextrins: Characterization by

FT-Raman spectroscopy
P.R. Krishna Mohan, G. Sreelakshmi, C.V. Muraleedharan, Roy Joseph
Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Satelmond Palace Campus, Thiruvananthapuram 695012, Kerala, India

a r t i c l e

i n f o

Article history:
Received 31 October 2011
Received in revised form 10 April 2012
Accepted 2 May 2012
Available online xxx
Keywords:
Curcumin
Cyclodextrin
Freeze dried complex
Water soluble curcumin

a b s t r a c t
Many recent reports on curcumin, a polyphenol from Curcuma longa, provide mounting evidence on
the pharmacological activity of this natural product. However, the pharmaceutical use of this molecule is
hampered due to its poor solubility in the aqueous media. Inclusion complex formation with cyclodextrins
has been reported as a means to enhance its aqueous solubility. Most of these studies provide infrared (IR)
spectroscopic data as an evidence to support inclusion complex formation. However, characterization of
the solid inclusion complexes using IR spectroscopy is hindered due to interfering vibrations of cyclodextrin. In this study, fully water soluble complexes of curcumin with three hydroxypropyl derivatives of
cyclodextrins were isolated and characterized. Decrease in the intensity of aromatic ring vibrations and
shift in peak position from 1626 cm1 observed in Raman spectrum provided fresh insights into the type
of interactions occurring in the water soluble complex. A new structure for the inclusion complex has
been proposed. From the results it was demonstrated that Raman spectroscopy would provide clearer
and better evidence of inclusion complex formation.
2012 Elsevier B.V. All rights reserved.

1. Introduction
Turmeric, derived from the rhizome of Curcuma longa has been
used by the people of Indian subcontinent for centuries with no
known side effects, not only as a component of food but also to
treat a wide variety of ailments [1]. Curcumin is the phytochemical that gives yellow color to turmeric. Extensive research within
the last half century has proven that most of these activities, once
associated with turmeric, are due to curcumin [2]. Curcumin is
reported to have a number of pharmacological activities including
antioxidant, HIV antiproteases activity, anti-inammatory, analgesic, anticancer, etc. [3]. Of late, its potent antiamyloidogenic
effects in treating Alzheimers disease have ignited widespread
research interest on this drug [4]. Pre-clinical and clinical trials have
revealed that curcumin is safe even up to a dose level of 8.0 g/kg and
this makes it all the more important [5]. But the pharmaceutical use
of this pharmacologically potential molecule is restricted due to its
poor aqueous solubility, resulting in reduced bioavailability [6].
One way to increase its aqueous solubility is to form inclusion complexes, i.e., to encapsulate curcumin as a guest within the
internal cavity of a water soluble host [7]. Cyclodextrins (CDs) are
cyclic oligomers of glucose that can form water-soluble inclusion

Corresponding author at: Sree Chitra Tirunal Institute for Medical Sciences and
Technology, BMT Wing, Satelmond Palace Campus, Poojapura, Thiruvananthapuram
695012, Kerala, India. Tel.: +91 471 2520225; fax: +91 471 2341814.
E-mail address: rjoseph1965@rediffmail.com (R. Joseph).

complexes with small molecules or fragments of large compounds

[8]. Cyclodextrins have been used extensively in pharmaceutical
research and development, and there are numerous cyclodextrincontaining pharmaceutical products marketed worldwide. The
most common pharmaceutical application of CDs is to enhance
drug solubility in aqueous solutions. CDs are also used for increasing stability and bioavailability of drugs, and other additional
applications [9]. Many studies on enhancement of solubility of
curcumin with cyclodextrins have been reported [1013]. Recent
reports on curcumin cyclodextrin complexes show the vast amount
of research going on in this eld worldwide [1417]. Solubility enhancement is seen even in physical mixtures of drug and
cyclodextrin. This is attributed to the self aggregation of cyclodextrins in solution [18]. Formulation with a physical mixture rather
than a complex is desirable from a pharmaceutical processing viewpoint, since the steps involved in making the complex could be
skipped in the manufacturing process. But studies with physical
mixtures have shown that it resulted in an insignicant level or
complete lack of bioavailability enhancement [19]. Bioavailability
enhancement is reported to be possible for inclusion complexes
rather than physical mixtures [20]. Characterization of the solid
inclusion complexes formed is usually carried out using analytical techniques such as Fourier transform infrared spectroscopy
(FTIR), differential scanning colorimetry, nuclear magnetic resonance spectroscopy, X-ray diffraction (XRD) spectroscopy, etc. FTIR
spectroscopy is widely used for studying inclusion complex formation [21]. Changes in the peak intensity or shifts in the wave number
are indicative of complex formation. In recent papers [15,16] also

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Please cite this article in press as: P.R.K. Mohan, et al., Water soluble complexes of curcumin with cyclodextrins: Characterization by
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FTIR spectroscopy was used for studying the complex formed

between curcumin and hydroxypropyl beta cyclodextrin. However,
H O H deformation bands present in cyclodextrins mask spectral
bands in the desired regions of 16001700 cm1 . In both reported
studies, only vague details are given as evidence for formation of
inclusion complexes using FTIR spectroscopy.
Raman spectroscopy has advanced tremendously in recent years
and has found increased applications in the pharmaceutical industry. It is suggested to be an excellent tool for studying inclusion
complex formation [22]. Raman spectra of cyclodextrins present
regions free of bands that can be used as windows for monitoring relevant guest modes, such as the stretching vibration of
double bonds ((C C), (C O), etc.) and of aromatic C H bonds
[23,24]. Spectral responses in the region 16001700 cm1 are quite
unique indicators for the presence of unsaturation in a molecule
and often indicate the presence of drug component within an excipient matrix [25]. Although Raman spectral study of curcumin has
been reported earlier [26,27], it has still not been used for characterizing curcumincyclodextrin solid inclusion complexes.
Freeze-drying is a widely used complexation technique
especially useful for heat labile guests and water soluble hydroxypropylated cyclodextrin complexes [28]. The stoichiometry
between cyclodextrins and curcumin has been studied by Tang et al.
[12] and reported to be 2:1. This has been conrmed by uorescence
measurement studies [10]. In this study, inclusion complexes of
curcumin with three derivative cyclodextrins were studied using
Raman spectroscopy. CDs and curcumin were taken in the molar
ratio 2:1 and fully soluble complexes were freeze dried and used
for Raman spectroscopic studies. Complexes were also prepared by
co-evaporation technique to generate supporting information.
2. Experimental
2.1. Materials
Curcumin, trade named BiocurcumaxTM , used for this study
was obtained from M/s. Arjuna Naturals Ltd., Aluva, Kerala State,
India. Hydroxypropyl derivatives of parent cyclodextrins, namely,
hydroxypropyl alpha cyclodextrin (HPCD), hydroxypropyl beta
cyclodextrin (HPCD) and hydroxypropyl gamma cyclodextrin
(HPCD), were procured from Sigma Aldrich, USA. Ethanol (99.9%
absolute) was procured from M/s. SD ne Chemicals, Mumbai. All
the above compounds were used without further purication.
2.1.1. Methods used for the preparation of complexes
Water soluble inclusion complexes and physical mixtures of
cyclodextrins and curcumin were prepared by taking both compounds in the molar ratio 2:1, respectively. Inclusion complexes
were prepared by freeze drying technique according to a method
reported elsewhere with slight modication [29]. In brief, 1 g CD
was dissolved in 30 ml water taken in a 250 ml stoppered conical ask. The solution was stirred for 10 min till a clear solution
was obtained. Curcumin was added to this solution, shaken well
and placed in an incubator shaker for 7 days at 37 C. The reaction
mixture was ltered through 0.45 m lter and the clear solution
was taken. The ltrate thus obtained was freeze dried to obtain
the solid complexes. The red colored complex thus obtained were
ground to a ne powder and kept in a desiccator for characterization. Physical mixtures of curcumin and CDs were prepared by
thoroughly mixing both compounds in a pestlemortar for a period
of 1 h. Curcumincyclodextrin complexes and physical mixtures
were prepared with HPCD, HPCD and HPCD. In order to study
the effect of mole ratio on the characteristics of the resultant product, HPCD and curcumin were taken mole ratio 1:1 and a batch of
freeze-dried complex was prepared as per the procedure described

above. Inuence of method of preparation on the characteristics of

the complex formed was studied by preparing the complex by coevaporation technique. For this, HPCD and curcumin were taken
in the mole ratio 2:1 and individually dissolved in ethanol. Both
solutions were mixed together in an amber colored beaker and
stirred at 45 C until it turned into a paste. The paste was further
dried at 40 C under vacuum for a period of 48 h. The dry powder
obtained was sealed in an aluminum foil to protect it from light and
stored in a desiccator.
2.2. Characterization techniques
2.2.1. FTIR spectroscopy
FTIR spectra of curcumin, cyclodextrins, physical mixtures and
complexes were recorded on a Bruker IR spectrophotometer,
Model-500. The scanning range used was 4504000 cm1 with 32
scans and resolution was set at 4 cm1 . Diffuse reectance method
was used here with TGS detectors.
2.2.2. FT Raman spectroscopy
The room temperature FT-Raman spectra were recorded on a
RFS-100 Bruker FT spectrometer using a Nd:YAG laser with the
excitation wavelength of 1064 nm. Each spectrum is the average
of two repeated measurements of 200 scans each and of 2 cm1
resolution. Laser power of the source was maintained at 100 mW
throughout all measurements and a liquid nitrogen cooled Ge
detector was used.
2.2.3. XRD spectroscopy
The patterns of pure curcumin, HPCD and freeze dried complex
of curcumin with HPCD were obtained using the X-ray diffractometer (XPERT PRO) with Cu radiation source. Measurements
were performed at a voltage of 40 kV and 30 mA. The scanned angle
was set from 10 2 70 and the scan rate was 2 min1 .
2.2.4. UVVis spectroscopy
Curcumin content in the complex was determined by using
a UVVis spectrophotometer (model UV-1800, Shimadzu, Japan).
For this 10 mg complex was dissolved in 10 ml of ethanol and the
absorbance of the solution at 430 nm was recorded. The curcumin
content was estimated from a standard XY plot of curcumin (dissolved in ethanol) vs. concentration. The path length of the quartz
cell was 10 mm. For each measurement the baseline was established by placing blank ethanol in the reference compartment. All
measurements were carried out at 25 1 C.
2.2.5. Differential scanning calorimetry (DSC)
DSC measurements were carried out in a DSC Q100 V9.6 Build
290 differential scanning calorimeter (TA Instruments Inc., USA)
based on ASTM E 537-07 standard. Heating rate employed was
10 C/min and the samples were scanned in the temperature range
25210 C. The measurements were carried out under dry nitrogen
at a ow rate of 50 5 ml/min.
3. Results and discussion
Although many studies have been carried out on
curcumincyclodextrin complexes, characterization of fully
water soluble complexes have not been reported yet. Characterization techniques used in earlier studies, especially FTIR, could
not provide adequate evidence for inclusion complex formation
[15,16]. The method used for preparing inclusion complexes
is another important factor to be considered. In the present
study, the soluble curcumincyclodextrin complexes were ltered
through 0.45 m lter in order to remove any insoluble curcumin
present. The ltrate thus obtained, was freeze dried to obtain solid

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Fig. 1. FTIR spectrum of curcumin.

Fig. 2. FTIR spectra of cyclodextrins. (a) HPCD, (b) HPCD and (c) HPCD.

complexes. In all earlier reported studies the investigators had

not ltered out their complexes with curcumin and as a result the
characterized products were mixtures of uncomplexed curcumin,
complexed curcumin and uncomplexed cyclodextrin. Due to this
reason FTIR spectral study used in the earlier reported works is not
likely to provide adequate information on the inclusion complex
formation.

in Table 1. As expected, the IR spectrum of the physical mixture

(Fig. 3b) contained peaks corresponding to both the components
(Fig. 3a and d) present. IR spectrum of HPCD (Fig. 3d) and that
of freeze dried complex (Fig. 3c) appear identical. Since the complex is fully soluble in water signicant changes in the IR spectra
such as shift in peak positions were anticipated. The sharp peak at
3508 cm1 due to free hydroxyl (OH) group of curcumin (Fig. 3a),

3.1. FTIR spectroscopy

3.1.1. FTIR spectrum of curcumin
A detailed study on the vibrational spectra of curcumin has been
reported earlier by Kolev et al. [26]. The FTIR spectrum of curcumin is shown in Fig. 1. A broad peak at 3293 cm1 and the sharp
one at 3508 cm1 indicate the presence of OH. The strong peak at
1626 cm1 has a predominantly mixed (C C) and (C O) character [26]. Another strong band at 1601 cm1 is attributed to the
symmetric aromatic ring stretching vibrations (C Cring ) [27]. The
1508 cm1 peak is assigned to the (C O), while enol C O peak
was obtained at 1272 cm1 , C O C peak at 1023 cm1 , benzoate
trans-CH vibration at 959 cm1 and cis CH vibration of aromatic
ring at 713 cm1 .
3.1.2. FT-IR spectra of cyclodextrins
The overlaid FTIR spectra of HPCD, HPCD and HPCD are
given in Fig. 2. The FTIR peaks of all the hydroxypropyl derivatives
of cyclodextrins are almost identical with slight variations in their
intensities. The OH group stretching vibrations at 33003400 cm1
is a characteristic peak of the cyclodextrins. An intense peak
at 2929 cm1 due to C H assym/symm stretching is seen. The
H O H deformation bands of water present in cyclodextrins
are seen at 1658 cm1 . C H overtone stretching vibrations are
seen at 1155 cm1 and 1082 cm1 , while at 1082 cm1 C H, C O
stretching vibrations are present. Absorption at 1300700 cm1
corresponds to skeletal C C vibrations and that at 1155 cm1
corresponds to C O C vibrations. Since there are no signicant
variations in the spectra of different derivative cyclodextrins, complexes of curcumin with HPCD was selected for detailed analysis.
3.1.3. FT-IR spectra of physical mixture and freeze dried complex
FT-IR spectra of curcumin, HPCD, physical mixture of curcumin
and HPCD and the freeze dried complex of curcumin with HPCD
are shown in Fig. 3. The peak assignments of all the spectra are given

Fig. 3. FTIR spectra of: (a) curcumin, (b) physical mixture (curcumin + HPCD),
(c) freeze dried complex (curcumin + HPCD) and (d) HPCD. [*] Indicates that
peaks due to (C Cring ) and mixed (C C), (C O) are masked due to the OH peaks
of cyclodextrin.

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Table 1
IR peak assignments of curcumin [26], HPCD, physical mixture (PM) and freeze dried complex (FDC).
Curcumin  [cm1 ]

HPCD  [cm1 ]

PM  [cm1 ]

FDC  [cm1 ]

3360

3360

3360

2929
1658

2928

2929
1658

3508
3293
2972
2945

1626
1601
1508
1429

1372
1272

1530

1458
1367

1626
1601
1510
1429

1516

1456
1367

1155

1367
1280
1155

1082
1032

1082
1031

1082
1032

944
851
753
711

948
852
753
711

950
851
753
711

1155

1150

1023
959
852
713

is found to have merged with broad OH peak of HPCD present at

3360 cm1 . It may be argued that merging of the peaks is due to
the interactions that occur with cyclodextrin during complex formation. However, it may be counter-argued that only the broad
peak of HPCD is present and there is no evidence of complex formation. Moreover the curcumin content in the complex is very low.
Other aspects that are usually taken as evidence of complex formation are peak shifts of aromatic C C at 1601 cm1 and that of the
carbonyl C O peaks at 1626 cm1 . But the molecular vibrations of
cyclodextrins in the range 17001550 cm1 mask these peaks. The
(H OH) bending of water molecules attached to cyclodextrins has
a broad and intense band at 1658 cm1 and this overlaps with other
useful vibrations associated with complex formation. The peak at
1508 cm1 due to the (C O), (CCC) and (CC O) seen in the case
of curcumin and physical mixture undergoes a shift to 1516 cm1
in the case of freeze dried complex and this may be taken as an
evidence of complex formation but the intensity is too low to be
unambiguously detected. The peaks due to (CCH) of the phenol
and skeletal (CCH) at 1150 cm1 due to in-plane bending vibrations are masked by the C O vibrations of the cyclodextrin [16,26].
The in-plane bending vibrations of aromatic keto group (CCH) and
out of plane vibrations of CH3 , i.e., (CH3 ) found at 1023 cm1 ,
out of plane bending of skeletal CCH and the aromatic CCH at
852 cm1 of curcumin are masked by the C O C glucose units
and the ring structure C O C peak of cyclodextrin [16,26]. The
peaks at 713 cm1 of aromatic in plane bending, stretching vibrations of C C and in plane bending of skeletal CCH of curcumin are
masked by corresponding vibrations of cyclodextrin. The peak at
1272 cm1 due to aromatic keto in plane vibrations (CCH), (CCC)
and keto-enol (COH) are found to have merged with IR vibrations
of HPCD molecule. In short all the major peaks of curcumin shown
in Fig. 3 are hidden by the cyclodextrin peaks in the similar regions.
Thus, IR spectroscopy fails to explain inclusion complex formation
of curcumin in detail.

Peak assignment
OH stretching of phenol group, intra-molecular H bond
OH stretching
CH stretching, intermolecular H bond stretching
Asymmetric CH stretch of CH3
CH stretch of OCH3
Asymmetric CH stretching of CH2
HOH of water of crystallization, C C stretching
C O, Cring C C stretching
Aromatic C C stretching
C O stretching, CCC, CC O in plane bending
In plane bending of aromatic (CCC, CCH), enolic (COH), CH in plane
bending due to CH2
In plane bending of CH3
In plane bending of CH, enolic COH, skeletal CCC
CH in plane bending of C CH, aromatic C O stretching
CH overtone stretching, C O C stretching
In plane bending of aromatic CCH, skeletal CCH
C O, C C stretching, in plane bending of OCH
C O, C C, CCO, C O C stretching of glucose units
C O C stretching, out of plane bending of CH3 , in plane bending of
aromatic CCH
C O stretching, in plane bending of CCH
CH out of plane bending of aromatic CCH and skeletal CCH
Skeletal C C stretching, CH out of plane bending
In plane bending of skeletal CCH and aromatic CCH, C C stretching

reported for characterizing curcumincyclodextrin solid inclusion

complexes. Raman spectrum of curcumin is shown in Fig. 4. Studies suggested that curcumin exists in the enol form rather than
in the diketone form [30]. This is indicated by the absence of
(C O) peaks in the region of 16501800 cm1 in our studies. The
bands corresponds to (C C) and (C O) appear to be superposed
at 1626 cm1 having been reduced from their normal values by
conjugation. This band with a mixed (C C) and (C O) character was selected for analysis in the present study. Another strong
band, the 1601 cm1 due to aromatic ring vibrations (C Cring ) was
also selected for studying the inclusion complex formation of curcumin with cyclodextrin derivatives. Raman spectra of curcumin,
HPCD, physical mixture of both curcumin and HPCD and freeze
dried complex of both were analyzed and compared in Fig. 5. As
the Raman intensities of HPCD (Fig. 5d) are very weak, the spectrum of the physical mixture appeared to be identical to that of
curcumin (Fig. 5a and c). In the case of curcuminHPCD freeze
dried complex (Fig. 5b), the peak at 1626 cm1 has shifted towards
1635 cm1 . This indicates that strong interactions have occurred

3.2. Raman spectroscopy

Raman spectroscopy has been used in earlier studies for the
characterization of both inclusion complexes [25] and curcumin
[26]. However, use of Raman spectroscopy has not yet been

Fig. 4. Raman spectrum of curcumin.

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Fig. 6. Raman spectrum of curcumin overlaid with curcuminHPCD complexes:

(a) curcumin, (b) freeze dried complex 1:1 mole ratio, (c) freeze dried complex
2:1 mole ratio, and (d) co-evaporated complex 2:1 mole ratio.

Fig. 5. Raman spectra of: (a) curcumin, (b) freeze dried complex of curcumin with
HPCD, (c) physical mixture of curcumin with HPCD, and (d) HPCD.

between curcumin and HPCD. As a result of inclusion complex

formation with HPCD, the conjugation of (C C) and (C O) is
reduced considerably resulting the peak shift towards 1635 cm1 .
The ring strain of cyclodextrin also contributes to this shift. This
shift in peak position was observed irrespective of the molar ratios
taken for complexation and the method used for complexation.
Fig. 6 compares the spectra obtained from the complexes prepared by taking HPCD and curcumin in the mole ratios 2:1 and
1:1. The Raman spectrum of co-evaporated complex is also overlaid for comparison. These results suggest that peak shift is the
direct result of complex formation. Sanphui et al. [31] reported a
similar shift in peak position when commercial curcumin was cocrystallized with 4-hydroxypyridine from ethanol solution at room
temperature. They found that a different polymorph of curcumin
that exists in orthorhombic state was formed on co-crystallization
with 4-hydroxypyridine.
Molecules in the commercial curcumin crystallize in monoclinic lattice and exist in a curved, slightly twisted conformation
whereas in the orthorhombic form the molecules exhibit a linear
and planar conformation [31]. In the monoclinic form there are phenol O H O hydrogen bonds on both sides to different molecules
which are in turn connected to a fourth curcumin molecule in
a macrocyclic hydrogen bond ring. However, due to the linear
molecular shape no such ring motif could be dissected in the
orthorhombic form [31]. Weak C H O interactions also play an
important role in the overall molecular aggregation of both crystal
forms. Since the curcuminHPCD complex is fully water soluble,
it is likely that two types of interactions occur here: One is inclusion

complex formation and other is the type of interactions postulated

by Sanphui et al. for the orthorhombic form of curcumin. In the
presence of cyclodextrin derivatives one end of the curcumin goes
into the cyclodextrin cavity [10] and the enolic part of curcumin
undergoes OH O bond with the hydroxyl groups of cyclodextrin.
The other end of the curcumin would interact with neighboring
curcumin molecule by their respective phenolic OH groups forming OH O linkages. Weak CH O interactions are also possible
between CH3 O of one molecule with OCH3 of the other. The entry
of one end of curcumin molecule into the cavity of cyclodextrin
and the molecular interactions of the type discussed above for
the orthorhombic polymorph of curcumin may contribute to the
increased solubility of the complex. The peak shift observed in the
case of complex from 1626 cm1 to 1635 cm1 is probably due to
the interaction between the hydroxyl group of cyclodextrin and
enolic OH of curcumin (Scheme 1). The Raman spectra of commercial curcumin and physical mixture of curcumin with cyclodextrin
shown in Fig. 5 display no peak shift from 1626 cm1 to 1635 cm1
like that is seen in the freeze dried system. It is evident that there
is no polymorph formation or complexation in the physical mixture. This conrms that in freeze dried complexes there exists high
level of molecular interaction between curcumin and the respective cyclodextrins. Similar effect is seen in the Raman spectrum of
HPCD complex and HPCD complex (Fig. 7).
An interesting evidence for inclusion complex formation is
provided by the symmetric aromatic ring stretching vibrations
(C Cring ) of curcumin at 1601 cm1 (Fig. 7). The intensity of
the 1601 cm1 peak is considerably reduced suggesting that the
aromatic ring has gone inside the cavity of the cyclodextrin as postulated by Baglole et al. [10]. Though a decrease in the peak intensity
of (C Cring ) was observed in the case of polymorphs of curcumin

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Scheme 1. Proposed inclusion complex formation of curcumin with cyclodextrin.

by Sanphui et al. [31], their decrease in peak intensity was associated with a peak shift of about 9 cm1 . In the present case little
shift in peak position was observed and we can expect a different
type of interaction. It is likely that when the complex is formed the
benzene ring at one end of the curcumin will move into the cavity
of cyclodextrin where the enolic OH of curcumin form OH O bond
with the hydroxyl group of the cyclodextrin. This is depicted as a
cartoon in Scheme 1.
The cyclodextrin cage may restrict the aromatic vibrations in
Raman spectra leading to decreased peak intensity. The intensities
of the peak at 1601 cm1 (I1601 ) of curcumin and complexes, shown

in Fig. 7, were compared with the intensities of peak at 1626 cm1

(I1626 ) (for curcumin) or that at 1635 cm1 (I1635 ) (for the complexes). When the ratio I1626 /I1601 was calculated the value was
found to be 0.59 for curcumin (Table 2). However, for the complexes the ratio, I1635 /I1601 was 1. The decrease in intensity of
(C Cring ) stretching modes of aromatic ring motifs of curcumin in
the freeze dried complex suggests the presence of a surrounding
obstacle opposing the Raman active vibrational mode. The reduction in intensity is apparently due to shielding of the benzene ring
under the inuence of the cyclodextrin cavity. Quenching of the
guest structural electron polarisability occurs due to the interaction
with the frozen localized electron density of the polar carbohydrate
host. This clearly suggests that the aromatic ring of the curcumin
moiety gets included in the cyclodextrin cavity. The aromatic group
at the other end of the molecule is not entrapped in the cyclodextrin cavity and this would interact with neighboring molecules in
a linear pattern and exist in a water soluble polymorphic form.
The curcumin content in the complexes was determined by
UVVis spectroscopy and the data obtained is shown in Table 2.
Though the Raman spectra of all complexes appear similar, the
curcumin content in the complexes are widely different. Based on
the curcumin content obtained, the complex formation efciency
of hydroxypropyl derivatives of cyclodextrins may be rated in the
order: HPCD < HPCD < HPCD.
3.3. XRD analysis
The XRD spectra of curcumin, HPCD and freeze dried complex
of curcumin with HPCD are shown in Fig. 8. Results reveal that the
commercial curcumin exists in a crystalline form whereas HPCD
is amorphous in nature. In the case of freeze dried complex, the
spectrum exhibits features of a compound that lacks a well dened
crystalline structure.
3.4. Differential scanning calorimetry

Fig. 7. Raman spectra of freeze dried complexes of curcumin with , , and

hydroxyl propyl cyclodextrins: (a) HPCD complex, (b) HPCD complex, (c) HPCD
complex, and (d) curcumin.

DSC is a very useful tool for collecting qualitative information on

the physico-chemical state of guest in a complex where hostguest
interactions take place [15]. The complex formation with a guest
molecule may result complete disappearance of endothermic peak
or shifting of peak to the other temperatures indicating changes
in crystal lattice, melting, boiling or sublimation points. Since
HPCD has shown to have the highest complexation efciency,
HPCDcurcumin complex was used for DSC analysis. Thermograms of curcumin, HPCD, physical mixture and freeze dried
complex are overlaid and are shown in Fig. 9. DSC thermogram
of curcumin (Fig. 9a) shows an endothermic peak at 175.26 C indicating the melting of curcumin. Thermogram of HPCD (Fig. 9b)
shows a broad peak at 84.28 C due to loss of water. Being

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Table 2
Raman intensity values and curcumin content in the freeze dried complexes.
Sample details

Absorption band
position A

Raman
intensity IA

Absorption band
position B

Raman
intensity IB

IA /IB

Curcumin content
in the complex/%

Curcumin
HPCD:Curcumin (2:1) complex
HPCD:Curcumin (2:1) complex
HPCD:Curcumin (2:1) complex

1626
1635
1635
1635

3.747
0.022
0.021
0.081

1601
1603
1604
1601

6.304
0.022
0.018
0.072

0.59
1.00
1.17
1.13

0.47
0.30
2.39

Complex formation increased the bulk of curcumin molecule and

prevented close packing and crystallization of curcumin. Thus, the
data obtained from DSC supported molecular level interactions and
inclusion complex formation in water soluble cyclodextrin curcumin complexes.
4. Conclusion

Fig. 8. XRD spectra of: (a) HPCD, (b) freeze dried complex of curcumin with HPCD
and (c) curcumin.

Raman spectroscopy provided clear and distinct evidence for

inclusion complex formation of curcumin with derivative cyclodextrins. Absence of Raman signals in cyclodextrin in the region
15001800 cm1 provided an opportunity to reveal shift in the
Raman bands of curcumin due to complex formation. Curcumin
absorbed strongly in the Raman region and the molecular interactions occurred in the complex could be studied even when the
curcumin content in the complex was below 1 wt.%. Decrease in
the intensity of aromatic ring vibrations and shift in peak position from 1626 cm1 could be taken as the evidence of inclusion
complex formation. Complexes were found to be formed when
CDs and curcumin were taken in the mole ratio 2:1 and 1:1. Coevaporation technique also yielded inclusion complex. XRD and
DSC data showed that water soluble complex formed was amorphous in nature.
Acknowledgements

amorphous, it did not show any melting endotherm. Physical mixture shows peaks corresponding to the melting of curcumin and
loss of water from HPCD (Fig. 9d). However, shift in peak positions are observed in this case and the melting peak is not very
sharp. It may be noted that the curcumin content in the physical
mixture was only 10 wt.%. The dilution effect by HPCD contributed
to the sharp decrease in intensity of the melting peak and its shift
towards higher temperatures. Thermogram of freeze dried complex
appears exactly like that of HPCD. The total absence of melting
endotherm of curcumin indicates that changes occurred in the
molecular level prevented crystallization of curcumin molecule.

Fig. 9. DSC analysis of: (a) curcumin, (b) HPCD, (c) freeze dried complex of curcumin with HPCD, and (d) physical mixture of curcumin with HPCD.

Authors wish to acknowledge Dr. V.K. Krishnan for the provision of spectroscopy data. They also thank the Director, SCTIMST,
Trivandrum for the facilities extended and the kind permission to
publish this work.
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