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Current Drug Discovery Technologies, 2012, 9, 17-24

17

Quercetin-Phospholipid Complex: An Amorphous Pharmaceutical System


in Herbal Drug Delivery
Devendra Singh1, Mohan S.M. Rawat1,*, Ajay Semalty2 and Mona Semalty2
1

Department of Chemistry, H. N. B. Garhwal University, Srinagar (Garhwal) 246 174, Uttarakhand, India; 2Department
of Pharmaceutical Sciences, H. N. B. Garhwal University, Srinagar (Garhwal) 246 174, Uttarakhand, India
Abstract: Development of amphiphilic drug-lipid complexes is a potential approach for improving therapeutic efficacy of
the drugs by increasing solubility, release profile and oral bioavailability. Quercetin (3, 3', 4', 5, 7-pentahydroxyflavone), a
polyphenolic flavonoid, shows several biological effects like anti-inflammatory, anti-cancer, antiproliferative, antimutagenic and apoptosis induction but its use is limited due to its low aqueous solubility. To overcome this limitation, a
value added phospholipid complex of quercetin was developed to improve its aqueous solubility for better absorption
through the gastrointestinal tract and this might result in improved bioavailability. The quercetin-phospholipid complex
thus prepared was evaluated for various physico-chemical parameters like infra red spectroscopy (FT-IR), differential
scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), scanning electron microscopy (SEM) and solubility
study. The In vitro antioxidant activity was also studied. The phospholipid complex of quercetin was found to be fluffy
and porous with rough surface in SEM. FTIR, DSC and XRPD data confirmed the formation of phospholipid complex.
The water solubility of quercetin was improved by 12 folds (from 3.44 g/ ml to 36.81 g/ ml) in the prepared complex.
There was no statistical difference between the quercetin complex and quercetin in the In vitro anti-oxidant activity, indicating that the process of complexation did not adversely affect the bioactivity of the active ingredient.

Keywords: Amorphous product, antioxidant activity, phosphatidylcholine, phospholipid complex, quercetin, solubility
behavior.
1. INTRODUCTION
Upon oral ingestion, a drug is dissolved into the gastric
fluid (hydrophilic environment) initially followed by the
permeation across the biological membranes (lipophilic environment) and finally reaches the blood stream. Most of the
biologically active polyphenolic phytoconstituents are associated with the problem of either poor absorption or the poor
permeation through the biological membrane, thereby limiting their absorption and overall availability to the body system [1, 2]. Poor absorption may be due to their poor water
solubility. While the poor permeation may be due to the nature of structure of the drug (multiple-ring molecules like
many herbal drugs may be too large to be absorbed by
simple diffusion) or due to the poor miscibility with oils and
other lipids thereby, severely limiting their ability to pass
across the lipid-rich outer membranes of the enterocytes of
the small intestine [3, 4]. For good bioavailability, a herbal
drug must have an adequate hydrophilicity (for dissolution in
to gastrointestinal fluid) as well as an adequate lipophilicity
(to permeate across the lipidic biomembrane).
Flavonoids are a widely distributed group of polyphenolic compounds characterized by a common benzo-pyrone
structure. Flavonoids have a broad pharmacological profile
*Address Correspondence to this author at the Department of Chemistry, H.
N. B. Garhwal University, Srinagar (Garhwal) 246 174, Uttarakhand, India;
Tel: +91 1346 252229; Fax: +91 1346 252174;
E mail: msmrawat@gmail.com

1875-6220/12 $58.00+.00

such as anti-lipoperoxidant, anti-inflammatory, anticancer


and chemo preventive activities. Among these, quercetin
(3,3',4',5,7-pentahydroxyflavone, Fig. 1a) is a naturally occurring flavone mostly found in onion leaves, black and
green tea (Camellia sinensis), papaya shoots, green vegetables [5] and shows several biological activities like, antiinflammatory [6], anti-cancer [7, 8], renoprotective, neuroprotective and hypertensive effects [9-11]. In spite of this
wide spectrum of pharmacological properties, its absorption
and hence the bioavailability is limited due to its low aqueous solubility. The rate of release of a drug is a function of
its intrinsic solubility and is influenced by particle size, crystallinity, drug derivatization and formation of more-soluble
complexes [12-18]. Recently, natural polymers like phospholipids, polysaccharides and proteins have received much
attention in the pharmaceutical field owing to their good
biocompatibility and biodegradability [19-22].
Phospholipids (like phosphatidylcholine, Fig. 1b) play a
major role in drug delivery due to their amphiphilic nature
that can modify the solubility behavior and rate of drug release for the enhancement of drug absorption across the biological barriers. Development of amphiphilic drug-lipid
complexes may prove to be a potential approach for improving therapeutic efficacy of the drugs by modifying the solubility and release (sustained or controlled release) for improvement of oral bioavailability. These amphiphilic druglipid complexes are stable and more bioavailable with low
interfacial tension between the system and the gastrointestinal (GI) fluid, thereby facilitating membrane, tissue, or cell
2012 Bentham Science Publishers

18 Current Drug Discovery Technologies, 2012, Vol. 9, No. 1

wall transfer, in the organism [4, 23, 24]. Among the phospholipids, phosphatidylcholine (PC) is an important natural
carrier which can play a major role to improve solubility and
dissolution profile of the drug. It is compatible with pharmaceuticals, highly bioavailable and also exerts its own therapeutic benefits (like hepatoprotection). Moreover, it is also
an excellent emulsifier that enhances the bioavailability of
constituents with which it is co-administered [23, 25].
The present study deals with the development of quercetin-phospholipid complex with the aim of improving the
aqueous solubility of quercetin for better absorption through
the GI tract, which might result in improved bioavailability.
The prepared complex was characterized for various physico-chemical parameters FTIR, DSC, XRD, Solubility, SEM
and the In vitro antioxidant activity.
OH
O

HO

OH
OH

R2

CH2
O

CH2
P

CH2

The crystalline state of drug (quercetin) in the different


samples was evaluated with X-ray powder diffraction. Diffraction patterns were obtained on a Bruker Axs-D8 Discover Powder X-ray diffractometer (Germany). The X-ray
generator was operated at 40 KV tube voltages and 40 mA of
tube current, using the K  lines of copper (wavelength
0.1541 nm) as the radiation source. The scanning angle
ranged from 5 to 50o of 2 in step scan mode (step width
1o/min).

CH3

CH

C
O

2.5. X-Ray Powder Diffractometry

SEM imaging of the complex was performed using a


Scanning Electron Microscope (JEOL JSM 5600).

Thermograms of quercetin, phosphatidylcholine (80%)


and the quercetin-PC complex were recorded using a
differential scanning calorimeter (2910 Modulated DSC
V4.4E, TA Instruments, US). The thermal behavior was
studied by heating 2.0 0.2 mg of each individual sample in
a covered sample pan under nitrogen gas flow. The investigations were carried out over the temperature range 0-300 C
with a heating rate of 10C min-1.

2.6. Scanning Electron Microscopy

Quercetin

2.4. Differential Scanning Calorimetry

OH

R1

Singh et al.

CH2

CH3
CH3

Phosphatidylcholine

Fig. (1). (a) Quercetin (b) Phosphatidylcholine.

2. MATERIALS AND EXPERIMENTAL METHODS


2.1. Materials
Quercetin (95%) was purchased from Sigma Aldrich
Mumbai (India). Soya phosphatidylcholine (LIPOID S-80)
was obtained as a gift sample from LIPOID, Germany. Butylated hydroxy anisole (BHA) and 2, 2 diphenyl 1-picryl hydrazyl (DPPH) were purchased from E. Merck, Mumbai. All
chemical reagents were of analytical grade.
2.2. Method of Preparation
The quercetin-phospholipid complex was prepared by
refluxing the quercetin and phosphatidylcholine in (1:1) molar ratio. Both the reactants were placed in 100 ml round
bottom flask containing 20 ml of dichloromethane and the
reaction proceeded by refluxing the reaction mixture at 4550C until all the quercetin had dissolved. Thereafter the
volume of resulting solution concentrated to 2-3 ml and then
the sufficient amount of n-hexane was added to get the complex as amorphous product. The complex was filtered,
washed, dried under vacuum and stored in an air tight container until further use.
2.3. Infrared Spectroscopy
The IR spectra were recorded on a Perkin Elmer FTIR
RX-1 spectrophotometer in KBr tablets.

2.7. Apparent Solubility Study


Apparent solubility was determined by adding excess of
quercetin and quercetin-phospholipid complex to 5ml of
water or n-octanol in sealed glass containers at room temperature (25-30C). The liquid was agitated for 24 hours then
centrifuged for 20 min at 1,000 rpm to remove excess of
quercetin. The supernatant was filtered through a membrane
filter (0.45 m) then 1 ml filtrate was mixed with 9 ml of
distilled water or n-octanol to prepare dilutions and these
samples were measured at 322 nm UV spectrophotometrically.
2.8. Anti-Oxidant Activity
The free radical scavenging activity of quercetin and
quercetin complex was measured and compared with the
activity of BHA for free radical-scavenging ability using the
stable free radical DPPH [26, 27]. The free radical scavenging activities of quercetin, quercetin complex and BHA were
measured by decrease in the absorbance of methanolic solution of DPPH at 517 nm.
0.1 mM solution of DPPH in methanol was prepared and
1.5 ml of this solution was added to 3.5 ml methanolic solution of quercetin, quercetin-phospholipid complex and BHA
of different concentration (20-250 g/ml). Thirty minutes
later, the absorbance was measured at 517 nm. Lower absorbance of the reaction mixture indicates higher free radical
scavenging activity. The capability to scavenge the DPPH
free radical was calculated using the following equation:
DPPH Scavenged (%) = [(Acont - Atest) / Acont] x 100
Where, Acont = Absorbance of the control and Atest =
Absorbance in the presence of the sample of the
drug/complex.

Quercetin-Phospholipid Complex

Current Drug Discovery Technologies, 2012, Vol. 9, No. 1

19

3.1. Infrared Absorption

In case of quercetin, the main characteristic bands for the


hydroxyl (O-H) stretching at 3325cm-1, C=O stretching at
1614cm- 1and benzene ring vibrations near about 1522cm- 1
were observed. The FTIR of the complex showed the significant changes in the spectrum and the absorption peaks of
hydroxyl (O-H) and keto (C=O) group of the quercetin have
been shifted to higher wave number, whereas the P=O absorption band of the phosphatidylcholine remarkably broadened.

The possible interaction between quercetin and PC in the


phospholipid complex was studied by IR spectroscopy and
presented in Fig. (2). In IR spectra the characteristic C-H
stretching band of long fatty acid chain at 2918cm-1 and
2850cm-1, carbonyl stretching band at 1738cm-1, P=O
stretching band at 1236cm-1, P-O-C stretching band at 1091
cm-1 and N+ (CH3)3 stretching at 970cm-1 in phosphatidylcholine molecule.

The spectrum of the physical mixture was quite different


from the spectrum of the complex and showed same vibrational frequencies as that of the individual components and
seemed to be only a summation of both the constituents.
Therefore, the spectroscopic changes showed that, the shifting of hydroxyl and keto group frequencies of quercetin
from their original place accounts for the interaction of quercetin to polar end of the phospholipid.

3. RESULTS AND DISCUSSION


Due to the amorphous characteristics and improved solubility, the quercetin phospholipid complex may provide an
increased clinical value and absorb better than the free crystalline state of the drug in the gastrointestinal tract, which
could improve the overall availability of the drug within the
body.

50. 0

45

40

35

30
1468.74

%T

25
1236.30
1091.50

3435.63

20

1738.81

15

10

2850.22

2918.11

Ph ospholipiod-1
0. 0
4000. 0

3600

3200

2800

2400

2000

1800
cm -1

1600

1400

1200

1000

800

600

450.0

600

450.0

600

450.0

600

450.0

(a)
89. 0

85

80

75
1015.31

824.16

70

%T

2360.41

65

60
1385.28

1199.93

55
3325.06

1169.08
1319.87

50

1264.77

1522.24
1614.99

45. 0

Que rcetin

4000. 0

3600

3200

2800

2400

2000

1800
cm -1

1600

1400

1200

1000

800

(b)
82. 1
80

75

70

822.69

65

60
2360.34

55

1471.62
1653.66

3391.88

%T

1733.84

50

1199.95
1087.44

45

40

35

2850.49
2918.27

30

25. 0

Que rcetin Comple x (DCM)

4000. 0

3600

3200

2800

2400

2000

1800
cm -1

1600

1400

1200

1000

800

(c)
53. 5
50

45

40

35

721.52
970.76

30
%T

25
1468.02

20
1237.07
1091.28

15

3413.46

1739.56

10

2850.06
2917.82

0. 0

Que rce tin-Pc Phy . Mix.

4000. 0

3600

3200

2800

2400

2000

1800
cm -1

(d)

Fig. (2). IR spectra: (a) Phospholipid (b) Quercetin (c) Quercetin.

1600

1400

1200

1000

800

20 Current Drug Discovery Technologies, 2012, Vol. 9, No. 1

Singh et al.

3.2. Differential Scanning Calorimetry


Differential scanning calorimetry (DSC) is a fast and
reliable method to detect drug-excipient compatibility to
provide maximum information regarding the possible interactions. In DSC, an interaction is concluded by elimination
of endothermic peaks, appearance of new peaks and changes
in various parameters of thermogram (like peak shape, its
onset, peak temperature/ melting point and relative peak area
or enthalpy). The thermal curves of pure components (quercetin), phospholipid and of the drug-phospholipid system are
shown in Fig. (3).

pholipid may be melted during this phase, yielding a sharp


peak. This melting might have occurred in two phases which
subsequently gave another peak (107.90C) which is relatively less sharp. Quercetin in the DSC curve showed a sharp
endothermic peak at 122.38C. On the other hand, the complex showed a complete disappearance of the melting endothermic peaks of the individual components (quercetin,
phospholipid) with reduced enthalpy and melting points. It
showed a noticeable reduction in the enthalpy of 71.48 J/g
along with its lowest melting point (60.02C) in comparison
with free quercetin, indicating the formation of the complex
and supports to the previous study [28, 29].

Phospholipid showed two major endothermic peaks at


83.21C and 107.90C and a small peak at 64.45C. The first
one peak of phospholipids is mild peak (at 64.45C), which
is probably due to the heat-induced movement of phospholipids polar head group. The second (83.21C) peak is very
sharp and it appears due to phase transition from gel to liquid
crystalline state. The non-polar hydrocarbon tail of phos-

Reduction in melting point and enthalpy account for increased solubility and reduced crystallinity of the drugs [30,
31]. This phenomenon can be assumed the interactions between component and the phospholipid in the complex system and can be considered as indicative of drug amorphization and/ or complex formation as supported by IR spectroscopy results also.

(a)

(b)

(c)
Fig. (3). DSC Thermograms: (a) Phospholipid (b) Quercetin (c) Quercetin- Phospholipid Complex

Quercetin-Phospholipid Complex

Current Drug Discovery Technologies, 2012, Vol. 9, No. 1

3.3. X-ray Powder Diffractometry

21

amorphous state. Thus, XRD data supports the DSC studies


which indicated the reduced crystallinity of drug in the prepared complex by exhibiting lower values of enthalpy and
melting points and well supported by previous literature [3235]. As the amorphous form of the drug absorb better than
their crystalline counterpart [36, 37], the quercetinphospholipid complex may serve as a potential approach for
effective oral delivery of their parental analogue.

Fig. (4) shows the X-ray diffraction patterns of the quercetin, phospholipid and the complex. In the X-ray diffractogram quercetin showed intense diffraction peaks of crystallinity at a diffraction angle of 2 and suggested that the drug
is present as a crystalline material. The phospholipid showed
a single diffraction peak. A total drug amorphization was
induced by complex formation where X-ray diffraction patterns of quercetin-phospholipid complex were characterized
only by large diffraction peaks in which it is no longer possible to distinguish the characteristic peaks of the drug. The
results, confirmed that quercetin is no longer present as a
crystalline material and its phospholipid complex is in the

3.4. Scanning Electron Microscopy


The scanning electron micrographs of quercetin and the
complex are given in Fig. (5). The quercetin was characterized as needle-like crystals of smaller size and regular shape

(a)

(b)

(c)
Fig. (4). X-ray diffraction patterns: (a) Phospholipid (b) Quercetin (c) Quercetin-Phospholipid Complex.

22 Current Drug Discovery Technologies, 2012, Vol. 9, No. 1

Singh et al.

(a)

(b)

Fig. (5). SEM micrographs: (a) Quercetin (b) Quercetin-Phospholipid Complex.

with an apparently smooth surface. In contrast, a drastic


change in the morphology and shape of particles was observed in the phospholipid complex and showed fluffy, porous and rough surface, revealing an apparent interaction in
the solid-state which might have resulted in improved solubility and enhanced dissolution rate as compared to pure
drug.
3.5. Solubility Study
Quercetin is extremely hydrophobic (log P, 1.82 0.32)
[38] in nature and slightly soluble in aqueous media. Its poor
solubility leads to its poor absorption/ permeation across the
intestinal epithelial cells of the gastrointestinal (GI) tract
leading to low bioavailability of the drug. Aqueous solubility
of quercetin (3.44 g/ml) improved by 12 folds (36.81 g/
ml) in the prepared complex (Table 1). As an amphiphilic
surfactant, phospholipids could increase the solubility of the
drug by the action of wetting, dispersion and micellisation;
the phospholipid complexation increased the solubility behavior of herbal active due to the amphiphilic and amorphous nature of the product. Micellisation is an important
approach capable of solubilizing a hydrophobic drug in a
hydrophilic environment comprised of biodegradable drug
carrier micelle and a hydrophobic drug wherein the drug is
compatible and not strongly bonded to the polymeric drug
carrier micelle. The complex showed enhanced solubility
due to its amphiphilicity, which in turn may show the improved absorption across the biological barriers for improving oral bioavailability of the active component.

3.6. Anti-Oxidant Activity


Quercetin and its complex showed 90.76% and 89.82%
inhibition of DPPH at a concentration of 20 g/ml and
90.82%, 90.70% at a concentration of 200g/ml respectively. There was no statistical (n = 6, p  0.01) difference in
the percent inhibition of DPPH between quercetin and its
complex, on all the dose levels (Fig. 6). Therefore, the antioxidant activity of the quercetin remains unchanged even
after the complex formation and it can be concluded that the
process of complexation did not adversely affect the antioxidant activity of quercetin.
4. CONCLUSIONS
Based on the results of the study, it can be concluded that
the phospholipid complex may be considered as promising
drug delivery system for improving the bioavailability of the
quercetin molecule. The physicochemical properties of quercetin changed significantly after it was complexed with the
phospholipid and these characteristics especially, the improved solubility might contribute to improve oral absorpTable 1.

Solubility Study (H2O/ n-Octanol) at 25C

Sample

Aqueous Solubility

n-Octanol Solubility

(g/ml)

(g/ml)

Quercetin

3.44

52.17

Quercetin complex

36.81

51.92

Quercetin-Phospholipid Complex

Fig. (6). Anti-oxidant activity:

Current Drug Discovery Technologies, 2012, Vol. 9, No. 1

BHA;

Quercetin;

Quercetin-Pc Complex.

tion of the drug. Further, it was found that, there was no statistical difference in the percent inhibition of DPPH between
quercetin and its complex on all the dose levels. This indicates that, the bioactivity was maintained when quercetin
was complexed with phospholipid and the production process of the complex did not change or destroy the molecular
structure of active ingredient (quercetin) in the complex. As
these amphiphilic drug-lipid complexes have been reported
to be stable and more bioavailable, the phospholipid complex of quercetin may serve as a value added herbal drug
delivery system.

[6]

[7]

[8]
[9]

[10]

CONFLICT OF INTEREST
Declared none.

[11]

ACKNOWLEDGEMENTS
The authors are thankful to the Department of Science
and Technology, Government of India for the research grant
(SRSO/ HS/ 72/ 2006). The authors acknowledge LIPOID
GmbH Germany for providing the gift sample of phosphatidylcholine for the research work. Facilities provided by
UGC-DAE Consortium for Scientific Research, Indore (India), are gratefully acknowledged.

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Revised: April 21, 2011

Accepted: April 26, 2011

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