Studies on Occlusion Complexes of Aceclofenac with β-Cyclodextrin
and Hydroxypropyl -β- Cyclodextrin
Patil GB*1,
Deshmukh PK2 and Belgamwar VS1
1Department
of Pharmaceutics,
2H.R.Patel
Women’s College of Pharmacy, Near Karwand Naka, Shirpur, Dist-Dhule-425405,
ABSTRACT
The present study is aimed at improving the dissolution of poorly water
soluble Aceclofenac by complexation
with β-cyclodextrin and Hydroxypropyl-β-cyclodextrin. Bioavailability of such drug may be enhanced
by improving its solubility and dissolution rate. The objective of present
study is to increase the solubility and dissolution rate of Aceclofenac
by preparing its occlusion complexes with β-cyclodextrin
and Hydroxypropyl-β-cyclodextrin
in different molar ratios using kneading method. The prepared complexes were
characterized for drug content, differential scanning calorimetry,
FTIR spectral studies, phase solubility and in-vitro
dissolution profile. DSC and FTIR spectral studies performed on solid complexes
have confirmed the inclusion complexation between
drug and Cyclodextrins. It has been observed that
solubility and dissolution rate increased to greater extent for Hydroxypropyl-β-cyclodextrin
than β-cyclodextrin and that of pure drug.
KEYWORDS: Aceclofenac, β-cyclodextrin, Hydroxypropyl-β-cyclodextrin, Inclusion complex, DSC, FTIR, solubility,
Dissolution Enhancement.
INTRODUCTION
The poor
dissolution of relatively water insoluble drugs has long been a problem in the
formulation of oral dosage forms, which affect rate of absorption and
bioavailability. Several approaches have been followed in improving solubility
of drugs, one being complexation using cyclodextrin and its derivatives. Cyclodextrin
and its derivatives play an important role in formulation development due to
their effect on solubility, dissolution rate, chemical stability and absorption
of drugs. Aceclofenac (Brodgen and Wiseman, 1996) (AC) is a new generation nonsteroidal anti-inflammatory (NSAID) drug. According to biopharmaceutics classification system, it is a BCS class
II. The pharmacokinetic characteristics like peak plasma concentration are
influenced by its limited aqueous solubility.
Cyclodextrins (Raymond et al., 2003) are oligosaccharides which have
ability to form inclusion complexes with many lipophilic
drugs, thus changing their physicochemical and biopharmaceutical properties.
However it is known that the application of β-cyclodextrin
(β-CD) in the pharmaceutical field is limited by its rather low aqueous
solubility which led to a search for more soluble derivatives of cyclodextrins. Hydroxypropyl
derivative of cyclodextrins have the advantage of
enhanced solubility as well as lower hemolytic activity and produced nephrotoxicity (Tayade and Vavia, 2006; Elisma et al.,
2002).
EXPERIMENTAL
Materials and methods
Aceclofenac was a gift
sample from Wockhardt Research Centre,
Table
1: Determination of drug content in inclusion complex
|
Composition |
Ratio |
Drug
content (mg/ml) |
%
drug content |
|
AC- β-CD complex |
1:1 1:2 1:3 1:4 |
6.27 (10) 7.02 (10) 7.98 (10) 8.36 (10) |
62.73 70.20 79.84 83.60 |
|
AC-HP-β-CD complex |
1:1 1:2 1:3 1:4 |
6.53 (10) 8.97 (10) 9.35 (10) 9.86 (10) |
65.30 89.71 93.55 98.60 |
Fig.
1; Phase solubility diagram of aceclofenac:
Fig.
2: Phase solubility diagram of aceclofenac: hydroxypropyl Β- cyclodextrin
Phase solubility studies (Varma
et al., 2005; Catarina et al. 2002)
Solubility studies
were carried out according to the method of Higuchi and Connor’s (Higuchi,
1965) Excess amount of Aceclofenac (100mg) was added to 10ml of distilled water
containing various concentration of cyclodextrin (20,
40, 60, 80,100 mili moles) and were shaken for 24
hours at room temperature (25±0.50 C) on mechanical stage shaker at
120-130 rpm. 5 ml aliquots were filtered through Whatman No. 44 filter paper
and filtrate were suitably diluted and analyzed spectrophotometrically at 275
nm.
Preparation
of physical mixture:
The physical mixture8 of AC with β-CD and HP-β-CD in molar ratio 1:1 (0.3542gm of
AC, 1.135gm of β-CD and 1.548gm of HP-β-CD) were prepared separately,
by mixing with the help of spatula and passed through the sieve of mesh no.100
used as a reference in characterization.
Fig.
3: DSC of aceclofenac: Β- cyclodextrin
Preparation
of complexes by kneading method:
The occlusion
complexes9 of
AC with β-CD and HP-β-CD were prepared by kneading technique. Cyclodextrin was taken in a glass mortar and sufficient
quantity of water was added slowly and mixed to obtain a homogeneous paste.
Accurately weighed quantity of AC was added slowly and kneading of paste was
continued for one hour so as to obtain paste like consistency. The paste was
dried at 500 C for 24 hours. The dried mass was pulverized and
sieved through mesh no. 100.
The same procedure was
adopted for complexation of drugs with β-CD and
HP-β-CD in different molar ratios.
Characterization
of occlusion complexes:
Drug
content:9
Content of AC in
β-CD complexes was estimated by UV spectrophotometric method. Cyclodextrin complexes equivalent to 10 mg of AC was
accurately weighed and dissolved in 100ml of phosphate buffer (pH 7.4) from
that 1ml was withdrawn and again diluted up to
10ml.The resulting
solution was assayed for drug content using UV spectrophotometer (Shimadzu 2450)
at 275 nm. The data is shown in Table no. 1.
|
Time (mins) |
Cumulative
% Release of Aceclofenac |
|||||||
|
AC- β-CD complex |
AC-HP-β-CD complex |
|||||||
|
1:1 |
1:2 |
1:3 |
1:4 |
1:1 |
1:2 |
1:3 |
1:4 |
|
|
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
5 |
49.06 |
53.55 |
60.22 |
62.44 |
58.53 |
59.81 |
63.12 |
68.19 |
|
15 |
55.26 |
64.42 |
68.95 |
76.73 |
67.39 |
70.15 |
73.18 |
79.86 |
|
30 |
70.49 |
80.58 |
83.99 |
86.23 |
78.14 |
82.14 |
85.19 |
87.69 |
|
45 |
82.30 |
87.28 |
91.28 |
93.26 |
85.72 |
88.79 |
92.48 |
94.12 |
|
60 |
88.57 |
94.79 |
96.78 |
97.48 |
91.14 |
95.20 |
97.52 |
99.15 |
Table
2:
In-vitro drug release of aceclofenac- cyclodextrin complex
Fig.
4: DSC of aceclofenac: hydroxypropyl
Β- cyclodextrin
Fourier
transform infrared spectroscopy:
Fourier transform IR
spectra were recorded on a FTIR-8400S
Shimadzu. The spectra of AC, β-CD, HP-β-CD and occlusion
complexes were recorded. Samples were prepared in KBr
discs and the scanning range was 400-4000 cm-1 was used.
Differential
scanning calorimetry:
Differential scanning calorimetry (DSC) was performed to characterize the thermogram of the pure AC, β-CD, HP-β-CD,
occlusion complexes and physical mixture.
Fig.5:
FTIR spectra of AC, B-CD, HP-B-CD,AC:B-CD, AC:HP-B-CD
In- vitro dissolution rate studies:10,11
In-vitro
dissolution studies of pure drug and the various inclusion complexes were
carried out in 900ml of phosphate buffer (pH 7.4) using USP XXII dissolution
test apparatus with a paddle stirrer. Sample equivalent to 100mg of AC, at
speed of50 rpm and temperature of 37±10C were used in each test. 5ml
aliquots were withdrawn at intervals 5, 15, 30, 45, 60 minutes and replaced
with 5ml of fresh dissolution medium. The filtered samples were suitably
diluted if required and analyzed spectrophtometrically
at 275 nm and percentage drug dissolved was calculated. The data is shown in
Table no.2.
Fig.
6: in-vitro release profile of aceclofenac: Β- cyclodextrin
RESULTS
AND DISCUSSION:
The phase solubility
diagram (Fig. 1.and 2.) obtained with β-CD and HP-β-CD showed a
linear relationship between the amount of AC solubilized
and concentration of cyclodextrin in solution (
DSC
studies shows that there is a complexation between
drug and cyclodextrin. The thermogram
of pure drug, physical mixture and various complexes are shown in fig.3 and 4.
The DSC curve of AC was typical of a crystalline substance with a sharp
function endotherm (T peak =149-15000).
Liberation of crystal water from β-CD was observed as a broad endothermal peak at around 1000C. HP-β-CD
is an amorphous material and does not exhibit a melting point, as would be
observed for crystalline material. Characteristic peaks (due to drug melting)
were well recognizable in the physical mixtures of drug with both β-CD and
HP-β-CD. The disappearance of an endothermic peak may be attributed to an
amorphous state and/or to an inclusion complexation.
In IR spectral studies
the broadening of the peak was probably due to restriction of bending and
stretching vibrations of the molecule due to the cyclodextrin
cavity. The FTIR spectra of drug, polymer and complexes are shown in fig.5.
This may be indicative
of the drug monomeric dispersion as a consequence of
the interaction with cyclodextrins through hydrogen
bonding which could result in its inclusion in to hydrophobic cavity of the cyclodextrin.
The dissolution
studies revealed that all the occlusion complexes showed an increase
dissolution rate as shown in fig.6 and fig.7. The enhanced dissolution could be
attributed to the reduction in particle size, amorphous state, increased wettability and occlusion complexation.
From the plot of % cumulative drug dissolved verses time, it is observed that
the amount of drug dissolved is higher for HP-β-CD than for β-CD
complexes. The dissolution rate of AC from various occlusion complexes was
found to be in order AC: HP-β-CD > AC: β-CD > AC.
Fig.
7: in-vitro release profile of aceclofenac: hydroxypropyl Β- cyclodextrin
CONCLUSION:
From
the present studies it can be observed that AC forms occlusion complexes with cyclodextrins. The solubility and dissolution
characteristics of AC were found to be significantly improved after complexation with cyclodextrins.
Hence HPβCD is an excellent complexing
agent for AC in order to improve its dissolution rate and thus its absorption
and bioavailability.
ACKNOWLEDGEMENTS:
Authors are thankful
to Wockhardt Research Centre,
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Received on
04.06.2009
Accepted on
10.07.2009
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Journal of Pharmaceutical Dosage Forms and Technology. 1(3): Nov. – Dec. 2009, 200-203