Design and Evaluation of Matrix-Based Controlled Release Tablets of
Diclofenac Sodium and Chondroitin Sulphate
Submitted: December 27, 2006; Accepted: May 26, 2007; Published: October 19, 2007
Amelia Avachat1
and Vikram Kotwal2
1
Department of Pharmaceutics, Sinhgad College of Pharmacy, Vadgaon (Budruk), Pune, India
2
Department of Pharmaceutics, Allana College of Pharmacy, Azam Campus, Camp, Pune, India
ABSTRACT
The purpose of the present study was to develop and characterize
an oral controlled release drug delivery system for
concomitant administration of diclofenac sodium (DS) and
chondroitin sulfate (CS). A hydrophilic matrix-based tablet
using different concentrations of hydroxypropylmethylcellulose
(HPMC) was developed using wet granulation technique
to contain 100 mg of DS and 400 mg of CS. Formulations
prepared were evaluated for the release of DS and CS over
a period of 9 hours in pH 6.8 phosphate buffer using United
States Pharmacopeia (USP) type II dissolution apparatus.
Along with usual physical properties, the dynamics of water
uptake and erosion degree of tablet were also investigated.
The in vitro drug release study revealed that HPMC K100CR
at a concentration of 40% of the dosage form weight was
able to control the simultaneous release of both DS and CS
for 9 hours. The release of DS matched with the marketed
CR tablet of DS with similarity factor (f2) above 50. Water
uptake and erosion study of tablets indicated that swelling
followed by erosion could be the mechanism of drug release.
The in vitro release data of CS and DS followed KorsmeyerPeppas
and zero-order kinetics, respectively. In conclusion,
the in vitro release profile and the mathematical models indicate
that release of CS and DS can be effectively controlled
from a single tablet using HPMC matrix system.
KEYWORDS: Chondroitin sulphate, diclofenac sodium,
hydroxypropylmethylcellulose, controlled releaseR
INTRODUCTION
Chondroitin sulfate (CS) belongs to a family of heteropolysaccharides
called glycosaminoglycans or GAGs. Glycosaminoglycans
were formerly known as mucopolysaccharides.
GAGs in the form of proteoglycans comprise the ground
substance in the extracellular matrix of connective tissue. CS is
made up of linear repeating units containing D-galactosamine
and D-glucuronic acid. CS is found in humans in cartilage,
bone, cornea, skin, and the arterial wall. This type of CS is
sometimes referred to as chondroitin sulfate A or galactosaminoglucuronoglycan
sulfate. The molecular weight of CS
ranges from 5000 to 50 000 d and contains ~15 to 150 basic
units of D-galactosamine and D-glucuronic acid.
The mechanism of action and absorption of orally administered
CS has not been clearly understood. Possible actions
include promotion and maintenance of the structure and function
of cartilage (referred to as chondroprotection), pain relief
of osteoarthritic joints and anti-inflammatory activity.1-4
CS in combination with hyaluronic acid is available as a
combination product in the United States. It is used as a viscoelastic
agent in cataract surgery. CS is available generically
from numerous manufacturers.
Diclofenac sodium (DS) is usually prescribed as once-a-day
controlled release tablets for management of painful arthritis
conditions to reduce the inflammation and thereby reduce
pain. CS is coprescribed in many instances for its chondroprotective
action and cartilage rebuilding. It was hypothesized
that combining both drugs in a controlled release dosage form
would reduce pill burden and increase patient compliance.
An effort was therefore made to develop simple and effective
controlled release DS and CS tablets using a polymer matrix
system with uniform in vitro release properties. Hydroxypropylmethylcellulose
(HPMC) is the most commonly and
successfully used hydrophilic retarding agent for the preparation
of oral controlled drug delivery systems.5
The transport
phenomena involved in the drug release from hydrophilic
matrices are complex because the microstructure and macrostructure
of HPMC exposed to water is strongly time dependent.
Upon contact with the gastrointestinal fluid, HPMC
swells, gels, and finally dissolves slowly.6
The gel becomes
a viscous layer acting as a protective barrier to both the
influx of water and the efflux of the drug in solution.7,8
As
reported by Ford et al,9
as the proportion of the polymer in
the formulation increases, the gel formed is more likely to
diminish the diffusion of the drug and delay the erosion of
the matrix. Narasimhan and Peppas10
showed that the dissolution
can be either disentanglement or diffusion controlled
depending on the molecular weight and thickness of the
diffusion boundary layer. The rate of polymer swelling and
Received: December 27, 2006; Final Revision Received: May 17, 2007; Accepted: May 26, 2007; Published: October 19, 2007
AAPS PharmSciTech 2007; 8 (4) Article 88 (http://www.aapspharmscitech.org).
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Corresponding Author: Amelia Avachat, Department of
Pharmaceutics, Sinhgad College of Pharmacy, Vadgaon
(Budruk), Pune - 411041, India. Tel: (020) 3293 1893;
Fax: (020) 2435 4720; E-mail: prof_avachat@yahoo.com
dissolution as well as the corresponding rate of drug release
are found to increase with either higher levels of drug
loading or with use of lower viscosity grades of HPMC.11
The aim of this study was to develop a controlled release
dosage form of DS and CS and to evaluate the drug release
kinetics from the HPMC matrix.
MATERIALS AND METHODS
Diclofenac sodium United States Pharmacopeia (USP) was
supplied by Lupin Ltd (Pune, India). HPMC (Methocel
K100M CR) was procured from Colorcon (Dartford, UK).
Chondroitin sulfate was procured from Biocon (Banglore,
India) and polyvinylpyrrolidone (PVP) K90 USNF was purchased
from BASF (Ludwigshafen, Germany). All other
ingredients used throughout the study were of USP grade
and were used as received.
Preparation of Tablets
Matrix tablets were prepared by wet granulation method.
The composition of various formulations is given in Table 1.
DS, CS, and HPMC K100 were mixed in a polybag, and
the mixture was passed through mesh (No. 40). Granulation
was done using a solution of PVP K90 in sufficient isopropyl
alcohol. The wet mass was passed through mesh No 8.
The wet granules were air dried for ~2 hours. The granules
were then sized by mesh No. 16 and mixed with aerosil
(Aerosil-200, Degussa Corp, Dusseldorf, Germany) and talc.
Tablets were compressed at 900 mg weight on a 10-station
mini rotary tableting machine (General Machinery Co, Mumbai,
India) with 18-mm oval-shaped punches. Four different
formulas, having different concentrations of HPMC K100
(15%, 20%, 30%, and 40%), were developed to evaluate the
drug release and to study the effect of polymer concentration
on drug release.
Evaluation of Tablets
As mentioned in the Preparation of Tablet section, to study
the effect of polymer concentration on drug release, 4 different
formulas, having different concentrations of HPMC
K100, were developed. Because determination of CS is a
complex process, the optimized formula was selected on the
basis of DS release characteristics only. As shown in Figure 1,
F4 formulation showed prolonged release and thus was
chosen for further studies.
The prepared tablets were tested as per standard procedure
for weight variation (n = 20), hardness (n = 6), drug content,
thickness (n = 20), friability, water uptake, and erosion characteristics.
Hardness of tablet was determined by using a
Monsanto tablet hardness tester (Campbell Electronics, Mumbai,
India). Friability test (n = 20) was conducted using Roche
friabilator (F. Hoffmann-La Roche Ltd, Basel, Switzerland).
Thickness of the tablets was measured by digital Vernier caliper
(Mitutoyo Corp, Kawasaki, Japan). Drug content of DS
was analyzed by measuring the absorbance of standard and
samples at λ = 275 nm using UV/Visible spectrophotometer
(Jasco model V-530, Tokyo, Japan). Drug content of CS was
analyzed by using method described by Zhang et al11
and
measuring the absorbance of complex at λ = 662.5 nm and
comparing the content from a standard calibration curve.
Further the similarity factor (f2) for the release of DS between
the test product and that of marketed formulation,
Voveran SR (Novartis, Basel, Switzerland), was performed.
Quantification of the Water Uptake and
Erosion Determination
For conducting water uptake studies, the dissolution jars
were marked with the time points of 0.5, 1, 2, up to 9 hours.
Table 1. Different Tablet Compositions*
Name of Component
Quantity (mg) per Tablet†
F1 F2 F3 F4
Diclofenac sodium 100 100 100 100
Chondroitin sulfate 400 400 400 400
HPMC K100 100 134 235 360
Isopropyl alcohol qs qs qs qs
PVP K90 10 10 12 14
Magnesium stearate 8 7 7 8
Talc 8 8 8 9
Aerosil 8 8 8 9
Total 634 667 770 900
* HPMC indicates hydroxypropylmethylcellulose; qs, quantity
sufficient; PVP, polyvinylpyrrolidone.
†
Formulations: F1, 15% HPMC; F2, 20% HPMC; F3, 30% HPMC; and
F4, 40% HPMC.
Figure 1. Percentage average release of diclofenac sodium
from matrices containing different concentrations of hydroxypropylmethylcellulose.
Error bars represent the standard deviation
±G3%.
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One tablet was placed in each dissolution jar containing
1000 mL of phosphate buffer pH 6.8 at 37-C ± 0.5-C, and
the apparatus was run at 100 rpm using paddle. The tablets
were taken out after completion of the respected stipulated
time span as mentioned above and weighed after the excess
of water at the surface had been removed with filter paper.
The wetted samples were then dried in an oven at 40-C up
to constant weight. The increase of the weight on the tablet
reflects the weight of the liquid uptake. It was estimated
according to Equation 1:
Q ¼ 100ðWw − WiÞ=Ww ð1Þ
where Q is the percentage of the liquid uptake, and Ww and
Wi are the masses of the hydrated samples before drying
and the initial starting dry weight, respectively.12
The degree of erosion (expressed as percentage erosion of
the polymer content, E) was determined using Equation 2:
E ¼ 100ðWi − Wf ÞWi ð2Þ
where Wf is the final mass of the same dried and partially
eroded sample.
The entire process was repeated to get 3 values for each
time point, and the average was calculated.
In Vitro Drug Release Characteristics
Drug release was assessed by dissolution test under the
following conditions: n = 6 (in triplicate), USP type II dissolution
apparatus at 100 rpm in 1000 mL of phosphate
buffer at pH 6.8 maintained at 37-C ± 0.5-C. Ten milliliters
of the sample was withdrawn at regular intervals and replaced
with the same volume of prewarmed (37-C ± 0.5-C)
fresh dissolution medium. The samples withdrawn were filtered
through Whatman filter paper (No. 1, Whatman, Maidstone,
UK) and drug content in each sample was analyzed
after suitable dilution. DS was analyzed at λ = 275.0 nm.
Release of CS was studied by means of a dye complexation
method11
using methylene blue (MB), a cationic dye; and
absorbance of complex was measured at 662.5 nm.
The suitability of several equations, which have been reported
in the literature to define drug release mechanism(s),13
was tested with respect to the release data. Some diffusion
models (Korsmeyer-Peppas) are expected to be valid up to
~60% cumulative drug released,14
therefore the data for
analysis were restricted to that range. To analyze the mechanism
of drug release from the matrix tablets, data obtained
from the drug release studies were analyzed according to
Equations 3, 4, and 5 of the zero-order model,15-17
Higuchi
model, and the Korsmeyer-Peppas model,18,19
respectively:
Mt ¼ Mo þ Kot ð3Þ
Mt ¼ Mo þ KH t0:5
ð4Þ
Mt ¼ Mo þ Kktn
ð5Þ
In all mathematical expressions, Mt is the amount of the
drug dissolved in time t; Mo is the initial amount of drug in
the solution; Ko is the zero-order release constant; KH is the
Higuchi rate constant; KK is the release constant; and n is
the release exponent, which characterizes the mechanism of
drug release.
Similarity Factor (f2) Analysis
In vitro release profile of the marketed DS sustained release
(SR) tablets, (Voveran SR, Novartis) was performed under
similar conditions as used for in vitro release testing of the
test product for the release of DS. The similarity factor between
the 2 formulations was determined using the data
obtained from the drug release studies. The data were analyzed
by the formula20
shown in Equation 6.
¼ 50logf½1 þ ð1=NÞ∑ðRi − TiÞ 2
Š
−0:5
 100g ð6Þ
where N = number of time points, Ri and Ti = dissolution of
reference and test products at time i. If f2 is greater than 50
it is considered that 2 products share similar drug release
behaviors.
RESULTS AND DISCUSSION
The combination product of DS and CS was conceptualized
based on the fact that, in clinical practice, DS is used as an
anti-inflammatory agent in the treatment of osteoarthritis,
and CS is usually supplemented for its reported cartilagerebuilding
ability. DS is known to be effective when taken
once daily, and the mechanism of action of CS and its pharmacokinetics
after oral administration is not clearly understood;
hence, the controlled release form of DS and CS
together was expected to be more beneficial. Because CS is a
mucopolysaccharide with a higher molecular weight, there is
difficulty in transportation of drug across the gastrointestinal
mucosa; therefore it was thought that if this drug were
released slowly, the absorption would be better.
Direct compression is the preferred technique for making
controlled release tablet formulations; however, in the
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authors’ experience, when the tablet contains a higher percentage
of active substance and especially when this active
substance is water soluble, the direct compression technique
is less effective. In this case, CS is a water-soluble, hydrophilic
material, which allows quicker penetration of water in
the system, resulting in faster drug release. This characteristic
has been controlled by adding HPMC to the system and
further adopting aqueous granulation.
Physical Properties
The results of the uniformity of weight, hardness, drug content,
thickness, and friability of the tablets are given in Table 2.
All the samples of the test product complied with the official
requirements of uniformity of weight. The drug content
was found to be close to 100% of the label claim for DS
and CS in all formulations. The low friability indicates that
the matrix tablets are compact and hard. The results were
reproducible, even on tablets that had been stored for about
6 months at 25-C and 60% relative humidity.
Liquid Uptake and Erosion
Since the rate of swelling and erosion is related and may
affect the mechanism and kinetics of drug release, the penetration
of the dissolution medium and the erosion of the
hydrated tablets were determined. Simultaneously with the
liquid uptake study, the degree of polymer erosion was measured.
The percentage liquid uptake and erosion of tablet at
various time intervals is shown in Figures 2 and 3.
During swelling of the HPMC tablets, an anisotropic swelling
phenomena (ie, more swelling in the axial direction than in
the radial direction on exposure to water) was seen. Similar
phenomena were observed by Lopes et al12
and Papadimitriou
et al,21
who related the predominantly axial relaxation
of the HPMC compacts to the relief of stress induced during
compaction and the unidirectional swelling to the orientation
of the molecules during compression. The reason for
such preferential swelling in an axial direction must be due
to the need for the directional stresses, imposed on HPMC
during tableting, to relax. It follows that the area change in
the swollen system is directly related to the area exposed to
water access.
In Vitro Release Studies
Low molecular weight HPMC is used predominantly for
tablet film coating, while high molecular weight HPMC is
used as a rate-controlling polymer to retard the release of
drugs from a matrix at levels of 10% to 80% wt/wt in tablets
and capsules.22,23
Therefore, prototype formulations with
Table 2. Physical Properties of Formulations Prepared*
Test
Results
F1 F2 F3 F4
Weight (mg) mean ± SD 634 ± 1.3 667 ± 2.0 770 ± 1.6 900 ± 1.0
Hardness (kp) 17–19 17–20 16–18 17–20
Drug content (%) DS 99.5 98.9 99.3 99.6
Thickness (mm) 4.9 ± 0.02 5.2 ± 0.02 5.8 ± 0.04 6.3 ± 0.03
Friability (%) 0.19 0.22 0.35 0.15
*SD indicates standard deviation; kp, kilopascals; DS, diclofenac sodium.
Figure 2. Percentage of liquid uptake by hydroxypropylmethylcellulose
at various time intervals (hours) after contact with
aqueous medium.
Figure 3. Percentage erosion resulting from hydroxypropylmethylcellulose
erosion of tablet at various time intervals (hours)
after contact with aqueous medium.
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drug content of DS (100 mg) and CS (400 mg) were developed
by simple wet granulation method using HPMC
K100 MCR USNF. The effect of polymer level on the release
of DS and CS was studied for tablets containing 15%,
20%, 30%, and 40% HPMC K100 (formulations F1, F2,
F3, and F4 respectively). Figure 1 shows that the amount of
HPMC affects the release rate of drug. Tablets containing
15% and 20% HPMC showed 97.8% and 98.6% release
after 5 and 6 hours, respectively. These formulations (F1
and F2) underwent erosion before complete swelling could
take place, resulting in faster release of drug. F3 formulation
showed faster dissolution rate in intermediate time of 2
to 6 hours, which did not match with the reference product.
On increasing the quantity of HPMC to 40%, prolonged
release of both the drugs was achieved up to 9 hours.
Identification of the Mechanism by Which the Drug
Is Released
Based on various mathematical models, the magnitude of the
release exponent “n” indicates the release mechanism (ie,
Fickian diffusion, case II transport, or anomalous transport).
In the present study, the limits considered were n = 0.45
(indicates a classical Fickian diffusion-controlled drug release)
and n = 0.89 (indicates a case II relaxational release
transport; non-Fickian, zero-order release). Values of n between
0.45 and 0.89 can be regarded as an indicator of both
phenomena (drug diffusion in the hydrated matrix and the
polymer relaxation) commonly called anomalous transport.13
From the release exponent in the Korsmeyer-Peppas model
(n = 0.8773), it can be suggested that the mechanism that
led to the release of CS was an anomalous transport with
constant release rate adequate for a sustained release dosage
form. The correlation (R2
) was used as an indicator of the best
fitting for each of the models considered (Table 3). The release
of CS and DS (Figure 4) apparently follows KorsmeyerPeppas
model (R2
9 0.9931) and zero-order kinetics (R2
9
0.9878), respectively. However, looking at the negligible
variation of R2
values for the release of DS, the release data
analysis applying these mathematical models can be purely
empirical, and no definitive conclusion can be drawn concerning
the dominating mass transport mechanism.
Similarity Factor
The principal purposes of dissolution testing are 3-fold: (1) for
quality control, to ensure the uniformity of product from batch
to batch; (2) to help to predict bioavailability for formulation
development; and (3) as a measure of change when formulation
changes are made to an existing formulation. The socalled
f2 method can be used to compare 2 dissolution profiles.
Similarity factor analysis between the prepared tablets and
Voveran SR tablet for the release of DS showed an f2 factor
(f2 = 68.98) greater than 50. As shown in Table 4 and
Table 3. Dissolution Parameters for Diclofenac Sodium and Chondroitin Sulfate From Formulation F4*
Drug
Korsmeyer-Peppas Equation Zero-Order Equation Higuchi Equation
n R2
K0 R2
KH R2
DS 0.9438 0.9871 11.8000 0.9878 29.3380 0.9415
CS 0.8773 0.9931 12.0741 0.9851 30.1612 0.9557
* DS indicates diclofenac sodium; CS, chondroitin sulfate.
Figure 4. In vitro release profiles of diclofenac sodium (DS) and
chondroitin sulfate (CS) from Formulation F4.
Table 4. f2 Factor Results
Time
Average % Release
f2
‡
Reference* Test†
0 0.00 0.00 0.00
1 18.79 14.87 76.54
2 29.16 20.08 61.84
3 38.30 35.69 64.15
4 56.10 51.05 64.20
5 67.32 63.70 65.10
6 76.35 78.21 66.45
7 86.51 87.71 67.73
8 91.38 92.39 68.87
9 99.08 95.22 68.98
* Voveran SR tablet.
†
Prepared Tablet.
‡
Average value of f2 = 68.98.
AAPS PharmSciTech 2007; 8 (4) Article 88 (http://www.aapspharmscitech.org).
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Figure 5, the f2 factor confirms that the release of DS from
the prepared tablets was similar to that of the marketed
tablet.
CONCLUSION
Results of the present study demonstrate that CS and DS can
be co-administered in the form of a single controlled release
matrix tablet. It is evident that the investigated controlled
release matrix of HPMC at 40% concentration was capable
of prolonging the release of both drugs simultaneously for
9 hours. The mechanism of drug release was observed to be
following Korsmeyer-Peppas model and zero-order kinetics
for CS and DS, respectively.
REFERENCES
1. Tomford WW. Chondroprotective agents in the treatment of articular
cartilage degeneration. Oper Tech Sports Med. 2000;8:120Y121.
2. Uebelhart D, Thonar EJ, Delmas PD, et al. Effects of oral chondroitin
sulfate on the progression of knee osteoarthritis: a pilot study.
Osteoarthrit Cartil. 1998;6:39Y46.
3. Pipitone VR. Chondroprotection with chondroitin sulfate. Drugs Exp
Clin Res. 1991;17:3Y7.
4. Ronca F, Palmieri L, Panicucci P, Ronca G. Anti-inflammatory
activity of chondroitin sulfate. Osteoarthrit Cartil. 1998;6:14Y21.
5. Colombo P. Swelling-controlled release in hydrogel matrices for oral
route. Adv Drug Del Rev. 1993;11:37Y57.
6. Siepmann J, Kranz H, Bodmeier R, Peppas NA. HPMC-matrices for
controlled drug delivery: a new model combining diffusion, swelling,
and dissolution mechanisms and predicting the release kinetics. Pharm
Res. 1999;16:1748Y1756.
7. Colombo P, Bettini R, Santi P, Peppas NA. Swellable matrices for
controlled drug delivery: gel-layer behaviour, mechanisms and optimal
performance. Pharm Sci Technol Today. 2000;3:198Y204.
8. Kiil S, Dam JK. Controlled drug delivery from swellable
hydroxypropylmethylcellulose matrices: model-based analysis of
observed radial front movements. J Control Release. 2003;90:
1Y21.
9. Ford J, Rubinstein M, Hogan J. Propranolol hydrochloride and
aminophylline release from matrix tablet containing hydroxypropyl
methylcellulose. Int J Pharm. 1985;24:339Y350.
10. Narasimhan B, Peppas NA. Molecular analysis of drug delivery
systems controlled by dissolution of the polymer carrier. J Pharm Sci.
1997;86:297Y304.
11. Zhang L, Li N, Zhao F, Li K. Spectroscopic study on the interaction
between methylene blue and chondroitin 4-sulphate and its analytical
application. Ana Sci. 2004;20:445Y450.
12. Lopes CM, Lobo JMS, Costa P, Pinto JF. Directly compressed mini
matrix tablets containing ibuprofen: preparation and evaluation of
sustained release. Drug Dev Ind Pharm. 2006;32:95Y106.
13. Costa P, Lobo JMS. Modeling and comparison of dissolution
profiles. Eur J Pharm Sci. 2001;13:123Y133.
14. Ritger PL, Peppas NA. A simple equation for description of solute
release. I. Fickian and non-fickian release from non-swellable devices
in the form slabs, spheres, cylinder or discs. J Control Release.
1987;5:23Y36.
15. Donbrow M, Samuelov Y. Zero order drug delivery from
double-layer porous films: release rate profiles from ethyl cellulose
and polyethylene glycol mixtures. J Pharm Pharmacol. 1980;32:
463Y470.
16. Higuchi T. Rate of release of medicament from ointment bases
containing drugs in suspension. J Pharm Sci. 1961;50:874Y875.
17. Higuchi T. Mechanism of sustained-action medication: theoretical
analysis of rate of release of solid drugs dispersed in solid matrices.
J Pharm Sci. 1963;52:1145Y1149.
18. Korsmeyer RW, Gurny R, Doelker EM, Buri P, Peppas NA.
Mechanism of solute release from porous hydrophilic polymers. Int J
Pharm. 1983;15:25Y35.
19. Peppas NA. Analysis of Fickian and non-Fickian drug release from
polymers. Pharm Acta Helv. 1985;60:110Y111.
20. Bolton S, Bon C. Pharmaceutical Statistics: Practical and Clinical
Applications. New York, NY: Marcel Dekker; 2004.
21. Papadimitriou E, Buckton G, Efentakis M. Probing the mechanisms
of swelling of hydroxypropyl methylcellulose matrices. Int J Pharm.
1993;98:57Y62.
22. Melia CD. Hydrophilic matrix sustained release systems based on
polysaccharide carriers. Crit Rev Ther Drug Carrier Syst. 1991;8:
395Y421.
23. Rowe RC, Sheskey RJ, Weller PJ. Handbook of Pharmaceutical
Excipients. London, UK: Pharmaceutical Press; 2003.
Figure 5. Comparative in vitro diclofenac sodium release profile
for f2 test: reference is Voveran SR tablet and test is prepared
tablet.
AAPS PharmSciTech 2007; 8 (4) Article 88 (http://www.aapspharmscitech.org).
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