Design and Characterization of Sustained Release Aceclofenac Matrix Tablets Containing Tamarind Seed Polysaccharide

Basavaraj*, Someswara Rao B, S.V Kulkarni, Pramod Patil and Chetan Surpur

Sree Siddaganga College of Pharmacy, B H Road, Tumkur- 572102

*Corresponding Author E-mail: pharmabasava.@gmail.com

ABSTRACT:

Sustained release formulation of Aceclofenac based on monolithic matrix technology was developed and evaluated. It is practically insoluble in water so it is suitable to develop sustained release matrix tablet using hydrophilic polymer. Aceclofenac is non-steroidal anti-inflammatory drug (NSAID) used extensively in the treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. It is newer derivative of diclofenac and having less GIT complication, with short biological half-life 4 hrs, so developed formulation provides the advantages of sustained release formulations. The tamarind seed polysaccharide (TSP) was extracted from tamarind kernel powder and this polysaccharide was utilized in the formulation of matrix tablets containing Aceclofenac by wet granulation technique and evaluated for its drug release characteristics. TSP is a hydrophilic and rate controlling polymer. Granules were prepared and evaluated for loose bulk density, tapped bulk density, compressibility index and angle of repose, shows satisfactory results. Formulation was optimized on the basis of acceptable tablet properties (hardness, friability, drug content and weight variations), in vitro drug release and stability studies. All the formulations showed compliance with pharmacopieal standards. The in vitro release study of matrix tablets were carried out in phosphate buffer pH 7.4 for 12 hr. Among all the formulations, F 5 shows 98.062% better controlled release at the end of 12 hr. The results indicated that a decrease in release kinetics of the drug was observed by increasing the polymer concentration. The release data was fitted to various mathematical models such as, Higuchi, Korsmeyer-Peppas, First-order, and Zero order to evaluate the kinetics and mechanism of the drug release. The drug release of optimized formulations F-5 follows zero order kinetics and the mechanism was found to be diffusion coupled with erosion (non-Fickian diffusion/anomalous). The stability studies were carried out according to ICH guideline which indicates that the selected formulations were stable.

KEYWORDS: Aceclofenac, Extracted tamarind seed polysaccharide, Matrix tablet, Sustained release, Wet granulation.

INTRODUCTION:

Oral route is the most preferred route for administration of drugs. Tablets are the most popular oral formulation available in the market and preferred by the patients and physician alike. In long-term therapy for the treatment of chronic disease conditions. Conventional formulations are required to be administered multiple doses and therefore have several disadvantages.¹

The primary benefit of a sustained release dosage form, compared to a conventional dosage form, is the uniform drug plasma concentration and therefore uniform therapeutic effect.

Over the past two decades, sustained release dosage forms have made significant progress in terms of clinical efficacy and patient compliance. Matrix devices, due to their chemical inertness, drug embedding ability and drug release character, have gained steady popularity for sustaining the release of a drug.²

Hydrophilic matrices are an interesting option when developing an oral sustained release formulation. The drug release from such matrices can be controlled through their physical properties. Polysaccharides are the choice of materials among the hydrophilic polymers used, because they are nontoxic and acceptable by the regulating authorities. The various polysaccharides used in drug delivery application are cellulose ethers, xanthan gum, locust bean gum and guar gum. Another natural polysaccharide, Tamarind seed polysaccharide (TSP) obtained from the seed kernel of Tamarindus indica, possesses properties like high viscosity, broad pH tolerance, noncarcinogenicity, mucoadhesive nature, and biocompatibility. It is used as stabilizer, thickener, gelling agent, and binder in food and pharmaceutical industries. The TSP constitutes about 65% of the tamarind seed components.³

Aceclofenac is non-steroidal anti-inflammatory (NSAID) drug used extensively in the treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. Aceclofenac is newer derivative of diclofenac and having less GIT complication, with short biological half-life 4 hrs, and dosing frequency more than one time make it an ideal candidate for modified release multiple unit preparation. To reduce the frequency of administrations and to improve patient compliances, aceclofenac is suitable for making sustain release dosage form.⁴

The aim of present study is to design and characterization sustained release matrix tablet of Aceclofenac containing tamarind seed polysaccharide.

MATERIALS AND METHODS:

Materials:

Tamarind kernel powder, collected from plant source, aceclofenac was obtained as gift sample from Karnataka Antibiotics Pvt Ltd., Bangalore. Microcrystalline cellulose (Avicel PH 101), magnesium stearate, talc were purchased from SD Fine chemicals Ltd. Absolute ethanol, diethyl ether and all the chemicals used were of analytical grade.

Extraction of Tamarind Seed Polysaccharide:

To 20g of tamarind kernel powder, 200ml of cold distilled water was added and slurry was prepared. The slurry was poured into 800ml of boiling distilled water. The solution was boiled for 20 mints under stirring condition in a water bath. The resulting thin clear solution was kept overnight so that most of the proteins and fibers settled out. The solution was then centrifuged at 5000 rpm for 20 mints. The supernatant was separated and poured into twice the volume of absolute ethanol by continuous stirring. The precipitate was washed with absolute ethanol, diethyl ether and and then dried at 50-60º C under vacuum. The dried material was ground and sieved to obtain granules of different particle size range. The particle size range of 150-75 microns was used for preparation of tablets.⁵

Preparation of matrix tablets:

Tablet formulations were prepared by wet granulation method. A non-aqueous granulation process was adopted to prepare Aceclofenac tablets. Granules were prepared as follows. Proportion of excipients with drug was as given in Table 1. All ingredients were sifted through sieve no. 60. And microcrystalline cellulose was mixed with Aceclofenac manually and the obtained blend was mixed with TSP (F1 to F6) to form final blend. PVPK 30 was dissolved in PVA (5% w/v) and used for wet granulation of the final blend. The wet mass was passed through sieve no. 12 and wet granules were dried at 50°C in an oven for 30 mints. Dried granules were sized by passing it through sieve no.16 and lubricated with magnesium stearate and talc for 1 mint. Tablets were compressed using Rotary tablet machine with 12.08 mm standard concave punch. Tablet weight was (500 mg) kept constant as shown in table 1.

Evaluation of granules:

The angle of repose was measured by using funnel method which indicates the flow ability of the granules.⁶ Loose bulk density (LBD) and tapped bulk density (TBD) were measured using the formula: LBD= weight of the powder / volume of the packing.⁷ TBD= weight of the powder / tapped volume of the packing. Compressibility index of the granules was determined by using the formula: CI (%) = [(TBD-LBD/TBD)] ×100.⁸The physical properties of granules were shown in Table 2.

Evaluation of tablets:

All prepared matrix tablets were evaluated for its uniformity of weight, hardness, friability and thickness according to official methods.⁹ shown in Table 3

Uniformity of drug content:

Accurately weighed quantity of the powder tablet equivalent to 100 mg of the drug was transferred to 100 ml volumetric flask. 50 ml of buffer solution of pH-7.4 was added. Mix with the aid of ultrasound for 10 min, and then the volume was made up to 100 ml with the same buffer solution, mixed solution was filtered through the membrane filter disc with an average pore diameter not greater than 0.45µm. 5 ml of the filtrate was diluted to 100 ml with same buffer solution and examined under U.V Spectrophotometer at 274 nm.

In vitro drug release studies:

In-vitro drug release studies were carried out using USP XXII dissolution apparatus type 2 (Electrolab, Mumbai, India) at 50 rpm. The dissolution medium consisted of 900 ml of pH 7.4-phosphate buffer, maintained at 37 + 0.5⁰ c. The drug release at different T intervals was measured using an UV spectrophotometer (Lab india, Mumbai, India) at 274 nm. The study was performed in triplicate.

Characterization of Drug Release Kinetics:

The Korsmeyer and Peppas equation was used to analyze the data obtained from the in vitro release studies to evaluate the kinetic models and release mechanism of aceclofenac from the matrices. The Korsmeyer and Peppas equation is: Mt/M∞ = k tⁿ.¹⁸ Where M_t/M_∞ is the fraction of drug released at time t, k is a constant incorporating the properties of the macromolecular polymeric system and the drug and n is an exponent used to characterize the transport mechanism. For example, n = 0.45 for Case I or Fickian diffusion, 0.45 < n < 0.89 for anomalous behavior or non- Fickian transport, n = 0.89 for Case II transport, and n > 0.89 for Super Case II transport. Fickian diffusional release occurs by the usual molecular diffusion of the drug due to a chemical potential gradient. Case II relaxational release is the drug transport mechanism associated with stresses and state-transition in hydrophilic glassy polymers, which swell in water or biological fluids. This term also includes polymer disentanglement and erosion.^{10, 11}

Table 1: Tablet composition of different formulations of Aceclofenac sustained release matrix tablets with Tamarind seed polysaccharide as a release retardant

Formulation No.	Aceclofenac (mg/tablet)	Tamarind seed polysaccharide (mg/tablet)	Microcrystalline cellulose (mg/tablet)	PVP K 30 (5%) (mg/tablet)	Magnesium Stearate (mg/tablet)	Talc (mg/tablet)
F1	200	50	222	25	02	01
F2	200	75	197	25	02	01
F3	200	100	172	25	02	01
F4	200	125	147	25	02	01
F5	200	150	122	25	02	01
F6	200	175	97	25	02	01

Table 2: Granular properties of formulations F1 to F6 of Aceclofenac sustained release tablets using TSP as release retardant

Formulation No.	Angle of repose*	Loose bulk density (LBD) (g/ml) *	Tapped bulk density (TBD) (g/ml) *	Compressibility index (%)*
F1	27.22 ± 1.6	0.495 ±0.004	0.547 ± 0.019	13.29 ± 0.75
F2	27.15 ± 1.31	0.494 ±0.003	0.555 ± 0.016	12.10 ± 1.63
F3	26.22 ± 1.58	0.470 ± 0.003	0.526 ± 0.012	10.64 ± 1.33
F4	29.45 ± 1.42	0.470 ±0.009	0.520 ± 0.013	13.40 ± 1.48
F5	28.12 ± 1.57	0.465 ± 0.006	0.536 ± 0.014	16.21 ± 0.78
F6	25.90±1.22	0.465 ± 0.005	0.512 ± 0.011	15.16±1.35

Table 3: Tablet properties of formulations F1 to F6 of Aceclofenac sustained release matrix tablets with TSP

Formulation No.	Hardness* (kg/cm^2)	Thickness* (mm)	% Friability	Weight Variation*(mg)	% Drug content
F1	5.8 ± 0.10	3.88 ± 0.16	0.16 ± 0.13	501.0	99.45
F2	6.0 ± 0.24	3.89 ± 0.18	0.22 ± 0.41	500.2	99.89
F3	5.7 ± 0.14	3.85 ± 0.32	0.32 ± 0.21	500.4	100.04
F4	5.9 ± 0.12	3.90 ± 0.03	0.26± 0.12	500.1	99.65
F5	6.3 ± 0.35	3.93 ± 0.16	0.42 ± 0.35	500.1	99.36
F6	6.2 ±0.13	3.96 ± 0.14	0.49 ± 0.21	500.5	99.51

Stability Study:

The optimized formulation was subjected to stability at 40 ± 2⁰C and 75 ± 5 % RH for period of six months. After each month tablet sample was analyzed for physical characteristics and drug release profile.¹²

RESULT & DISCUSSION:

DSC STUDY:

According to the thermo grams, aceclofenac presented a sharp endothermic peak at 153.10ºC corresponding to the melting point of the drug in the crystalline form. While the thermo gram of physical mixture of aceclofenac and TSP was 154ºC The comparative study of thermograms indicated that the drug even in its drug mixture sample form has not much deviated from the literature melting point 149-153ºC ¹³ appreciably indicating that the drug has not undergone any type of interaction with the polymer (TSP) used for the formulation. The spectra of the DSC are shown in Figure 1-2.

FTIR spectroscopy:

Infrared spectra of drug and polymers were used to study the compatibility between them. No change in peak shows that there was no interaction between drug and polymers. The IR spectrum of the pure drug (Aceclofenac) and optimized formulation F5 is given in figure 3-4.

Figure 1: DSC of pure aceclofenac

Figure 2: DSC of pure aceclofenac +tamarind seed polysaccharide

Figure 3: FTIR Spectroscopy of pure drug

Figure 4: FTIR Spectroscopy Formulation 5

Characterization of granular properties

Granules prepared for compression of matrix tablets were evaluated for their flow properties, the results were shown in Tables 2. Angle of repose was in the range 24.10 ± 1.6⁰ to 29.82 ± 1.42⁰, which indicates excellent flow of the powder for all formulations. The bulk density of the powder formulation was in the range of 0.465 ±0.006 to 0.495 ±0.004 gm/cc; the tapped density was in the range of 0.555 ± 0.016 to 0.512 ± 0.011 gm/cc, which indicates that the powder was not bulky. The Carr’s index was found to be in the range of 16.21 ± 0.78 to 10.64 ± 1.33; indicating compressibility of the tablet blend is good. These values indicate that the prepared granules exhibited good flow properties.

Physicochemical evaluation of matrix tablets

Tablets with a weight of 500 mg, a diameter of 12.08 mm were obtained and subjected to quality control tests such as hardness, friability and drug content (Table 3). The contents of the formulations were found to be uniform, since the amount of the active ingredient in each of the10 units tested was within the range of 100.04% – 99.36% and the relative standard deviations were less than 2.0%, indicating uniform mixing of tamarind gum, microcrystalline cellulose and drug. The mean values for hardness were over 5. 6kg/cm² and all formulations exhibited a friability of not more than 0.6% during the friability determination.

The punches used to compress the tablets were 12.08mm, spherical shaped. The shape and size of the tablets were found to be within the limit. The hardness of the tablets was found to be in the range of 5.6 ± 0.13 to 6.4 ± 0.34 Kg/ cm². It was within the range of monograph specification.

Thickness of the tablets was found to be in the range of 3.74 ± 0.03 to 3.96 ± 1.6 mm. The friability of the tablets was found to be less than 1% and it was within the range of standard specification.

In-Vitro Release Study

In- vitro release studies were carried out for all the formulations as per USP XXII tablet dissolution tester employing rotating paddle at 50 rpm using 900 ml of phosphate buffer of pH 7.4 as dissolution medium. The results were evaluated for 12 hr. As per the results of dissolution study formulations F1, F2, F3, F4, F5, F6, showed 98.62, 96.93, 98.43, 97.68, 98.06 and 94.12% respectively. This showed that the drug release from the tablet was sustained for 4 to 12 hr. F1 with 10% TSP showed 98.62 % release within 5 hr. where as in formulation F5 with 30% TSP as a retardant showed 98.06 % release upto 12hr. This is mainly due to increasing polymer concentration or increasing path length diffusion. By using the different concentrations of TSP as a release retardant, drug release from TSP and showed sustained for 4 to 12hr by varying the concentration of polymer matrix composition. Formulation F5 and F6 with TSP showed reasonable release 98.06, 94.12 % respectively. From the above results, it was found that the drug release is depleted as the concentration of TSP polymer was increased in polymeric matrix composition.

Hence, formulation F5 with 30% TSP was found to be most promising formulation as they showed sustained release (98.06 %) as well as maintained excellent matrix integrity during the period of 12 hr study. Hence formulation F5 was selected as the optimized formulation.

Figure 5: In-vitro dissolution profile of F1 to F6 formulations.

Determination of the release kinetics

The regression coefficient (R²) value of Zero order, First order, Higuchi’s, and Peppas plots for formulation F5 were found to be 0.984, 0.870, 0.971, 0.974. The optimized formulation F5 (0.971) follows Higuchi’s plot since the regression coefficient (R²) is found to be linear, this confirms that the drug release through the matrix was diffusion and slope (n) value of optimized formulations F5 was found to be 0.761 .

Table 4: Release kinetics parameters of designed sustained release matrix tablets of Aceclofenac

Formulations	Zero order plots◘	First order plots▪	Higuchi’s plots●	Korsmeyer et al’s plots□
	R^2	R^2	R^2	R^2	Slope(n)
F1	0.988	0.735	0.952	0.982	0.807
F2	0.982	0.832	0.991	0.992	0.794
F3	0.979	0.821	0.947	0.936	0.729
F4	0.972	0.899	0.949	0.937	0.756
F5	0.984	0.87	0.971	0.974	0.761
F6	0.973	0.961	0.976	0.981	0.729

◘Zero order equation, C=K₀ t, ▪First order equation, Log C=log Cₒ-Kt/2.303, ●Higuchi’s equation, Q= Kt½, □Korsmeyer et al’s equation, Mt/Mα= Ktn.

Thus, non-Fickian diffusion/anomalous was the main mechanism. The regression coefficient (R²) values of zero order in the optimized formulation F5 was greater than the R² values of first order. Thus, the drug release follows zero order kinetics.

CONCLUSION:

The matrix tablets were found to be effective in sustaining the drug release upto 12 hr. This is mainly due to formation of a thick gel structure that delays drug release from tablet matrix, Drug release was found to be diffusion coupled with erosion. Stability studies revealed that there was no significant change in drug content and dissolution profile of matrix tablets. DSC and FTIR studies revealed that there was no shift in peaks, indicating there is no interaction between aceclofenac and other ingredients used. It can be concluded that stable formulation could be developed by incorporating hydrophilic polymer (TSP) in a definite proportion, so that the controlled released profile is maintained for an extended period.

ACKNOWLEDGEMENT:

The authors are thankful to the Management, Sree Siddaganga College of Pharmacy Tumkur for providing necessary facilities to carry out this work.

REFERENCES:

1. Ravi PR, Ganga S and Saha RN. Design and study of lamivudine oral controlled release tablets. American Association of Pharmaceutical Scientists Pharm Sci Tech. 8 (4); 2007: 1-9.

2. Basak SC, Kumar KS and Ramalingam M. Design and release characteristics of sustained release tablet containing metformin HCl. Brazilian Journal of Pharmaceutical Sciences. 44 (3); 2008: 477-482.

3. Deveswaran R, Abraham S, Bharath S, Basavaraj BV, Furtado S, Madhavan V. Design and characterization of diclofenac sodium tablets containing tamarind seed polysaccharide as release retardant. International Journal of PharmTech Research. 1(2): 2009; 191-195.

4. Trivedi P, Verma AML and Garud N. Preparation and characterization of aceclofenac microspheres. Asian Journal of Pharmaceutical Sciences. 2 (2); 2008: 110-115.

5. Sumathi S, Ray AR. Release behaviour of drugs from tamarind seed polysaccharide tablets. Journal of Pharmacy and Pharmaceutical Science.5 (1); 2002: 12-18.

6. Cooper J, Gunn G. Powder flow and compaction, In; Tutorial pharmacy, CBS Publisers and distributers, New Dehli. 1986.

7. Shah DY, Rampadhan M. Development and evaluation of controlled release diltiazem hydrochloride microparticles using cross-linked polymer. Drug Development and Industrial Pharmacy. 23 (6); 1997: 567-574.

8. Aulton ME, well TI. Pharmaceutics: The Sciences of Dosage form Design, Churchill Livingstone, London, England.1998.

9. Lachman L and Lieberman HA. Pharmaceutical Dosage Forms: Tablets. In: The Theory and Practice of Industrial Pharmacy, Edited by Lea and Febiger, U.S.A.1991; 3rd ed: pp.293-345.

10. Ritger PL, Peppas NA. A simple equation for description of solute release II Fickian and anomalous from swellable devices. Journal of Controlled Release.5 (1); 1987: 37-42.

11. Peppas NA, Sahlin JJ. A simple equation for the description of sustained release III Coupling of diffusion and relaxation. International Journal of Pharmaceutics. 57 (2); 1989: 169-172.

12. Cartensen JT. Drug Stability: Principle and Practices, Edited by Marcel Dakker. New York.1995; 2^nd ed: pp. 538-550.

13. Available from: http://www.chemblink.com/products/89796-99-6.htm.

Received on 27.02.2011 Accepted on 22.03.2011

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