Formulation and Evaluation of Diclofenac Sodium Matrix Tablets Based on Tamarindus indica Seed Mucilage

 

ABSTRACT:

In the present investigation, tamarind seed mucilage was evaluated as sustained release matrix forming material in Diclofenac sodium tablet formulations. The physicochemical properties, tamarind seed mucilage such as loss on drying, viscosity, swelling index, pH and melting point were studied. Matrix tablets were prepared by wet granulation technique using isopropyl alcohol as a granulating agent. Sustained release matrix tablets of diclofenac sodium, were developed by using different drug: polymer ratios, such as AF1 (1:0.5), AF2 (1:1), AF3 (1:1.5), AF4 (1:2) and AF5 (1:2.5). All the lubricated formulations were compressed using flat faced punches. Compressed tablets were evaluated for uniformity of weight, content of active ingredient, friability, hardness, thickness, in vitro dissolution using paddle method, and swelling behavior. All the formulations showed compliance with pharmacopoeial standards. Tablets prepared with Hydroxypropylmethylcellulose (HPMC 50cps) and Xanthan gum as matrix forming material for the comparative study. Among different formulations, AF2 showed sustained release of drug for 12 hours with 92.75% release. The dissolution profiles of the HPMC (GF1) and Xanthan gum (FF1) based matrix tablets were close to the profile obtained by tamarind seed mucilage based matrix tablets AF2. The kinetic treatment showed that the release of drug follows zero order model and anomalous diffusion for AF2 and FF1 while the drug release of GF1 was best explained by Higuchi’s model and anomalous diffusion. The selected formulation (AF2) was subjected to stability studies for three months at 45° temperature with RH 75±5%, and showed stability with respect to release pattern. It is cleared that the drug release from matrix tablets prepared by using tamarind gum can be sustained for more than 12 hrs and release of drug vary with concentration of polymer in matrix tablets.

 

 

INTRODUCTION:

Drug products designed to reduce the frequency of dosing by modifying the rate of drug absorption have been available for many years¹. Polymers have been successfully employed in the formulation of solid, liquid and semi-solid dosage forms and are specifically useful in the design of modified release drug delivery systems. Both synthetic and natural polymers have been investigated extensively for this purpose², but the use of natural polymers for pharmaceutical applications is attractive because they are economical, readily available, non-toxic, capable of chemical modifications, potentially biodegradable and with few exceptions, also biocompatible^3-4. There are various types of natural hydrophilic polymers which have been used as release retardant as well as binder in tablet formulations. Among these, gums and mucilages are most widely used.

 

Gums and mucilages are polysaccharide complexes formed from sugar and uronic acid units. They can absorb large quantity of water and swell. They find a wide range of pharmaceutical applications that include their use as a binders and disintegrants in tablets, emulsifier, suspending agents, and gelling agents. They also are used as sustaining agents in tablets⁵. Tamarind gum was xyloglycon present in tamarind seed. It is a hydrophilic polymer and had been limited for use as gelling, thickening, suspending and emulsifying agents. Diclofenac sodium is sodium 2-[(2, 6-dichlorophenyl)-amino] phenyl acetate. Diclofenac is an acetic acid nonsteroidal antiinflammatory drug (NSAID) with analgesic property⁶. The aim of present study is to evaluate the sustained release ability of tamarind seed mucilage comparatively HPMC; which have good sustained release ability of drugs.

 

MATERIALS AND METHODS:

Materials:

Diclofenac sodium was obtained as a gift sample from Srikem Laboratories Pvt. Ltd. Mumbai. Seeds of Tamarindus indica was purchased from local market and authenticated at Krishi Vigyan Kendra, Sultanpur, U.P. India. All the chemicals and other reagents used in the study were of AR grade.

 

Methods:

Isolation of seed mucilage:

The seeds were washed with water to remove dirt and debris, and dried. The dried seeds were crushed and powdered in ball mill. To 20g of seed 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 minutes 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 material was squeezed from an eight-fold muslin cloth bag to remove the marc from the solution. Acetone was added to the filtrate to precipitate the mucilage in a quantity of three times the volume of the total filtrate. The mucilage was separated, dried in an oven at a temperature < 50 °C, collected, dried-powdered, passed through a sieve (number 80), and stored for further use in desiccators^{7, 8} .

 

Characterization of mucilage:

The physicochemical properties such as loss on drying, viscosity and swelling index were determined according to Indian pharmacopoeial procedure⁹. The pH of the powder was determined using a digital pH meter and melting point was determined by digital melting point apparatus.

 

Preparation of Matrix Tablets:

Once daily sustained release matrix tablets of Diclofenac sodium with Tamarindus indica mucilage were prepared by using different drug: mucilage ratios viz. 1:0.5, 1:1,1:1.5, 1:2,1:2.5 (Table 2). Seed mucilage was used as matrix-forming material, while polyvinyl pyrrolidone (PVP K-30) (2%w/w) was used as a binder. Tablets prepared with Hydroxypropylmethylcellulose (HPMC 50cps) and Xanthan gum as matrix forming material for the comparative study. Magnesium stearate (1%w/w) and talc (1%w/w) were incorporated as lubricant. All ingredients were passed through a # 100 sieve, weighed, and blended. The tablets were prepared by dry granulation technique. Isopropyl alcohol was used as granulating fluid and it was added slowly to the power blend, and kneading was performed for few minutes until formation of wet mass. The wet mass was passed through a #16 sieve and dried at 50⁰C in a hot air oven for 3-5 hours. The dried granules were re-sieved through a # 20 sieve and thoroughly mixed with the lubricants. The lubricated granules were compressed by a single station tablet punching machine. The batch size of 100 tablets was prepared.

 

Evaluation of Matrix Tablets:

Thickness

The thickness of the tablets was determined using a thickness screw gauge (Mitutoyo, New Delhi, India). Five tablets from each batch were used and average values were calculated.

 

Uniformity of Weight

To study weight variation, 20 tablets of each formulation were weighed using an electronic balance (Denver APX- 100, Arvada, Colorado) and the test was performed according to the official method⁹.

 

Hardness and Friability

The hardness and friability of tablets for each formulation, were determined using the Monsanto hardness tester (Cadmach, Ahmadabad, India) and the Roche friabilator (Campbell Electronics, Mumbai, India), according to the official method⁹.

 

Estimation of Diclofenac Sodium: An ultraviolet spectrophotometric method based on measurement of absorbance at 276 nm in phosphate buffer of pH 6.8. The method obeyed Beer-Lambert’s law in the concentration range of 1-20 μg/mL. When a standard drug solution was assayed for 6 times, the accuracy and Precision were found to be 0.96% and 1.17% respectively. No interference was observed from the excipients used¹⁰.

 

In vitro drug release study of matrix tablets of Diclofenac sodium:

in vitro drug release was studied using USP 2 apparatus, with 900 ml of dissolution medium of pH 6.8 phosphate buffer maintained at 37±0.5°C for 12 h, at 50 rpm. 5ml of sample was withdrawn at definite time intervals, and was replaced by an equal volume of fresh dissolution medium of same pH. Collected samples were analyzed spectrophotometrically at 276 nm, and cumulative percent drug release was calculated. The study was performed in triplicate and average value was calculated¹⁰.

 

Kinetic treatment of dissolution data:

In order to describe the kinetics of the release process of drug in the different formulations, zero- order (Qt = Q0 + K0t), first order (ln Qt = ln Q0 + K1t), Higuchi (Qt =KHt1/2) and Korsmeyer- Peppas (Qt/Q8= Ktn) models were fitted to the dissolution data of optimized formulations BF1, HF2 and XF1 using linear regression analysis. A value of n = 0.5 indicates case I (Fickian) diffusion or square root of time kinetics, 0.5<n<1 anomalous (non- Fickian) diffusion, n=1 Case – II transport and n>1 Super Case II transport^11-14.

 

Swelling behavior of SR matrix tablets:

The extent of swelling was measured in terms of % weight gain by the tablet. The swelling behavior of diclofenac sodium S.R. tablets based on different matrices was studied. The swelling of matrices was monitored by immersing the tablet into a basket of USP 2 dissolution rate test apparatus containing 900 ml of dissolution medium (pH 6.8 phosphate buffer) maintained at 37±0.5°C for 12 h. at 50 rpm. At the specific time interval, the tablets were withdrawn, soaked with tissue paper, and weighed and the process was continued till the end of 12 h. % weight gain by the tablet was calculated by formula; S.I = {(Mt-Mo) / Mo} X 100, where, S.I = swelling index, Mt = weight of tablet at time‘t’ and Mo = weight of tablet at time t = 0^{11, 15}.

 

Accelerated stability studies:

Accelerated stability study was carried out to observe the effect of temperature and relative humidity on optimized formulations (BF1), by keeping at 40°C, in airtight high density polyethylene bottles for three months, at RH 75±5%. Physical evaluation and in vitro drug release was carried out each month for three months.

 

RESULTS AND DISCUSSION:

Results of the physicochemical evaluation of T. indica mucilage were summarized in Table 1. The loss on drying value indicated it would need to be dried further if it is to be used as a diluent in the formulation of hydrolysable drugs. All other parameters were acceptable to use it as matrix material in tablet formulations. 

 

Table 1: Physicochemical properties of T. indica mucilage

Parameter (s)	Results
Loss on drying (%) Viscosity (cps) Swelling index (ml/g) pH Melting point (0C)     Carr’s index (%) Angle of Repose (0)	7.16 72.66 13.20 6.8-7.4 Brown at temperature 150 - 155°C and charred at 173 - 175°C. 35.13 38.32

Matrix tablets, each containing 100 mg of Diclofenac sodium, were prepared using T. indica seed mucilage in various drug: mucilage ratios (Table 2).

 

The formulated matrix tablets met the pharmacopoeial requirement of uniformity of weight. All the tablets conformed to the requirement of assay, as per I.P. Hardness, % friability, diameter and thickness were well within acceptable limits (Table 3),

 

Diclofenac sodium release profile of T. indica seed mucilage based matrix tablets was shown in Fig.1. As regards the effect of gum concentration, decrease in drug release rate was observed when gum content in the matrix was increased. This may be due to the reason that the gums in higher concentrations in the tablets might have produced dense matrix around the drug particles, providing more barriers for them to escape and dissolve¹⁶. Tablets with Drug–Polymer ratio 1:1 (AF2) showed more than 70% total drug release at the end of 12 h. However, tablets with greater Drug –Polymer ratio were found effective in sustaining the drug release beyond 12 h. Hence formulation AF2 is optimized formulation among T. indica seed mucilage based matrix tablets. Xanthan gum and HPMC based matrix tablets of Diclofenac sodium were used for comparative study.

 

The effect of the amount of Xanthan gum (a natural derivative of cellulose), i.e. D:P ratio (1:0.5, 1:1, 1:1.5, 1:2, and 1:2.5) on the Diclofenac sodium release is shown in Fig. 1.

 

 

Table 2: Composition of Diclofenac Sodium Matrix tablets

Ingredients	Quantity/ Tablet(mg)
	AF1	AF2	AF3	AF4	AF5
Diclofenac sodium Seed Mucilage of T.indica/Xanthan gum/ HPMC Lactose monohydrate PVP K-30 (2%w/w) Magnesium sterarate (1%) Talc (1% w/w) Isopropyl alcohol Total Weight Drug: Polymer ratio	100 50 234 8 4 4 q.s. 400 1:0.5	100 100 184 8 4 4 q.s. 400 1:1	100 150 134 8 4 4 q.s. 400 1:1.5	100 200 84 8 4 4 q.s. 400 1:2	100 250 34 8 4 4 q.s. 400 1:2.5

 

Table 3: Physical properties of Diclofenac Sodium matrix tablets

Formulation Code	Average diameter (mm)	Average thickness (mm)	Hardness (Kg/cm2	Friability (%)	Drug content (%)
AF1 AF2 AF3 AF4 AF5 FF1 FF2 FF3 FF4 FF5 GF1 GF2 GF3 GF4 GF5	11.47 11.52 11.55 11.51 11.66 11.55 11.61 11.54 11.59 11.57 11.63 11.55 11.58 11.60 11.57	3.86 3.91 3.89 3.88 3.95 3.92 3.95 3.91 3.87 3.74 3.88 3.81 3.94 3.87 3.81	4.3 5.1 4.8 4.2 3.9 5.5 5.1 5.2 4.9 4.8 3.8 4.1 4.7 4.6 4.2	0.41 0.23 0.27 0.32 0.28 0.24 0.27 0.35 0.12 0.30 0.22 0.15 0.24 0.23 0.21	96.54 102.31 99.57 98.42 97.65 99.52 101.43 98.79 97.52 98.11 99.75 102.88 104.11 98.47 97.58

 

Fig. 1:  Drug release profile of Diclofenac sodium matrix tablets

 

Diclofenac sodium release decreased as the percent amount of Xanthan gum level in the tablet increased. In the Xanthan gum based formulations drug release is controlled by the hydration- erosion mechanism. The dissolution profile of Xanthan gum based matrix tablets showed that at levels of Drug –Polymer ratio (1:0.5), the profile was close to the profile obtained T. indica seed mucilage based matrix tablets AF2.

 

Fig. 2: Relationship between swelling index and time of optimized formulations

 

The effect of the amount of HPMC, i.e. Drug –Polymer ratio (1:0.5, 1:1, 1:1.5, 1:2, and 1:2.5) on the Diclofenac sodium release is shown in Fig. 2. Diclofenac sodium release decreased as the percent amount of HPMC level in the tablet increased. Drug release is controlled by the hydration of HPMC, which forms a gelatinous barrier layer at the surface of the matrix. In addition, the resistance of such a gel layer to erosion is controlled by the viscosity grade of the HPMC¹⁷. Dissolution profile of the HPMC based matrix tablets showed that at levels of Drug –Polymer ratio (1:0.5), the profile was close to the profile obtained by T. indica seed mucilage based matrix tablets AF2.

 

The kinetic data of optimized matrix tablets were shown in Table 4. The kinetic treatment reflected that release data of AF2 showed r² value of 0.9914 for zero order model which is close to 1, indicating that release of drug follows zero order kinetics followed by Higuchi’s model (0.8949) and first order (0.8031). Zero-order kinetics indicating that the concentration was nearly independent of drug release¹¹. When Xanthan gum was used as the retarding hydrophilic polymer in formulation FF1, drug release significantly follows a zero-order kinetic model, as the plot showed the highest linearity (r² = 0.9757).

 

Table 4: Kinetic treatment of dissolution data of optimized formulations

Formulation	Zero- order (r2)	First- order (r2)	Higuchi (r2)	Korsmeyer- Peppas (n)
AF2 FF1 GF1	0.9914 0.9757 0.9492	0.8031 0.7084 0.7423	0.8949 0.9698 0.9521	0.792 0.7455 0.7403

 

The release data of HPMC based formulation GF1 showed r² value of 0.9521 for Higuchi model is close to 1, indicating that release of drug follows Higuchi kinetics followed by zero order (r² = 0.9492) and first order (r² = 0.7423). It explains why the drug diffuses at a comparatively slower rate as the distance for diffusion increases, which is referred to as square root kinetics. Further Korsmeyer and Peppas equation resulted into the value of n belongs to 0.5<n<1 for all release profiles, which appears to indicate a coupling of the diffusion and erosion mechanism—so-called anomalous diffusion and may indicate that the drug release is controlled by more than one process. Reddy et al observed similar results with a matrix tablet of nicorandil with an n value of 0.71, and Fassihi and Ritschel with a matrix tablet of theophylline with an n value of 0.7. Both these groups of researchers also considered the corresponding n values to indicate an anomalous release mechanism^{11, 17}.

 

The swelling behavior of optimized formulations was shown in Table 5 and Fig. 2. As time increases, the swelling index was increased, because weight gain by tablet was increased proportionally with rate of hydration. Later on, it decreases gradually due to dissolution of outermost gelled layer of tablet into dissolution medium. The direct relationship was observed between swelling index and polymer concentration, and as polymer concentration increases, swelling index was increased. It has been observed that the cumulative percent drug release decreases with increasing concentration of polymer and swelling index. The reason attributed to this fact is slow erosion of the gelled layer from the tablets containing higher polymer concentration^{15, 17}.

 

Table 5: Swelling behavior of Optimized Diclofenac sodium matrix tablets

S.No.	Time (hrs.)	Swelling Index (%)
		AF2	FF1	GF1
1 2 3 4 5 6 7	0 2 4 6 8 10 12	0 88.76 115.43 132.55 87.12 70.45 55.97	0 86.98 104.76 112.24 77.84 63.96 56.87	0 121.40 146.66 124.74 112.97 102.16 78.54

 

Further the results of stability studies of matrix tablets of diclofenac sodium (AF2). It revealed that there was no significant change in hardness, friability, drug content, and dissolution profiles. Thus, formulation was stable at accelerated conditions of temperature and humidity.

 

CONCLUSION:

From the results of present study, it is concluded that the tamarind seed mucilage can be used as an effective release retardant of drugs in matrix tablets like other established polymers.

 

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Received on 04.07.2012       Modified on 16.07.2012

Accepted on 29.07.2012      © RJPT All right reserved