INTRODUCTION:

The oral route is the most common and convenient of the current administration routes for the systemic delivery of drugs. Sustained release (SR) delivery systems for oral dosing are effective in achieving optimal therapy with drugs that have a narrow therapeutic range of blood concentration or eliminate rapidly. Sustained release oral dosage forms have become more important in therapy as a means of reduced dosing frequency, hence potentially improving patient compliance and consequently efficacy.¹ Introduction of matrix tablet as sustained release (SR) has given a new break through for novel drug delivery system (NDDS) in the field of pharmaceutical technology.^2,3 It excludes complex production procedures such as coating and pellatization during manufacturing and drug release rate from the dosage form is controlled mainly by the type and proportion of the polymer used in the preparations.⁴

Diclofenac sodium is one of the potential NSAIDS which is commonly used as an anti inflammatory, analgesic and anti pyretic. It is used for the long term symptomatic treatment of several alignments such as osteoporosis, rheumatoid arthritis, ankylosing spondolitis.

Diclofenac is rapidly and completely absorbed after oral administration and peak plasma concentration is reached within 2-3 hr. It undergoes extensive first pass metabolism; hence only 50% of diclofenac is available systemically. Its half life in plasma is 1-2 hr. It is also used for acute musculo-skeletal injury, acute painful shoulder post operative pain; dysmenorrhea.¹ From several investigations it was found that diclofenac sodium was feasible for the development of sustained release formulation.⁵

For developing a sustained release tablet dosage form, an important issue is to design an optimized formulation with an appropriate dissolution rate in a short time period and minimum number of trials. Many statistical experimental designs have been recognized as useful techniques to optimize the process variables. For this purpose, a computer based optimization technique with a response surface methodology (RSM) utilizing a polynomial equation has been widely used. Response surface methodology (RSM) is a collection of statistical and mathematical techniques, useful for developing, improving and optimizing processes (Joshi et al., 2008; Myers and Montgomery, 1995). Different types of RSM designs include 3 - level factorial design, central composite design (CCD), Box-Behnken design and D-optimal design. The technique requires minimum experimentation and time, thus providing to be far more effective and cost effective than the conventional methods of formulating sustained release dosage forms.^{6, 7}

In recent years, considerable attention has been focused on natural gums in the design of oral controlled drug delivery systems because of their flexibility to obtain a desirable drug release profile, cost-effectiveness and broad regulatory acceptance. Literature review revealed that matrix tablets of diclofenac sodium were formulated by using various gums, synthetic and semi synthetic polymers. In the present study matrix tablets of diclofenac sodium were formulated by using a natural gum, i.e. gum Tiruman.

Gum Tiruman, also known as gum ghatti is obtained from Anogeisus latifolia. Gum ghatti is an extremely complex polysaccharide that occurs in nature as mixed calcium and magnesium salts of uronic acid or ghattic acids. It mainly consists of L-arabinose, D-galactose, D-mannose, D-xylose and D-gluconic acid in the ratio of 10: 6: 2: 1: 2.Gum Ghatti’s main function is to impart stability through its binding and its emulsifying properties. It is useful in beverage emulsions where it forms fairly thick emulsions with different products. Gum Ghatti forms thick mucilages for coating application as a tablet binder. The objective of the present study is to formulate and optimize the matrix tablets of diclofenac sodium having gum tiruman.⁸

MATERIALS:

Diclofenac was obtained as a gift sample from Hetero Drugs, Hyderabad. Gum Tiruman (GT) was obtained from Girijan co-operative corporation Ltd, Visakhapatnam. All other ingredients are of analytical grade.

METHODS:

Experimental design

A full 3² factorial design was developed where the type of diluent (soluble – lactose, insoluble – calcium carbonate, sparingly soluble – starch) (X₁) and concentration of the gum (X₂) were selected as factors. The levels of the two factors were selected on the basis of the preliminary studies carried out before implementing the factorial design. The percent of drug release in 1h, 4h, 8h, time to release 50% drug (t_50%) and zero order rate constant (K) were taken as response variables. The experimental design was given in Table 5. The response surface graphs and mathematical models were obtained by Design Expert 8.0.3.1 (Stat- Ease, USA) software. Composition of matrix tablets was given in table 1.

Granules Preparation

The granules were prepared by wet granulation method using PVP K-30 as the binding agent, alcohol as the wetting agent with appropriate quantities of gum tiruman and various diluents (calcium carbonate, lactose, starch). After enough cohesiveness was obtained, the mass was passed through sieve no10 # mesh and were dried at 50°C in hot air oven till constant weight was reached. The dried granules were then passed through sieve no16#. The granules obtained were evaluated.

Characterization of Granules

Granules were evaluated for their characteristic parameters. Angle of repose was determined by funnel method, bulk density (BD) and tapped density (TD) were determined by cylinder method. Carr’s index (CI) and Hausner ratio were calculated using following equations.⁹ The results were tabulated in table 2.

Characterization of Matrix Tablets

After evaluation of granules, the blend was compressed using Cadmac tablet compression machine, equipped with beveled 8 mm flat-faced punches. The prepared matrix tablets were evaluated for hardness, friability, thickness, uniformity of the weight and content uniformity. Hardness was determined by using Pfizer hardness tester. Friability was determined using Roche friability testing apparatus. Thickness was measured using vernier calipers. Uniformity of the weight and content uniformity were performed according to the I.P method.^10,
11 The results were tabulated in table 3.

Drug Release Study

In vitro drug release studies from the matrix tablets formulated using different diluents were conducted for a period of 8h using a six station USPXXII type II apparatus at 50 rpm. The dissolution studies were carried out at 37±0.5ºc in triplicate using 900 ml 0.1N HCl for 2 hr followed by phosphate buffer (p^H 6.8 ) for subsequent 6 hours. 5 ml of sample was withdrawn from the dissolution medium at predetermined intervals and then replaced with the fresh medium to maintain the sink condition. After filtration and appropriate dilution, the sample was analyzed at 276nm by a UV-spectrophotometer. The dissolution experiments were conducted in triplicate and average values were taken. The results of dissolution studies were tabulated in table 4.The dissolution profiles were depicted in fig 1A,fig 1B,fig 1C.Comparative dissolution curves for the formulations having highest concentration of gum and formulated using various diluents were depicted in fig 2.

Table 1: Formulation of the matrix tablets

Ingredient	F₁	F₂	F₃	F₄	F₅	F₆	F₇	F₈	F₉
Diclofenac sodium (mg)	100	100	100	100	100	100	100	100	100
Gum Tiruman (%)	5	10	15	5	10	15	5	10	15
Lactose (mg)	-	-	-	80	70	60	-	-	-
Starch (mg)		-	-	-	-	-	80	70	60
Calcium carbonate (mg)	80	70	60	-	-	-	-	-	-
PVP K-30 (mg)	6	6	6	6	6	6	6	6	6
Magnesium stearate (%)	1	1	1	1	1	1	1	1	1
Talc (%)	1	1	1	1	1	1	1	1	1

Formulation	Bulk density (g/ml)	Tapped density (g/ml)	Carr’s index	Hausner’s ratio	Angle of repose (°)
F₁	0.44 ± 0.003	0.49 ± 0.003	11.36 ± 0.01	1.11 ± 0. 002	26.56 ± 0.001
F₂	0.52 ± 0.0043	0.58 ± 0.0032	10.34 ± 0.034	1.11 ± 0.001	22.71 ± 0.033
F₃	0.58 ± 0.00823	0.65 ± 0.0067	10.76 ± 0.23	1.12 ± 0.0056	25.46 ± 0.031
F₄	0.543 ± 0.0051	0.56 ± 0.0051	3.03 ± 0.028	1.03 ± 0. 001	27.38 ± 0.288
F₅	0.561 ± 0.0057	0.615 ± 0.0069	8.72 ± 0.086	1.09 ± 0.0012	29.0 ± 0.433
F₆	0.529 ± 0.0085	0.556 ± 0.0095	4.786 ± 0.138	1.04 ± 0.0057	26.3 ± 0.404
F₇	0.42 ± 0.003	0.44 ± 0.001	4.54 ± 0.033	1.04 ± 0.001	18.43 ± 0.311
F₈	0.42 ± 0.003	0.45 ± 0.001	6.66 ± 0.024	1.07 ± 0.001	21.80 ± 0.324
F₉	0.48 ± 0.023	0.51 ± 0.001	5.88 ± 0.002	1.06 ± 0.003	20.55 ± 0.004

Table 3: Characterization of matrix tablets

Formulation	Hardness (N)	Thickness (mm)	Friability (%)	Drug content (%)	Average Weight(g)
F₁	67.2 ± 0.33	3.3 ± 0.01	0.3	99.55	198±0.001
F₂	66.4 ± 0.30	3.2 ± 0.02	0.35	99.73	199±0.001
F₃	67.3 ± 0.31	3.4 ± 0.01	0.45	98.91	201±0.001
F₄	64 ± 0.34	3.3 ± 0.01	0.35	99.55	199±0.001
F₅	68 ± 0.30	3.2 ± 0.02	0.3	100.73	202±0.001
F₆	69.3 ± 0.30	3.4 ± 0.01	0.4	99.11	198±0.001
F₇	69.2 ± 0.33	3.3 ±0.011	0.45	98.34	199±0.001
F₈	67.5 ± 0.03	3.4 ± 0.01	0.35	99.42	200±0.001
F₉	68.6 ± 0.11	3.2 ± 0.01	0.4	98.8	198±0.001

Table 4: Dissolution characteristics of formulations in a 3²full factorial design

Formulation code	Coded factors		Percent drug released			Zero Release rate constant (k)	T_{50 (h)}
Formulation code	X1	X2	Q₁	Q₄	Q₈	Zero Release rate constant (k)	T_{50 (h)}
F1	-1	-1	62.48	99.88	100	52.29	0.95
F2	-1	0	41.61	98.78	99.99	31.90	1.56
F3	-1	1	31.94	93.94	99.99	25.03	1.99
F4	0	-1	0.598	83.17	99.89	16.26	3.07
F5	0	0	1.59	41.016	93.06	11.24	4.44
F6	0	1	0.318	9.8	82.32	6.41	7.80
F7	1	-1	1.59	56.23	99.98	12.85	3.89
F8	1	0	1.845	52.15	88.69	10.37	4.82
F9	1	1	1.31	11.31	78.29	7.23	6.91

Figure 1A: Release profiles of matrices containing calcium carbonate .

Figure 1B: Release profiles of matrices containing lactose

Figure 1C: Release profiles of matrices containing starch

Figure 2: Comparative release profile of matrix tablets

having highest concentration of the gum with different diluents

Release Kinetics

To analyze the mechanism of drug release from the matrix tablets, the release data was fitted into various mathematical models viz., Zero order, first order and Higuchi equation.¹² These models fail to explain drug release mechanism due to swelling (upon hydration) along with the gradual erosion of the matrix. Therefore, the dissolution data was also fitted to the well known experimental equation (Koresmeyer- Peppas equation), which is often used to describe the drug release behavior from polymer systems.¹³

Where, M_tis the amount of drug release at time t, M_f is the amount of drug release after infinite time; K is a release rate constant incorporating structural and geometrical characteristics of the tablet and n is the differential exponent indicative of the mechanism of drug release.

To clarify the release exponent for the different batches of matrix tablets, the log value of %drug was plotted against log time for each batch according to the equation 4. A value of n=0.45 indicates Fickian (case I) release; >0.45 but <0.85 for non Fickian (anomalous) release; > 0.89 indicates super case II type of release. Case II gradually refers to the erosion of the polymeric chain and anomalous transport (non- Fickian) refers to a combination of both diffusion and erosion controlled drug release.¹⁴ Mean dissolution time (MDI) was calculated for dissolution data using the following equation .¹⁵

Where n= release exponent and K= release rate constant. The kinetic data was tabulated in table 5.

Statistical analysis

The results from statistical analysis of the factorial design batches were performed by multiple regression analysis using Microsoft excel. To evaluate contribution of each factor with different levels on responses, two way analysis of variance (ANOVA) was performed using Graph pad, India, to graphically demonstrate the influence of each factor on responses, the response surface plots were generated using Design Expert 8.0.3.1 (Stat- Ease, USA) software. The results of statistical study was tabulated in table 6 and table 7.The response surface plots were given in fig 3A, fig 3B, fig 3C, fig 4A and fig 4B.

Table 5: Mathematical modeling of matrix tablets

Formulation code	Zero order		First order		Higuchi		Korsemeyer-Peppas
Formulation code	K	R	k	r	k	r	k	r
F₁	52.29	0.987	2.303	0.927	67.725	0.995	62.484	1.00
F₂	31.90	0.983	0.633	0.972	49.311	0.983	43.727	0.951
F₃	25.035	0.982	0.584	0.948	43.372	0.982	32.951	0.994
F₄	16.266	0.982	0.37	0.929	32.45	0.823	0.526	0.936
F₅	11.243	0.966	0.242	0.89	25.537	0.851	1.459	0.969
F₆	6.414	0.839	0.106	0.718	13.908	0.681	0.275	0.996
F₇	12.857	0.963	0.267	0.913	27.512	0.853	1.404	0.950
F₈	10.37	0.909	0.193	0.848	24.032	0.835	2.008	0.942
F₉	7.237	0.871	0.117	0.809	15.8	0.714	0.801	0.971

Table 6: summary of the regression output of significant factors for the measured responses

Parameters	Coefficients of regression parameters
Parameters	b₀	b₁	b₂	b₁₂	b₁₁	b₂₂	R²
Q1	-0.07	-21.88	-5.18	7.57	22.63	1.36	0.978
Q4	48.44	-28.63	-20.33	-10.30	23.86	-5.67	0.90
Q8	92.24	-5.66	-6.38	-5.19	2.51	-0.67	0.965
Zero order Release rate constant (k)	0.061	-0.49	-0.36	0.39	0.44	0.27	0.914
T₅₀	3.39	1.59	1.48	0.61	-1.31	0.55	0.913

Table 7: ANOVA table for dependent variables

For Q1
Regression	Sum of Squares	Degrees of freedom	Mean square	F value
Treatment	4290.41	5	858.08	27.25
Residual	94.48	3	31.49
Total	4384.89	8
For Q4
Treatment	9026.44	5	1805.29	5.45
Residual	994.35	3	331.45
Total	10020.80	8
For Q8
Treatment	557.32	5	111.46	16.97
Residual	18.71	3	6.37
Total	577.03	8
For ‘k’
Treatment	3.35	5	0.67	4.53
Residual	0.44	3	0.15
Total	3.80	8
For t50%
Treatment	33.78	5	6.76	6.45
Residual	3.14	3	1.05
Total	36.92	8

Figure 3A: Response surface plot of tablet formulations

after 1 hour dissolution

Figure 3B: Response surface plot of tablet formulations after 4 hours dissolutio

Figure 3C: Response surface plot of tablet formulations after 8 hours dissolution

Figure 4A: Response surface plot of tablet formulations showing the effect of polymer on T 50%

Figure 4B: Response surface plot of tablet formulations showing the effect of polymer on zero order rate constant

RESULTS AND DISCUSSIONS:

The granules of Diclofenac sodium matrix tablets were prepared by wet granulation method according to the formula given in Table 1. The granules were characterized with respect to angle of repose, BD and TD. The angle of repose was less than 29° indicates satisfactory flow behavior. Physical characteristics of the prepared granules were given in table 2.

The matrix tablets were evaluated for hardness, friability, content uniformity, uniformity of weight and in vitro drug release studies. The hardness of the tablets in all the batches was found to be in the range of 64 - 69.3N. The friability of the tablets was in the range of 0.3 – 0.45 %. The drug content was found to be uniform for all the batches of tablets prepared and was found to be within 99±2% of labeled claim. The thickness of the tablet ranges from 3.2 – 3.4mm. Evaluation data of the matrix tablets were given in Table 3. The hardness and friability values indicated good handling properties of the prepared matrix tablets. The prepared matrix tablets were also studied to in vitro drug release studies. Table 5 indicates the data analysis of release profiles according to different kinetic models. Drug release from the matrix tablets was found inversely proportional to the concentration the gum and depends on type of diluent. . The drug release fitted zero order kinetics and mechanism of release is by diffusion. The dissolution profile of matrix tablets was depicted in Figures 1 and 2.

A 3² factorial design was adopted to optimize the formulation variables. In the present design, type of diluent (X₁) and concentration of GT (X₂) were selected as independent variables. Percentage drug release at 1h, 4h, 8h, t_50%and zero order kinetics were taken as dependent variables. The fitting of an empirical polynomial equation to the experimental results facilitates the optimization procedure. The general polynomial equation is as follows:

Y = b₀+ b₁X₁ + b₂X₂ + b₁₂X₁ X₂ + b₁₁X₁²+ b₂₂X₂²

Where Y is the dependent variable, b₀ is the arithmetic mean response on nine runs and b₁ is the estimated coefficient for factor X₁. The main effects (X₁, X₂) represent the average values of changing one factor at a time from its low to high value. The interaction terms (X₁X₂) show how the response changes when two factors are changed simultaneously. The polynomial terms (X₁²and X₂²) are included to investigate nonlinearity. The drug release at Q₁, Q₄, Q₈, t_50% and zero order rate constant for nine batches showed wide variations and the results were given in table 4 and table 5. The data clearly indicates that the values of the dependent variables are strongly dependent on the independent variables. The fitted equations are given below and the regression coefficients are given in Table 6.

Q₁ = -0.070-21.88X₁-5.18X₂+7.57X₁X₂+22.63X₁²+1.36 X₂²

Q₄=+48.44-28.63X₁-20.33X₂-10.30X₁X₂+23.86X₁²-5.67X₂²

Q₈= +92.24-5.66 X₁-6.38 X₂-5.19X₁X₂+2.51 X₁² -0.67 X₂²

t_50%= +3.39+1.59X₁+1.48 X₂+0.61 X₁X₂-1.31X₁²+0.55 X₂²

K = +0.061-0.49X₁-0.36X₂ +0.39 X₁X₂ +0.44 X₁²+0.27 X₂²

The high levels of correlation coefficients for the dependent variables indicate a good fit i.e., good agreement between the dependent and independent variables. The polynomial equation can be used to draw a conclusion after considering the magnitude of the coefficient and the mathematical sign it carries (positive or negative). Positive sign before a factor in polynomial equations represents that the response increases with the factor, while a negative sign means the response and factors have reciprocal relation.

To describe the entire drug release profile, three time level points (percentage of drug release at 1h(Q₁), 4h(Q₂) and 8h(Q₃) , zero order rate constant and t_50% were selected as dependent variabes. From the equations it was quite clear that the release of drug from matrix tablets had negative effect on the type of diluent (X₁) and amount of gum (X₂). The results indicated that Q₁ is maily based upon the X₁ compared to X₂. The release of drug in 4 hours and in 8 hours depends on the both independent variables. The release of drug in 8 hours mainly depends upon concentraion of GT than type of diluent. It is indicating that the release of the drug from the dosage form initially depends upon diluent finally depends upon concentration of gum. From the t_50% equation it is clear that , both the independent variables exhibiting positive affect on t_50% value.

The influence of type of diluent and concentration of gum on drug release parameters were depicted in Figure 3 and 4 respectively as 3D response surface plot. ANOVA table data of the dependent variables was given in table 7. Multiple regression analysis for Q₈ showed that both factors had significant effect (p<0.05).

ACKNOWLEDGEMENTS:

The authors are thankful to Chalapathi Institute of Pharmaceutical Sciences for providing facilities for bringing out this work.

ABBREVIATIONS:

GT = Gum Tiruman. BD = Bulk density. TD = Tapped density. CI = Carr’s index.

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Received on 16.05.2012 Modified on 31.05.2012

Research J. Pharm. and Tech. 5(6): June 2012; Page 846-852