Comparative Evaluation of Matrix Tablet of Diclofenac Sodium Employing Wet Granulation and Direct Compression Method Using Blend of Polymers

 

Aisha Khanum* and Gayathri Devi S

 

Al-Ameen College of Pharmacy, Hosur road Bangalore-27

* Corresponding Author E-mail: aishakhanum@rediffmail.com

 

ABSTRACT

Matrix tablets Diclofenac sodium were formulated consisting of polymers such as polyethylene oxide (PEO) Mw 900,000 and sodium alginate in combination with different ratios by direct compression and wet granulation method with an aim to attain zero order release after the initial burst release and compare the of release kinetics of the drug from matrices prepared from wet granulation and direct compression method. Preformulation studies were carried out to investigate drug polymer interaction. This was done by carrying out Differential scanning calorimetry (DSC). FTIR spectra revealed that there was no shift in the peaks for pure drug and the selected polymers in the formulation indicating that there was no interaction between drug and the polymers. Matrix tablets were subjected to in-vitro drug release in 0.1N HCl pH 1.2 for 2 hrs followed by phosphate buffer pH 7.4 for remaining hours. In-vitro dissolution kinetics followed zero order drug release from (F6) formulation containing (drug: 30% PEO: 30% sodium alginate) which may be due to constant diffusional path length. Analysis of variance showed a significant difference (p>0.05) in drug release among the formulations. SEM study confirmed both diffusion and erosion mechanisms to be operative during drug release from the optimized batch of matrix tablet. Thus best formulation F6 (DC) prepared by direct compression exhibited almost similar drug release profile in different dissolution media as that of the marketed product F7 and prolonged the release for more than 10 hrs. The obtained best formulation showed good stability and satisfactory preclinical anti-inflammatory activity. Therefore the blend of hydrogels in appropriate proportions can release the drug for prolonged period of time. Hence polymer blend of PEO and sodium alginate are ideal for formulating controlled release, cost effective matrix tablets.

 

KEY WORDS Diclofenac sodium, polyethylene oxide (PEO), matrix tablet and swelling index.

 

INTRODUCTION:

Diclofenac sodium is a non steroidal anti-inflammatory drug administered orally in the treatment of rheumatic arthritic disease. Because of its characteristic short biological half life (1-2 hrs) and the hazards of adverse GI reactions, the development of oral sustained release formulation of this drug is highly preferred.1 In order to achieve a desirable and improved therapeutic effect, efficient compliance with negligible side effects and improved patient compliance controlled release technology in the formulation of sustained released dosage form has become essential.2 Increasing complications and expense involved in market of new drug entity has focused greater attention on development of sustained release(SR) or controlled release(CR) drug delivery system.3

 

Matrix system is the most innumerable method used in the development of CR formulations. It is the release system which prolongs and control release of drug that is dissolved or dispersed4. In fact, a matrix is defined as a well-mixed composite of one or more drugs with a gelling agent i.e. hydrophilic polymer. Monolithic or matrix devices are possibly the most common of the devices for controlling the release of the drugs, possibly because they are relatively easy to fabricate, high level of reproducibility and stability of the raw material.5 Hence to achieve this, matrix tablet of diclofenac sodium was prepared by direct compression method using different polymers in combination. Many controlled-release products are designed on the principle of embedding or dispersing the drug in a porous matrix. Liquid penetrates the matrix and dissolves the drug, which then diffuses into the exterior liquid.6 Hence a controlled plasma level profile of drug can be obtained by judicious combination of polymers and modulation of the polymer content in the matrix tablet.

 

MATERIALS AND METHODS:

Diclofenac sodium (Obtained from Smithline Beecham), Sodium alginate (Loba Chemie), spray dried lactose (Loba chemicals) potassium dihydrogen orthrophosphate (Qualigens fine chemicals) and poly ethylene oxide (Acros Organics).

 

PREPARATION OF THE MATRIX TABLETS BY DIRECT COMPRESSION METHOD

The matrix tablets were prepared using combination polymers such as polyethylene oxide Mw 900,000 and sodium alginate using diclofenac sodium as a model drug. The matrices of selected polymers in different ratios were prepared by direct compression method. The drug, polymer and other exicipients used were passed through sieve # 80. The prepared powder mixture of drug, polymers and a diluent was physically admixed. The blend was then lubricated with 1% Wt/Wt talc and 2% Wt/Wt magnesium stearate to study flow properties of the powder mixture such as bulk density, angle of repose, carrs index and rate of flow. Results shown in table-2

 

PREPARATION OF THE MATRIX TABLETS BY WET GRANULATION METHOD

The matrix tablets were prepared using combination polymers such as polyethylene oxide Mw 900,000 and sodium alginate using diclofenac sodium as a model drug. The matrices of selected polymers in different ratios were prepared by wet granulation method. The drug, polymer and other exicipients used were passed through sieve # 80. The granules were prepared by using isopropyl alcohol as granulating agent by passing the cohesive mass through sieve no 14 and regranulating using sieve no. 14/22 to obtain uniform size granules. The granules were then lubricated with 1% Wt/Wt talc and 2% Wt/Wt magnesium stearate to study flow properties of the powder mixture such as bulk density, angle of repose, carrs index and rate of flow. Results shown in table-2

 

Table-1: Formula for development of matrix tablet

Ingredients

Quantity(mg)

F1

(WG)*

F2

(WG) *

F3

(WG)*

F4

(DC)*

F5

(DC)*

F6

(DC)*

Diclofenac

sodium

75

75

75

75

75

75

Sodium

alginate

10

20

30

10

20

30

Polyethylene

oxide Mw

900,000

10

20

30

10

20

30

Lactose

101

91

81

101

91

81

Magnesium

Stearate

04

04

04

04

04

04

Talc

02

02

02

02

02

02

Total weight

(mg)

200

200

200

200

200

200

(WG)* wet granulation (DC) *Direct compression

 

EVALUATION OF MATRIX TABLETS

The powder mixture along with the drug were punched into tablets using 10 station rotary tablet punching machine (CIP machinery) equipped with 8 mm circular, flat punches to obtain a matrix tablet of 200 2.0 mg to obtain hardness in the range of 5-7 Kg/cm2.The physical tests for the obtained matrix tablets for all the formulations were performed and average values were calculated individually, the average weight was calculated. Weight variation was carried using 20 tablets and the percent variation was calculated, drug content and uniformity in weight was carried as per I.P. The other parameters like hardness, friability, thickness and diameter of the tablet were also determined using Roche friabilator, Pfizer hardness tester and Vernier calliper respectively. Results shown in table-3

 

DRUG CONTENT ESTIMATION:

The drug content of the matrices was determined in triplicate by equilibrating an accurately weighed quantity of the diclofenac sodium in phosphate buffer of pH 7.4. The samples were filtered, suitably diluted and assayed spectrophotometrically at 276 nm. 8

 

SWELLING AND EROSION STUDIES:

The design of this experiment using matrices containing the combination or blend of polymers only aim to differentiate between polymer swelling and erosion from the solubility of the drug, excipient or other components within the formula. On exposure of matrices to aqueous fluid, the tablet surface becomes wet and starts to hydrate to form viscous layer, diffusion and subsequent erosion of the matrix results in the release of drug from the matrices. In order to understand the influence of the polymer system on the release pattern of the drug from the matrices swelling and erosion studies were conducted.

 

Table-2 Flow properties of granules by direct compression and wet granulation

Flow

propertiesof powders

andgranules

F1

(WG)*

F2

(WG) *

F3

(WG) *

F4

(DC)*

F5

(DC)*

F6

(DC)*

Bulk

density* (gm/ml)

0.909

0.869

0.877

0.875

0.909

0.924

Compressibility

*(%)

9.23

11.33

8.42

8.63

10.25

9.02

Rate of

flow* (gm/sec)

0.083

0.099

0.096

0.076

0.134

0.166

Angle of

repose* (degrees)

3002

2944

2650

2832

3022

2532

Moisture

content *

2.7

2.4

2.9

2.8

2.3

2.4

* Avg of three readings

 

Procedure for Swelling studies:

Prepared polymer matrix tablets of diclofenac sodium were placed in buffer solution of pH 7.4 maintained at 37C2C. Tablets were removed from the medium after 4 hrs and the weights of the swollen polymer tablets were weighed. Further the swollen tablets were dried using vacuum oven at 40◦C for 48 hrs and weighed. The percentage of swelling was calculated according to the following formula, where S is the weight of the matrix after swelling and R is the weight of the eroded matrix. The percentage erosion was calculated according to the following formula, where S is the weight of the matrix after swelling, R is the weight of the eroded matrix and T is the initial weight of the matrix.9 Results are shown in table-4

 

% Swelling = (S/R) 100 % Erosion = (T-R/T) 100

 

Fig 1: Cumulative drug release studies of formulated diclofenac sodium matrix tablet and Marketed formulation ( F1 (WG), F2(WG), F3(WG), ח F4(DC), * F5(DC), F6(DC),

| F7Marketed Formulation)

 

IN-VITRO RELEASE STUDY:

Release of drug, diclofenac sodium from the matrix tablet was determined using USP Paddle method (automated electoral dissolution system, model TDT-06PL) six flask dissolution rate test apparatus I (Thermolab ).The dissolution rate was studied using 900 ml of 0.1N HCl pH 1.2 for 2 hrs followed by phosphate buffer pH 7.4 for the remaining hours at 37C 0.5C and at 50 rpm using 900ml of dissolution medium. 5ml Samples withdrawn at predetermined time intervals, Samples of 5 ml each were Withdrawn at time intervals i.e., 5,10,15,20,25,30,60,120 upto 600 hrs, each sample withdrawn was replaced with an equal amount of fresh dissolution medium. Samples were analyzed for diclofenac sodium drug content using spectrophotometer Shimadzu model 1700 (Pharmaspec) at 276 nm.10

 

The rate and mechanism of release of diclofenac sodium from the prepared matrix tablets were analyzed by fitting the dissolution data into zero order equation Q=Q0-K0t, where Q is the amount of drug t and K0 is the release rate constant. First order equation, Ln Q= Ln Q-KIt, where KI is the release rate constant and Higuchis equation Q =K2 e/2, where Q is the amount of drug release at time t and K2 is the diffusion rate constant. The dissolution data was further analyzed to define the mechanism of release by applying the dissolution data following the empirical equation,

Mt/ Ma=Kf,

Where, Mt/ Ma is the fraction of the drug release at time t. K is a constant and characterizes the mechanism of the drug release from the formulations during dissolution process. The study was performed in triplicate. Results shown in table-5

 

DIFFERENTIAL SCANNING COLORIMETRY AND FT-IR STUDY:

DSC was performed to determine whether the physical mixture of drug and the different excipients used in the formulations were compatible or there was any interaction. Infrared spectrum was taken in the Perkin- Elmer FT - IR (spectrum RX) by scanning the optimized formu1ations in potassium bromide discs. The sample of pure drug, physical mixtures (1: 1) of both drug and polymers were taken in a diffuse reflectance samples and IR spectra recorded by scanning in a wavelength of 400 to 4000cm in a FTIR Spectrophotometer.11

 

Scanning electron microscopy of the DC (F6) matrix tablet during dissolution at 0 hr, 4 hrs and 7 hrs

ANTI-INFLAMMATORY ACTIVITY:

Carrageenan-induced rat paw edema model was used to assess the anti-inflammatory effect of the pure drug, optimized matrix tablet. Wister rats weighing between 160- 200 g were used for the study. The overnight fasted animals were divided into four groups (n=6) and treated as following:

1st group (control): 2.5 ml of 0.5% sodium carboxy methyl cellulose (CMC)

2nd group (pure drug): 10 mg/kg in 0.5% CMC

3rd group: composition of optimized tablet (F6), 10 mg/kg in 0.5% CMC

4th group: composition of marketed tablet (FM7), 10 mg/kg in 0.5% CMC

 

Table-3: Post compressional evaluation of matrix tablets prepared by different techniques

Matrix Tablet evaluation parameters

F1 (WG)*

F2 (WG) *

F3 (WG) *

F4 (DC)*

F5 (DC)*

F6 (DC)*

Hardness (Kg/cm sq)

5.40.4

6.20.3

5.40.2

5.40.3

6.20.5

5.80.3

Friability (percentage)

0.220.3

0.290.1

0.340.4

0.340.3

0.500.2

0.200.4

Thickness (mm)

3.990.01

3.970.02

3.980.3

3.990.03

3.970.03

3.990.03

Diameter (mm)

7.980.02

7.990.02

7.970.4

7.960.02

7.990.03

7.990.03

* Avg of three readings

 

Table-4: Kinetics of drug release from different matrix formulations and comparative study with bioequivalent marketed product

Formulations

Drug release kinetics, correlation co-efficient r

Release exponent (n)

Zero order

First order

Higuchi equation

F1 (WG)*

0.938

0.990

0.988

0.553

F2 (WG)*

0.956

0.991

0.998

0.575

F3 (WG)*

0.964

0.990

0.988

0.609

F4 (DC)*

0.978

0.996

0.991

0.644

F5 (DC)*

0.998

0.997

0.996

0.624

F6 (DC)*

0.997

0.925

0.994

0.785

F7 Marketed product

0.966

0.990

0.992

0.654

 

Table-5 : Effect of Diclofenac sodium on the paw edema induced by Carrageenan in wistar rats

Time in hr

Control

Paw volume(ml)

Puredrug

Paw volume(ml)

F6(DC)

Paw volume(ml)

F7 MKT

Paw volume (ml)

Pure drug

% Inhibition

F6 (DC)

% Inhibition

F7 MKT

% Inhibition

1

0.150.02

0.130.04

0.140.02

0.150.02

18.230.02

18.230.02

12.230.02

2

0.220.03

0.110.03

0.130.02

0.150.08

38.600.02

44.600.02

35.600.12

3

0.320.06

0.100.09

0.130.05

0.140.05

70.210.04

69.200.04

71.210.04

4

0.510.03

0.090.12

0.150.03

0.160.03

76.560.06

72.500.06

73.560.05

5

0.680.07

0.130.03

0.120.07

0.110.07

78.260.12

88.260.10

87.260.02

6

0.700.06

0.150.05

0.130.08

0.130.07

80.260.06

89.260.09

88.260.07

 

Table-6: Drug content, mass swelling index and erosion study of matrix tablets:

Formulations

DrugContent

(mg/tablet) Mean SD, n=3

(%)Swelling

Degree (Q) Mean SD, n=3 pH 7.4

(%)Erosion

value Mean

SD, n=3 pH 7.4

F1 (WG)*

98.21 1.79

497.09

43.61

F2 (WG)*

89.25 0.75

267.54

42.58

F3 (WG)*

97.59 1.24

427.34

62.38

F4 (DC)*

98.60 0.58

267.54

35.24

F5 (DC)*

98.36 1.89

539.02

32.05

F6 (DC)*

97.58 1.25

624.23

20.85

 

After 30 min of drug administration, rats of all groups were challenged by a subcutaneous injection of 0.05 ml of 1% solution of carrageenan in saline into the plantar site of the left hind paw. The paw volumes were measured with a plethysmometer, prior to administration of carrageenan and after 1, 2, 3, 4, and 5 h of administration. The percent inhibition of edema for specific time intervals was then calculated.12 The anti-inflammatory activity of pure drug or tablet compositions was evaluated on the basis of its ability to inhibit the edema produced in hind paw of rats after challenging with carrageenan. The difference in paw volume values before and after drug administration was calculated.

 

BATCH REPRODUCIBILITY AND STABILITY ON STORAGE:

Accelerated stability studies were carried out to observe the effect of temperature and relative humidity on optimized formulation F6 (DC), by placing the best formulation in the stability chamber Model: Newtronic, temperature/ humidity control oven-QLH-2004 0-4C, RT 28C and at 45C in air tight high density polyethylene bottles for 3 months, at RH 755%. Physical characteristics and release profiles of the formulations were studied Color, Hardness, friability and drug content were analyzed.

 

RESULTS AND DISCUSSION:

The prepared matrices of diclofenac sodium met the standard pharmacopoeial requirement of uniform weight, matrices conformed to the requirement of assay, as per I.P, Hardness, % friability and thickness was well within acceptable limits.

 

The swelling index was calculated with respect to time. It was seen that as the time increase the swelling index increased proportionally with rate of hydration up to 3 hr. later on, it decreased gradually due to dissolution of outermost gelled layer of tablet into dissolution medium. Formulation F6 showed highest swelling and least erosion. The least erosion would have attributed in maintaining the integrity of the tablet. The drug-polymer interaction was determined by IR spectroscopy and Differential Scanning Calorimeter, which suggest that the drug and the polymer did not show any incompatibility.

 

The kinetic treatment reflected that release data F6 showed R2 value 0.9 and 0.997 for first order and zero order equation respectively, indicating the drug followed zero order kinetics. The formulation F6 was found to be the best which prolonged the release for more than 10 hr.

 

The pure drug exhibited comparatively rapid anti- inflammatory activity. The % inhibition values of pure drug were higher than those of test and marketed formulation, except at 360 min. the anti-inflammatory activity with the composition of test formulation F6 and marketed formulation was slowly attained but at the end of the experiment both exhibited highest activity. The results indicated that the prepared tablet F6 and the marketed tablet formulations produce sustained action.

 

Stability studies revealed that there was no significant physical change in color, hardness, friability, drug content and dissolution profile of F6 (DC). Thus the best formulation was stable at different conditions.

 

CONCLUSION:

Hence, the matrices of diclofenac sodium containing (30%) PEO Mw 900,000 in combination with (30%) sodium alginate along with spray dried lactose, diluents and lubricants can be prepared satisfactorily by direct compression method. The results show the matrices prepared by direct compression method release the drug for a period of 10 hrs compared to matrices prepared by wet granulation method. It could be concluded that polyethylene oxide Mw 900,000 in combination with sodium alginate can be used as an effective matrix former to retard the release of diclofenac sodium for extended period of time by employing direct compression method which is an cost effective method.

 

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9.     Yoele PG, Galgatte VC, Balle IB and Nakhat PD Design and evaluation of Xanthan gum based sustained release matrix tablets of diclofenac sodium: Indian J Pharm.Sci., 2006. 68:185-189

10.  Manjunath KH., Ramanna MV., Satynarayana D.Design and evaluation of diclofenac sodium controlled drug delivery system: Indian J.Pharm. Sci 2007: vol 69 (5):384-389

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Received on 27.09.2008 Modified on 29.09.2008

Accepted on 30.09.2008 RJPT All right reserved

Research J. Pharm. and Tech. 1(3): July-Sept. 2008; Page 265-269