Effect of Hydrophilic and Hydrophobic Polymers on the Release of Naproxen from Sustained Release Tablets.

 

Maushumi Kulkarni*, Rahul Thube, Kiran Bhise and Mohammed Kakajiwala

M.C.E. Society’s, Allana College of Pharmacy, Camp, Pune-01. (Maharashtra)

*Corresponding Author E-mail: mkakajiwala@hotmail.com

 

ABSTRACT:

The purpose of this research was to formulate sustained release tablets matrices of Naproxen with hydrophilic and hydrophobic polymers like Sodium alginate, Xanthan gum and Ethyl cellulose and their combinations in different ratios.

Matrix tablets were formulated using polymers like Sodium alginate, Xanthan gum and Ethyl cellulose and their combinations at different ratios. The effect on release profiles and matrix swelling in phosphate buffer pH 7.4 was studied and treated with release kinetic models. Accelerated stability studies were conducted as per ICH Guidelines at 40°C/75% RH for 6 months. Sodium alginate and Xanthan gum retarded the drug release more than Ethyl cellulose. It can be concluded that that hydrophilic polymers compared to hydrophobic polymers can be effectively used for oral sustained release dosage form.

 

KEYWORDS: Naproxen, hydrophilic, hydrophobic, sustained release

 


INTRODUCTION:1-5

Naproxen is a non-steroidal anti-inflammatory drug. It is chemically described as 2-naphthaleneacetic acid, 6-methoxy-a-methyl-, (S)-. It is  commonly used for the reduction of moderate to severe pain, fever, inflammation and stiffness caused by conditions such as osteoarthritis, rheumatoid arthritis, psoriatic arthritis, gout, ankylosing spondylitis, menstrual cramps, tendinitis, bursitis, and the treatment of primary dysmenorrhea. It works by inhibiting both the COX-1 and COX-2 enzymes. It has a biological half life of 10hrs.and can be used as sustained release dosage form. Generally, primary objectives of controlled drug delivery are to ensure safety and to improve efficacy of drugs as well as patient compliance, which can be achieved by better control of plasma drug levels and less frequent dosing. The most convenient way to achieve controlled release of active agent involves physical blending of drug with polymer matrix, followed by direct compression, compression molding, injection molding, extrusion, or solvent casting which results either in monolithic device or in swellable hydrogel matrix. For any controlled-release dosage form it is very important to use minimum number of excipients with minimum processing steps in order to reduce the tablet-to-tablet and batch-to-batch variations, hence direct compression is the most suitable and easily up-scalable technique.

 

On contact with an aqueous medium, the hydrophilic polymer matrix gradually begins to hydrate from the periphery towards the centre forming a gelatinous swollen mass, which controls the diffusion of drug molecules through the polymeric material into the aqueous medium. On the other hand the hydrophobic polymer matrix retards the diffusion of drug molecules into the aqueous media. The objective of this study was to develop sustained-release tablets of Naproxen using suitable hydrophilic systems and comparison with the hydrophobic matrices. Hydrophilic system used was Sodium alginate and Xanthan gum, hydrophobic system used was Ethyl cellulose.

 

MATERIALS AND METHODS:-

Materials:

The drug Naproxen was procured as gift sample from (Ranbaxy Laboratories Ltd., New Delhi), Sodium Alginate was procured from (Loba Chemie Pvt. Ltd. Mumbai.), Xanthan Gum and Ethyl Cellulose was procured from (Research-Lab Fine Chem. Industries, Mumbai.). All other chemicals purchased and were of analytical grade.

 

Preparation of Matrices:

Naproxen, Sodium alginate, Ethyl cellulose and Xanthan gum were mixed separately in various ratios individually and in combinations with each other in a laboratory mixer and were passed through 10and12 mesh screen. The tablets were compressed by direct compression method by using 8 Station Tablet Punching Machine – Karnavati - Minipress D-II Link, Mumbai fitted with 11-mm diameter flat-faced punches. Powder admixtures were manually filled into the die, and 1 compaction cycle was performed. For each batch, 50 tablets were produced.

 

Fourier Transform Infrared Spectrometry:

Fourier Transform Infrared (FTIR) spectra of, Naproxen, Sodium alginate, Ethyl cellulose and Xanthan gum, physical mixtures, were recorded on FTIR spectrometer (model FTIR-4100 Plus, Jasco).

 

Figure 1: Fourier transform infrared (FTIR) spectra patterns

·                    Naproxen

 

Evaluation of Tablets:6

The tablets were also evaluated as per IP1996 for weight variation (n=20), hardness (n=6), thickness (n=20), and friability. Hardness was determined by using a Monsanto tablet hardness tester (Campbell Electronics, Mumbai, India). Friability test was conducted using Roche friabilator (F. Hoffmann-La Roche Ltd, Basel, Switzerland).

Thickness of the tablets was measured by digital Vernier calipers (Mitutoyo Corp, Kawasaki, Japan).

 

Determination of Drug Content:

0.200gms. drug was dissolved in 70ml. of alcohol and 5ml. of 0.01M HCl was added. Potentiometric titration using 0.1M NaOH and the volume added between two points of inflexion was read.

 

In Vitro Drug Release Studies:

The release rate of Naproxen tablets was determined using USP Dissolution Testing Apparatus II. The dissolution test was performed using 900 ml of 7.4pH phosphate buffer, at 37° ± 0.50°C and 50 rpm. A sample (5 ml) of the solution was withdrawn from the dissolution apparatus hourly for 12 hrs and the samples were replaced with fresh dissolution medium. The samples were filtered through Whatman filter paper no. 41. Absorbance of these solutions was measured at 332 nm. Cumulative percentage drug release was calculated using an equation obtained from a standard curve.

 

DSC studies:7

Naproxen along with the combination with different polymers was weighed (4-8mg) into a 40µl standard aluminum crucible and hermetically sealed with perforated aluminium lid. Sample were subjected to thermal study using model mettler Toledo 82 le .The system was purged with N2 gas at rate of 100 ml/min to maintain inert atmosphere .Heating of samples was done from -30 to 3500 C at rate of 100 C/min.

 

Figure 2: Thermal analysis

(a)               Xanthan gum + Sodium alginate 1:10

 

(b)               Xanthan gum + Sodium alginate + Ethyl  cellulose 1:10+5%

 

Water Uptake Studies:8-9

Water uptake studies were performed by using equation stated by Roy and Rohera et al8, 9. The rate of test medium uptake by the polymer was determined by equilibrium weight gain method. The dry drug and polymer matrices were weighed, placed in dissolution baskets, and immersed in phosphate buffer (pH 7.4) maintained at 37±0.50°C in the dissolution vessels. At regular intervals, the pre-weighed basket–matrix system was withdrawn from the dissolution vessel, lightly blotted with a tissue paper to remove excess test liquid and re-weighed. The percent water uptake, i.e., degree of swelling, was estimated at each time point from using equation:

 

Water Uptake (%) = Ws- Wi

                                   Wp

Where,

Ws is the weight of the swollen matrix at time t, Wi is the initial weight of the matrix and Wp is the weight of the polymer.

Drug release kinetics:10

Data from the in vitro drug release were analyzed by different equations and kinetic

models in order to evaluate the release mechanism of Naproxen from the matrices.

The kinetic models used were as follows:

(a) Korsmeyer and Peppas model

Mt / M∞ = k x tn

Where, Mt / M∞ is the fraction drug released, k is kinetic constant, t is the release time, n is the diffusional exponent for drug release.

 

Peppas claimed that, the above equation could adequately describe the release of solutes from slabs, spheres, cylinders, and tablets (discs), regardless of release mechanism. The value of ‘n’ gives an indication of release mechanism. When n = <0.5 the drug release follows fickian diffusion; and the value of n =>0.5<1.0 then anomalous non fickian release would be implicated. n is the slope value, of log Mt / M∞ vs log time curve.

b) Zero-Order Release:

Qt = Q0+ K0t

where Q is the amount of drug dissolved in time t, Q is initial amount of drug in the solution (most times, Q0=0) and Ko is the zero order release constant

c) First Order Kinetics:

logQt=log Q0+ K1t/2.303

d) Hixon-Crowell Model:

W01/3 - Wt1/3 =Kst

e) Higuchi Model:

Qt=KHt1/2

 

Stability Studies:11

Stability studies were conducted on Naproxen sustained matrix tablets containing Sodium alginate, Ethyl cellulose, Xanthan gum and their various combinations to assess their stability with respect to their physical appearance, drug content, and drug release characteristics after storing them in Stability chamber (Thermolab) at 40°C/ 75%(RH) for 6 months.

 

RESULTS AND DISCUSSION:-

Water Uptake Study:

Swelling index of matrices comprising of Sodium alginate, Ethyl cellulose and combination of all the polymers is show in Table No. 1 (a and b) It is seen that as the amount of polymer in the matrix increases swelling increases for all the polymers. In the case of Sodium alginate maximum swelling is observed at 45% polymer concentration. Due to its excessive hydration ability with simultaneous swelling. In Sodium alginate high initial swelling is observed with erosion in the latter stages with the amount of polymer at 20%.The swelling index increases as the amount of polymer in the matrix increases. Hence a more quantity of polymer is required to achieve sustained release of drug from Sodium alginate polymer. In case of Ethyl cellulose matrices, high initial swelling is observed at polymer concentration of 5% due to its high hydration ability and forms a thick gel from which the drug diffuses. The swelling of Ethyl cellulose matrices increases as the amount of polymer in the matrix is increased with polymer concentration at 20% and the amount of drug release is reduced. When Sodium alginate and Xanthan gum are combined together swelling increases due to the amount of Xanthan gum present in the matrices increases. The matrices containing Xanthan gum and Sodium alginate in the ratio 1:10 do not swell rapidly. When Xanthan gum, Sodium alginate and Ethyl cellulose in the ratio of 1:10+5% are combined together high swelling is observed due to excessive hydration of polymers.

 

Table 1: Water uptake studies:

(a) Swelling Index of Drug and Polymer matrices (%)

Formulation

code.

2hrs.

4hrs.

6hrs.

8hrs.

NS1

152.2

251.5

319.3

321.9

NS2

146.8

248.7

295.5

310.3

NS3

142.0

232.9

274.2

296.5

NS4

134.9

210.6

268.9

284.6

NS5

128.8

200.6

255.8

270.4

NS6

167.4

192.4

250.7

265.3

NE1

65.0

133.4

187.1

221.7

NE2

64.1

122.7

180.4

212.0

NE3

62.8

113.9

173.8

203.6

NE4

60.5

101.4

164.3

195.4

 

(b) Swelling Index of Drug and Combination of Polymer matrices (%)

Formulation

code.

2hrs.

 

4hrs.

6hrs.

8hrs.

NSX1

133.8

194.6

237.1

256.2

NSX2

124.1

184.7

221.3

246.8

NSX3

118.2

170.9

210.5

240.4

NSEX1

95.4

168.4

209.2

235.7

NSEX2

90.1

163.9

204.5

230.6

NSEX3

83.7

154.3

197.4

225.7

NSEX4

75.9

142.6

183.9

215.5

 

Table 2 – Effect of hydrophilic polymer concentration:

(a) Tablet Formulations Containing Relative Quantities of Drug and Polymer (Naproxen & Sodium alginate)

Formulation no.

Drug

(naproxen)

Polymer

(sodium alginate)

NS 1

33.33%

20%

NS 2

33.33%

25%

NS 3

33.33%

30%

NS 4

33.33%

35%

NS 5

33.33%

40%

NS 6

33.33%

45%

* Formulations contains dose of drug (naproxen) i.e. 200mg (33.33%)

Weight of the polymer 120mg (20%), 150mg (25%), 180mg (30%),

210mg (35%), 240mg (40%), 270mg (45%)

 

Effect of Hydrophilic Polymer Concentration:-

The formulations of different ratios as depicted in Table No.2 (a) were prepared and their in-vitro studies were carried out in phosphate buffer 7.4pH.The release pattern of the drug in combination with sodium alginate (Table No.2(b)) varied with the amount of the polymer. The release varied with the amount of polymer concentration, 20%alginate showing a faster release (97.035) as compared to alginate concentration containing 45%(82.914) in 8h time interval. At a fixed Naproxen dose, the total content of sodium alginate shows a dramatic change in their dissolution profile. At lower alginate content, rapid swelling of matrices with less tight hydrogel structure resulted in higher drug release. Conversely when a natural polymer like Xanthan gum is added in different ratios it affected the release pattern (Table No.4 (a)). The ratio of 1:10 of Xanthan gum and sodium alginate showed an optimized release.

 


(b)  Percentage Release of Naproxen from Drug and Polymer matrices (Naproxen and sodium alginate)

Time (hrs.)

ns1 (20%)

ns2 (25%)

ns3 (30%)

ns4 (35%)

ns5 (40%)

ns6 (45%)

0

0

0

0

0

0

0

1

23.250

22.644

23.023

22.833

22.340

21.923

2

36.733

34.829

34.414

33.679

33.302

30.832

3

43.577

43.221

42.696

40.896

40.203

39.621

4

53.306

51.759

51.218

49.913

48.944

48.329

5

63.071

61.254

60.902

59.067

58.733

57.751

6

72.721

72.094

71.191

70.233

69.071

68.113

7

81.670

80.589

80.076

78.206

76.117

74.633

8

97.035

94.466

91.550

89.182

86.303

82.914

 

 


As the amount of Xanthan gum in the matrix increased, there would be a greater degree of hydration with simultaneous swelling which results in a lengthening of the drug diffusion pathway and reduction in drug release rate and the drug showed a release of 91.249% in 12h. time (Table No.4 (a)).

 

Effect of Hydrophobic Polymer Concentration12:-

The formulations of different ratios as depicted in Table No.3(a) were prepared and their in-vitro studies were carried out in phosphate buffer 7.4pH. The release pattern of the drug varied with the amount of the polymer (Table No. 3(b)). Due to it hydrophobic nature ethyl cellulose showed a greater retardation and a decrease in amount of drug release. Ethyl cellulose with 5 % concentration showed decreased drug diffusion due to less amount of swelling, and with the amount of the polymer concentration increasing 20% it retard further the drug release due to a much decreased in swelling and showed a release of 37.529% in 12h. time compared to 41.854% in 12h. time (Table No.3 (b))

 

Table 3 - Effect of hydrophobic polymer concentration:

(a)Tablet Formulations Containing Relative Quantities of Drug and Polymer (Naproxen & Ethyl cellulose)

Formulation no.

Drug

(naproxen)

Polymer

(ethyl cellulose)

NE 1

33.33%

5%

NE 2

33.33%

10%

NE 3

33.33%

15%

NE 4

33.33%

20%

* Formulations contains dose of drug (naproxen) i.e. 200mg (33.33%)

Weight of the polymer 30mg (5%), 60g (10%), 90mg (15%), and 120mg (20%)

 

(b) Percentage Release of Naproxen from Drug and Polymer matrices (Naproxen and ethyl cellulose)

Time (hrs.)

NE 1

NE 2

NE 3

NE 4

0

0

0

0

0

1

6.434

5.316

4.178

3.875

2

10.678

9.509

9.415

8.435

3

15.643

12.756

12.774

11.856

4

19.507

17.662

17.662

16.208

5

23.308

21.622

20.880

19.990

6

25.405

24.024

23.913

23.674

7

27.845

27.039

27.589

27.515

8

31.111

30.692

30.364

29.525

9

33.974

33.286

32.869

32.126

10

36.749

35.218

34.497

34.173

11

38.629

38.790

36.713

36.247

12

41.854

40.413

38.561

37.529

 

Table 4 – Effect of combination of polymer concentration:

(a)  Percentage Release of Naproxen from Drug and Polymer combination matrices (Naproxen+ sodium alginate+ Xanthan gum)

Time

(hrs.)

NSX 1

(1:6)

NSX 2

(1:8)

NSX 3

(1:10)

0

0

0

0

1

20.937

22.189

22.625

2

28.004

28.777

31.058

3

31.522

32.190

34.803

4

36.472

37.311

39.175

5

40.177

41.975

43.429

6

44.262

48.612

49.644

7

50.112

55.243

56.728

8

53.669

61.850

63.198

9

57.217

67.163

69.753

10

60.757

70.861

75.651

11

63.660

75.603

82.801

12

67.095

79.092

91.249

 

(b) Percentage Release of Naproxen from Drug and Polymer combination matrices (Naproxen+ sodium alginate+ Xanthan gum+

Ethyl cellulose)

Time

(hrs.)

NSEX 1

(1:10+5%)

NSEX 2

(1:10+10%)

NSEX 3

(1:10+15%)

NSEX 4

(1:10+20%)

0

0

0

0

0

1

21.355

20.937

20.558

20.369

2

28.362

25.365

24.988

24.554

3

34.410

30.472

29.629

28.204

4

37.833

34.850

33.825

32.557

5

41.048

39.213

38.212

37.026

6

45.055

43.211

41.368

39.949

7

50.313

47.271

45.713

42.928

8

54.889

50.735

49.623

46.489

9

59.029

55.369

53.177

50.260

10

64.017

58.217

55.371

52.472

11

69.390

60.759

54.485

54.869

12

73.610

63.214

60.491

56.023

 

 

Effect of Combination of Polymer Concentration13-14:-

Different ratio of concentrations of Sodium alginate and Xanthan gum were done to determine the optimum amount of both the polymers as shown in Table No.4 (a).for retarding the Naproxen release. Xanthan gum and Sodium alginate based formulations were screened to select those that showed slow release of Naproxen over 12 h.  The ratio of 1:10 showed a greater retarding effect. Due to the presence of Xanthan gum content, the initial drug release was diminished and drug diffuses slowly continuously for more than 12 h. with the amount of Xanthan gum in the matrix, there would be a greater degree of hydration with simultaneous swelling which results in a lengthening of the drug diffusion pathway and reduction in drug release rate. A release of 91.249%   was seen with 1:10 ratio compared to the other ratio which showed much less release (Table No. 4(a)). The optimized ratio of 1:10 Xanthan gum and Sodium alginate were also combined with different concentrations of Ethyl cellulose as shown in Table No.4 (b). The different ethyl cellulose concentration due to its hydrophobicity showed decreased amount of drug release with an increasing amount of polymer as seen from Table No.4(b) with the ratio 1:10+5% showing a release of 73.610% in 12h. time. Therefore a combination of Xanthan gum and Sodium alginate showed a much better release as compared to its combination with Ethyl cellulose.

 

Stability Studies:

At the end of the testing period, the matrix tablets were observed for changes in physical appearance, analyzed for drug content, and subjected to in vitro drug release studies. No visible changes in the appearance of the matrix tablets were observed and a significant change was not seen in the drug content and drug release at the end of the storage period.

 

CONCLUSION:

In Hydrophilic matrix system the amount of Sodium alginate resulted in decreasing the release rate of drug while increasing the amount of Ethyl cellulose in hydrophobic matrix did not affect the rate of drug release. The combination of Sodium alginate and Xanthan gum sustained the release of drug effectively by retarding the drug release compared to the combination of all the three polymers. Hydrophilic and Hydrophobic polymers can be effectively used in the modulation of drug release. These findings could thus be of importance in developing a suitable model for sustained release technology.

 

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Received on 17.08.2009       Modified on 02.03.2010

Accepted on 08.04.2010      © RJPT All right reserved

Research J. Pharm. and Tech.3 (3): July-Sept. 2010; Page 776-780