Optimization of Various Grades of HPMC for Development of Sustained Release Matrix Tablets of Theophylline.

 

Godbole Ajeet Madhukar1, Patel Bhautik V2, Somnache Sandesh Narayan1*,Prajapati Ashish R2, Yadav Pradeep2

1Department of Pharmaceutics, PES’S Rajaram and Tarabai Bandekar College of Pharmacy, Farmagudi,

Ponda-403401, Goa, India.

2Department of Pharmaceutics, S.E.T’S College of Pharmacy, Dharwad, Karnataka (India).

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

 

ABSTRACT:

Theophylline is a bronchodilator drug, used in treatment of asthma. The conventional dosage forms of Theophylline releases the entire drug in just few minutes and therefore the therapeutic concentrations will be maintained for a short period of time. This may leads to administration of subsequent dose. To overcome this, present study was aimed to develop the dosage form of Theophylline which will release the drug up to 12 hours.  The matrix tablets of Theophylline were developed using different concentrations of various grades of HPMC and were evaluated for various pre-compression and post compression parameters. The data obtained was analyzed using linear model (Historical Data) of Design Expert 8.0.7.1(Trial version). Based on the results obtained, it was concluded that the Formulation F9 containing HPMC E15LV is suitable to develop sustained release matrix table of Theophylline which can release more than 50 % drug in first 5 hours and more that 90 % of the drug at the end of 9th hour extended up to 12 hours.

 

KEY WORDS: Swellable polymer, optimization of formulation, design of experiment, theophylline matrix tablet.

 

 


INTRODUCTION:

Asthma is a common chronic inflammatory disease of the airways, characterized by hyper responsiveness to a variety of stimuli. It may be classified as mild intermittent or mild, moderate or severe persistent.1 Theophylline is a methyl xanthine derivative and it is widely used as a bronchodilator in the chronic treatment of bronchial asthma and bronchospastic reaction.2,3 It is well absorbed from GIT but has short biological half-life i.e. 8 hours in adult.4

 

Theophylline shows rapid and complete absorption. But relatively short half-life and narrow therapeutic window of theophylline, make it necessary to design the formulation which gives the sustained release of drug for longer duration of time. The plasma drug concentration of 5-20 μg/ml is required to produce therapeutic effect of theophylline. The therapeutic dose is needed to be maintained for a period of 12 hours. The conventional dosage forms release the entire drug in just few minutes and therefore the therapeutic concentration is maintained for a short period of time generating a need for repeated administration of another dose. Therefore a sustained release formulation of Theophylline which would release the drug over a time period of 12 hours is beneficial. Sustained release preparations initially provide an immediate dose required for the normal therapeutic response, followed by the gradual release of drug in amounts sufficient to maintain the therapeutic response for a extended period of time.5,6 This is the ideal condition for treatment of the asthma. Thus in present study, work was carried out to develop sustained release tablet of Theophylline. Matrix tablet was chosen as dosage form because of cost effectiveness. The effect of various grades of HPMC on formulation parameters was evaluated.

 

MATERIALS AND METHODS:

Theophylline was received as a gift sample from Ami Life Science Pvt. Ltd. Gujarat. Lactose and HPMC K 100M were purchased from Himedia Laboratories Pvt Ltd,  HPMC was purchased from, Loba Chem Pvt Ltd, HPMC E15LV was purchased from Yarrow Chem Product  Mumbai and Microcrystalline cellulose purchased from Basco Products. All excipients and ingredients used were of analytical grade. 

 

Formulation of matrix tablets of Theophylline:

The sustained release tablets of Theophylline were prepared by wet granulation technique using varying concentrations of different grades of HPMC as shown in formulation table Table No. 1. Micro crystalline cellulose and Lactose were used as diluent. All the ingredients were passed through sieve no 60. Then weighed accurately, mixed in geometric order and granulated using isopropyl alcohol as a granulating agent.  After enough cohesiveness was obtained the mass was passed through sieve number 14. The granules were allowed at dry room temperature (27±20C). The dried coarse granules were passed through sieve no 22 superimposed on sieve no 44. 10% of fines of the total weight of granules were added along with magnesium stearate as lubricating agent and talc as glidant. The granules were then compressed on 10 stations Rotary Tablet Compression Machine (Cadmac) equipped with 12 mm concave punch and die set. Each tablet contained 300 mg of Theophylline and other pharmaceutical ingredients as listed in formulation table. A compression force of 4 kg/cm2 and a total weight of 600 mg was maintained for all the tablets.


 

 

Table No.1:  Formulation for theophylline matrix table.

Sl. No

Ingredient

F1

F2

F3

F4

F5

F6

F7

F8

F9

1

API (Theophylline)

300

300

300

300

300

300

300

300

300

2

HPMC K100M

40

50

60

-

-

-

-

-

-

3

HPMC E5LV

-

-

-

228

240

252

-

-

-

4

HPMC E15LV

-

-

-

-

-

-

168

180

192

5

PVP K-30

15

15

15

15

15

15

15

15

15

6

MCC

15

15

15

33

21

9

93

81

69

7

Lactose

206

196

186

-

-

-

-

-

-

8

Talc

15

15

15

15

15

15

15

15

15

9

Mg Stearate

9

9

9

9

9

9

9

9

9

11

Iso Propyl Alcohol

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

12

Total weight

600mg

600mg

600mg

600mg

600mg

600mg

600mg

600mg

600mg

 

 


Evaluation of tablets for Precompression parameters: Angle of Repose:7

Angle of repose of prepared granules was determined by the funnel method. The accurately weighed granules were allowed to flow through the funnel freely on to the surface. The diameter of the granules cone was measured and angle of repose was calculated using the equation

θ = Tan-1 h/r.

 

Determination of Density:8

The granules from each formulation were introduced in to a 10 ml glass measuring cylinder separately. The initial volume and weight was noted. The cylinder was tapped 50 times on to a hard surface from a height of 2.5 cm at an interval of one second. Tapped volume was noted. Based upon the data obtained Untapped Bulk Density and Tapped Bulk Density were calculated.

 

Compressibility Index and Hausner’s Ratio:8

Compressibility Index and Hausner Ratio of prepared granules was determined by using Tapped bulk density and Untapped bulk density.

Evaluation of tablets for Post compression studies:

Hardness:9

A diametral crushing test was performed on prepared tablets according to European Pharmacopoeia method 2.9.8 using Monsanto Hardness Tester.

 

Friability:10

The friability test was carried out according to the Pharmacopoeal guidelines. The tablet weight (600mg) was always less than 650 mg, hence a random sample of whole tablets corresponding to 6.5 g was used for friability testing. Weighed samples of tablet first dedusted, accurately weighed, and placed in the drum of a Roche Friability tester (Mfg by Koshiash Industries). Drum was rotated at 25 rpm for 4 minutes and tablets were removed, dedusted, and accurately weighed. A The % friability of not more than 1.0% was acceptable.

 

Uniformity of weight:10

As per IP guidelines, 20 tablets were selected randomly from each batch and their average weights were calculated using a digital weighing balance (Essae Teraoka Ltd). Percentage weight difference was calculated and checked with IP specifications.

 

Determination of drug content:11,12

Twenty tablets from each formulation were weighed and powdered. 100 mg of the powder was weighed accurately and dissolved in 100ml of Phosphate buffer pH 6.8. The mixture was sonicated (Equitron) for 180 seconds and filtered through Whatman filter paper No. 40. The filtrate was suitably diluted with Phosphate buffer pH 6.8 and absorbance was measured at 271 nm using Lab India UV-3000 UV/Vis spectrophotometer. By using slope of standard calibration curve the amount of Theophylline was determined.

 

In-Vitro Drug Release Profile:13

The In vitro drug release study was carried out using USP ΧΧΙV dissolution apparatus at the speed of 100 rpm using 900 ml of acid buffer (pH 1.2) for the initial period of 2 hours, followed by phosphate buffer (pH 6.8) until completion of dissolution. Temperature of dissolution medium was maintained at 370 C ± 0.50 C.   10ml of the dissolution sample was collected from the dissolution apparatus at interval of 1 hour and replaced the same with fresh dissolution medium. The amount of drug released was estimated using UV Spectrophotometry (Lab India UV-3000 UV/Vis spectrophotometer) at 271nm.

 

Swelling Index:14

The extent of swelling was measured in terms of the percentage weight gained by the tablets. One tablet from each formulation was placed in Petridish containing 6.8 pH Phosphate buffer. After 1hour, tablets was withdrawn, dabbed with tissue paper and reweighed. Then after every 2 hours weight of the tablet was noted. The percentage weight gained by the tablets was calculated by the formula:

 

S.I= {(Mt-Mo/Mo)x 100.

Where,    S.I =Swelling Index

Mt = weight of the tablet at the time ‘t’

Mo =weight of the tablet at the time t=o

 

Optimization of prepared sublingual tablet: 15,16,17,18,19

The results of evaluation studies of prepared formulations were subjected to  historical data mixture design 8.0.7.1(Trial Version) and based on numerical optimization the global best formulation (best values of excipients) was determined. In a mixture design, the level of a single component cannot be changed independently and the sum of the mixture components has to be equal to 100%. In present work Theophylline (300 mg) tablets were formulated with constant weight of PVK K 30, Talc and Magnesium stearate as, 15 mg, 15 mg and 9 mg respectively, and varying concentrations of different grades HPMC were evaluated. By adding microcrystalline cellulose and lactose as diluent and filler binder, Weight of individual tablet was adjusted to 600mg. Therefore, the experimental range lies between 0 and 261 mg. The restrictions imposed on the mixture component proportions are shown in Table No. 2. Dependent variables considered in this study were 90% drug release, 50% drug release, first order release kinetic, weight variation and content uniformity which are shown in Table No.3 along with their predetermined acceptable ranges.

 

Table No. 2: Design constraints

Mixture Coding:

Actual Constraint

 

Low

0.000

0.000

9.000

 

A:HPMC E5LV

B:HPMC E15LV

C:MCC

A+B+C

High

252.000

192.000

93.000

261.000

 

Table No. 3: Dependent variables with their acceptable ranges for a sustained release tablet

Sl. No

Dependent Variable

Acceptable ranges

Goal

1

90% Drug release

8-12 Hours

Maximum

2

50% Drug release

4-6 Hours

Maximum

3

First order release kinetic (r value)

0.9 to 1

In range

4

r value for Higuchi and Peppe’s

0.9 to1

In range

5

Weight variation

570-630

Targeted to 600

6

Content uniformity

85 to 115 %

Targeted to 100%

 

RESULTS AND DISCUSSIONS:

Preformulation studies carried out proves the suitability of selected excipients for development of sustained release matrix tablet of theophylline. The result obtained in precompression study showed that the prepared granules have sufficient flow property, bulkiness and necessary compressibility. The results of the same are summarized in the Table No.4.


 

 

 

Table No. 4: Results of Pre-compression study.

Batch

Angle of Repose(º)

Bulk Density (g/ml)

Tapped Density (g/ml)

Compressibility Index

Hausner’s Ratio

F1

20.30

0.357

0.454

21.36%

1.271

F2

27.47

0.348

0.454

23.34%

1.304

F3

25.17

0.298

0.397

24.93%

1.332

F4

27.47

0.294

0.312

5.76%

1.061

F5

6.56

0.312

0.357

12.60%

1.442

F6

28.81

0.312

0.357

12.60%

1.442

F7

28.36

0.250

0.303

17.49%

1.212

F8

28.81

0.270

0.322

16.14%

1.192

F9

28.81

0.361

0.391

6.66%

1.083

Table No. 5: Result of Post Compression Study.

Formulation code

Evaluation parameter

Thickness± S.D. (mm)  (n = 3)

Hardness ± S.D. (kg/cm2) (n = 3)

Friability (%)

Average weight variation (n=20) mg

Drug content (%)

F1

4.53±0.047

8.33±0.471

0.18±0.009

498.75±4.968

99.33%

F2

4.55±0.040

7.66±0.471

0.19±0.004

500.20±3.124

99.83%

F3

4.53±0.047

8.66±0.471

0.38±0.004

498.75±4.072

98.5%

F4

5.33±0.235

8.66±0.471

0.16±0.009

596.65±4.639

97.6%

F5

5.33±0.235

8.33±0.942

0.16±0.009

599.1±5.717

101.7%

F6

5.16±0.235

8.66±0.471

0.47±0.018

599.2±4.760

99.2%

F7

5.33±0.235

8.33±0.471

0.63±0.641

599.4±4.953

99.13%

F8

5.33±0.235

8.33±0.471

0.32±0.014

600.35±4.661

98%

F9

5.55±0.235

8.66±0.471

0.31±0.041

598.45±2.376

97.4%

 


Prepared tablets were evaluated for various post compression parameters. The results thus obtained are summarized in Table No.5.

 

In vitro drug release study was carried out for all formulation. The cumulative percent drug release data of all formulations is given in Table No. 6 and In vitro drug release profile is represented graph No. 1a,1b and 1c.


 

Table No. 6: Results of In-vitro Drug release study.

Time (Hours)

F1 HPMC K100M (8%)

F2 HPMC K100M (10%)

F3 HPMC  K100M (12%)

F4  HPMC E5LV (38%)

F5  HPMC E5LV (40%)

F6  HPMC E5LV (42%)

0

0

0

0

0

0

0

1

18.28±0.124

22.21±0.124

23.53±0.205

35.69±0.108

23.42±0.163

25.26±0.124

2

34.46±0.124

28.06±0.249

28.29±0.081

57.61±0.047

49.81±0.169

41.27±0.205

3

55.15±0.307

53.42±0.224

31.24±0.211

74.89±0.188

75.18±0.279

61.36±0.419

4

62.21±0.287

65.80±0.361

35.59±0.228

90.35±0.441

80.13±0.249

76.39±0.460

5

72.59±0.274

74.34±0.148

42.43±0.200

97.87±0.240

88.16±0.291

81.65±0.424

6

79.46±0.170

78.10±0.401

52.32±0.192

99.19±1.878

97.46±0.268

86.45±1.090

7

83.70±0.192

79.14±0.382

65.28±0.176

---

99.81±0.313

87.05±1.043

8

94.72±1.548

80.02±0.249

72.51±0.154

---

---

90.86±1.835

9

98.92±0.415

90.47±2.437

85.39±1.874

---

---

95.92±1.886

10

---

99.85±1.364

89.07±0.775

---

----

---

11

---

---

95.35±3.536

---

---

---

12

---

---

97.49±1.203

---

---

---

 

Table No. 6: Continue……..

Time (Hours)

F7 HPMC  E15LV (28%)

F8 HPMC E15LV (30%)

F9 HPMC E15LV (32%)

0

0

0

0

1

12.80±0.124

9.21±0.320

9.11±0.205

2

34.16±0.094

29.14±0.205

28.51±0.163

3

55.32±0.131

47.96±0.355

37.39±0.248

4

60.31±0.073

57.91±0.397

47.64±0.312

5

69.75±0.265

70.20±0.265

57.49±0.514

6

76.62±0.193

84.47±0.361

66.16±0.251

7

80.11±0.256

92.86±0.316

78.79±0.670

8

93.53±0.162

97.02±0.297

87.62±0.276

9

98.51±0.010

97.76±1.276

90.12±0.310

10

---

99.39±1.278

92.51±0.250

11

---

---

95.58±0.238

12

 

 

 

 


 

Graph No. 1a: In-vitro drug release profile for formulation F1, F2 and F3

 

Graph No. 1b:  In-vitro drug release profile for formulation F4, F5, and F6

 

Graph No. 1c: In-vitro drug release profile for formulation F7, F8, F9

 

The results obtained from In vitro drug release study showed that as the concentration of the HPMC increases, the drug release rate is decreases and the formulation releases the drug for prolonged period of time. This may be due to swelling capacity of the HPMC. As concentration of HPMC increases, there is formation of dense swellable matrix, which may retard the release of drug from the formulation. Effect of different grades of HPMC, showed that, HPMC with higher viscosity, shows better control over release of the drug. As viscosity increases, polymeric matrix becomes more dense, which may lead to decreased drug release.

 

DRUG RELEASE KINETICS:

The prepared formulations were subjected to In vitro drug release kinetic. The result of this study is summarized in table No.7

 

Table No. 7: In vitro Drug release kinetics:

Batch

First order

Higuchi

Korsmeyer-Peppa’s

r2

r2

r2

F1

0.846

0.977

0.976

F2

0.940

0.962

0.939

F3

0.868

0.928

0.917

F4

0.933

0.986

0.980

F5

0.921

0.967

0.939

F6

0.974

0.968

0.949

F7

0.838

0.965

0.942

F8

0.945

0.949

0.941

F9

0.954

0.963

0.956

 

Optimization of prepared sustained released matrix tablet: 26,27,28,29,30

The prepared formulations were evaluated for various pre-compression and post compression parameters. The data obtained was analyzed using linear model of design expert 8.0.7.1(Trial version). The response contour plots predicted from the linear model for dependent variable are shown in Graph Nos. 2a, 2b, 2c, 2d and 2e.


 

Graph No. 2a: 90% Drug Release of tablet:

 

Graph No. 2b: 50% Drug Release of tablet:

 

Graph No.2c: r value First order kinetics of tablet:

 

Graph No. 2d: r value Higuchi and Peppa’s of tablet:

 

Graph No. 2e: Weight Variation:

 


Historical data mixture optimization results:

The aim of the optimization was to obtain the defined targets for all responses simultaneously with respect to the predefined constraints. At this stage, the defined desirable areas of all responses were superimposed and the region of interest was generated. Three formulations with high desirability were suggested in this procedure by Design expert 8.0.7.1 (Trial Version). The details of the same are given in Table No.8. The overlay plot for three formulation suggested in optimization procedure is shown in Graph No. 3a and 3b.

 

Table No. 8: Formulations Suggested by Design expert 8.0.7.1 by numerical optimization:

Sl. no

Ingredient

FA

FB

1

API( Theophylline)

300

300

2

HPMC E5LV

12.813

0

3

HPMC E15LV

192

192

4

PVP K-30

15

15

5

MCC

56.187

69

6

Talc

15

15

7

Mg Stearate

9

9

8

Iso Propyl Alcohol

q.s

q.s

9

Total weight

600mg

600mg

 


 

Graph No. 3a: Formulation A:

 

Graph No. 3b: Formulation B:

 


 


 

Table No. 9: Comparative values of predicted and observed responses of FA, FB:

Response

Formulation A

Formulation B

Predicted Value

Observed value

Predicted Value

Observed value (F9)

90% Drug release

10.24 hrs

8 hrs

9.28 hrs

9 hrs

50% Drug release

4.81 hrs

5 hrs

4.95 hrs

5 hrs

r value of first order release kinetic

1

0.978

0.953

0.954

r value of Higuchi and Peppa’s

0.973

0.945

0.955

0.963

Weight variation

598.20

599

598.44

598.25

Content uniformity

97.85

96.58

97.94

97.4

 

 

 


These suggested formulations were prepared and analyzed regarding the responses. Comparative values of predicted and observed responses along with the formulation components were reported in Table No. 9.

 

Among the above mentioned formulations, the Formulation B proposed by Design Expert 8.0.7.1 (Trial Version) is same as Formulation F9 of the present work. Formulation B and Formulation F9 shows all desirable physical characteristics as well as good correlation was obtained between the predicted and the observed results. Thus Formulation B /Formulation F9 were chosen as optimized formulation.

 

SUMMARY AND CONCLUSION:

Sustained release matrix tablets of 300 mg of Theophylline were prepared by wet granulation technique using various grades of HPMC viz., HPMC K-100 M, HPMC E5LV, HPMC E15LV. Lactose monohydrate and Micro-crystalline cellulose was used as diluent, Magnesium stearate as lubricating agent and Talc was used as glidant. The prepared formulations were subjected to various pre compression and post compression studies. The results showed the suitability of chosen excipients for design of sustained release matrix tablet.  Pre compression studies showed better flow property and compressibility index with respect to prepared granules ready for compression. The granules were compressed using 10 station rotary tablet compression machine. The study of post compression parameters showed that the prepared tablets exhibited ideal pharmaceutical characteristics. In vitro drug release study showed that as the concentration of HPMC increased, there was an increase in retardation of drug release.  The increased in viscosity grade of HPMC gave better retardation to drug release. The optimized studies showed that formulation F9 with HPMC E 15LV is the best formulation with excellent release retardant i.e. up to 12 hours for sustained release of Theophylline from its matrix.

 

ACKNOWLEDGEMENT:

Authors are thankful to the Principal, Board of Management SET’s College of Pharmacy, Dharwad for providing the necessary facilities to carry out the research work. We are also thankful to Ami Life Science Pvt. Ltd. Gujarat for providing Theophylline as a gift sample.

 

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Received on 15.12.2016       Accepted on 12.01.2017     

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2017; 7(1): 19-26.

DOI: 10.5958/2231-5713.2017.00004.6