Formulation and Evaluation of Extended Release Tablets of

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extended release tablets. Pentoxifylline containing HPC (20%) batch F6 can be taken as an ideal or optimized formulation for 12 hour release as it fulfills the ...
International Journal of Pharmaceutical Research and Technology Volume 2, Number 2, July-December 2010, pp. 81-85

Formulation and Evaluation of Extended Release Tablets of Pentoxifylline B. Jayakar*, Chandira Margret, Bhowmik Debjit** and K. P. Sampath Kumar

ABSTRACT: The controlled or sustained release dosage forms are designed to complement the pharmaceutical activity of the medicament in order to achieve better selectivity and longer duration of action.The aim of this study is to formulate and evaluate the extended release tablets of Pentoxifylline.Pentoxifylline is prescribed to patients who are suffering from chronic peripheral heart diseases.Pentoxifylline in the Extended release may be used to improve the bioavailablity and to improve the Patient non -compliance.The present study is to investigate the possibility of developing extended release dosage form for the drug Pentoxifylline by using polymers HPMC-K100M and HPC in different ratios as matrix.It can be achieved by planning for trials until the desired release pattern is obtained. The aim is to evaluate the release profile of drug from extended release tablets. Pentoxifylline containing HPC (20%) batch F6 can be taken as an ideal or optimized formulation for 12 hour release as it fulfills the requirements for extended release tablet. Keywords: Pentoxifylline, HPC, extended release tablet. chronic peripheral heart diseases.

INTRODUCTION Oral controlled release dosage forms are being developed for the past three decades due to their advantages. Oral route remains the preferred route of administration of therapeutic agents, because of low cost of therapeutic and ease of administration leads to high levels of patient compliance. Due to poor bioavailability of orally administered drugs extensive advancements in drug discovery process are made.The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to promptly achieve and maintain the defined drug concentration. In pharmaceutical practice, drug administration to patient exists in several approaches, one of which is conventional, i.e. drug is given several times a day, to produce desired therapeutic effect.Due to frequent dosing, fluctuation in the drug blood level occurs; hence maintenance of defined drug level can be above or below the minimum therapeutic level. The conventional tablet provides only a * Vinayaka Missions College of Pharmacy, Salem, Tamilnadu ** Department of Pharmaceutical Sciences, Coimbatore Medical College, Coimbatore, E-mail: [email protected]

single transient release of drug.Hence the above potential problem can be minimized or reduced by formulating the drug in release control matrix i.e. sustain release system. This system minimizes or eliminates side effects, provides patient compliance, economically and promptly achieves and maintains the desired effect. Controlled release dosage forms are those dosage formulations designed to release an active ingredient at rates which differ significantly from their corresponding conventional dosage forms. The controlled release drug delivery systems are aimed at controlling the rate of drug delivery, sustaining the duration of therapeutic activity and/or targeting the delivery of drug to a tissue. Drug release from these systems should be at a desired rated, predictable and reproducible. MATERIALS AND METHODS Pentoxifylline is procured by Cipla India Ltd.mumbai, Hydroxy propyl methyl cellulose K100 M is procured by Signet chemical corporation, Mumbai, Gelatin, Magnesium stearate, Magnesium stearate, Talc, Sodium benzoate, Lactose are procured by Loba chem., Cochin,

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International Journal of Pharmaceutical Research and Technology 2(2) 2010

FORMULATION OF PENTOXIFYLLINE MATRIX TABLETS The drug and the selected polymers along with the diluents are mixed well in a mortar and made into wet mass by adding binder solution. The wet mass was made into granules by passing through sieve # 10 and dried in a hot air oven at 600C for 30 mins. The dried granules are passed through sieve # 20. The granules of same size are mixed well with lubricants and compressed in punching machine having die size 16/32. Finally the matrix tablet was prepared. EVALUATION OF TABLETS Weight Variation Twenty tablets were randomly selected form each batch and individually weighed. The average weight and standard deviation of 20 tablets was calculated. The batch passes the test for weight variation test if not more then two of the individual tablet weight deviate from the average weight by more than the percentage shown in Table and none deviate by more than twice the percentage shown.

Uniformity of Content Five randomly selected tablets were weighed and powdered. The powdered tablet equivalent to 20 mg drug in one tablet was taken and transferred in a 250ml flask containing 100ml of phosphate buffer pH6.8. The flask was shaken on a flask shaker for 24 hours and was kept for 12 hours for the sedimentation of undissolved materials. The solution is filtered through Whatman filter paper (0.45µm). 10ml of this filtrate was taken and appropriate dilution was made. The samples were analyzed at 274 nm using UV/Vis Spectrophotometer. The drug content was determined from the standard curve prepared at λmax 274nm. In Vitro Dissolution Studies

Twenty tablets were randomly selected form each batch and there thickness and diameter was measured by using digital vernier caliper.

In Vitro dissolution study was carried out using USP I apparatus (basket apparatus) in 900 ml of phosphate buffer pH6.8 for 12hours. The temperature of the dissolution medium was kept at 37± 0.5oC and the basket was set at 50 rpm. 1 ml of sample solution was withdrawn at specified interval of time. The absorbance of the withdrawn samples was measured at λmax 274 nm using UV/ Vis Spectrophotometer. The concentration was determined from the standard curve of pentoxifylline prepared in distilled water at λmax 274 nm.

Tablet Hardness

DISCUSSION

The crushing strength Kg/cm­2 of prepared tablets was determined for 10 tablets of each batch by using Monsanto tablet hardness tester. The average hardness and standard deviation was determined.

Pentoxifylline is Vasodilator with half life of 0.4 to 0.8 hours and requires multiple daily doses to maintain adequate plasma concentrations. So it is selected for preparing an extended release tablet. The objective of this present study is to develop an extended release of Pentoxifylline which releases the drug in an extended manner over a period of 12 hours, by using different polymers and study on effect of polymer concentration on release pattern.The present study was undertaken with an aim to formulate and evaluate Pentoxifylline extended release tablets using different polymers as release retarding agents.Preformulation study was done initially and results directed for the further course of formulation. Based on preformulation studies different batches of Pentoxifylline were prepared using selected excipients. Powders were

Thickness

Friability Method Twenty tablets were weighed and placed in the Electrolab friabilator and apparatus was rotated at 25 rpm for 4 minutes. After revolutions the tablets were deducted and weighed again. The percentage friability was measured using the formula, % F = {1-(Wt/W)} ×100 Where, % F = friability in percentage W

= Initial weight of tablet

Wt

= weight of tablets after revolution

Formulation and Evaluation of Extended Release Tablets of Pentoxifylline

evaluated for tests angle of repose, bulk density, tapped density, compressibility index, and Hausner’s ratio before being punched as tablets. Various formulations of extended release tablets of Pentoxifylline were developed using various polymers viz, HPMC K-100M, HPC, in different proportions and combinations by Wet Granulation technique and the tablets were evaluated for physical characterization, in vitro release study and stability studies.Results of in vitro release profile indicate that formulation F6 was the most promising formulation. The extent of drug release from this formulation was high when compare to other prototype formulations.Finally, the dissolution profile of the batch F6 matches with the innovator’s drug profile.Stability study was conducted for the Batch F6, stored at 30 °C (Room Temperature) and 40 °C for a period of one month. Tablets were evaluated for hardness, friability, drug content and in-vitro release profile. After one month there is no significant changes were observed in any of the studied parameters during the study period, thus it could be concluded that formulation was stable CONCLUSION It was concluded that the batch F6 had in vitro drug release Percentage of 72.14 in 12 hrs. It was observed that tablets of batch F6 followed the Huguchi release and zero order profiles. From the above results and discussion it was concluded that formulation of extended release tablet of Pentoxifylline containing HPC (20%) batch F6 can be taken as an ideal or optimized formulation for 12 hour release as it fulfills the requirements for extended release tablet. REFERENCE [1]

Sastry C. S., Naidu P. Y. Determination of Pentoxifylline in Pharmaceutical Formulations using Iodine as Oxidizing Agent Talanta. 1998; 46(6): 13571362.

[2]

Tamizharasi S., Rathi J. C., Rathi V. Formulation, and Evaluation of Pentoxifylline-Loaded Poly(epsiloncaprolactone) Microspheres Indian Journal Pharmaceutical Science 2008; 70(3): 333-337.

[3]

Baumgartner S., Pavli M., Kristl J. Effect of Calcium Ions on the Gelling and Drug Release Characteristics of Xanthan Matrix Tablets European Journal Pharmacy Biopharmaceutics 2008; 69(2): 698-707.

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

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Surapaneni M. S., Das S. K., Das N. G. Effect of Excipient and Processing Variables on Adhesive Properties and Release Profile of Pentoxifylline from Mucoadhesive Tablets Drug Devlivery System in Indian Pharmacy. 2006; 32(3): 377-387. Noaimi A. A., Fadheel B. M. Treatment of Perniosis with Oral Pentoxyfylline in Comparison with Oral Prednisolone Plus Topical Clobetasol Ointment in Iraqi Patients Saudi Medical Jounal. 2008; 29(12): 1762-1764. Raz I., Ben-David J., Hussein Z., Samara E. Comparative Pharmacokinetic Analysis of Novel Sustained-release Dosage forms of Pentoxifylline in Healthy Subjects International Journal Clinical Pharmacology Therapeutic Toxicology. 1988; 26(4): 206208. El-Gazayerly O. N. Release of Pentoxifylline from Xanthan Gum Matrix Tablets Drug Devliery system in Indian Pharmacy. 2003; 29(2): 241-246. Ozsoy Y, Caybaşi P, Terzioğlu N., Ozkirimli S., Tunçel T. In Vitro Studies on the Transdermal Formulation Containing Pentoxifylline Microspheres with poly-Llactide Boll Chim Farm. 2002; 141(1): 29-32. Yuen K. H., Wong J. W., Peh K. K., Julianto T., Choy W. P. Comparative Bioavailability Study of Two Controlled-release Pentoxifylline Tablet Preparations Drug Devlivery system in Indian Pharmacy. 2000; 26(7): 803-807. Slósarczyk A., Szymura-Oleksiak J., Mycek B. The Kinetics of Pentoxifylline Release from Drug-loaded Hydroxyapatite Implants Biomaterials. 2000; 21(12): 1215-1221. Srinivasu P., Rambhau D., Rao B. R., Rao Y. M. Pharmacokinetics of Pentoxifylline after Oral Administration of a Sustained Release Tablet at Two Different Times of the Day Arzneimittelforschung. 1999; 49(9): 750-753. Otsuka M., Matsuda Y. Programmable Drug Release of Highly Water-soluble Pentoxifylline from Drycoated Wax Matrix Tablets Journal of Pharmaceutical Science. 1995; 84(4): 443-447. Rakeshpetel Formulation Development and Process Optimization of Theophylline Sustained Release Matrix Tablets. International Journal of Pharmacy and Pharmaceutical Science 2009: 10-12. Tadros M. I. Controlled-release Effervescent Floating Matrix Tablets of Ciprofloxacihydrochloride: Development, Optimization and in Vitro-in vivo Evaluation in Healthy Human Volunteers European Journal of Pharmacy Biopharmaceutics. 2009, 11: 22. Tajiri S., Kanamaru T., Makoto K., Konno T., Nakagami H. Dosage form Design and in Vitro/in vivo Evaluation of Cevimeline Extended-release Tablet Formulations International Journal of Pharmacy. 2010: 4; 383(1-2): 99-105. Balasubramaniam, Matrix Tablets of Cisapride and Atenolol were Prepared with Varying Proportions of Hydroxypropylmethylcellulose of Different Viscosity Grades. Indian Journal of Pharmaceutical Sciences, 2005, 67(4): 414-421.

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International Journal of Pharmaceutical Research and Technology 2(2) 2010 Table 1 Formulation of Pentoxifylline Matrix Tablets

Ingredients Pentoxifylline Hydroxypropyl Methyl Cellulose K100m Hydroxypropyl Cellulose Gelatin Magnesium Stearate Talc Sodium Benzoate Lactose Total Weight

Table 4 Results of Thickness, Weight Variation, Hardness, Friability, Uniformity Content and Drug Content

F1

F2

F3

F4

F5

F6

400 70

400 105

400 140

400 -

400 -

400 -

Batch Weight code Variation (mg)

-

-

-

70

105

140

F1

698±1.0 4.1±0.04 7.2±1.21

0.52

99.31 98.52±1.21

35 10 15 2 168 700

35 10 15 2 133 700

35 10 15 2 98 700

35 10 15 2 168 700

35 10 15 2 133 700

35 10 15 2 98 700

F2

704±2.1 4.2±0.12 7.3±1.50

0.46

98.24 98.91±0.91

F3

709±3.5 4.1±0.07 7.6±0.98

0.36

98.26 98.95±0.88

F4

698±1.7 4.2±0.17 7.2±0.89

0.42

99.78 99.00±0.59

F5

704±3.4 4.2±0.10 7.3±0.56

0.45

98.80 98.17±0.76

F6 698±1.41 4.2±0.15 7.7±0.60

0.34

99.79 98.60±0.91

Thickness (mm)

Hard- Friabi- Drug ness lity content (kg/cm2) (%) (%)

Content uniformity (%)

• The values were expressed as mean ± SD

• All the quantities are in mg

In Vitro Dissolution Studies

Evaluation of Pure Drug and Excipients Table 2 Preformulation Studies of Pure Drug and Excipients Parameters

Pentoxifylline Hpmc K100

Hpc

Bulk Density (gm/Ml)

0.37±0.13

0.31±0.24

0.46±0.17

Tapped Density (gm/Ml)

0.48±0.21

0.42±0.22

0.52±0.31

Carr’s Index (%)

30.0

26.19

11.54

Hausner’s Ratio

1.30

1.35

1.13

Angle of Repose(·)

37.03±0.24

S. Time No (Hrs)

Table 3 Preformulation Studies of Granules Bulk density (gm/ml)

Tapped density (gm/ml)

F1

0.41±0.13 0.46±0.12

F2

0.42±0.17

Table 5 Cumulative % Release of Drug of Various Formulations

39.59±0.31 33.28±0.27

Evaluation of Granules

Batch code

Table 6 shows the data for in vitro release of Pentoxifylline from extended release tablet of batches F1, F2, F3, F4, F5 and F6 respectively. As follows the dissolution profiles shows the comparative release profile of Pentoxifylline with different concentration of different polymer from batches F1, F2, F3, F4, F5 and F6 extended release tablet.

Carr’s Hausner’s index ratio (%)

F1 (%)

F2 (%)

F3 (%)

F4 (%)

F5 (%)

0

0

0

0

0

2.

0.50 11.23

10.57

10.22

12.96 10.84 8.94 10.82

3.

1 16.32

15.98

15.49

17.72 15.55 14.00 14.38

4.

1.50 22.46

21.22

21.00

22.14 21.79 18.28 20.16

5.

2 31..54

28.21

27.76

27.10 26.76 23.45 24.93

3 41.55

39.56

38.78

31.14 30.69 27.58 29.21

1. Angle of repose(·)

0

F6 Inno(%) vator (%) 0

0

10.8

1.12 23.39±0.21

0.46±014

8.7

1.10 24.89±0.20

6.

F3

0.44±0.14 0.50±0.17

12.0

1.14 25.60±0.30

7.

4 51.93

50.18

50.96

38.73 37.61 34.91 36.72

F4

0.38±0.19 0.44±0.12

13.63

1.16 22.62±0.31

8.

6 62.59

61.92

59.95

46.91 45.86 42.58 44.42

F5

0.41±0.21 0.47±0.15

12.77

1.14 26.10±0.21

9.

8 69.41

67.38

63.79

55.45 54.48 51.83 53.85

F6

0.44±0.13 0.50±0.11

12.00

1.14 28.28±0.30

10.

10 78.65

77.96

72.68

66.15 65.85 61.12 62.56

11.

12 88.01

86.96

81.50

77.56 76.19 72.14 73.85

• The values were expressed as mean ± SD

Pure Drug (Miglitol Physico-Chemical Evaluation of Extended release Tablet The results of the Thickness, Hardness, weight variation, drug content, friability and uniformity content of tablet are shown in Table 5.

Formulation and Evaluation of Extended Release Tablets of Pentoxifylline

Figure 1: Cumulative % Release of Drug of Various Formulations

Figure 2: Invitro Cumulative % Drug Releasd V/S Time for Formulation (F1 to F6) of Pentoxifylline Extended Release Tablets [Zero Order Rate]

Figure 3: Log Cumulative % Drug Retained V/S Time for Formulation (F1 to F6) Of Pentoxifylline Matrix Tablets [First Order Rate]

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Figure 4: Cumulative % Drug Released V/S Root Time for Formulation (F1 to F6) of Pentoxifylline Extended Release Tablets [Higuchi Matrix]

Figure 5: Log Cumulative % Drug Released V/S Log Time for Formulation (F1 to F6) of Pentoxifylline Extended Release Tablets [Peppas]

Figure 6: Cube Root of % Drug Retained V/S Time for Formulation (F1 to F6) of Pentoxifylline Extended Release Tablets [Hixson-Crowell]