International Journal of Innovative Pharmaceutical Sciences and Research

RESEARCH ARTICLE K.Venkata Narapa Reddy et al. / IJIPSR / 1(1), 2013, 145-155 Department of Pharmaceutics ISSN (online) 2347-2154 International Jo...
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RESEARCH ARTICLE

K.Venkata Narapa Reddy et al. / IJIPSR / 1(1), 2013, 145-155

Department of Pharmaceutics

ISSN (online) 2347-2154

International Journal of Innovative Pharmaceutical Sciences and Research www.ijipsr.com FORMULATION AND DEVELOPMENT OF EXTENDED RELEASE MATRIX TABLETS OF CLOPIDOGREL 1 1

K.Venkata Narapa Reddy*, 2Chandra Sekhar Sahoo

Chilkur Balaji Institute of Pharmacy, R.V.C.Nagar, Moinaba Road, AP, India- 500075 2

Formulation R&D, Hetero Labs, Unit-3, Hyderabad, India-500055

Abstract The present work on the preparation of extended release matrix tablets of Clopidogrel utilize release retarding ability of different grades of HPMC polymers and Eudragit RS 100 to extend the release of drug over 24hrs period and thereby improve its bioavailability. The different grades of HPMC polymers (HPMC K4, HPMC K15 and HPMC K100) showed better control on the drug release and all physical parameters are within the limits. Formulation F3, showed better-controlled drug release and release 99.31±2.08% of drug in 24hrs time period. Hence, formulation F3 was selected as optimized formulation. Among the polymers used to control the drug release, HPMC K15M and HPMC K100M showed better control over drug release for desired period of time but only 92% and 87% drug released in 24hrs time period respectively. From the above results also indicated that at higher viscosity grades of polymer concentrations drug release was retarded greatly. Drug-excipients interaction of pure drug and optimized formulations was carried out by using FTIR study. In this analysis drug – excipients compatibility interactions were not observed. The hydrophilic matrix tablets were a promising approach to achieve appropriate controlled release dosages. Key words: Clopidogrel, Extended release Tablet, Eudragit RS 100, HPMC

Corresponding Author: K.Venkata Narapa Reddy Chilkur Balaji Institute of Pharmacy Email: [email protected] Mobile: 9885889993 Available online: www.ijipsr.com

September Issue

145

RESEARCH ARTICLE

K.Venkata Narapa Reddy et al. / IJIPSR / 1(1), 2013, 145-155

Department of Pharmaceutics

ISSN (online) 2347-2154

INTRODUCTION For many decades treatment of acute diseases or chronic illnesses have been mostly accomplished by delivery of drugs to patients using various pharmaceutical dosage forms including tablets, capsules, suppositories, creams, ointments, liquids, aerosols and injectables. Even today these conventional dosage forms are the primary pharmaceutical vehicles commonly seen in the prescription and over the counter drug market. The oral conventional types of drug delivery systems are known to provide a prompt release of the drug. Therefore to achieve as well as to maintain the drug concentration within the therapeutically effective range needed for treatment, it is often necessary to take this type of drug delivery system several times a day. This results in a significant fluctuation in drug levels often with a sub-therapeutic and or toxic levels and wastage of drug. Recently several technical advancements have resulted in the development of new systems of drug delivery capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity and targeting the delivery of drug to a tissue.[1] Extended release [2] denotes that the system is able to provide some actual therapeutic control whether be it of temporal or spatial nature or both. In other words, the system attempts to provide a constant drug concentration in the target tissue. It is this nature of this system that makes it different from sustained release systems. Regulatory considerations in extended release products: [3] The bioavailability data requirement as specified by FDA for the controlled release products are: The drug product meets the controlled release claims made for it. The bioavailability profile established for the drug product rules out the possibility of any dose dumping. The drug product’s steady-state performance is equivalent to a currently marketed non-controlled release or controlled release drug product with the same active ingredient or therapeutic moiety, which has been subjected to an approved full new drug application. The drug product’s formulation provides consistent pharmaco-kinetic performance between administrations. The reference standard for comparative studies should include one of the following. Clopidogrel an AntiPlatelet, having an elimination half life of 8 hrs and its maximum daily dose is 300mg. Hence it is an ideal candidate for extended release formulation. The objective of the study is to prepare Clopidogrel Extended release tablets by direct compression technology using different polymer grades to achieve the desired dissolution pattern and to determine the Kinetic Modeling of Drug Release. Available online: www.ijipsr.com

September Issue

146

RESEARCH ARTICLE

K.Venkata Narapa Reddy et al. / IJIPSR / 1(1), 2013, 145-155

Department of Pharmaceutics

ISSN (online) 2347-2154

MATERIAL & METHOD: Clopidogrel obtained as gift sample from Micro lab, Hosur, HPMC K4M, HPMC K100M obtained as gift sample from Colorcon Asia Pvt. Ltd., Goa, HPMC K15M obtained from Micro lab Hosur, Eudragit RS 100 obtained from Nice chemicals laboratory. Talc, Lactose & Magnesium stearate purchased from Arco Labs, Bangalore. METHOD: Extended release matrix tablets of Clopidogrel were prepared by direct compression according to the formulae given in table. Accurately weighed quantities of polymer and lactose were taken in a motar and mixed geometrically; to this required quantity of Clopidogrel was added and mixed slightly with pestle. The whole mixture was collected in a plastic bag and mixed for 3minutes. To this magnesium stearate was added and mixed for 2minutes. The mixture equivalent to 75mg was compressed into tablets with 11mm round concave punches at a hardness of 6kg/cm2. The composition of various formulations using HPMC K4M, HPMC K15M, HPMC K100M and Eudragit RS100 was given in the following table: Table 1: Composition of Extended release matrix tablets of Clopidogrel F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

F11

F12

(mg)

(mg)

(mg)

(mg)

(mg)

(mg)

(mg)

(mg)

(mg)

(mg)

(mg)

(mg)

Clopidogrel

75

75

75

75

75

75

75

75

75

75

75

75

HPMC K4M

250

300

350

-

-

-

-

-

-

-

-

-

HPMC K15M

-

-

-

250

300

350

-

-

-

-

-

-

HPMC K100M

-

-

-

-

-

-

250

300

350

-

-

-

Eudragit RS 100

-

-

-

-

-

-

-

-

-

250

300

350

Lactose

115

65

15

115

65

15

116

65

15

115

65

15

Talc

5

5

5

5

5

5

5

5

5

5

5

5

magnesium stearate

5

5

5

5

5

5

5

5

5

5

5

5

Total

450

450

450

450

450

450

450

450

450

450

450

450

Formulation

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September Issue

147

RESEARCH ARTICLE

K.Venkata Narapa Reddy et al. / IJIPSR / 1(1), 2013, 145-155

Department of Pharmaceutics

ISSN (online) 2347-2154

RESULTS AND DISCUSSION:

Preparation of Standard Curve of Clopidogrel Standard curve of Clopidogrel was determined by plotting absorbance V/s concentration at 219 nm and it follows the Beer’s law. The results were shown in Table No.2. The R2 is 0.998 respectively. Table 2: Standard Calibration Curve S.No

Concentration µg/ml

UV Absorbance at 219 nm

1

0 µg/ml

0.00

2

10µg/ml

0.301±0.02

3

15µg/ml

0.449±0.02

4

20µg/ml

0.596±0.02

5

25µg/ml

0.73±0.02

6

30µg/ml

0.85±0.02

Figure 1: Standard graph of Clopidogrel in 0.1N Hcl

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RESEARCH ARTICLE

K.Venkata Narapa Reddy et al. / IJIPSR / 1(1), 2013, 145-155

Department of Pharmaceutics

ISSN (online) 2347-2154

Fourier transforms Infrared spectroscopy (FTIR) studies: The pure drug, physical mixtures were subjected for FTIR analysis. The samples were prepared on KBrpress (Star tech Lab, India). The sample were scanned over a range of 4000-400 cm-1 using Fourier transformer infrared spectrophotometer (8600, Shimaszu Corporation, Japan). Spectra were analyzed for drug polymer interactions.

Figure 2: FTIR of Clopidogrel

Figure 3: FTIR of Clopidogrel and Other Excipient

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149

RESEARCH ARTICLE

K.Venkata Narapa Reddy et al. / IJIPSR / 1(1), 2013, 145-155

Department of Pharmaceutics

ISSN (online) 2347-2154

Precompression studies: The powder for matrix tablets were characterized with respect to angle of repose, bulk density, tapped density, Carr’s index, and Hausner’s ratio. Angle of repose was less than 30° and Carr’s index values were less than 26 for the granules of all the batches indicating good to fair flow ability and compressibility. Hausner’s ratio was less than 1.256 for all the batches indicating good flow properties. The drug content was more Table 3: Pre compression studies Extended release matrix tablets of Clopidogrel Formulatio

Bulk

Tapped

Angle of

Compressibility

ns

density

density

repose

index

F1

0.46

0.55

22.62

16.36

1.19

F2

0.59

0.68

22.29

13.04

1.15

F3

0.53

0.63

20.29

15.8

1.18

F4

0.47

0.59

28.23

20.3

1.25

F5

0.42

0.53

23.24

26.19

1.26

F6

0.48

0.57

27.4

14.04

1.14

F7

0.46

0.57

22.26

23.91

1.23

F8

0.44

0.53

23.62

20.45

1.2

F9

0.48

0.56

25.24

16.66

1.16

F10

0.52

0.63

24.69

21.15

1.21

F11

0.51

0.62

23.26

21.56

1.21

F12

0.43

0.54

25.19

25.58

1.25

Hausner ratio

Post compression studies: The results of the uniformity of weight, hardness, thickness, friability, and drug content of the tablets are given in the above Table. All the tablets of different batches complied with the official requirements of uniformity of weight as their weights varied between 450 and 454 mg. The hardness of the tablets ranged Available online: www.ijipsr.com

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RESEARCH ARTICLE

K.Venkata Narapa Reddy et al. / IJIPSR / 1(1), 2013, 145-155

Department of Pharmaceutics

ISSN (online) 2347-2154

from6.5-7.0 kg/cm2 and the friability values were less than 0.4% indicating that the matrix tablets were compact and hard. All the formulations satisfied the content of the drug as they contained 96 to 98 % of Clopidogrel and good uniformity in drug content was observed. Thus all the physical attributes of the prepared tablets were found be practically within control. Table 4: Post-compression studies Extended release matrix tablets of Clopidogrel Friability

Weight

Content

Kg/cm

(%)

variation

uniformity

F1

6.7

0.28

454

98.06

F2

6.6

0.25

453

97.56

F3

7.0

0.32

452

98.36

F4

6.6

0.42

453

96.48

F5

6.5

0.23

451

97.58

F6

6.6

0.39

450

96.98

F7

6.9

0.29

452

98.23

F8

7.0

0.36

451

97.76

F9

6.7

0.37

453

98.35

F10

6.8

0.25

455

96.69

F11

7.0

0.36

450

96.45

F12

6.5

0.41

452

96.21

Formulations

Hardness 2

In- Vitro Release study: In-Vitro drug release studies were carried out using Tablet dissolution test apparatus USPXXIII at 50 rpm. The dissolution medium consisted of 900 ml of Standard buffer 0.1N Hcl. Temperature maintained at 37±1.The sample of 5ml was withdrawn at predetermined time intervals and an equivalent amount of fresh dissolution fluid equilibrated at the same temperature was replaced. The samples withdrawn were filtered

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RESEARCH ARTICLE

K.Venkata Narapa Reddy et al. / IJIPSR / 1(1), 2013, 145-155

Department of Pharmaceutics

ISSN (online) 2347-2154

through Whatt man filter paper (No.1) and drug content in each sample was analyzed by UV-visible spectrophotometer at 219nm. Formulation code

1hr

2hr

4hr

6hr

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

46 44 24 32 26 22 19 23 18 34 26 22

58 56 32 41 35 29 24 31 22 42 38 32

66 62 43 51 46 33 41 42 27 56 46 41

72 69 49 63 51 40 42 46 38 64 52 48

8hr 10hr 12hr 14hr 16hr 18hr Percentage Cumulative Drug Release 78 84 89 94 98 71 73 76 81 89 96 56 65 71 79 82 87 69 82 89 93 95 97 59 68 77 82 85 91 45 56 61 69 76 84 47 52 59 67 74 86 54 61 70 77 84 88 46 53 58 63 69 79 73 81 89 94 98 64 76 83 88 99 56 62 69 74 85 93

20hr

22hr

24hr

99 92 98.85 94 87 89 91 89 98

97 96 90 91 93 94 -

99 97 92 93 95 96 -

Table 5: In-Vitro Release Data of Extended release matrix tablets of Clopidogrel

Figure 4: Dissolution profile F1, F2 & F3

Figure 5: Dissolution profile F4, F5 & F6

Figure 6: Dissolution profile F7, F8 & F9

Figure 7: Dissolution profile F10, F11 & F12

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RESEARCH ARTICLE

K.Venkata Narapa Reddy et al. / IJIPSR / 1(1), 2013, 145-155

Department of Pharmaceutics

ISSN (online) 2347-2154

Release kinetics [4-6] The results of in vitro release profile obtained for optimized formulation were plotted in modes of data treatment as follows. 1. Log cumulative percent drug remaining versus time (first order kinetic model) 2. Cumulative percent drug release versus square root of time (Higuchi’s model) 3. Cumulative percent drug release versus time (zero order kinetic model) 4. Log cumulative Percent Drug released versus log time (korsmeyers model) Regression coefficient (R2) values for optimized Formulation F3: Formulation F3

Zero order 0.993

First order 0.723

Higuchi 0.940

Korsemeyer -pappas 0.932

Figure: Zero order for Optimized Formulation F3

Figure: First order for Optimized Formulation F3

Figure: Higuchi model for Optimized Formulation F3

Figure: Korsmeyer-pappas model for Optimized Formulation F3

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RESEARCH ARTICLE

K.Venkata Narapa Reddy et al. / IJIPSR / 1(1), 2013, 145-155

Department of Pharmaceutics

ISSN (online) 2347-2154

The mechanism of release for the optimized formulation was determined by finding the R2 value for each kinetic model viz. Zero-order, First-order, Higuchi, and Korsmeyer-Peppas corresponding to the release data of formulations. For most of the formulations the R2 value of Higuchi and Zeroorder model is very near to 1 than the R2 values of other kinetic models (table ). Thus it can be said that the drug release follows Higuchi and Zero-order model mechanism.

CONCLUSION: The present work on the preparation of extended release matrix tablets of Clopidogrel utilize release retarding ability of different grades of HPMC polymers and Eudragit RS 100 to extend the release of drug over 24hrs period and thereby improve its bioavailability. The

different

grades

of

HPMC

polymers (HPMC K4, HPMC K15 and HPMC K100) showed better control on the drug release and all physical parameters are within the limits. Formulation F3, showed better-controlled drug release a n d r e l e a s e 9 9 . 3 1 ±2.08% of d r u g i n 24hrs time period. Hence, formulation F3 was selected as optimized formulation. Among the polymers used to control the drug release, HPMC K15M and HPMC K100M showed better control over drug release for desired period of time but only 92% and 87% drug released in 24hrs time period respectively. From the above results also indicated that at higher viscosity grades of polymer concentrations drug release was retarded greatly. Drug-excipients interaction of pure drug and optimized formulations was carried out by using FTIR study. In this analysis drug – excipients compatibility interactions were not observed. The hydrophilic matrix tablets were a promising approach to achieve appropriate controlled release dosages.

REFERENCES 1. Chien YW Potential developments and new approaches in oral controlled release drug de;ivery systems, 1983, Page No. 1294-1330 2. Chien YW.oral controlled and modulated drug delivery systems, Encyclopedia of Pharmaceutica Technology. New York: Dekker ; 1990 Page No. 281-313 3.

Chein YW. Controlled and modulated drug delivery systems, Encyclopedia of Pharmaceutical Technology, New York, Dekker, 1982. p. 1296-1335.

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Department of Pharmaceutics

4.

ISSN (online) 2347-2154

Schwarw BJ, Simonelli AP, Miguchi WI. Drug release from wax matrices analysis of data with first order kinetics and with the diffusion controlled model. Journal of Pharmaceutical Sciences. 1998; 57: 274 – 277.

5. Varelas C.G., Dixon D.G., Steiner C. Zero order release from biphasic hydrogels, Journal of Control Release. 1995; 34:185 – 192. 6.

Colombo P., Bettini Release., Catellani P.L. Drug volume fraction profile in the gel phase and drug release kinetics in hydroxypropyl methyl cellulose matrices containing a soluable drug, European Journal of Pharmaceutical Sciences. 2002;86: 323 – 328.

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