Floating Tablets Of Atenolol

Research Article

Optimization and In Vitro Evaluation of Floating Tablets of Atenolol Vijay Daulatrao Havaldar1 *, Ajit Shankarrao Kulkarni 1 , Remeth Jacky Dias 1 , Kailas Krishnat Mali.1 1 Satara College of Pharmacy, Plot.No.1539, New Additional M.I.D.C, Degaon, Satara, 415004, M.S. India For correspondance. Vijay Daulatrao Havaldar, Satara College of Pharmacy, Plot.No.1539, New Additional M.I.D.C, Degaon, Satara, M.S. India PIN 415004 E mail: [email protected] Received on: 10-06-2008; Accepted on :14-07-2008

ABSTRACT: The main aim of this study was to optimize and evaluate the floating tablets of atenolol that prolongs the gastric residence time. Semisynthetic polymers, HPMC K4M, HPMC K100M and natural polymer, Xanthan gum were used as release retarding agents. Sodium bicarbonate was used as a gas-generating agent. Dicalcium phosphate was used as a channeling agent. The floating matrix tablets of Atenolol were prepared by direct compression method. The concentration of polymers and a gas-generating agent was optimized to get the controlled release of atenolol for 8h. The prepared tablets were evaluated for physicochemical parameters and found to be within range. A significant difference in drug release at 0.5, 1, 4 and 8 h (p < 0.0001) was observed. The floating lag time of all the formulations was within the prescribed limit (< 10 min.) Release pattern of Atenolol was fitted to different models based on coefficient of correlation (R). All the formulations showed good matrix integrity. All the formulations retarded the release of drug for 8 h. Based on the diffusion exponent (n) value, drug release was found to be diffusion controlled. The swelling studies of all the formulations showed that formulations containing Xanthan gum has higher swelling indices than HPMC K100M and HPMC K4M. Further it was observed that the formulations, which are having higher swelling indices, retarded the release of drugs than those having low swelling indices.

Key words: Floating, Atenolol, Swelling index, HPMC.

INTRODUCTION: Several techniques are used to design gastro retentive dosage forms. These include floating; swelling; inflation; adhesion; high-density systems and low density systems that increase the gastric residence time 1, 2, 3. Gastric retention is useful for those drugs which (i) act locally; (ii) have a narrow absorption window in the small intestinal region; (iii) unstable in the intestinal environment; and (iv) low solubility at high pH environment 4. Various dosage forms have been developed for gastric retention; these include, floating tablets 5; floating beads 6; pellets 7; floating granules8; and floating microspheres 9. In this investigation, an attempt was made to design floating tablets of Atenolol by using different release retarding polymers along with a gas-generating agent. Atenolol is a beta 1 cardio selective adrenergic receptor blocker, widely used in the treatment of hyJournal of Pharmacy Research

pertension. The drug is insoluble in water and has halflife of 6 to 8 h with oral bioavailability of 50% due to smaller dose of drug (less than 50mg) 10, 11. In the present study, an attempt was made to optimize the concentration of natural and semi synthetic polymers for the controlled release of drug and to evaluate the tablets for physicochemical parameters. HPMC K4M, HPMC K100M and Xanthan gum were used as a release retarding agents for Atenolol. Sodium bicarbonate was used as a gas generating agent and dicalcium phosphate (DCP) was used as a channeling agent. The release pattern and swelling indices of all the formulations were analyzed using different mathematical models 12. MATERIALS AND METHODS: Materials: Atenolol was procured from Flamingo Pharma-

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Vijay Daulatrao et al Optimization and In Vitro Evaluation of Floating Tablets of Atenolol

ceuticals, Mumbai. HPMC K4M, HPMC K100M and Xanthan gum (Rheogel) 120-mesh size were received from Ajanta Pharmaceuticals Ltd, Mumbai. Flamingo Pharmaceuticals, Mumbai, supplied directly compressible lactose (DCL 15). Other ingredients used were of analytical grade. Methods: Optimization of formulation: Optimization of formulation was carried out for the controlled release of drug, floating characteristics and hardness of tablet. This was carried out by studying the effect of different concentrations of the polymers and effervescent at different compression pressure The trial preparations of the formulations were prepared by using 10 to 40% concentrations of the polymers to study the drug release whereas 3 to 12% sodium bicarbonate was used to optimize the concentration of effervescent. Hardness was optimized from 2.5 to 6.5 Kg/cm2. Preparation of Floating Tablets Floating tablets of Atenolol were prepared by direct compression method employing sodium bicarbonate as a gas-generating agent. HPMC K4M, HPMC K100M and Xanthan gum were used as a rate controlling polymers. All the ingredients (Table I) were weighed accurately. The drug was mixed with the release rate retarding polymers and other excipients in ascending order of their weight. The powder mix was blended for 20 min. so as to have uniform distribution of drug in the formulation. 350 mg of the powder mix was weighed accurately and fed into the die of single punch machinery (Cadmach, Ahemedbad, India.) and compressed at 3 N compression force using 10mm concave punches. Floating Characteristics: Floating characteristics of the prepared formulations were determined by using USPXXIII paddle apparatus (Electrolab, TDT- 06P, Mumbai, India.) under

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sink conditions. The dissolution medium was 900ml of 0.1 N HCl (pH 1.2) and temperature of which was maintained to 37±0.5 0 C throughout the study. The time between the introduction of tablet and its buoyancy on the gastric fluid, floating lag time and the time during which dosage forms remain buoyant (Floatation duration) were measured. The integrity of the test tablets was observed visually during study (Matrix integrity). Drug Release: Dissolution tests were conducted in triplicate for all formulations in a USPXXIII tablet dissolution apparatus (Electrolab, TDT- 06P, Mumbai, India). The dissolution medium used was 900 ml 0.1N HCl (pH 1.2) at 37±0.50 C with a stirring speed of 50 r.p.m. At a predetermined time intervals, 2 ml sample was withdrawn and the sink conditions were maintained. The samples were analyzed for drug release by measuring the absorbance at 225 nm using spectrophotometric method (Shimadzu UV, 1700, Japan). The release data was analyzed to study release kinetics using zero order, first order, Korsemeyer- Pappas and Higuchi equations 13,14. Percent dissolution efficiency and mean dissolution time was calculated for all formulations 15, 16. Determination of Swelling Index: The swelling behavior of a dosage unit was measured by studying its weight gain. The swelling index of tablets was determined by placing the tablets in the basket of dissolution apparatus using dissolution medium as 0.1N HCl at 37±0.50 C. After 0.5, 1, 2, 3, 4, 5, 6, 7 and 8h, each dissolution basket containing tablet was withdrawn, blotted with tissue paper to remove the excess water and weighed on the analytical balance (Schimdzu, AX 120). The experiment was performed in triplicate for each time point. Swelling index was calculated by using the following formula 17. (Wet weight of tablet – Dry weight of tablet) Swelling index =

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Dry weight of tablet.

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Vijay Daulatrao et al Optimization and In Vitro Evaluation of Floating Tablets of Atenolol

1.8

120

80

SWELLING INDEX

%DRUG RELEASE

1.6

100 F1

60

F2 F3

40 20

1.4 1.2

F1

1

F2

0.8

F3

0.6 0.4 0.2

0

0

0

0.5

1

2

3

4

5

6

7

8

0

1

2

3

TIME (h)

In vitro release profile of Atenolol from for mulations F1, F2 and F3 containing 20%, 30% and 40% HPMC K 100 M respectively.

Fig.4.

140

1.2

120

1

100 F4

80

F5

60

F6

40 20 0

6

7

8

0.8 F4 0.6

F5 F6

0.4 0.2 0

0

0.5

1

2

3

4

5

6

7

8

0

1

2

3

TIME (h)

Fig.2

5

Swelling Indices of Atenolol from formulations F1, F2 and F3 containing 20%, 30% and 40% HPMC K 100 M respectively.

SWELLING INDEX

% DRUG RELEASE

Fig.1.

4

TIME (h)

4

5

6

7

8

TIME (h)

In vitro release profile of Atenolol from for mulations F4, F5 and F6 containing 20%, 30%and 40% HPMC K 4M respectively.

Fig.5

Swelling Indices of Atenolol from formulations F4, F5 and F6 containing 20%, 30% and 40% HPMC K 4 M respectively.

3.2

90 80 70 60 50 40 30 20 10 0

SWELLING INDEX

% DRUG RELEASE

2.8

F7 F8 F9

2

F7

1.6

F8

1.2

F9

0.8 0.4 0

0

0.5

1

2

3

4

5

6

7

0

8

In vitro release profile of Atenolol from for mulations F7, F8 and F9 containing 20%, 30% and 40% Xanthan gum respectively.

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1

2

3

4

5

6

7

8

TIME (h)

TIME (h)

Fig.3.

2.4

Fig.6.

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Swelling Indices of Atenolol from formulations F7, F8 and F9 containing 20%, 30% and 40% Xanthan gum respectively.

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Vijay Daulatrao et al Optimization and In Vitro Evaluation of Floating Tablets of Atenolol

Table I. Formulations of Floating Matrix Tablets of Atenolol Ingredients / Formulations Atenolol HPMCK 100M HPMC K4M Xanthan gum Sodium bicarbonate Dicalcium phosphate (DCP) Magnesium. Stearate Directly compressible lactose (DCL) Talc

Total (mg)

F1

F2

F3

F4

F5

F6

F7

F8

F9

50 35 — — 35 17.5

50 70 — — 35 17.5

50 105 — — 35 17.5

50 — 35 — 35 17.5

50 — 70 — 35 17.5

50 — 105 — 35 17.5

50 — — 35 35 17.5

50 — — 70 35 17.5

50 — — 105 35 17.5

3.5 205.5

3.5 170.5

3.5 135.5

3.5 205.5

3.5 170.5

3.5 135.5

3.5 205.5

3.5 170.5

3.5 135.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

350

350

350

350

350

350

350

350

350

Table II. Evaluation of Physicochemical Parameters of Atenolol

Formulation Code

F1 F2 F3 F4 F5 F6 F7 F8 F9

Drug Content % ±S.D. (n=3)

Hardness ±S.D. (n=10)

98.25± 3.01 102.03± 2.45 99.70±3.5 100.81±0.72 97.23± 0.25 99.17± 1.42 101.47±2.89 100.01±3.01 97.86±3.5

4.4±0.28 4.3± 0.18 4.5±0.32 4.4± 0.31 4.4± 0.25 4.6±0.36 4.3±0.18 4.4±0.12 4.5±0.2

Floating lagtime (min.) ±S.D. 7±1.0 6±0.05 5±1.75 9±0.01 7±0.03 6±0.04 8±0.17 6±0.04 5±0.01

Floating Duration (h) (n=3)

Matrix integrity

Swelling Index ±S.D. (n=3)

22.7±0.05 23 ± 1.00 24±1.05 12±0.05 15±0.05 17±0.05 24±1.00 24±0.05 24±1.05

Very Good Very Good Very Good Very Good Very Good Very Good Very Good Very Good Very Good

0.720±0.015 1.0453± 0.008 1.5026±0.062 0.6215±0.026 0.7310±0.004 0.9495±0.012 1.1277±0.001 1.4767±0.018 1.7695±0.041

Table III. In vitro release profile of Atenolol Formulation Code F1 F2 F3 F4 F5 F6 F7 F8 F9 (n = 3)

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% Drug Release ± S. D.

% DE

MDT

92.50 ± 4.98 75.92± 4.18 64.09± 0.38 118.07±5.80 111.03±5.61 71.75±6.44 85.13±3.75 71.80±2.13 60.01±3.59

53.89 46.78 39.89 58.93 48.77 41.06 57.72 45.27 39.34

3.95 4.01 4.03 3.02 3.34 3.79 4.49 4.54 5.50

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Table IV. Analysis of in vitro release data of Atenolol. Formulation Code

F1 F2 F3 F4 F5 F6 F7 F8 F9

Zero order

First Order

R

k

0.9600 0.9411 0.9466 0.9689 0.9689 0.9662 0.9883 0.9727 0.9139

10.49 10.72 10.13 10.27 10.52 10.62 10.40 10.75 10.12

R

k

0.9385 0.9840 0.9785 0.9835 0.9786 0.9821 0.9495 0.9636 0.9733

Statistical Analysis: Analysis of variance (ANOVA) was performed to find out significant difference in drug released at 0.5, 1, 4 and 8 h, floating lag time at 0.5, 1, 4 and 8 h, swelling index at 1, 4 and 8 h from all formulations. RESULTS AND DISCUSSION: Optimization of concentration of polymers and an effervescent: A 10% concentration of sodium bicarbonate was found to be optimum to impart floating. It was observed that the concentration of sodium bicarbonate less than 10% led to slow reaction that prolonged the floating lag time up to 1.5h. Hardness of 4 to 4.5 kg/cm2 was found to be optimum to impart the compactness to the system. Swelling of the tablets depends on the type of polymer and its concentration. Floating Characteristics: When the floating matrix tablets containing gasgenerating agent were exposed to 0.1N HCl, hydrochloric acid reacted with sodium bicarbonate in the floating tablet inducing CO2 formation. The generated gas was entrapped into the matrix of swollen polymer matrix and was well protected by gel formed by hydration of polymers, which led to floating of the dosage forms 18. Floating lag time of the tablets was found to be the function of polymer concentration (Table II). This may be because of the fact that at lower concentrations, the polymers has lesser ability to form as gel 19. Journal of Pharmacy Research

Korsemeyer - Peppas

15.26 15.53 13.45 14.50 13.75 14.26 14.59 14.85 14.60

R 0.9849 0.9490 0.9840 0.9850 0.9824 0.9875 0.9760 0.9844 0.9946

k 18.55 16.13 16.07 18.90 16.06 18.78 15.92 15.78 15.12

Best Fit n 0.54 0.55 0.51 0.53 0.52 0.54 0.51 0.55 0.54

Peppas First Peppas Peppas Peppas Peppas Zero order Peppas Peppas

All the formulations showed good matrix integrity, which may be because of the compactness of the system, which is necessary to prevent the sweep of the tablet in lower part of gastrointestinal tract during interdigestive myoelectric cycle. The tablet floats on the dissolution medium for 24 h because of the presence of internal voids in the dry center of the tablets (porosity). In vitro drug Release: In vitro dissolution studies of all the formulations showed controlled release of drug for 8 h. When the floating tablets were exposed to dissolution medium, the medium penetrated into the free spaces between macromolecular chains of the polymer. After solvation of the polymer chain, the dimensions of the polymer molecule increased due to the polymer relaxation by stress of the penetrated solvent. This led to swelling which is characterized by the formation of a gel like network surrounding the tablet. HPMC is a hydrophilic polymer that forms a surface barrier around the matrix tablet 20. The higher rate and extent of drug release was observed from the formulations based on HPMC K4M and HPMC K100M than those based on Xanthan gum (Table III). It was observed that the formulations containing Xanthan gum showed slower release of drug (Fig.6) than those containing HPMC K100M (Fig 4) and HPMC K4M (Fig.5). This is because of higher degree of swelling due to water uptake and small amount of erosion due to polymer relaxation. The release of Atenolol from all the formulations fitted to different release kinetic models. The comparative effect of three

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different polymers on the release profile of Atenolol from the floating formulations in terms of % dissolution efficiency (%DE) showed that formulations containing Xanthan gum retarded the release of drug than those containing HPMC K100M and HPMC K4M. It was observed that the formulations having low values of mean dissolution time (MDT) indicated the faster release of drugs than the other formulations (Table III). Formulation F2 was found to follow first order model (R value 0.98). Formulations F6 showed zero order release model (R value 0.99) and other formulations showed Peppas model (R value0.91 to 0.98). When the drug release data was correlated to Korsemeyer Peppas equation that the value of diffusional exponent ‘n’ (0.52 to 0.99) indicated that the drug release was by Non- Fickian diffusion (Table IV). The drug release from hydrophilic matrix is determined by (i) polymer swelling; (ii) front movement; (iii) drug dissolution; (iv) diffusion and (v) matrix erosion 21. Swelling Index: The swelling of polymers used (HPMC K4M, HPMC K100M and Xanthan gum) were determined by water uptake. It was observed that the swelling indices were increased with increase in polymer concentration. Formulations containing Xanthan gum showed higher swelling indices as compared with other formulations containing the same amount of HPMC K4M and HPMC K100M (Table II). This is due to the fact that during dissolution, the tablet containing Xanthan gum instantly forms a viscous gel layer that slows down in sweep of dissolution fluid towards the core of matrix tablet. Swelling was a strong enough to avoid premature disintegration as well as burst effect and retarded the release of drug for a long period of time22. The results of these tests are provided in fig.4, 5 and 6. Usually swelling is essential to ensure floating. For floating the tablets, there should be appropriate balance between swelling and water uptake. It was observed that HPMC grade also affect the swelling. No effect of effervescent on the swelling index was observed. Swelling index values starts decreasing when polymer erosion starts in medium 22. A direct correlation between swelling and drug release was observed. It was found that the formulations having maximum swelling indices showed slower release of drugs. A lesser floating lag time and prolonged Journal of Pharmacy Research

floating duration can be achieved by using the polymer Xanthan gum. Also it was observed that the formulations containing Xanthan gum retarded the release of drug, as the polymer swelling is crucial in determining the release rate. REFERENCES: [1] Chawla G, Gupta P, Koradia V and Bansal AK. Gastro retention, A means to address regional variability in intestinal drug absorption. Pharm. Tech.2006; 50 -60. [2] Davis SS. Formulation strategies for absorption windows. DDT, Volume 10, 2005, 249-257. [3] Arora S, Ali J, Ahuja A, Khar RK and Baboota S. Floating drug delivery system. AAPS Pharm. Sci. Tech, Volume 6, Edn3, 2005, E372 – E390. [4] Rocca JG, Omidian H and Shah K. Progress in gastro retentive drug delivery system, Drug Delivery Oral. Pharm.Tech. 2003, 152 – 156. [5] Talukdar MM et al. In vitro evaluation of Xanthan gum as potential excipients for oral controlled release matrix tablet formulation. Int. J. Pharm. Volume 169, 1998, 105 – 113. [6] Choi BY, Park HJ, Hawng SJ and Park JB. Preparation of alginate beads for floating drug delivery system: effect of CO2 gas forming agents. Int. J. Pharm. Volume 239, 2002, 81 91. [7] Sungthongjeen S, Paeratakul O, Limmatvapirat S. Preparation and in vivo evaluation of a multiple unit floating drug delivery system based on gas formation technique. Int. J. Pharm. Volume 324, 2006, 136 -143. [8] Shimpi S, Chauhan B, Mahadik KR and Paradkar A. Preparation and evaluation of Diltiazem Hydrochloride- Gelucire 43/01 floating granules prepared by melt granulation. AAPS PharmSci Tech. Volume 5, Edn 3, 2004, 1- 6. [9] Tanwar YS, Floating microspheres: Development, characterization and application, Pharma infonet, 2007. http:/ www. Pharmainfo. Net. [10] Dollery C. Therapeutic Drugs, Edn1, Churchill Livingstone; Edinburgh, 1999, A.224-227. [11] Florey K, Analytical profile of drug substances, Edn 12, Vol 13, Elsevier, a division of Reed

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