Development and in vitro evaluation of gas generating floating tablets of metformin hydrochloride

 

P.S. Salve*

Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University Campus, Mahatma Fuley Shaikshanik Parisar, Amravati Road, Nagpur 440 033 (MS)

*Corresponding Author E-mail: pramodsalve77@yahoo.com

 

ABSTRACT:

Metformin HCl is an anti-hyperglycaemic agent having oral bioavailability of 525% due to its selective absorption from upper part of gastrointestinal tract. It has biological half-life of 1.740.2 hours, hence the development of floating sustained release drug delivery system is recommended in order to enhance the bioavailability. The high dose of metformin HCl in the form of SR dosage form results in increased tablet weight and dimensions making the dosage form difficult to be swallowed by the patient. The present investigation deals with use of minimum proportions of natural polymers for drug release control by utilizing the advantage of interactions of gums resulting in enhanced matrix strength.

 

Xanthan gum a heterodisperse system produces a highly ordered, helical or double helical molecular conformation and homodisperse system of locust bean gum is slowly soluble and ungelled at low temperatures. The xanthan gum component acts to produce a faster gelation of the homopolysaccharide component and the homopolysaccharide acts to cross-link the normally free heteropolysaccharide helices resulting in increased viscosity. The interaction of Xanthan and locust bean gum was confirmed by FT-IR spectroscopy and differential scanning calorimetry. Drug release from optimized batch containing metformin HCl: HPMC K100M in 1:1 and sodium bicarbonate 5, 10, 15% ratio has sustained the drug release for 12 hours. Metformin HCl: HPMC K100M in 1:1 and sodium bicarbonate 5, 10, 15% ratio with citric acid. Metformin: in combination of Xanthan and locust bean gum (2:8 optimum viscosity for synergism) in 1:0.5, 1:0.75 and 1:1 ratio with 5, 10, 15% sodium bicarbonate. Metformin: in combination of Xanthan and locust bean gum (2:8 optimum viscosity for synergism) in 1:0.5, 1:0.75 and 1:1 ratio with sodium bicarbonate and citric acid in 5, 10, 15% ratio respectively sustained the drug release upto 12 hours.

 

 


INTRODUCTION:

The gas generating system consists of hydrophilic matrices prepared with the swellable hydrocolloids like hydroxypropylmethylcellulose, hydroxypropylcellulose, chitosan. The effervescent components sodium bicarbonate or sodium bicarbonate in combination with citric acid or tartaric acid is used for the generation of CO2 gas. The optimized ratio of sodium bicarbonate: citric acid 1: 0.76 for generation of CO2 when the dosage form comes in contact with acidity of gastric contents. The CO2 is entrapped in the polymeric network providing the floating characteristics to the dosage form.

 

A decrease in the specific gravity causes the dosage form to float in the simulated gastric fluid. The Synergistic interactions of homopolymer and heteropolymer have control over drug release. A wide variety of hydrocolloid materials are used in controlled release drug delivery systems from synthetic, semi-synthetic or natural origin. A hydrogel controlled release excipient system can be processed into tablets by direct compression method. Also, wet granulation method can be used with the hydrocolloid excipients. The hydrogel system consists of a homo- and a hetero-polysaccharide together with a saccharide component. The system exerts synergistic action that aids tablet compaction and more effective control of drug release.

 

The properties and characteristics of a specific heterodisperse polysaccharide system are dependent on the individual characteristics of polysaccharide constituents, in terms of polymer solubility, glass transition temperatures, etc., as well as on the synergism between different polysaccharides and between polysaccharides and saccharides in modifying dissolution fluid-excipient interactions.

 

Xanthan gum a heterodisperse system produces a highly ordered, helical or double helical molecular conformation and homodisperse system of locust bean gum is slowly soluble and ungelled at low temperatures. The xanthan gum component acts to produce a faster gelation of the homopolysaccharide component and the homopolysaccharide acts to cross-link the normally free heteropolysaccharide helices resulting in increased viscosity. The heterodisperse excipient contains both hetero and homo-polysaccharides, which exhibit synergism. The xanthan gum component acts to produce a faster gelation of the homopolysaccharide component and the homopolysaccharide acts to cross-link the normally free heteropolysaccharide helices. The resultant gel is faster forming and more rigid. The viscosity and solubilization speeds are further potentiated by the saccharide component, and gel rigidity may also be potentiated further in the presence of some cations and anions.

 

Various advantages of homopolymer-heteropolymer interaction with hydrophilic tablets there is a direct relationship between release rate and tablet dimensions. A consequence of such behavior is that an increase in tablet size causes a decrease in drug release rate. Another effect of release variability is evident when tablet shape is changed. A marked difference in drug release occurs due to differences in dry and wetted porosities between the caplet and biconvex tablets. The other variable such as surface: volume ratios are also important; for example, the dry surface of biconvex tablets is only approximately 60% of the equivalent caplet surface. The influence of tablet shape and size is significantly greater with hydrophilic system than equivalent hydrophobic sustained release tablet formulations. The drug release from tablets produced using the heterodisperse polysaccharide drug delivery system were found to be tablet dimension independent, which may be an important formulation factor for achieving a desired release pattern within tablet weight and/or shape constrains. Comparable control of drug release from tablets of different dimensions was achieved by modifying the synergistic interactions between the homo and heteropolysaccharide and saccharide components of the heterodisperse polysaccharide excipient system.

 

Metformin HCl is an anti-hyperglycaemic agent having oral bioavailability of 525% due to its selective absorption from upper part of gastrointestinal tract. It has biological half-life of 1.740.2 hours, hence the development of floating sustained release drug delivery system is recommended in order to enhance the bioavailability. The high dose of metformin HCl in the form of SR dosage form results in increased tablet weight and dimensions making the dosage form difficult to be swallowed by the patient. The present investigation deals with use of minimum proportions of natural polymers for drug release control by utilizing the advantage of interactions of gums resulting in enhanced matrix strength.

 

MATERIALS:

Metformin HCL (Zim laboratories, Nagpur), Hydroxy propyl methyl cellulose (HPMC) K4M, K15M, and K100M (Colorcon Asia Pvt. Ltd., Goa), xanthan gum (Tic Gum Inc., USA), Locust bean gum (Tic Gum Inc., USA) Sodium bicarbonate (S.D. Fine Chem. Ltd., Mumbai), Citric acid (Loba Chemie Pvt. Ltd.), Microcrystalline cellulose (Signet Chemicals, Mumbai). All other chemicals and excipients were of analytical grade.

 

METHODS:

Development of tablets

The formulation of floating tablets of metformin HCl with HPMC K100M is shown in table 1. Metformin HCl, HPMC K100M and MCC PH 101 were sifted through 40# sieve. The blend was granulated with isopropyl alcohol and passed through 16# sieve. The granules were air dried till the solvent was evaporated and then dried in oven at 50 0C. Sodium bicarbonate and citric acid were heated at 105 0C for 2 hours to remove adsorbed water. To the granules, sodium bicarbonate or its blend with citric acid in 1:0.76 ratio was added and mixed well. The blend was lubricated with talc and magnesium stearate and compressed using 16 stations D tooling Cadmach compression machine. The tablet weight for compression was adjusted to 1200 mg. The punch dimensions were 9.76 X 20.56 mm capsule shaped punches with a bisecting line on one surface.

 

The formulation of floating tablets of metformin HCl with xanthan gum, locust bean gum and their combination gum is shown in table 2, 3, and 4. From viscosity studies, a 2:8 ratio of xanthan gum: locust bean gum was found to be the optimum ratio as evidenced from its high viscosity. Hence, 2:8 ratio of xanthan gum: locust bean gum was used for development of tablets. The tablets were developed using xanthan gum and locust bean gum individually to study their matrix forming property. Also, the ratio of metformin HCl: combination of xanthan and locust bean gum in 2:8 proportion was kept at 1:0.5, 1:0.75 and 1:1. The 5, 10, 15% sodium bicarbonate and similarly 5, 10, and 15% sodium bicarbonate with citric acid in 1:0.76 ratio was used as gas generating component to optimize the floating characteristic. Metformin HCl, xanthan gum, locust bean gum and MCC PH 101 were sifted through 40# sieve. The blend was granulated with distilled water and passed through 16# sieve. The granules were dried at 60 0C. To the dried granules, sodium bicarbonate or its blend with citric acid was added and mixed well. Before compression the blend was lubricated with talc and magnesium stearate and compressed using 16 station D tooling Cadmach compression machine. The tablet weight for compression was adjusted to 1200 mg.

 


Table 1 Formulation of metformin HCl floating tablets with HPMC K100M.

Formulation code.

Ingredients (mg)

F1

F2

F3

F4

F5

F6

Metformin HCl

500

500

500

500

500

500

HPMC K100M

500

500

500

500

500

500

MCC PH 101

120

60

-

120

80

30

Sodium bicarbonate

60

120

180

34.10

68.18

102.27

Citric acid

-

-

-

25.90

51.82

77.73

Talc

10

10

10

10

10

10

Magnesium stearate

10

10

10

10

10

10

Tablet weight (mg)

1200

1200

1200

1200

1200

1200

 

 

Table 2 Formulation of metformin HCl floating tablets with xanthan, locust bean gum and their combinations

Formulation code.

Ingredients (mg)

F7

F8

F9

F10

F11

F12

Metformin HCl

500

500

500

500

500

500

Xanthan gum

500

-

50

75

100

50

Locust bean gum

-

500

200

300

400

200

MCC PH 101

56

56

366

241

116

306

Sodium bicarbonate

120

120

60

60

60

120

Citric Acid

-

-

-

-

-

-

Talc

12

12

12

12

12

12

Magnesium stearate

12

12

12

12

12

12

Tablet weight (mg)

1200

1200

1200

1200

1200

1200

Table 3 Formulation of metformin HCl floating tablets with xanthan, locust bean gum and their combinations

Formulation code.

Ingredients (mg)

F13

F14

F15

F16

F17

F18

Metformin HCl

500

500

500

500

500

500

Xanthan gum

75

100

50

75

100

50

Locust bean gum

300

400

200

300

400

200

MCC PH 101

181

56

246

121

-

366

Sodium bicarbonate

120

120

180

180

180

34.09

Citric Acid

-

-

-

-

 

25.90

Talc

12

12

12

12

10

12

Magnesium stearate

12

12

12

12

10

12

Tablet weight (mg)

1200

1200

1200

1200

1200

1200

Table 4 Formulation of metformin HCl floating tablets with xanthan, locust bean gum and their combinations

Formulation code.

Ingredients (mg)

F19

F20

F21

F22

F23

F24

F25

F26

Metformin HCl

500

500

500

500

500

500

500

500

Xanthan gum

75

100

50

75

100

50

75

100

Locust bean gum

300

400

200

300

400

200

300

400

MCC PH 101

241

116

306

181

56

246

121

-

Sodium bicarbonate

34.09

34.09

68.18

68.18

68.18

102.27

102.27

102.27

Citric Acid

25.90

25.90

51.82

51.82

51.82

77.73

77.73

77.73

Talc

12

12

12

12

12

12

12

12

Magnesium stearate

12

12

12

12

12

12

12

12

Tablet weight (mg)

1200

1200

1200

1200

1200

1200

1200

1200


 

Physical evaluation of tablets

Floating tablets were evaluated for mechanical strength using Monsanto hardness tester and friability using Roche friability test apparatus. The in vitro buoyancy test was carried in pH 1.2 buffer containing 0.02% tween 80 using USP type II dissolution test apparatus (Veego Scientific) at 37 0.5 C. The time required for the tablet to come on the surface of buffer media was noted as floating lag time.

 

Drug Content

Five tablets were weighed and powdered. The quantity of powder blend equivalent to 500 mg of metformin HCl was weighed accurately and taken in 250 ml volumetric flask. To it 150 ml of pH 1.2 buffer was added and sonicated for 5

 

minutes. The volume was made upto 250 ml with pH 1.2 buffer and filtered. From the above solution, 1 ml was diluted to 50 ml with pH 1.2 buffer. The drug content was determined spectrophotometrically at 233 nm.

 

Dissolution studies

The in vitro release of metformin HCl floating tablets was carried out in pH 1.2 buffer. The studies were performed using USP type II dissolution test apparatus at 37 0.5 C and 75 rpm. Samples were hourly interval and analyzed for drug content at 233 nm.

 

 

 


Table 5 Viscosity values of aqueous dispersions of xanthan and locust bean gum and their combinations

Sr. No

Xanthan gum concentration

(%w/v)

Locust bean gum concentration

(%w/v)

Dial reading

Factor

Viscosity

(Dial readingX Factor)

Viscosity

(Mean)

Cps

1

2

3

1

2

3

1

1

-

37

38

40

10

370

380

400

383

2

-

1

5

6

5

10

50

60

50

53

3

0.1

0.9

30

41

41

10

1200

1640

1640

1493

4

0.2

0.8

66

55

59

10

2640

2200

2360

2400

5

0.3

0.7

15

13

15

10

600

520

600

573

6

0.4

0.6

19

20

18

10

760

800

720

760

7

0.5

0.5

17

14

16

10

680

560

640

627

8

0.6

0.4

13

10

13

10

520

400

520

480

9

0.7

0.3

14

12

14

10

560

480

560

533

10

0.8

0.2

10

12

14

10

400

480

560

480

11

0.9

0.1

10

13

12

10

400

520

480

467


 

RESULTS AND DISCUSSION:

Viscosity studies

As shown in table 5, the viscosity value of 2:8 ratio of xanthan: locust bean gum dispersion was found to be maximum as compared to the viscosity of individual xanthan or locust bean gum dispersions. Hence the ratio 2:8 of xanthan: locust bean gum was selected for further development of matrix tablets.

 

Interaction studies of xanthan and locust bean gum

X-ray diffraction studies

The x-ray diffraction patterns of xanthan gum, locust bean gum are shown in figure 1, and 2 respectively. The x-ray diffraction pattern has shown the diffused pattern indicating the amorphous nature of the gums. In order to confirm the structural changes due to interaction of xanthan and locust bean gum, the x-ray diffraction pattern of the interacted gum sample was recorded and it is represented in figure 3. It has also shown the diffused pattern indicating the interacted gum sample was present in the amorphous state. Hence, it was concluded that the polymorphic characteristic of xanthan, locust bean gum and their interaction was not changed.

 

Figure 1. X-ray diffraction pattern of xanthan gum

 

Figure 2 X-ray diffraction pattern of locust bean gum

 

Figure 3 X-ray diffraction pattern of interacted sample of xanthan gum and locust bean gum

 

FT-IR studies

4

Figure 4 FT-IR spectrum of xanthan gum

 

Figure 5 FT-IR spectrum of locust bean gum

 

Figure 6 X-ray diffraction pattern of interacted sample of xanthan gum and locust bean gum

 

The FT-IR spectrum of xanthan gum, locust bean gum and interacted sample of xanthan and locust bean gum is shown in figure 4,5 and 6 respectively. It was observed that the C-O stretching frequency at 1159 cm-1 which was observed in the spectrum of xanthan and locust bean gum was absent in case of spectrum of their interacted sample. Also, the C-H bending frequency at 1473 cm-1 was observed in case of interacted sample of xanthan and locust bean gum. The additional stretching frequencies at 1772 cm-1 due to C=O stretching, 1751 cm-1 due to amide δ lactam or RCONHR stretching, 1686 cm-1 due to C=C-COOH, 1647 cm-1 due to presence of amide C=O stretching amide I and 1578 cm-1 due to RCO2- were observed in the FT-IR spectrum of interacted sample of xanthan and locust bean gum. Hence, the structural changes might have occurred in the interaction process.

 

Differential scanning calorimetry studies

 

Figure 7 DSC thermogram of xanthan gum

The DSC thermogram of xanthan gum (figure 7) shows the endothermic thermal transitions at 67.24 0C with enthalpy value of (-) 297.10 J/g, and exothermic thermal transition at 276.09, and 370.77 0C with enthalpy values of 826.58 and 94.16 J/g respectively.

 

Figure 8 DSC thermogram of locust bean gum

 

The DSC thermogram of locust bean gum (figure 8) has shown the endothermic thermal transitions at 88.17 0C with enthalpy values of (-) 1158.18 J/g and exothermic thermal transition at 293.19, and 321.29 0C with enthalpy values of 59.75 and 830.10 J/g respectively.

Figure 9 DSC thermogram of interacted sample xanthan gum and locust bean gum

 

The DSC thermogram of xanthan and locust bean gum interacted sample (figure 9) has shown the endothermic thermal transitions at 71.07 0C with enthalpy values of (-) 139.64 J/g and exothermic thermal transition at 289.08 0C with enthalpy values of 742.24 J/g.

 

The thermal transitions and enthalpy values of xanthan gum, locust bean gum and their interacted sample are shown in table 6.

 

 

Table 6 Thermal transitions and enthalpies of xanthan, locust bean gum and interacted sample xanthan gum and locust bean gum

Sample

DSC thermal transition (0C)

Enthalpy (J/g)

Xanthan gum

67.24

276.09

370.77 0C

-297.10

826.58

94.16

Locust bean gum

88.17

293.19

321.29

-1158.18

59.75

830.10

Xanthan + locust bean gum interacted sample

71.07

289.08

-139.64

742.24

From the above DSC thermograms, it was observed that the melting peak of interacted sample at 370.77 0C was disappeared as compared to the melting peak observed in case of xanthan gum sample. Also, as seen from table 1, the enthalpy value of xanthan gum (-) 297.10 J/g was reduced to -139.64 J/g indicating a less disorderly structure due to interaction of xanthan and locust bean gum as homopolymer and heteropolymer interaction.

 

Dissolution studies

The dissolution profiles of formulation batches containing metformin HCl and HPMC K100M in 1:1 ratio and 5,10, and 15% sodium bicarbonate, also 5, 10 and 15% sodium bicarbonate and citric acid in 1:0.76 ratio is shown in figure 10. The formulation batches containing 5, 10, and 15% sodium bicarbonate has shown 13 to 15% drug release in 1 hour and 49 to 58% drug release was observed after 8 hours. Whereas, the formulation batches containing 5, 10, and 15% sodium bicarbonate and citric acid combination has shown upto 24% of drug release in 1 hour hour and 53 to 71% of drug release was observed after 8 hours. It indicates that the alkaline microenvironment provided by sodium bicarbonate has slightly reduced the drug release as compared to sodium bicarbonate and citric acid combination which has increased the drug release. Hence, the matrix forming agent HPMC K100M had shown a better control for the drug release. The formulation batches containing 5, 10 and 15% sodium bicarbonate (F1, F2, and F3) as well as containing 10% sodium bicarbonate and citric acid in 1:0.76 ratio has shown Peppas model of drug release. Similarly, the formulation batches containing 5 and 15% sodium bicarbonate and citric acid in 1:0.76 ratio has shown matrix drug release kinetic model.

 

Figure 10 Release profile of metformin HCl floating tablets containing HPMC K100M

 

Figure 11 Release profile of metformin HCl floating tablets containing xanthan and locust bean gum with 10% sodium bicarbonate and their combinations with 5% sodium bicarbonate

 

As shown in figure 11, the floating tablets containing metformin HCl: xanthan gum in ratio 1:1 and 10% sodium bicarbonate has shown 11.65% drug release in first hour of dissolution studies and upto 61.36% drug release was observed after 8 hours. Whereas, the tablet formulation containing metformin HCl : locust bean gum in 1:1 ratio and 10% sodium bicarbonate has shown 27.28% drug release in 1 hour and more than 90% drug release was observed after 8 hours. A faster drug release was observed in case of formulation batch containing locust bean gum as compared to xanthan gum. It was due to weak matrix forming tendency of locust bean gum. The combination of xanthan: locust bean gum in 2:8 ratio was used to increase the matrix strength. Also the constrain was to use low proportion of gums. Hence, the ratio of metformin HCl : combination of xanthan and locust bean gum in 2:8 proportion was kept at 1:0.5, 1:0.75 and 1:1 respectively. In these formulation batches, 5% sodium bicarbonate was used. The formulation batch with 1:0.5 ratio of metformin HCl: combination of xanthan and locust bean gum (2:8) has shown the release of 20% in 1 hour and 72% drug release was observed after 8 hours. The release was found to be 10% more than the tablet formulation containing 1:1 ratio of metformin HCl: xanthan but the release was 30% less as compared to tablet formulation containing metformin HCl : locust bean gum in 1:1 ratio. The drug release was further reduced to 65 and 62% after 8 hours when the ratios of metformin HCl : combination of xanthan and locust bean gum were further increased to 1:0.75 and 1:1 respectively.

 

The release profiles of xanthan and locust bean gum in 1:0.5, 1:0.75 and 1:1 ratio and 10% sodium bicarbonate are shown in figure 12.

 

As shown in figure 3, the release of tablet formulations containing xanthan and locust bean gum in 1:0.5, 1:0.75 and 1:1 and 10% sodium bicarbonate was found to be similar as with formulations containing 5% sodium bicarbonate and similar ratios of xanthan and locust bean gum. The formulation containing xanthan and locust bean gum in 1:0.5, 1:0.75 and 1:1 ratio has shown 19.05, 24.20 and 20.93% of drug release in 1 hour and 75.94, 66.91 and 68.58% of drug release was observed after 8 hours. The release was not substantially affected with the ratios of xanthan and locust bean gum.

 

 

Figure 12 Release profile of floating tablets of metformin HCl containing 1:0.5, 1:0.75 and 1:1 ratio of xanthan gum and locust bean gum and 10% sodium bicarbonate.

 

As shown in figure13, the release of tablet formulations containing xanthan and locust bean gum in 1:0.5, 1:0.75 and 1:1 and 15% sodium bicarbonate was found to decrease as the ratio of xanthan and locust bean gum was increased from 1:0.5 to 1:1. The formulation containing xanthan and locust bean gum in 1:0.5, 1:0.75 and 1:1 ratio has shown 30.78, 24.64 and 20.54% of drug release in 1 hour and 70.09, 70.27 and 63.27% of drug release after 8 hours.

 

 

Figure 13 Release profile of floating tablets of metformin HCl containing 1:0.5, 1:0.75 and 1:1 ratio of xanthan gum and locust bean gum and 15% sodium bicarbonate.

 

Figure 14 Release profile of floating tablets of metformin HCl containing 1:0.5, 1:0.75 and 1:1 ratio of xanthan gum and locust bean gum and 5% sodium bicarbonate and citric acid in 1: 0.76 ratio.

The release profiles of xanthan and locust bean combination with 5% sodium bicarbonate and citric acid in 1:0.76 ratio is shown in figure 14. The tablet formulation batch containing the 1:0.5 ratio of metformin HCl: combination of xanthan and locust bean gum has shown the burst release of 52.31% in 1 hour and the drug release was sustained for 8 hours. The drug release after 8 hours was found to be 86.17%. Whereas, the formulation with 1:0.75 ratio has shown a release of 25.50% after 1 hour and 76.25% drug release was observed after 8 hours. The drug release was further sustained in the formulation batch containing 1:1 ratio of metformin HCl: xanthan and locust bean gum combination. The formulation has shown a release of 22.94% after 1 hour and 73.25% drug release was observed after 8 hours.

 

Figure 15 Release profile of floating tablets of metformin HCl containing 1:0.5, 1:0.75 and 1:1 ratio of xanthan gum and locust bean gum and 10% sodium bicarbonate and citric acid in 1: 0.76 ratio

 

The release profiles of xanthan and locust bean combination with 10% sodium bicarbonate and citric acid in 1:0.76 ratio is shown in figure 15. The tablet formulation batch containing the 1:0.5 ratio of metformin HCl: combination of xanthan and locust bean gum has shown the burst release of 85.55% in first hour. Whereas, the formulation with 1:0.75 ratio has shown a release of 25.50% after 1 hour and 78.98% drug release was observed after 8 hours. The formulation containing 1:1 ratio has shown a release of 27.86% after 1 hour and 77.98% drug release was observed after 8 hours. Hence no substantial difference was observed in the drug release of formulation batch containing 1:0.75 ratio and 1:1 ratio of xanthan and locust bean gum.

 

Figure 16 Release profile of floating tablets of metformin HCl containing 1:0.5, 1:0.75 and 1:1 ratio of xanthan gum and locust bean gum and 15% sodium bicarbonate and citric acid in 1: 0.76 ratio.

The release profiles of xanthan and locust bean combination with 15% sodium bicarbonate and citric acid in 1:0.76 ratio is shown figure 16. The tablet formulation batch containing 1:0.5 ratio of metformin HCl: combination of xanthan and locust bean gum has shown a complete drug release in 1 hour. Whereas, the formulation with 1:0.75 ratio has shown a burst release of 55 % after 1 hour and complete drug release was observed after 6 hours. The formulation containing 1:1 ratio has shown a release of 23.78% after 1 hour and 72.72% drug release was observed after 8 hours.

 

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20.     Indian Pharmacopeia. Controller of Publication, Delhi. 1996; Vol II : pp. A144, 796.

21.     Hand book of pharmaceutical excipients, R.C. Rowe, P.J. Sheskey, S.C. Owen (Ed.) third edition, American Pharmaceutical Association, Washington, D.C.

 

 

 

Received on 25.09.2011 Accepted on 02.10.2011

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Asian J. Res. Pharm. Sci. 1(4): Oct.-Dec. 2011; Page 105-112