FORMULATION AND EVALUATION OF SUSTAINED RELEASE … · 2017-12-18 · of the tablet is therefore...

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632

Sandhya et al. World Journal of Pharmaceutical Research

FORMULATION AND EVALUATION OF SUSTAINED RELEASE

TABLETS OF MEFORMIN HYDROCHLORIDE

Sandhya Adimulka* and Adukondalu Devandla

Vaagdevi College of Pharmacy, Hanamkonda, Warangal, Telangana.

ABSTRACT

In this research project, we are assigned a topic to study on the

designing of sustained r elease dosage forms and in vitro evaluation of

Metformin tablets. The main focus of this research is to develop a

better sustained release tablets and conduct all preformulation studies,

pre compression and post compression evaluation tests including

dissolution test on the tablets to determine the compliance of patient.

Dissolution testing is a method for evaluating physiological availability

that depends upon having the drug in a dissolved state. The release

profiles obtained from in vitro dissolution tests can be used for

predicting release kinetics to predict mechanism of drug transport. The

effectiveness of such dosage forms relies on the drug dissolving in the fluids of the

gastrointestinal tract prior to absorption into the systemic circulation. The rate of dissolution

of the tablet is therefore crucial. In this research, our aim s to determine the best formulation

among the designed and prepared sustained release dosage form by using an in vitro test

method simulating physiological conditions in the GI tract. The dissolution media used

closely resembles the GI fluid in the stomach. By conducting various evaluation studies

confirmed the best dosage form for sustained release dosage for reduce dosing frequency and

improve patient compliance.

KEYWORDS: In-vitro; dissolution test, relese kinetics and Metformin.

INTRODUCTION

An alternative to administering another dose is to use a dosage form that will provide

sustained drug release and therefore maintain plasma drug concentrations, beyond what is

typically seen using immediate-release dosage forms. In recent years, various modified-

release drug products have been developed to control the release rate of the drug and/or the

World Journal of Pharmaceutical Research SJIF Impact Factor 7.523

Volume 6, Issue 17, 632-648. Research Article ISSN 2277– 7105

Article Received on

26 October 2017,

Revised on 16 Nov. 2017,

Accepted on 06 Dec. 2017

DOI: 10.20959/wjpr201717-10303

*Corresponding Author

Sandhya Adimulka

Vaagdevi College of

Pharmacy, Hanamkonda,

Warangal, Telangana.


633


time for drug release. The term modified-release drug product is used to describe products

that alter the timing and/or the rate of release of the drug substance. A modified-release

dosage form is defined "as one for which the drug-release characteristics of time course

and/or location are chosen to accomplish therapeutic or convenience objectives not offered by

conventional dosage forms such as solutions, ointments, or promptly dissolving dosage forms

as presently recognized". An appropriately designed sustained-release drug delivery system

can be a major advance towards solving problems concerning the targeting of a drug to a

specific organ or tissue and controlling the rate of drug delivery to the target tissue. Matrix

tablets are an interesting option when developing an oral controlled release formulation. The

use of polymers in controlling the release of drugs has become important in the formulation

of pharmaceuticals.[1]

Metformin is a biguanide antihyperglycemic agent used for treating non-insulin-dependent

diabetes mellitus (NIDDM). It improves glycemic control by decreasing hepatic glucose

production, decreasing glucose absorption and increasing insulin-mediated glucose uptake.

Metformin is the only oral antihyperglycemic agent that is not associated with weight gain.

718-1552 mL/minute following single oral dose of 0.5-1.5 g. 6.2 hours. Duration of action is

8-12 hours.[2,3]

Polymers like HPMC and eudragits are used for preparation of various types

of novel drug delivery systems and controlled release dosage forms for water soluble

drugs.[4,8]

Present research work aimed to develop sustained release tablets of metformin hydrochloride

tablets using polymers like HPMC and eudragit to reduce dosing frequency improve patient

compliance.

1. Materials: Metformin hydrochloride, Hydroxy propyl methyl cellulose, Eudragit,

Magnessium stearate, lactose, microcrystalline cellulose, Potassium hydrogen phthalate,

sodium hydroxide.

2. Methods

Preparation of calibration curve of Metformin

50mg of Metformin active pharmaceutical ingredient (API) is dissolved in a 50 ml volumetric

flask with ethanol. Then it is made up to volume with pH 6.8 phosphate buffer. From this

solution 1ml is taken and diluted to 10 ml with pH 6.8 in a 10 ml volumetric flask. From this

stock solution 0.5ml, 0.75ml, 1ml, 1.25ml, 1.5ml, of solution is taken in different volumetric


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flasks and volume made up to 10 ml with pH 6.8 phosphate buffer. Absorbance is measured

at 238nm using Beer’s range (3-30 mcg/ml).

Fourier Transforms Infra Red Spectroscopy (FT-IR)

Fourier-transform infrared (FTIR) spectroscopy was performed on each of the samples to

determine the structure of the organic compounds and to identify the presence of specific

functional groups within a sample. Furthermore, drug-polymer interactions were examined

using the resulting spectra. Spectra are obtained by passing infrared radiation through a

sample and determining what fraction of incident radiation is absorbed at a particular energy.

The energy of a peak in the spectrum corresponds to the frequency of vibration of part of the

sample compound. 3-5 mg of composite sample was added to approximately 100 mg of KBr

(s). The mixture was then ground to a fine powder using a mortar and pestle and transparent

discs were formed using a pellet press. The discs were then placed in the FTIR spectroscopy

apparatus, and spectra were collected. The range of the collected spectra was 4000-400cm-1

Metformin Sustained Release Matrix Tablets of F1-F9 Formulations

Differeent formulations of metformin were designed by varying proportions of HPMC and

Eudragit (125-375mg).

Table 1: Metformin Sustained Release Matrix Tablets of F1-F9 Formulations.

INGREDIENTS F1 F2 F3 F4 F5 F6 F7 F8 F9

METFORMIN (mg) 250 250 250 250 250 250 250 250 250

HPMCE5(mg) 125 250 375 - - - - - -

HPMCK100(mg) - - - 125 250 375 - - -

EUDRAGIT(mg) - - - - - - 125 250 375

Mg.STEARATE(mg) 2 2 2 2 2 2 2 2 2

LACTOSE(mg) 50 50 50 50 50 50 50 50 50

MCC(mg) 108 98 88 108 98 88 108 98 88

Formulation of Sustained Release Tablets of Metformin by Wet Granulation Method

The active drug used in the formulation is Metformin. The excipients used in the formulation

are HPMC, HPMCK100, Eudragit, Magnesium Stearate, Lactose, Micro crystalline

Cellulose.

Steps Involved In Wet Granulation Method for Preparation of Tablets

1. Mixing of the drug(s) and excipients 2. Preparation of binder solution. 3. Mixing of binder

solution with powder mixture to form wet mass. 4. Coarse screening of wet mass using a

suitable sieve (6-12 screens). 5. Drying of moist granules. 6. Screening of dry granules


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through a suitable sieve (14-20 screen). 7. Mixing of screened granules with glidant, and

lubricant.

PREFORMULATION STUDIES

Angle of Repose: The angle of repose of the powder blend was determined by using funnel

method. The accurately weighed powder was taken in a funnel. The height of the funnel was

adjusted in such a way that the tip of the funnel just touched the apex of the heap of the

powder. The diameter of the powder cone was measured and angle of repose was calculated

by using the equation and value is shown in Table No.5 respectively.

Bulk Density: The bulk density was determined by transferring the accurately weighed

sample of powder to the graduated cylinders calculated by using the following formula.

Tapped Density: Weighed powder sample was transferred to a graduated cylinder and was

placed On the tap density apparatus, was operated for fixed number of taps (500). The tapped

density was determined by the following formula.

Carr’s Index: Based on the apparent bulk density and the tapped density, the percentage

Compressibility of the bulk drug was determined by the following formula.

Hausner’s Ratio: It indicates the flow properties of powder and is measured by the ratio of

tap density to bulk density.

EVALUATION OF TABLETS

Hardness: For each formulation, the hardness of five tablets was checked using the hardness

tester.

Thickness: The thickness of the tablets was determined using a Vernier Caliper. Six tablets

from each batch were used.

Friability: For each formulation, twenty tablets were selected randomly and weighed.

Tablets were then placed in friability testing apparatus i.e. Roche Friabilator (Lab India),

which was rotated at a speed of 25 rpm for 4 minutes. Tablets were then weighed and

friability values were determined.

Weight Variation: To study weight variation, 20 tablets of each formulation were weighed

using an electronic balance, average weights was calculated, individual tablet weights were


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compared with the average weight. Not more than two individual weights deviate from the

average weight by more than the percentage shown in following Table.

Assay: 10 tablets are weighed and triturated. Tablet triturate equivalent to 100 mg of

Nifedipine dissolved in 100 ml of pH 6.8 phosphate buffer and absorbance measured at

238nm.

In-vitro dissolution studies: The in vitro dissolution studies are carried out in USP

dissolution test apparatus type 2.[9]

Drug Release Kinetics -Model Fitting of the Dissolution Data

Whenever a new solid dosage form is developed or produced, it is necessary to ensure that

drug dissolution occurs in an appropriate manner. The pharmaceutical industry and the

registration authorities do focus, nowadays, on drug dissolution studies. Drug dissolution

from solid dosage forms has been described by kinetic models in which the dissolved amount

of drug (Q) is a function of the test time, t or Q=f(t). Some analytical definitions of the Q(t)

function are commonly used, such as zero order, first order, Hixson–Crowell, Higuchi,

Korsmeyer–Peppas models. (Mulye and Turco, 1995; Colombo et al., 1999; Kim et al., 1997;

Manthena et al., 2004; Desai et al., 1996; Higuchi et al., 1963). Different models expressing

drug release kinetics were given in Table given below.

Zero order kinetics

Q1 = Q0 +K0t

Where Q1 is the amount of drug dissolved in time t, Q0 is the initial amount of drug in the

solution (most times, Q0=0) and K0 is the zero order release constant.

ft = K0 t

Where ft = 1-(Wt/W0) and ft represents the fraction of drug dissolved in time t and K0 the

apparent dissolution rate constant or zero order release constant. In this way, a graphic of the

drug-dissolved fraction versus time will be linear if the previously established conditions

were fulfilled.

Use: This relation can be used to describe the drug dissolution of several types of modified

release pharmaceutical dosage forms, as in the case of some transdermal systems, as well as


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matrix tablets with low soluble drugs, coated forms, osmotic systems, etc. The

pharmaceutical dosage forms following this profile release the same amount of drug by unit

of time and it is the ideal method of drug release in order to achieve a pharmacological

prolonged action.

First order kinetics

Kinetic equation for the first order release is as follows:

Log Qt = log Q0 + K1t/2.30

Where Qt is the amount of drug released in time t, Q0 is the initial amount of drug in the

solution and K1 is the first order release constant. In this way a graphic of the decimal

logarithm of the released amount of drug versus time will be linear. The pharmaceutical

dosage forms following this dissolution profile, such as those containing water-soluble drugs

in porous matrices, release the drug in a way that is proportional to the amount of drug

remaining in its interior, in such way, that the amount of drug released by unit of time

diminishes.

Higuchi model

ft = KH t1/2

Where KH is the Higuchi dissolution constant treated sometimes in a different manner by

different authors and theories. Higuchi describes drug release as a diffusion process based in

the Fick’s law, square root time dependent. This relation can be used to describe the drug

dissolution from several types of modified release pharmaceutical dosage forms, as in the

case of some transdermal systems and matrix tablets with water-soluble drugs.

Hixson–Crowell model

Hixson and Crowell (1931) recognizing that the particle regular area is proportional to the

cubic root of its volume derived an equation that can be described in the following manner.

W0 1/3

-Wt 1/3

= Kst

Where W0 is the initial amount of drug in the pharmaceutical dosage form, Wt is the

remaining amount of drug in the pharmaceutical dosage form at time t and Ks is a constant

incorporating the surface–volume relation. This expression applies to pharmaceutical dosage

form such as tablets, where the dissolution occurs in planes that are parallel to the drug


638


surface if the tablet dimensions diminish proportionally, in such a manner that the initial

geometrical form keeps constant all the time.

A graphic of the cubic root of the unreleased fraction of drug versus time will be linear if the

equilibrium conditions are not reached and if the geometrical shape of the pharmaceutical

dosage form diminishes proportionally over time. This model has been used to describe the

release profile keeping in mind the diminishing surface of the drug particles during the

dissolution.

Mechanism of Drug Release

To find out the drug release mechanism due to swelling (upon hydration) along with gradual

erosion of the matrix, first 60% drug release data can be fitted in Hixson–Crowell model

which is often used to describe the drug release behavior from polymeric systems.

Log (Mt / M∞) = Log KKP + n Log t

Where, Mt is the amount of drug release at time t, M∞ is the amount of drug release after

infinite time, KKP is a release rate constant incorporating structural and geometrical

characteristics of the tablet and n is the release exponent indicative of the mechanism of drug

release.[10]

Stability studies of sustained release matrix tablets of Metformin

The sustained release tablets are packed in suitable packaging and stored under the following

conditions for a period as prescribed by ICH guidelines for accelerated studies.

(i) 25°C / 60% RH

(ii) 30°C / 75% RH

(iii) 40°C / 75% RH

The tablets were withdrawn after a period of 3 months and analyzed for physical

Characterization (Hardness, Friability, Disintegrations and Dissolution etc.) and drug

content.[11]

RESULTS AND DISCUSSION

Preparation of calibration curve of Metformin

50mg of Metformin active pharmaceutical ingredient (API) is dissolved in a 50 ml volumetric

flask with ethanol. Then it is made up to volume with pH 6.8 phosphate buffer. From this

solution 1ml is taken and diluted to 10 ml with pH 6.8 in a 10 ml volumetric flask. From this


639


stock solution 0.5ml, 0.75ml, 1ml, 1.25ml, 1.5ml, of solution is taken in different volumetric

flasks and volume made up to 10 ml with pH 6.8 phosphate buffer. Absorbance is measured

at 238nm using Beer’s range (3-30 mcg/ml).

Fourier Transforms Infra Red Spectroscopy

Fourier-transform infrared (FTIR) spectroscopy was performed on each of the samples to

determine the structure of the organic compounds and to identify the presence of specific

functional groups within a sample. Furthermore, drug-polymer interactions were examined

using the resulting spectra. Spectra are obtained by passing infrared radiation through a

sample and determining what fraction of incident radiation is absorbed at a particular energy.

The energy of a peak in the spectrum corresponds to the frequency of vibration of part of the

sample compound.

Fig. 1: Ftir Spectra of Pure Drug Metformine.


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Fig. 2: Ftir Spectra of Hpmce5.

C:\OPUS_7.0.122\MEAS\HPMC K100.0 HPMC K100 7/18/2013 8:28:25 PM

3728.3

4

3439.6

5

2976.9

8

2888.0

02833.5

5 2312.7

0

1639.2

4

1451.9

5

1374.1

3

1313.9

4

1047.7

1

942.6

3

100015002000250030003500

Wavenumber cm-1

70

75

80

85

90

Tra

nsm

itta

nce [

%]

Fig 3. Ftir Spectra of Hpmck100.


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C:\OPUS_7.0.122\MEAS\EUDRAGIT.0 EUDRAGIT 7/18/2013 8:15:32 PM

3728

.32

3643

.59

3439

.83

2977

.02

2887

.53

2833

.16

2350

.21

2312

.09 16

39.0

4

1451

.92

1374

.67

1048

.97

942.

64

100015002000250030003500

Wavenumber cm-1

7580

8590

Tran

smitt

ance

[%]

Fig. 4: Ftir Spectra of Eudragit.

Fig. 5: Ftir Spectra of Optimised F9 Formulation.


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FTIR studies revealed that there is no interactions of excipients with Metformin. All the

absorption bands of the functional groups are within the range.

Table no 2: Interpretation of pure drug.

Functional Groups Frequency Observed Frequency

Methyl group 2872 cm-1

2889 cm-1

Pyridine 1622 cm-1

1642 cm-1

Aryl nitro compound 828 cm-1

837 cm-1

Table 3: Precompression Parameters.

The flow properties of the prepared blend were studied with given IP limits. The hausner’s

ratio was found to be excellent and passable in the range of 1.09-1.33 and compressibility

index in range of 8.6%-25%.

POST COMPRESSION PARAMETERS

Table 4: Post Compression Parameters.

FORMULA THICKNESS

(mm)

HARDNESS

(Kg/cm2)

%FRIABILITY

(w/w)

WEIGHT

VARIATION

(mg)

DRUG

CONTENT

(%)

F1 3.2±0.05 4.0±0.1 0.24±0.03 201.8±1.02 99.47±0.3

F2 3.1±0.02 5.5±0.1 0.07±0.02 203.8±1.12 98.89±0.5

F3 3.3±0.07 5.0±0.4 0.19±0.03 202.4±1.02 98.35±0.9

F4 3.2±0.03 4.5±0.2 0.07±0.01 202.1±1.15 97.12±0.5

F5 3.2±0.04 5.3±0.1 0.16±0.04 199.1±1.13 97.56±0.6

F6 3.1±0.02 5.4±0.3 0.07±0.03 198.1±1.15 98.35±0.3

F7 3.3±0.02 5.5±0.4 0.07±0.01 198.6±1.15 98.40±0.4

F8 3.2±0.05 5.4±0.2 0.24±0.02 197.6±1.15 97.84±0.3

F9 3.2±0.03 5.7±0.2 0.04±0.01 201.6±1.15 99.64±0.1

The hardness was constantly maintained between 4-6 kg/cm2 for all formulations during

compression. Shows the friability values all the formulations. The results indicated that the %

FORMULATIONS

ANGLE

OF

REPOSE(0)

BULK

DENSITY

(gm/ml)

TAPPED

DENSITY

(gm/ml)

CARR’S

INDEX

%

HAUSNER’S

RATIO

F1 26.6±0.2 0.555±0.1 0.714±0.1 22.22 1.285

F2 26.0±0.3 0.384±0.4 0.434±0.3 11.53 1.130

F3 26.7±0.4 0.416±0.2 0.476±0.3 12.50 1.142

F4 25.1±0.1 0.476±0.3 0.526±0.2 9.52 1.105

F5 28.3±0.4 0.625±0.1 0.833±0.1 25.00 1.333

F6 24.4±0.4 0.521±0.3 0.631±0.3 17.39 1.121

F7 27.1±0.1 0.588±0.3 0.666±0.4 11.76 1.333

F8 25.2±0.1 0.277±0.2 0.312±0.2 11.11 1.133

F9 23.2±0.2 0.434±0.2 0.476±0.3 8.695 1.095


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friability was between the range. The low values of friability indicate that tablets were

mechanically hard enough. The drug content of tablets ranged between 97-100. The weight

variation of all formulations was in the range of 197.61.15-203.81.12.

In vitro Dissolution studies

The dissolution conditions used for studying the drug release from Dosage form:

Apparatus : USP apparatus II (Paddle)

Agitation speed (rpm) : 100rpm

Medium : 6.8pH phosphate buffer

Volume : 900 ml

Temperature : 37.0 ± 0.5 C

Time : 1, 4, 8, 12,16 and 20 hrs.

Wavelength : 238nm

The samples were withdrawn at predetermined time points and were analyzed

spectrophotometrically at 238nm.

Table 5: Results of percentage cumulative drug release profile for F1-F9 formulations.

TIME (Hrs) F1 F2 F3 F4 F5 F6 F7 F8 F9

1 20.45

±0.51

15.0

±0.46

16.36

±0.31

19.77

±0.42

18.40

±0.35

14.61

±0.58

16.70

±0.15

15.20

±0.25

14.27

±0.12

2 44.65

±0.23

26.59

±0.32

28.63

±0.26

42.27

±0.23

32.04

±0.54

30.52

±0.75

31.70

±0.50

28.63

±0.32

25.5 ±

0.31

4 66.13

±0.33

42.61

±0.62

40.22

±0.53

61.36

±0.32

50.93

±0.34

46.06

±0.25

48.06

±0.55

45.18

±0.63

39.36

±0.25

8 82.5

±0.21

61.02

±0.22

53.86

±0.23

82.84

±0.25

75.22

±0.44

62.34

±0.65

62.04

±0.51

60.09

±0.34

57.04

±0.63

12 99.20

±0.36

82.84

±0.52

73.29

±0.65

97.84

±0.35

80.52

±0.42

80.02

±0.51

83.86

±0.15

76.43

±0.62

74.38

±0.32

16 98.52

±0.24

85.56

±0.65

87.84

±0.33

85.45

±0.23

98.18

±0.32

83.52

±0.52

81.11

±0.11

20 98.18

±0.21

97.84

±0.31

88.29

±0.51

97.84

±0.61

95.0

±0.21

24 97.18

±0.23

99.20

±0.31

The prepared tablets were subjected to dissolution studies in order to know the amount of

drug released and the results of percentage drug release are shown in table 16. As the

concentration of polymer increased, the drug release decreased. In vitro drug release studies

revealed that release of Nifedipine from different formulations varies with characteristics and


644


composition of matrix forming polymers. The release rate increased with decreasing

concentration of HPMC. These findings are in compliance with the ability of HPMC to form

complex matrix network which leads to delay in release of drug from device. Eudragit is

hydrophobic polymer which delays the drug release in F7 to F9 formulations.

Percentage cummulative drug release profile of F1-F9 formulations

Figure-6: Percentage cummulative drug release profile of F1-F9 formulations.

The above figure shows the in vitro release profiles of Metformine sustained release matrix

tablets of formulations F1-F9. Effect of different polymers on the release profile of

Metformine was studied. In formulations F1, F2, F3 different concentrations of HPMCE5

were used. The release of the drug from the tablet was up to 20 hours only, so these polymers

(with in this concentrations) not having the capacity to extend the release up to 24 hours.

In formulations F4, F5, F6 different concentrations of HPMCK100 were used. The release of

the drug from the tablet was up to 24 hours these polymers (with in this concentrations)

having the capacity to extend the release up to 24 hours.

In formulations F7, F8, F9 different concentrations of Eudragit were used. The release of the

drug from the tablet was up to 24 hours these polymers (with in this concentrations) having

the capacity to extend the release up to 24 hours.

4.7. Release kinetics and mechanism

To know the release mechanism and kinetics of Valsartan optimized formulations (F14) were

attempted to fit into mathematical models and n, r2 values for zero order, First order, Higuchi


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and Peppas models were represented in Table 20. The peppas model is widely used, when the

release mechanism is not well known or more than one type of release could be involved.

Table 6: Kinetic modeling of F1-F9 formulations.

Formulation

code

Zero

Order

(R2)

First

Order

(R2)

Higuchi

(R2)

Hixon

Crowell

(R2)

Korsemeyer Peppas

R2

n

F1 0.873 0.9161 0.9785 0.9771 0.9345 0.607

F2 0.8856 0.9683 0.9872 0.9695 0.9967 0.664

F3 0.9565 0.8778 0.992 0.966 0.991 0.578

F4 0.8927 0.9689 0.9846 0.9902 0.9464 0.624

F5 0.8652 0.9526 0.9779 0.9689 0.9673 0.544

F6 0.8782 0.9292 0.9816 0.9711 0.957 0.571

F7 0.9442 0.8917 0.9906 0.9689 0.9802 0.5957

F8 0.9215 0.9211 0.9916 0.9747 0.9803 0.5957

F9 0.9313 0.9498 0.9827 0.9874 0.9887 0.4357

Figure-7: First order plot of optimized F9 formulation.

Figure-8: Zero order plot of optimized F9 formulation.


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Figure-9: Higuchi plot of optimized F9 formulation.

Figure-10: Hixon Crowell plot of optimized F9 formulation.

Figure-11: Kores Meyer Peppas plot of optimized F9 formulation.


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Stability Studies

There was no significant change in physical and chemical properties of the tablets of

formulation F-9 after 3 Months. Parameters quantified at various time intervals were shown.

Table-7: Stability study data of optimized F9 formulation.

Formulation

Code Parameters

Initial %

CDR

1st Month

% CDR

2nd

Month

% CDR

3rd

Month

% CDR

F9

250C/60%RH

99.20

99.18 99.17 99.15

300C/75% RH 99.18 99.17 99.15

400C/75% RH 99.18 99.17 99.15

CONCLUSION

Metfortmin is used in Diabetic. In the present work sustained release tablet was successfully

formulated by using different polymers by wet granulation method. From the in vitro

dissolution analysis the following conclusions are drawn. Formulation batches with HPMC

K100 and EUDRAGIT showed better release than the HPMCE5. It was observed that by

ncreasing the viscosity of polymer a retarding effect on the release from the polymer matrix.

From the dissolution profile modeling it was found that the optimized formulation F9

followed first order kinetics. It also followed Koresmayer Peppas model. Since n>0.5 non

Fickian or anomalous diffusion behavior is generally observed. When the stability results of

best formulae was studied at 400

C and 75% RH for 3 months were compared with their

initial results it was found that there was no significant difference in hardness, friability, drug

content and drug release of optimized formulation.

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