Design, Development and Evaluation of Enteric Coated Tablets of Glimepiride

 

Rutuja S. Shah, Rutuja R. Shah, Manoj M. Nitalikar, Chandrakant S. Magdum

Department of Pharmaceutics, Rajarambapu College of Pharmacy,

Kasegaon, Tal- Walwa, Dist-Sangli-415404

*Corresponding Author E-mail: rutujashah557422@gmail.com

 

ABSTRACT:

The main objective of work was to develop pharmaceutically elegant and stable enteric coated tablet formulation for highly unstable drug in acidic environment using pH dependent polymer. Development of Enteric coated tablets were done for Controlled Release of drug. Coating was done by using methacrylic acid copolymer (Eudragit L 100). Characterization of Drug and Excipients was carried out including compatibility studies of drug and excipients. Solid dispersion of glimepiride was formulated using carrier PEG20000 was prepared by the Fusion method. Evaluation of Solid was carried out using suitable parameters like solubility, percentage yield, drug content, in-vitro drug release, FTIR and SEM. Further granules were formulated from the optimized batch of formulated SDs. Pre-compression studies of granules were carried out like Tapped density, Bulk density, Angle of repose, etc. of Granules. Four different batches were formulated of tablets. The tablets were evaluated for various parameters like weight variation, hardness, friability, thickness, disintegration and in-vitro drug release. For Dissolution studies, 7.4 phosphate buffer media was used. The optimized batch of tablets was further subjected to enteric coating using pan coating. Eudragit L100 was used as coating polymer and isopropyl alcohol, acetone and triethyl citrate were used as vehicle in solution. Eosine was used as colorant. The coating solution was prepared in three different concentrations viz., 1%, 2%, and 3%. The coating solution was sprayed on tablets using spray gun and after drying the tablets were evaluated for different parameters like in-vitro drug release and disintegration, Hardness, thickness, friability, drug content and weight variation. Here, as the tablet was enteric coated, 2 dissolution medias were used 7.4 phosphate buffer and 0.1 N HCl. Further Stability studies were carried out of optimized batch. Results obtained after the stability studies confirmed that prepared enteric coated tablets were stable at applied conditions and were complied with the initial results.

 

KEY WORDS: Solid dispersion, Tablets, Enteric coating, Eudragit L100, Stability studies.

 

 

 


INTRODUCTION:

Enteric coated tablets are unit solid dosage forms meant for oral administration and are designed to bypass the stomach and release the drug in small intestine.

 

An enteric coating is a barrier which controls the location of oral medication in the digestive system where it is absorbed. The enteric coated polymers remain unionized at low pH, therefore it remains insoluble. As the pH increases in the GIT, the acidic functional groups are capable of ionisation, in the intestinal fluid the polymer swells or becomes soluble.1 Main reasons for preparing enteric coating tablets may be enumerated as follows:

 

-          To protect the stomach wall from the harmful effect of the drug in a dosage form.

-          To prevent degradation of the drug by gastric contents.

-           To release the drugs with site-specific absorption in the intestine.2

 

Diabetes is an intestinal disorder; hence site-specific release of drug is necessary. Enteric coating prevents release of medication before it reaches the small intestine.1 Glimepiride is used for treatment of type 2 diabetes. Glimepiride belong to class II of the biopharmaceutical classification system showing poor solubility and high permeability. Glimepiride is an oral blood glucose lowering drug belonging to the second generation Sulphonylurea (SU) class that is currently available for treating hyperglycemia in Non-Insulin Dependent Diabetes Mellitus (NIDDM).3 Glimepiride belongs to Sulphonylurea primarily activating Sulfonylurea receptors (SURs) on pancreatic cell- membrane. When SUs are bound to SURs, ATP-sensitive potassium channels close, thus resulting in an augmented trans-membrane calcium flux and insulin release from cells. Among SUs, only glimepiride is internalized in the cell and is able to stimulate both first and second phases of insulin secretion.4

 

Solid Dispersion technique has often proved to be the most successful in improving the dissolution and bioavailability of poorly soluble active pharmaceutical ingredients because it is simple, economical and more advantageous.5 Therefore solubility of glimepiride drug will be enhanced by Solid Dispersion technique and further enteric coated tablet will be formulated by using Pan Coater. Pan coating is a technique in which the core material is coated with the drug substance following a secondary coating process in which the release controlling polymer material is introduced.6

 

MATERIALS AND METHODS:

Materials:-

The Glimepiride (GMP) was supplied as a gift sample by USV chemicals, Lote. All other chemicals used were of analytical reagent grade.

 

Methodology: -

1. Formulation of Solid Dispersion by using Fusion or Melting Method:

a. Preparation of Solid dispersion of Glimepiride:

The SDs of glimepiride in PEG 20000 containing four different weight ratios (1:1, 1:3, 1:5, 1:7) (glimepiride: PEG 20000) and denoted as SD1, SD2, SD3 and SD4 respectively, were prepared by melting method. In this method, glimepiride was added to the molten PEG 20000 at temperature 56-60 ºC. It was thoroughly mixed with glass rod; the mixture was rapidly cooled in an ice bath, for 5 minutes. The solidified mixture was then powdered in a mortar was sieved through a 100-mesh screen, and stored in a screw-cap vial, at room temperature. The composition of solid dispersion is shown in table no.1.

 

Table No. 1. Formulation of SDs

Ingredients

SD1(1:1)

SD2(1:3)

SD3(1:5)

SD4(1:7)

Glimepiride(mg)

8

8

8

8

PEG 20000(mg)

8

24

40

56

 

b. Characterization of Solid Dispersion:

a.        Percentage practical yield:

Percentage practical yields were calculated to know about percent yield or efficiency of the method, thus it helps in selection of appropriate method of production. Solid dispersions were collected and weighed to determine practical yield (PY) from the following equation:

Equation 6.1

 

b.        Determination of % Drug Content (7):

Solid dispersions equivalent to 10 mg of Glimepiride were weighed accurately and dissolved in suitable quantity of solvent mixture methanol. The drug content was determined at 252 nm by UV spectrophotometer. Each sample analyzed in triplicate. The percent drug content was determined using the following equation:

Equation 6.2

 

c.        Fourier Transform Infrared Spectrometry (FTIR):

Fourier-transform infrared(FT-IR) spectra were obtained by using an FTIR spectrometer-4600 (Jasco, Japan). The samples (glimepiride or SDs) were previously ground. They were placed in sample holder. Scans were obtained at a resolution from 4000 to 650 cm-1.(8)

 

d.        Scanning Electron Microscopy (SEM):

SEM of solid dispersion was carried out using JSM 6360, JEOL India Pvt. Ltd. to study the morphological characteristics of the optimized batch of solid dispersion.

 

e.        In-vitro dissolution studies of Glimepiride solid dispersion systems (9):

Accurately weighed preparations equivalent to 10 mg of GMP were added to 900 ml of dissolution media (7.4 phosphate buffer) in a USP dissolution apparatus II (Paddle type) and stirred at a speed of 50 rpm at 37±0.5oC. Ten millilitre aliquots were withdrawn at 10, 20, 30, 40, 50, 60 minutes and replaced by 10ml of fresh dissolution media (37 o c). The collected samples were analyzed after suitable dilution (if required) at λ max 252 nm using UV-visible spectrophotometer against the blank. Drug release studies were carried out in triplicate.

 

2. Formulation of Enteric Coating Glimepiride Tablets:

Table No.2 represents the compositions of the core tablet of Solid dispersion. Based on the superior dissolution profile of SD4 Batch of Solid dispersion particles in 7.4 pH buffer, Glimepiride solid dispersion with hydrophilic carrier ratio of 1:1 of PEG20000 was selected to incorporate in Enteric coated tablets. Avicel PH-101, Crospovidone were blended in a glass mortar followed by addition of Magnesium Stearate and talc as lubricant and glidant respectively. The resultant powder blend was then manually compressed under constant pressure using Rotray Press 8-Station Tablet punching machine into 500mg tablet using 13mm die.


 

Table No. 2 Composition of SDs containing core Tabets

Sr No.

Ingredients

Quanity (mg)

Role

F1

F2

F3

F4

1

SD

16

16

16

16

Drug + carrier

2

Crospovidone

160

130

100

70

Disintegrant/ binder

3

Avicel pH 101

294

324

354

384

binder

4

Talc

20

20

20

20

lubricant

5

Magnesium Sterate

10

10

10

10

glidant

 


Micrometric Evaluation of powder blend of SDs containing core tablets (5, 10)

a.        Angle of repose:

Angle of repose is defined as the maximum angle possible between the surface of pile of powder and horizontal plane. Angle of repose has been used as indirect method of quantifying powder flow ability. The grading of powder flow properties is shown in table no.2. Angle of repose for blend of each formulation was determined by fixed funnel method. The fixed funnel method employs a funnel that is secured with its tip at given height, h, which was kept 2 cm, above graph paper that was placed on a flat horizontal surface. With r, being the radius of base of conical pile, angle of repose can be determined using following equation:

 

…..Equation 6.3

Where; θ = Angle of repose

r = Radius of the base

h =Height from tip of funnel to the surface of graph paper.

 

Table No. 3 Grading of powder flow property according to angle of repose.

Angle of repose

Flow Property

<25

Excellent

25-30

Good

30-40

Passable

>40

Very poor

 

b.        Bulk density:

It is the ratio of mass to bulk volume. It is required to decide the appropriate packing of dosage forms. An accurately weighed 20 gm powder was allowed to flow in a fine stream into a graduated cylinder and final volume was noted. The bulk density was obtained by dividing the weight of the sample in grams by final volume in cm3and it was determined by equation given below:

        Equation 6.4

 

c.        Tapped density:

An accurately weighed 20 gm powder was allowed to flow in a fine stream into a graduated cylinder of a mechanical tapping device. The measuring cylinder was tapped for 100 times and final tapped volume was noted. The tapped density was obtained by dividing the weight of the sample in grams by final tapped volume in cm3and it was calculated by using equation given below:

        Equation 6.5

 

d.        Compressibility index:

It is also one of the simple methods to evaluate flow property of a powder by comparing the bulk density and tapped density. The percentage compressibility of a powder is a direct measure of the potential powder arch or bridge strength and stability. The grading of compressibility of powder according to carr’s index is shown in table no.3. It is also known as Carr’s index. It can be calculated by following equation:

Equation 6.6

 

 

Table No. 4 Grading of compressibility of powder according to Carr’s index

Carr’s Index

Flow Property

5-15

Excellent

12-16

Good

18-21

Fair to passable

23-35

Poor

33-38

Very Poor

 >40

Extremely Poor

 

e.        Hausner’s ratio:

Hausner found that the ratio of tapped density/bulk density was related to inter particle friction as such, and could be used to predict powder flow properties. He showed that the powder with low inter particle friction had ratio of approximately 1.2, whereas more cohesive less free flowing powders have ratio greater than 1.6. Hausner’s ratio of less than 1.25 indicates good flow properties of the powder blends or granules.

      Equation 6.7

 

b. Post compression study of prepared SDs Tablets (11, 12):

a.        Weight variation test:

The USP weight variation test was run by weighing 20 tablets individually, calculating the average weight, and comparing the individual tablet weights to the average. The tablets meet the USP test if no more than 2 tablets are outside the percentage limit and if no tablet differs by more than 2 times the percentage limit.

 

b.        Friability:

6 tablets were weighed and placed in the Roche friabilator test apparatus, the tablets were exposed to rolling and repeated shocks, resulting from free falls within the apparatus. After 100 revolutions, the tablets were de-dusted and weighted again. The friability was determined as the percentage loss in weight of the tablets. The loss of less than 1% in weight is generally considered acceptable. Percent friability was calculated as follows:

 Equation 6.8

 

c.        Hardness:

Hardness was measured using the Monsanto hardness tester. The tablet is compressed between the holding anvil and piston connected to a direct force reading gauge. The dial indicator remains at the reading where the tablet breaks and it returned to zero by depressing a reset button.

 

d.        Dimensions:

The thickness of the tablets was determined using a Vernier calliper. Three tablets from each batch were used and average values were calculated.

 

 

e.        Drug content studies (9):

The drug content in tablets were determined by randomly choosing ten tablets from all core tablets formulations and powdered using mortar and pestle. A quantity equivalent to 8 mg of Glimepiride it was weighed and dissolved in methanol (diluted if necessary), then absorbance was taken on 252 nm on (Shimadzu Corp., Japan) at wavelength 252 nm.

 

f.         In-vitro disintegration test:

The in-vitro disintegration time was determined using Disintegration Test Apparatus. This device uses six glass tubes that are three inches long, open at the top, and held against a 10-mesh screen at the bottom end of the basket rack assembly. To test for disintegration, one tablet was placed in each of the six tubes of apparatus and one disc was added to each tube. The basket rack assembly was positioned in pH 7.4 phosphate buffer at 37±2ºC. The time taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured in minutes.

 

g.       In-vitro dissolution test for tablet formulations:

The in-vitro dissolution studies for all the fabricated tablets were carried out using USP paddle method in 900 ml of phosphate buffer (pH 7.4) as dissolution media, maintained at 37±0.5ºC at 50 rpm. Ten milliliter aliquots were withdrawn at 15, 30, 45, 60, 75, 90, 105, 120 minutes and replaced by 10ml of fresh dissolution media (37ºC). The collected samples were analyzed after suitable dilution (if required) at 252 nm using UV-visible spectrophotometer against phosphate buffer (pH 7.4) as the blank. The release profile data were analyzed for cumulative percent dissolved at different time intervals.

 

3. Formulation for Coating Solution:

a. Preparation of Enteric Coated Solution:

Coating solution was prepared using material like Eudragit L100, TEC, IPA, Acetone and Eosin. Solution was prepared such that total 1%, 2% and 3% weight gain should take place in core tablet. Required quantities of polymer were dissolved in mixture of solvents of acetone and isopropyl alcohol and stirred with magnetic stirrer to get homogeneous coating solution. Triethyl citrate was added in above solution as plasticizer after getting homogeneous coating solution. Composition of Coating Solution is shown in Table No. 4 Coating Solution for Core Tablet:


Table No.5 Coating Solution for Core Tablet:

Sr No.

Ingredients

Quantity (for 30 tablets)

Role

E1 (1%) (g)

E2 (2%) (g)

E3 (3%) (g)

1

Eudragit L 100

0.950

1.425

1.900

Coating Agent

2

TEC

0.790

1.185

1.580

Plasticizer

3

IPA

0.400

0.400

0.400

Solvent

4

Acetone

50

50

50

Solvent

5

Eosine

q.s.

q.s.

q.s.

Colorant

 


b. Post compression study of prepared Enteric Coated Glimepiride Tablets:

a.        Weight variation test:

b.        Friability:

c.        Hardness:

d.        Dimensions:

e.        Drug content studies (9):

The drug content in tablets were determined by randomly choosing ten tablets from all core tablets formulations and powdered using mortar and pestle. A quantity equivalent to 8 mg of Glimepiride it was weighed and dissolved in methanol (diluted if necessary), then absorbance was taken on 252 nm on ( Shimadzu Corp., Japan) at wavelength 252 nm.

 

f.         In-vitro Disintegration Test (13):

Disintegration time was determined using the disintegration apparatus USP (Electrolab, Bangalore, India) in 0.1N HCl for 2 h and then in phosphate buffer pH 7.4 maintaining the temperature at 37 ±2°C. According to Indian Pharmacopoeia the conditions for enteric-coated tablets are:

 

·         All the six tablets tested should not disintegrate in 2 hours in 0.1N HCl and should not show any sign of cracks or swelling.

·         All the six tablets tested in 0.1N HCl for 2 hours should disintegrate within 60 min in phosphate buffer pH 7.4.

 

g.       In-vitro Drug Release Study:

Dissolution of the SD containing Glimepiride enteric coated tablets was determined using the USP type II apparatus at 37 ± 0.5°C with a paddle which rotated at 100 rpm. The dissolution medium was 0.1 N HC1 (900 ml) solution and phosphate buffer pH 7.4 (900 ml). The dissolution for all the formulations was carried out according to US Pharmacopoeia for 2 hours in 0.1N HCl and then media was changed into phosphate buffer pH 7.4 for further 2 hours. 10 ml samples were removed from the release medium, filtered and the concentration were determined by means of UV spectrophotometry at 252 nm. The same procedure was used in the stability studies for the evaluation of dissolution properties.

 

4. Accelerated stability study according to ICH Q1a (R2) guidelines:

The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, enabling recommended storage conditions, re-test periods and shelf-lives. Generally, the observation of the rate at which the product degrades under normal room temperature requires a long time. To avoid this undesirable delay, the principles of accelerated stability studies are adopted. For Accelerated stability study optimized batch selected. Forty tablets were wrapped in aluminium foil and were placed in amber colored glass container, stored at 40°C ± 2°C temperature with the relative humidity of 75%RH ± 5%RH. The samples were withdrawn after one-month period and evaluation was done for appearance, hardness, drug content and cumulative % drug release (9).

 

RESULT AND DISCUSSIONS:

1. Characterization of Solid Dispersion:

a.        Percentage Practical Yield:

Percentage practical yield were calculated to know about percent yield or efficiency of any method, thus it helps in selection of appropriate method of production. The results of percent practical yield studies are shown in Table No.6. The % Practical yield of the prepared solid dispersions by fusion method was found to be in the range of 55-90 %. The maximum yield was found 90 % in SD1 batch.

 

Table No. 6 % Practical Yield of SD by Fusion method

Sr No.

Batch No.

% Practical Yield

1

SD1

90±0.75

2

SD2

70±0.15

3

SD3

54.66±0.77

4

SD4

55±1.37

 

b.        Drug content:

The SDs compositions had drug content of 81.87- 88.59% of Glimepiride, suggesting that the Fusion method of SD was successful in achieving good encapsulation of the drug. Percent drug content of Glimepiride in solid dispersions was found to be increased in the (1:1) Drug: polymer ratio i.e. SD1 batch. The percent drug content values of Glimepiride in different solid dispersion batches are shown in Table No.7.

 

Table No. 7 Drug content of prepared SDs

Sr No.

Batch No.

% Drug Content

1

SD1

88.59±0.12

2

SD2

81.87±0.16

3

SD3

82.21±0.14

4

SD4

87.24±0.19

 

c.        Solubility Study of Pure drug and SD:

The mean of three consecutive readings of solubility of pure drug was found to be 0.0062mg/ml suggesting a strong need to enhance the solubility of drug. The solubility was increased in the formulated SD containing PEG20000. Notable increase in solubility was shown in ratio (1:1) of formulated SD i.e. SD1

 

Table No. 8 Solubility Studies

Solubility of Pure Drug(mg/ml)

Solubility of SD (mg/ml)

SD1

SD2

SD3

SD4

0.0062

0.322

0.242

0.221

0.156


d.        IR spectra of Glimepiride and PEG20000 (Solid Dispersion) of optimized batch:

 

Fig No.1 IR Spectra of Glimrpiride and PEG20000

 

Table No. 9 Comparative Dissolution Study of pure GMP and Formulated SDs

Sr no.

Time (mins)

Pure Drug

 % Cumulative Drug Release

SD1

SD2

SD3

SD4

1

10

21.45

15.35±2.29

5.25±1.73

-ve

4.27±1.98

2

20

23.59

30.34±1.77

13.34±1.10

-ve

12.37±1.11

3

30

27.06

44.49±0.53

23.33±0.32

-ve

31.5±0.30

4

40

28.80

57.78±0.48

38.39±0.84

-ve

47.25±0.46

5

50

30.35

67.65±7.49

40.45±1.41

-ve

65.25±1.04

6

60

29.97

82.44±36.38

44.52±1.32

-ve

77.62±1.89

 


 

The results revealed no considerable changes in the IR peaks of Glimepiride, when mixed with polymer PEG20000. These observations indicated the compatibility of PEG20000 with Glimepiride. The FTIR spectrum of PEG20000 and Glimepiride is in Fig. No.1. IR spectra indicated no well-defined interaction between the drug and polymer.

 

e.        In-vitro Dissolution Test:

The dissolution profiles were calculated and are shown in Table No.9. Compared with the pure powdered Drug, the presence of PEG20000 increased the dissolution of Glimepiride from the solid dispersions, which increases the dissolution rate.

 

The prepared solid dispersions SD1 and SD4 increase the dissolution rate up to % and %. It was evident that the pure drug exhibited a slow dissolution even after 60 minutes where the percentage of drug dissolved after 60 minutes only reached about % that could be related to the hydrophobicity, poor wettability and/or due to poor solubility which led to poor dissolution rate.

 

As general observations, the dissolution rate of Glimepiride from solid dispersion particles was higher than that of the pure drug. All solid dispersions showed enhanced dissolution rate compared to pure Glimepiride that might be due to the effect of hydrophilic carriers on drug wettability and dispersibility.

 

Among all the four batches of solid dispersion, batch SD1 showed the better dissolution profile in which ratio of hydrophilic polymer and Drug (1:1) was used. The combination of Glimepiride and PEG20000 in ratio of 1:1 has better dissolution profile than 1:7, 1:3 and 1:5 i.e. SD3 batch was failed as the %CDR readings obtained were negative. So, batch SD1 was taken to formulate enteric coated tablet of Glimepiride.

 

f.         Scanning Electron Microscopy of Batch SD1:

Scanning electron microscope (SEM) photomicrograph of the prepared Glimepiride solid dispersion is shown in Fig No. 2. All particles of Glimepiride were in sperical form and polymer particals were in flakes form. In SD the powder of GMP were dispersed in the polymer in the SD1 formulation. This stated that drug was thoroughly mixed with the polymer with loss of little spherical structure.

 


   

Fig No. 2 SEM images of: a) Pure PEG20000 b) Pure GMP c) SD1 (GMP: PEG20000) (1:1)

 

Table No. 10 Physical Parameters of formulation blends of all batches.

Sr No.

Batch

Bulk density(g/ml)

Tapped density(g/ml)

Angle of Repose(◦c)

Hausner’s ratio

Carr’s index (%)

1

F1

0.506±0.104

0.55±0.83

27.92±0.1

1.1±0.73

9.09±0.52

2

F2

0.52±0.64

0.59±0.57

26.56±0.22

1.13±0.93

11.86±0.14

3

F3

0.44±0.36

0.54±0.46

27.02±0.02

1.22±0.31

18.51±0.77

4

F4

0.50±0.6

0.57±0.5

25.70±0.3

1.14±0.45

12.28±0.90

 

Table No. 11 Post-compression Evaluation data of prepared SDs containing tablets of Glimepiride

Batch No.

Weight variation(mg)

Thickness(mm)

Friability (%)

Hardness (kg/cm2)

Disintegration Time (secs)

Drug Content (%)

F1

498.5±0.01

6.0±0.104

0.35±0.04

1.6±0.1

37±0.41

91.83±0.04

F2

499.5±0.00

6.2±0.14

0.39±2.80

1.52±0.47

21±0.72

93.87±0.14

F3

497.5±0.08

6.1±0.1

0.1±0.17

1.9±0.24

28±0.07

88.43±0.01

F4

499.5±0.01

5.8±0.05

0.37±0.06

1.6±0.1

33±0.38

89.79±0.06

 


 

2. Pre-compression Evaluation of tablet:

As per procedure noted in experimental part, the powder mixture was evaluated for angle of repose, bulk density, tapped density, Carr’s compressibility index, Hausner’s ratio and angle of repose. The results angle of repose and compressibility indicated that the flowability of blend is significantly good. The observations are as shown in table No.10.

 

3. Post compression evaluation of Enteric coated tablet:

All formulations were tested for physical parameters like hardness, thickness, weight variation, friability, thickness and disintegration time (Fig No. 3) found to be within the pharmacopoeial limits. The results of the tests were tabulated in (Table No. 11). All formulations show good compressibility. The formulated tablets were elegant and almost uniform thickness. Thickness of core tablets of Glimepiride was in the range of 5.8 to 6.2 mm. The weight variation of tablets of all batches was in the range of 470 mg to 510 mg. The range of hardness was found to be 1.6 to 2.2 kg/cm2. All the batches show less friability. In all formulation hardness test indicated good mechanical strength. In all the batches, friability was less than 1% which indicated good mechanical resistance and can withstand rigors of transportation and handling. The drug content of all the formulations was determined and was found to be within the permissible limit.

Disintegration Time:

Disintegration time is in between 21 to 37 seconds the results indicate that disintegration time of tablets is within 1minute. It was observed that the disintegrant power of crospovidone is more. It is observed that tablets with disintegration time decreased with decrease level of crospovidone. Tablets rapidly disintegrate with decreasing concentration of crospovidone. Thus these results suggest that disintegration time can be reduced by using wicking types of superdisintegrants.(fig no. 3)

 

Fig No.3 Depicts the disintegration behavior of the prepared tablets.

 

In-vitro dissolution studies:

The cumulative % of drug release of batch F1 prepared by direct compression showed 88.75% drug released at 60 min, F2 showed 90% drug released at 60 min, F3 showed 84.24. % drug released at 60 min, F4 showed 60.83% drug released at 60 min. Results of Cumulative % drug release of all the batches were tabulated in (table No.12) and graphically represented in (fig No.4)


 

Table No. 12 % Cumulative Drug Release

Sr

No.

Time

(secs)

 % Cumulative Drug Release

F1

F2

F3

F4

1

15

20.25±1.94

57.3±0.94

18.58±2.03

3.30±1.5

2

30

34.87±1.33

78.75±0.1

31.30±0.88

8.90±1.22

3

45

58.62±0.28

81±0.08

35.63±0.66

9.92±1.12

4

60

65.37±0.41

84.37±0.6

40.72±0.4

11.96±1.01

5

75

78.75±0.58

85.5±0.14

55.99±1.09

30.79±0.43

6

90

87.75±0.97

87.75±0.22

60.83±0.60

35.37±0.61

7

105

88.31±1.14

88.87±0.26

73.55±2.19

49.63±1.60

8

120

88.87±0.13

90±0.10

84.24±1.84

60.83±2.37

 

Table No. 13 Evaluation study of Formulated Enteric Coating Tablets

Batch No.

Weight variation (mg)

Thickness (mm)

Friability (%)

Hardness (kg/cm2)

Drug Content (%)

E1

509.25±0.03

6.26±0.67

0.26±0.68

2.7±0.11

91.83±0.02

E2

500.55±0.18

6.5±0.03

0.196±0.44

2.9±0.18

93.87±0.21

E3

514.1±0.15

6.23±0.02

0.306±0.05

1.6±0.29

88.43±1.62

 


 

Fig No. 4 Graphical representation of cumulative % drug release of tablets.

 

4. Evaluation of Controlled Release Enteric coating GMP Tablets:

a.        Evaluation of enteric coating tablets:

All formulations were tested for physical parameters like hardness, thickness, weight variation, friability, thickness and disintegration time found to be within the pharmacopoeial limits. The results of the tests were tabulated in (Table No.13 and Table No. 14). All formulations show good compressibility. The formulated tablets were elegant and almost uniform thickness. Thickness of core tablets of Glimepiride was in the range of 6.2 to 6.56 mm. The weight variation of tablets of all batches was in the range of 509 mg to 514 mg. The range of hardness was found to be 1.6 to 2.9 kg/cm2. All the batches show less friability. In all formulation hardness test indicated good mechanical strength. In all the batches, friability was less than 1% which indicated good mechanical resistance and can withstand rigors of transportation and handling. The drug content of all the formulations was determined and was found to be within the permissible limit.

b.        In-vitro Disintegration Test:

The tablets of batch E1 and E2 remained intact during the period of 2hrs when placed in 0.1N HCl and showed disintegration at 135 and 128 min after they were transferred in 7.4 pH Phosphate buffer. E2 showed fast disintegration as compared to E1. E3 batch got failed as the tablets from batch got disintegrated in 0.1N HCl medium. Therefore, further in-vitro studies E1 and E2 batches were done.

 

Table No. 14 Disintegration Tests

Sr No.

Medium

Time

(Mins)

Batch No.

E1

E2

E3

1

0.1N HCl

30

60

90

120

Intact tablet

Intact tablet

46±1.62

2

7.4 pH phosphate buffer

-

135±

3.25

128±

2.67

-

 

c.        In-vitro Dissolution Study:

Table No. 15 In-vitro Drug Release

Sr

No.

Time

% cumulative Drug Release

Medium

E1

E2

1

2

3

4

5

0

30

60

90

120

0

0

0

0

0

0

0

0

0

0

 

 0.1N HCl

6

135

3.37±2.15

61.87±0.73

 

 

.4 pH phosphate buffer

7

150

15.75±1.49

75.37±0.20

8

165

34.87±0.46

72±0.11

9

180

41.62±0.10

82.12±0.05

10

195

55.12±0.16

85.5±0.19

11

210

59.62±0.85

87.75±0.27

12

225

66.37±1.21

89.59±0.35

13

240

72±1.52

91.12±0.41

 

During the dissolution studies both E1 and E2 batch tablets remained intact in the 0.1N HCl for 2hrs.Further dissolution studies were carried out in 7.4 pH phosphate buffer for 2hrs. The cumulative % of drug release of batch E1 prepared by 1% weight gain coating solution showed 72% drug released at 240 min, 2% wt gain i.e. E2 showed 91.12% drug released at 240 min, F3 drug release at 46 mi. Therefore, E3 batch was failed for further dissolution studies. Results of Cumulative % drug release of E1 and E2 the batches showed controlled Released of drug. As E2 showed 91.12% drug release E2 was confirmed as optimised batch. (fig No.5) and (table no. 15)

 

5. Stability study of optimized formulation:

During the stability studies, no change in color was found in tablet formulation. From results, it was observed that there were no significant changes in hardness, appearance, drug content as well as percent drug release. Therefore, no evidence of degradation of drug was observed. All the values of evaluation after stability are tabulated in (Table No.16) and drug release study is shown in (Table No. 17). The optimized E2 formulation is evaluated for in-vitro drug release studies; the results (Table No.16) indicated that there was no significant change in in-vitro drug release studies which is similar to the formulations under optimum conditions.


 

Fig No.5 In-vitro Drug Release

 

Table No. 16 Result of Stability Studies of optimised batch of Enteric coated tablet:

Period (days)

Weight variation (mg)

Thickness (mm)

Friability

(%)

Hardness

(kg/cm2)

Disintegration

Time (mins)

Drug

Content (%)

Before Stability study

500.55±

0.18

6.2±

0.03

0.196±

0.44

2.9±

0.18

Intact tablet within 2hrs (0.1 N HCl)

93.87±

0.21

At 128 min (7.4 pH phosphate buffer)

After 30 days

500.25±

0.45

6.42±

0.02

0.19±

0.40

2.94±

0.17

Intact tablet within 2hrs (0.1 N HCl)

93.77±

0.22

At 122 min (7.4 pH phosphate buffer)

After 60 days

500.15±

0.58

6.40±

0.023

0.192±

0.48

2.80±

0.25

Intact tablet within 2hrs (0.1 N HCl)

91.47±

0.46

At 116 min (7.4 pH phosphate buffer)

After 90 days

500.01±

0.69

6.38±

0.035

0.195±

0.45

2.78±

0.34

Intact tablet within 2hrs (0.1 N HCl)

93.45±

0.31

At 125 min (7.4 pH phosphate buffer)

 

Table No. 17.16 % Cumulative drug Release of optimised batch during Stability Study:

Sr No.

Time

% cumulative Drug Release

Medium

Before stability study

After 30 days

After 60 days

After 90 days

1

0

0

0

0

0

 

 

 

0.1N HCl

2

30

0

0

0

0

3

60

0

0

0

0

4

90

0

0

0

0

5

120

0

0

0

0

6

135

61.87±0.73

56.50±0.91

62.42±0.68

61.51±0.73

 

 

 

7.4 pH phosphate buffer

7

150

75.37±0.20

61.45±0.70

68.54±0.60

69.14±0.61

8

165

72±0.11

69.72±0.61

74.04±0.53

72.14±0.13

9

180

82.12±0.05

77.41±0.55

79.51±0.47

79.54±0.55

10

195

85.5±0.19

81.32±0.41

84.14±0.35

85.21±0.25

11

210

87.59±0.27

84.14±0.32

88.38±0.31

89.28±0.45

12

225

89.59±0.35

86.73±0.22

91.21±0.25

91.54±0.23

13

240

91.12±0.41

88.48±0.10

93.32±0.09

93.04±0.12


CONCLUSION:

This study demonstrated the possibility of improving Glimepiride solubility and dissolution performance by the formulation of solid dispersions by Melting or Fusion method using hydrophilic polymer. The melting method for preparing solid dispersions was found to be satisfactory as it produced good product with high drug content. From FTIR spectroscopy, it was concluded that there was no well-defined interaction between Glimepiride and PEG20000, since no significant new peak could be observed. From solubility study, it can be concluded that the solubilization may be enhanced due complexation formed with the carrier PEG20000 led to the enhancement of the dissolution rate. From the SD, tablets were formulated, and all pre-and post-compression parameters were studied. The in-vitro studies carried out for tablets concluded that the there is remarkable increase in dissolution profile when compared with marketed plain Glimepiride tablet. Enteric coating was done to obtain the delayed release effects. The in-vitro studies for entric coating were done in 2 medium. Firstly, Enteric coated tablets were placed in 0.1N HCl for 2hrs and then in 7.4 pH Phosphate Buffer solution for 2 hrs. The tablets remained intact in HCl medium for 2hrs and started dissolving when placed in phosphate buffer. Due to coating the formulated tablets, the in-vitro results obtained, concluded that the controlled release of drug can be obtained from formulated SDs containing tablets of Glimepiride. Stability Studies concluded that the formulations were found to be stable under various conditions.

 

ACKNOWLEDGEMENTS:

The authors are thankful to Dr. C. S. Magdum; Principal and Dr. S. K. Mohite; Vice- Principal for providing research facilities necessary for the research work.

 

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Received on 20.10.2016          Accepted on 27.11.2016        

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2017; 7(3): 155-164.

DOI:  10.5958/2231-5691.2017.00024.7