Formulation and evalution of sustained release matrix tablets

FORMULATION AND EVALUTION OF SUSTAINED RELEASE MATRIX TABLETS

OF GLICLAZIDE

Santhosh Kotagiri

SCOPS

Department of Pharmaceutics 1

Contents;

IntroductionAim & ObjectiveList of materials and EquipmentDrug and Excipient profilesMethods usedResults and DiscussionSummary


Sustained release drug:sustained release as “Any dosage form that provide medication over an

extended time” and controlled release as “Any dosage form which is able to provide some actual

therapeutic control

Advantages of SR Drugs: Improved patient convenience and compliance due to less frequent drug

administration. Reduction in fluctuation in steady-state levels and therefore better control

of disease condition and reduced intensity of local or systemic side effects. Increased safety margin of high potency drugs due to better control of

plasma levels. Maximum utilization of drug enabling reduction in total amount of dose

administered. Reduction in health care costs through improved therapy, shorter

treatment period, less frequency of dosing and reduction in personnel time to dispense, administer and monitor patients


Disadvantages of SR Drugs:

Decreased systemic availability in comparison to immediate release conventional dosage forms; this may be due to incomplete release, increased first-pass metabolism, increased instability, insufficient residence time for complete release, site-specific absorption, pH-depent solubility, etc.

Poor in vitro-in vivo correlation. Possibility of dose dumping due to food, physiologic or formulation

variables or chewing or grinding of oral formulations by the patient and thus, increased risk of toxicity

Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions.

Higher cost of formulation


Diabetes mellitus:

Diabetes mellitus is a chronic metabolic disorder characterized by a high blood glucose concentration-hyperglycemia (fasting plasma glucose > 7.0 mmol/l, or plasma glucose > 11.1 mmol/l 2 hours after a meal)-caused by insulin deficiency, often combined with insulin resistance.

POLYMERS USED IN SR DRUG DELIVERY SYSTEMS:

Bio-degradable polymers: Alginates, Guar gum, Chitosan, Gelatin Bio-absorbable polymers: Polyethylene glycol and polyvinylpyrrolidone Bio-nondegradable polymers: Hydroxy propyl methyl cellulose


AIM & OBJECTIVE:

One tablet of Diamicron (Gliclazide) 80mg is comparable to One tablet of Diamicron30mg MR, a product of innovator.

To reduce side effects and to prevent fluctuations in concentrations between dosages.

IR tablets are having the dose of 80mg. To sustain the release and maintain the therapeutic conc. by reducing the dose to 30mg by MR.

To formulate and evaluate matrix tablets of Gliclazide to sustain the release of drug for 20 hrs.

Evaluation of optimized tablets in comparison to innovator’s product To perform a bioequivalence study of the optimized batch of

Gliclazide Sustained Release tablet and innovator’s product.


LIST OF MATERIALS AND EQUIPMENTS

Material Source

Gliclazide Bal Pharma Ltd., Bangalore.

Dibasic Calcium Phosphate dihydrate Rhodia, Mumbai.

Magnesium stearate Merck, Mumbai.

HPMC K4M Colorcon, Asia, Pvt. Ltd., Goa, India.

HPMC K100LV Colorcon, Asia, Pvt. Ltd., Goa, India.

Polyvinyl pyrrolidone BASF, Mumbai.

Poloxamer 188 BASF, Mumbai.

Collodial silicone dioxide Deggusa, Mumbai.


Equipment Suppliers

16 station Compression Machine Cadmach Machinery, Ahmedabad.

Balance Mettler Toledo, Germany.

Hardness Tester Pharma test, Ahmedabad.

Dissolution Apparatus, USP Electrolab, Mumbai.

Karl Fischer Instrument 701 KF titrino, Metrohm. Germany.

Rapid Mixing Granulator General Mechanical Industries, Mumbai.

UV-Visible Spectrophotomter Varian Cary C50 Conc, Germany.

Friability Tester Electrolab, Mumbai.

Sonicator Bandelin Electronic, Germany

Tap Density Tester (USP) Electrolab, Mumbai.

Vernier Calipers Mitutoyo, Japan.


DRUG PROFILE Synonym : Gliclazidum Chemical name : N-[[(Hexahydrocyclopenta[c]pyrrol-2(1H)-yl) amino] carbonyl]-4-

methylbenzenesulfonamide. Empirical formula : C15H21N3O3S Molecular weight: 323.4g/mol. Melting point : 163oC to 165°C Half-life: 6 to 14 h Bioavailability: About 79 to 100% Dissociation Constant: pKa 6.6

Chemical Structure

Mechanism of action:primary effect is to potentiate glucose-stimulated insulin release from functioning pancreatic islet β-cells.


EXCIPENTS

HYPROMELLOSE:Chemical name: Cellulose hydroxypropyl methyl ether

Povidone: Chemical Name: 1-Ethenyl-2-pyrrolidinone homopolymer

Poloxamer:

Magnesium stearateChemical name :Octadecanoic acid magnesium salt

Colloidal silicon dioxide:SiO2


METHODS USED :

1. Slugging method

All the ingredients were screened through sieve no. 30

Except lubricant all the ingredients were thoroughly blended in a blender for 5min

First the mixture was compressed using 23mm flat faced punch on 16 stages rotary tablet compress machine.

The above slugs were deslugged by using hammer and the deslugged material was passed through sieve no.30.

The granules which were passed through the sieve no.30 were then passed through sieve no.60.

The sieve no.60 passed granules were reslugged, finally the yield was 70:30 (70% granules and 30% fines), the above obtained granules were lubricated with magnesium stearate for 2min.

The above lubricated blend was compressed using 9.8X4.3mm caplet shaped punch.


Sl.no.Ingredients (mg)

Formulation Code F1 F2 F3

Intragranulation

1 Gliclazide 30.00 30.00 30.00

2 DCP(Di-Tab) 89.52 91.12 87.92

3 Aerosil-200 3.20 3.20 3.20

4 HPMC K4M 3.20 ….. …..

5 HPMC K100LV 32.00 33.60 36.80

6 Magnesium stearate 0.96 0.96 0.96

Extragranulation


Total wt of Tablet 160.00 160.00 160.00


Formulations with Poloxamer as wetting agent:

Sifting dry mixing: Weighed quantities of Gliclazide, Dibasic calcium

phosphate dehydrate (Di-Tab) and Colloidal Silicone Dioxide were mixed and sifted through #30 seive.

Granulation: The step 1a blend was granulated using poloxamer solution

as a granulating fluid. The obtained granules were dried for sufficient time at

50oC till LOD was less then 2% and later sifted through #30 sieve.

Extragranulation: the step 2b granules were added to the blend of HPMC

K4M and HPMC K100LV which was previously sifted though #30 sieve and mixed for 5min in blender.

Lubrication: The step 3a granules were lubricated with colloidal silicone

dioxide and magnesium stearate, which was previously sifted through #40 sieve and mixed for 2min in a blender.

Compression: The step 4a blend was compressed using 9.8X4.3 mm

capsular shaped punches.Department of Pharmaceutics 13

Sl.No.Ingredients (mg)

Formulation Code F4 F5 F6

Intragranulation

1 Gliclazide 30.00 30.00 30.00

2 DCP(Di-Tab) 88.16 86.56 87.76

3 Aerosil-200 4.80 4.80 4.80

4 Poloxamer-188 1.60 3.20 2.00

5 Purified Water Q.S Q.S Q.S

Extragranulation

6 HPMC K4M 10.00 10.00 10.00

7 HPMC K100LV 24.00 24.00 24.00

8 Aerosil-200 0.32 0.32 0.32


Total wt of Tablet 160.00 160.00 160.00


Formulations with PVP as a binding agent:

Sifting dry mixing: Weighed quantities of gliclazide, dibasic calcium phosphate dehydrate

(Di-Tab) and PVP K30 were mixed and sifted through #30 sieve.Granulation: The step 1a blend was granulated using water as a granulating fluid. The obtained granules were dried for sufficient time at 500C till LOD

was less then 2% and later sifted through #30 sieve.Extra granulation: The step 2b granules were added to the blend of HPMC K4M and

HPMC K100LV which was previously sifted though #30 sieve and mixed for 5 min in a blender.

Lubrication: the step 3a granules were lubricated with and magnesium stearate,

which was previously sifted through #40 seive and mixed for 2min in a blender.

Compression: The step 4a blend was compressed using 9.8X4.3 mm capsular shaped

punches.


Sl.No.Ingredients (mg)

Formulation CodeF7 F8 F9 F10

Intragranulation

1 Gliclazide 30.00 30.00 30.00 30.00

2 DCP(Di-Tab) 89.68 93.68 91.68 89.68

3 Povidone (PVP K30) 3.20 3.20 3.20 3.20

4 Purified Water Q.S Q.S Q.S Q.S

Extragranulation

5 HPMC K4M 12.00 10.00 10.00 10.00

6 HPMC K100LV 24.00 22.00 24.00 26.00

7 Magnesium stearate 1.12 1.12 1.12 1.12

Total wt of Tablet 160.00 160.00 160.00 160.00Department of Pharmaceutics 16

Evaluation of compressed tablets:

Measured physical properties of Tablets

Formulation Code F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

Avg.Tablet wt (mg) 160±2 159±3 161±1 160±2 160±2 160±1 159±2 160±2 160±1.5 159±2.3

Tablet thickness(mm) 3.2±0.1 3.2±0.2 3.2±0.3 3.2±0.4 3.2±0.5 3.2±0.6 3.2±0.7 3.2±0.8 3.2±0.9 3.2±0.1

Punch set (mm) 9.8×4.3 9.8×4.3 9.8×4.3 9.8×4.3 9.8×4.3 9.8×4.3 9.8×4.3 9.8×4.3 9.8×4.3 9.8×4.3

Hardness(Newtons) 83±7 83±3 86±2 82±3 80±6 85±2 82±7 81±6 86±3 85±5

Friability(%) 0.21 0.22 0.17 0.22 0.21 0.19 0.15 0.15 0.22 0.24

Assay (%), n=10 99 99.5 100.2 99.2 100 99 99.9 99.78 100.4 99.54

Amount (mg) 29.7 29.85 30.06 29.76 30 29.7 29.97 29.93 30.12 29.86


Calibration curve of gliclazide in different media:Development of gliclazide linearity curve by Ultraviolet spectroscopy at λmax: 227nm.

Conc.(µg/ml) pH 6.8 Phosphate buffer pH 7.4 Phosphate buffer

0.1 0.016 0.016

0.5 0.034 0.039

1 0.061 0.068

5 0.218 0.214

10 0.396 0.412

15 0.593 0.612

20 0.803 0.81

R2 0.9992 0.9994

Standard graphs of gliclazide in pH 6.8

and 7.4 pH phosphate buffers-appearance of the

two curves is almost identical.


Solubility profile of gliclazide in different media

API Media Solubility (mg/ml)

Gliclazide

pH 1.2(0.1N HCl) 0.131

pH 4.5 acetate buffer 0.029

pH 6.8 Phosphate buffer 0.669

pH 7.4 Phosphate buffer 1.607

Water 0.043

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

0 2 4 6 8

Media pH

So

lub

ility

(m

g/m

l)

The drug was found to possess pH dependent solubility. At pH

4.5 the drug showed lowest solubility. When the pH was

increased to 7.4 the drug solubility was increased by

many folds. However in acidic side of pH at 1.2 also a low

solubility was observed.


Solution Stability of gliclazide in different media:

Time (hrs) 0.1N HCl pH 4.5 pH 6.8 pH 7.4 Water

0 0.7033 0.6899 0.6506 0.6512 0.677

1 0.6997 0.6897 0.6506 0.6509 0.6744

2 0.689 0.6897 0.6503 0.6502 0.6707

4 0.6872 0.6877 0.6500 0.6502 0.6703

6 0.6727 0.6877 0.6500 0.6501 0.6701

24 0.6483 0.6877 0.6500 0.65 0.6701

Gliclazide was found to be practically

stable in all media except in 0.1N HCl during a day time.


Studies on In vitro drug release from the prepared tabletsCumulative drug release % from formulations prepared by Slugging method (n=6).

Time(hrs)

Diamicron

(Innovator’s

product)

F1 F2 F3

0 0.0 0.0 0.0 0.0

1 13.7±6.55 16.8±7.2 25.4±6.2 18.2±8.1

2 25.4±7.78 24.2±6.23 46.7±5.67 26.8±7.2

4 51.7±4.2 38.3±5.5 62.1±5.2 43.9±5.56

8 86.7±4.5 66.5±4.2 78.3±4.67 77.2±4.7

12 98.3±2 82±2.1 98.7±2.35 90.2±2.8

16 99.8±3.2 86±0.7 100±0.9 94±2

20 100±1.2 91.2±0.8 ---- 98±1.7

By using HPMC K4M and HPMC K100LV in formulation F1, the release rate was retarded. So, in formulation F2 the HPMC K4M was removed from the

formulation and the results showed that rapid burst release was seen. Hence, in formulation F3 the concentration of HPMC K100LV was slightly

increased to control the burst release and results were almost comparable to that of the innovator’s release profile. Subsequently, trials were conducted to optimize the formulation by adding poloxamer 188 at

different concentrations.


Cumulative drug release % from formulations with Poloxamer as wetting agent (n=6).

Time(hrs) Diamicron F4 F5 F6

0 0.0 0.0 0.0 0.0

1 13.7±6.55 15.6±7.2 14.4±7.3 26.5±7.2

2 25.4±7.78 25.7±7.8 27±6.8 27.5±5.6

4 51.7±4.2 46.7±4.1 53.7±4 54.4±4.5

8 86.7±4.5 78.7±2 86.9±2.3 80.3±3

12 98.3±2 95±0.6 100±0.2 -----

16 99.8±3.2 ----- ---- ----

20 100±1.2 ----- ----- -----

In formulation F4, F5 and F6 the release was increased with increasing the concentration of Poloxamer 188. In formulation F5, 100% of drug release was

observed at 12hrs. However, the results of formulation F6 were similar to that of the marketed product upto 8 hrs. Further, dissolution was not conducted beyoned 8 hrs. The formulation optimization was further

continued by changing the binding agent PVP.


Cumulative drug release % from tablet formulations - Effect of PVP as binding agent (n = 6).

Time(hrs)

Diamicron

(Innovator’s

product)

F7 F8 F9 F10

0 0.0 0.0 0.0 0.0 0.0

1 8.9±2 10.3±2 20.1±2.5 14.9±2.5 15.4±2.1

2 18.9±1.8 18.3±1.5 37±1.5 24.9±1.5 22.1±2

4 40±2.1 31.7±2 52.2±1.5 43.1±1.9 28.5±1.7

8 69±1.4 53.1±1.2 71.5±2 71.9±2 48.7±2

12 84.9±1.7 68.6±1.6 84.2±1.2 92.9±1.4 66±1.9

16 99.1±1.2 79.9±0.8 100±1.6 97.4±1.6 77.5±2

20 100±1.1 87.6±0.5 ---- 99.8±1.1 88.1±1.4

0

20

40

60

80

100

120

0 5 10 15 20 25

Time(hrs)

%d

rug

rele

ase

Diamicron

F7

F8

F9

F10

In formulation F7 the release rate was retarded due to the high conc. of HPMC K4M and HPMC K100LV. Consequently, in formulations F8, F9, F10 by keeping the conc of HPMC K4M as constant and the conc. of HPMC K100LV was increased gradually.The results showed that formulation F8 released the 100% of drug within 16hr. From all these formulations F9 release profile was almost matched with that of innovator’s formulation.


F2 VALUE DETERMINATION:

The dissolution release at different time points were taken for all the trial batches and compared with that of the innovator’s product. The f2 values, which indicate the extent of similarity between two products, were calculated. These results are shown in the following table.

f2 values of the all the prepared formulations.

Formulation code f2 Values

Influence on the dissolution

profiles in comparison to

innovator’s product as per FDA

standards

F1 44.7 Dissimilar

F2 46.2 Dissimilar

F3 59.8 Similar

F4 59.3 Similar

F5 60.4 Similar

F6 54.6 Similar

F7 44.9 Dissimilar

F8 47.3 Dissimilar

F9 66.13 Similar

F10 41.2 Dissimilar

FDA prescribed the range of 50 -100 for

similarity between two dissolution profiles.

Accordingly, F3, F4, F5, F6 and F9 trials had

similarity to innovator’s product. However, other

formulations were not similar. Formulation F9

was very close to the innovator’s product.


SUMMARY AND CONCLUSIONS:

The study was undertaken with an aim to formulate Gliclazide Sustained release Tablets. Currently the drug Gliclazide, is an ATP dependent potassium channel blocker, used for the treatment of diabetes.

First tablets were prepared by slugging method and wet granulation method. The wet granulated formulation with PVP as a binder got comparable drug release with that of innovator’s product

Tablets were evaluated for test assay and in - vitro dissolution. The optimized formulation F9 was tested for assay, in vitro dissolution test, in vivo tests were performed and f2 values were calculated for all trials.



Dissolution profile of formulation F9 matched with that of innovator’s product and f2 value, similarity factor was found as 66.13 and therefore to that of innovator’s product

The F9 formulation was subjected to three months stability study by keeping at 40ºC/ 75% RH. After this treatment also, no difference in the formulation was found in comparison to innovator’s product.

In vivo bioequivalent studies were done. In vivo studies revealed that the formulation F9 and innovator’s Diamicron were having similar pharmacokinetics parameters. Finally, in this study bioequivalent product Sustained Release Tablets were developed.

Formulation and evalution of sustained release matrix tablets

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