This document summarizes the formulation and evaluation of sustained release matrix tablets containing gliclazide. The objectives were to develop a once-daily tablet to reduce side effects and fluctuations in drug levels compared to immediate release tablets. Various polymers like HPMC K4M, HPMC K100LV, poloxamer 188, and PVP K30 were used to formulate sustained release matrix tablets by wet granulation. The tablets were evaluated for weight variation, hardness, friability, drug content and in vitro drug release over 20 hours. The optimized formulation showed comparable drug release to the innovator's product over the tested time period.

1. FORMULATION AND EVALUTION OF
SUSTAINED RELEASE MATRIX TABLETS
OF GLICLAZIDE
Santhosh Kotagiri
SCOPS
Department of Pharmaceutics 1

2. Contents;
Introduction
Aim & Objective
List of materials and Equipment
Drug and Excipient profiles
Methods used
Results and Discussion
Summary
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3. 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
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4. 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
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5. 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
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6. 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.
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7. 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.
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8. 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.
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9. 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.
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10. EXCIPENTS
HYPROMELLOSE:
Chemical name: Cellulose hydroxypropyl methyl ether
Povidone:
Chemical Name: 1-Ethenyl-2-pyrrolidinone
homopolymer
Poloxamer:
Magnesium stearate
Chemical name :
Octadecanoic acid magnesium salt
Colloidal silicon dioxide:
SiO2
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11. 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.
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12. 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
7 Magnesium stearate 1.12 1.12 1.12
Total wt of Tablet 160.00 160.00 160.00
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13. 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
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capsular shaped punches.

14. 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 PurifiedWater 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
9 Magnesium stearate 1.12 1.12 1.12
Total wt of Tablet 160.00 160.00 160.00
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15. 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.
Department of Pharmaceutics 15

16. Sl.No.
Ingredients (mg)
Formulation Code
F7 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 PurifiedWater 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
Department of Pharmaceutics Total wt of Tablet 16 160.00 160.00 160.00 160.00

17. 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
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18. 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.
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19. 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
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
-0.2
0 2 4 6 8
Media pH
Solubility (mg/ml)
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.
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20. 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.
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21. Studies on In vitro drug release from the prepared tablets
Cumulative 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.
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22. 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.
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23. 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
120
100
80
60
40
20
0
0 5 10 15 20 25
Time(hrs)
%drug release
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.
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24. 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.
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25. 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.
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26.  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.
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27. Department of Pharmaceutics 27