PREPARATION AND EVALUATION OF CONTROLLED RELEASE MATRIX TABLETS OF METFORMIN HYDROCHLORIDE

1. PREPARATION AND EVALUATION OF CONTROLLED RELEASE
MATRIX TABLETS OF METFORMIN HYDROCHLORIDE
.
Submitted by
Mr. MANOJ CHOUDHARY B. Pharm.,
Register No: 15PU036
Dissertation Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore, Karnataka
Under the Guidance of
Dr. Ravada Ramesh M.Pharm., Ph.D
Professor & Head
Department of Pharmaceutics,
DR. HLT COLLEGE OF PHARMACY,
KENGAL, CHANNAPATANA.

2. CONTROLLED RELEASE SYSTEM1
If the system is successful at maintaining constant drug level in the blood or
target tissues, it is considered as a controlled release system. The release of drug
ingredient from a controlled delivery system proceeds at a rate profile that is not only
predictable kinetically, but also reproducible from one unit to another.
Advantages
 Avoid patient compliance problems.
 Minimize or eliminate local rate effects & systemic side effects.
 Obtain less potentiating or reduction in drug activity with chronic use..
 Improve efficiency in treatment.
 Cure or control condition more promptly.
 Improve control of condition, i.e., reduces fluctuation in drug level.
 Improve bioavailability of some drugs.
INTRODUCTION

3. MATRIX TECHNOLOGY2
Matrix technologies are popularly used because of the simplicity of the
manufacturing processes required, level of reproducibility, stability of the raw
materials and dosage form as well as ease of scale up operation, validation and
favorable in-vitro in-vivo correlation (IVIVC). Classically, simple matrix delivery
systems exhibit first order or square root of time release kinetics. These systems
improve patient compliance and decreased incidence of adverse drug reactions.
the matrix tablets has additional advantage like, matrix tablets are resistant to dose
dumping. They are simple in nature of the formulations and due to robustness they
are unaffected by variations in ingredients.
Matrix tablets containing hydrophilic polymers are a common and commercially
successful means of prolonging oral drug delivery

4. OBJECTIVES OF THE STUDY
Oral controlled release dosage forms are the most common type of dosage forms
that offers highest attention in the area of novel drug delivery system. Such system
offers advantages.
• To improve therapeutic efficacy, maintain uniform drug levels
• To improve patient compliance
Hydrophilic gel forming matrix tablets are widely used as oral controlled release
dosage forms.
Development of oral controlled release matrix tablets for water soluble drugs with
constant release rate has always been challenge to the pharmaceutical technologist,
most of the drugs, if not formulated properly, may readily release the drug at a faster
rate and produce a toxic concentration of the drug on oral administration.

5. DRUG PROFILE3
Drug name: : Metformin Hydrochloride
Chemical structure :
Molecular formula : C4H11N5, HCl
Molecular weight : 165.6gmole
IUPAC name : 1,1-Dimethyl biguainide Hydrochloride
Description : A white, odorless, crystalline powder, odorless and has
a bitter taste, hygroscopic.
Solubility : Freely soluble in water, slightly soluble in alcohol,
practically in soluble in acetone.
Melting range : 225ºC
Storage : stored in an airtight Container, protected from light.
Therapeutic uses : It is used to treat type-2 diabetic mellitus

6. REVIEW OF LITERATURE
1. Basavaraj et al. Design and characterization of sustained release
aceclofenac matrix tablets containing tamarind seed polysaccharide by
using microcrystalline cellulose, magnesium stearate, talc etc. They
concluded that stable formulation could be developed by incorporating
hydrophilic polymer (Tamarind seed polysaccharide) in a definite
proportion so that the controlled released profile is maintained for an
extended period4.
2. Kulakarni et al. Development and evaluation of xyloglucan matrix tablets
containing naproxen by using ethyl cellulose, hydroxy propyl methyl
cellulose, cellulose acetate phthalate etc . They concluded that the tablets
containing xyloglucan in combination with cellulose acetate phthalate has
released 98.08% drug and release was extended over a period of 10
hours of dissolution study Hence, it is a good combination for the
5

7. 3. Alka A et al. Formulation, development and evaluation of sustained release matrix
tablets of lamivudine using tamarind seed polysaccharide by using tamarind kernel
powder and ethyl cellulose etc 6 .
4. Shivkumar HV et al. Formulation of sustained release diltiazem matrix tablets by
using microcrystalline cellulose, hydroxy propyl methyl cellulose, locust bean gum
and karaya gum 7.
5. Venkataraju MP et al. Xanthan and locust bean gum (from ceratonia siliqua)
matrix tablets for oral controlled delivery of propranolol hydrochloride by using
locust bean gum, xanthan gum 8.
6. Patel N et al. Development and evaluation of controlled release Ibuprofen matrix
tablets by direct compression technique, using eudragit RSPO and avicel PH 101 9.
7. Punna Rao et al. Oral controlled release matrix tablets of lamivudine were prepared
by using hydroxy propyl methyl cellulose as the retardant polymer 10.

8. Preparation of matrix tablets of metformin hydrochloride:
Matrix tablets containing 500mg of Metformin Hydrochloride along with various
amounts of polymers such as HPMC K 100, Carbapol934, and other excipients (such
as, magnesium stearate, MCC and talc) were used and tablets were prepared by direct
compression technique. MCC was passed through mesh No.40. In the first step, the
drug and ingredients with the exception of magnesium stearate were blended in a
turbula mixer for 5 minutes. Then magnesium stearate and talc was added and
formulation was mixed for an additional 2 minutes. Desired amount of blend was
directly compressed into tablets using rotary tablet compression machine (RIMEC,
MINI PRESS-1). Before compression, the surfaces of the die and punch were
lubricated with magnesium stearate. All the preparations were stored in airtight
containers at room temperature for further studies.
METHODOLOGY

9. Formulation of matrix tablets of Metformin Hydrochloride:
A total of 10 formulations have been prepared and each formulation type
contains 500 mg of drug, common filler such as microcrystalline cellulose. The
formulae are as follows;
INGREDIENTS F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
Metformin Hcl (mg) 500 500 500 500 500 500 500 500 500 500
HPMC K100(mg) 70 105 140 175 210 - - - - -
Carbapol 934(mg) - - - - - 70 105 140 175 210
Micro Crystalline
cellulose (mg)
215 180 145 115 080 215 180 145 115 080
Magnesium
stearate(mg)
10 10 10 10 10 10 10 10 10 10
Talc (mg) 5 5 5 5 5 5 5 5 5 5

10. EVALUATION FOR PRE-COMPRESSIVE PARAMETERS 11
1. Bulk Density;
2. Hausner’s factor:
3. Carr’s Compressibility Index:
4. Angle of Repose
EVALUATION FOR POST COMPRESSIVE PARAMETERS 12
1. Thickness and diameter
2. Weight variation test (IP 1996 method)
3. Hardness test
4. Friability test
5. Disintegration test
6. Swelling characteristics of matrix tablets
7. Uniformity of Drug Content
8. In-vitro Dissolution studies

11. Kinetic analysis of in-vitro release rates of controlled release tablets
of metformin hydrchloride:
The results of in vitro release profile obtained for all the formulations were
plotted in modes of data treatment as follows:-
1. Zero – order kinetic model – Cumulative % drug released versus time.
2. First – order kinetic model – Log cumulative percent drug remaining versus time.
3. Higuchi’s model – Cumulative percent drug released versus square root of time.
4. Korsmeyer equation / Peppa’s model – Log cumulative percent drug released
versus log time.
Drug: excipeint intraction study
This was established by using FTIR Spectroscopy method. The study was carried
out for only the excipients of optimized formulation.

12. RESULTS
Solvent Solubility in mg / ml
SGF (PH -1.2) 256
SIF (PH -6.8) 282
SIF (PH -7.4 ) 156
PREFORMULATION STUDIES
Solubility of drug in different media:
Melting point: It was found to be in the range of 222°C to 226°C.

13. FTIR Spectroscopy:
FT-IR spectra were recorded on samples in potassium bromide disks using shimadzu
FT-IR 8400S spectrophotometer.
GROUP WAVE
NUMBER
C-H str 2950.48 cm-
1
C= N str 1688.48 cm-
1
C-C str 1254.14 cm-
1
Shows FTIR peaks of various functional
groups of the Metformin Hydrochlorde:
FTIR interpretation of Metformin
Hydrochloride

14. U.V. Spectroscopy
Solvent max(nm)
Methanol 233nm
Absorbance maxima of Metformin
Hydrochloride in methanol)
STANDARD GRAPH OF METFORMIN HCL
y = 0.0812x - 0.0006
R2
= 0.9999
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
0 1 2 3 4 5 6 7 8 9 10
CONCENTRATION (mcg/ml)
ABSORBANCE
Standard graph of Metormin
Hydrochloride in methanol)

15. Conc.( Mcg/ml) Absorbance
0 0
1 0.081
2 0.163
3 0.243
4 0.325
5 0.406
6 0.482
7 0.565
8 0.648
9 0.731
10 0.815
Equation of line Y=0.0812×-0.0006
R2 0.9999
Beer’s law limit 1-10 mcg/ml
Λ max 233.0 nm
Absorbance-concentration data for standard curve in methanol

16. EVALUATION
FORMULATION
CODE
Angle of
repose
Loose Bulk
density
(g/ml)
Tapped
Density
( g/ml)
Hausner
Factor
Carr’s
Index (%)
F1 28.010.020 0.590.020 0.530.08 1.180.02 15.361.8
F2 29.670.044 0.610.030 0.500.03 1.190.04 14.360.8
F3 28.600.028 0.620.022 0.500.04 1.210.04 16.391.40
F4 27.590.054 0.630.130 0.660.12 1.230.04 16.901.56
F5 29.670.110 0.500.02 0.620.08 1.250.04 14.861.22
F6 27.820.028 0.670.28 0.550.05 1.230.12 13.950.92
F7 28.890.044 0.43030 0.450.03 1.160.03 13.850.9
F8 25.900.021 0.550.23 0.650.09 1.210.05 14.300.004
F9 27.550.054 0.520.18 0.510.03 1.170.07 13.970.92
F10 27.820.028 0.510.17 0.490.02 1.180.11 15.251.79
Powder prepared for direct compression method was evaluated by measuring the
parameters such as; bulk density, angle of repose, Hausner’s factor, compressibility
index and drug content. The results are shown in Table
All these results obtained indicate that the granules possessed satisfactory flowproperties,
compressibility, and uniform drug content

17. EVALUATION OF TABLETS:
Formulation
code
Thickness
(mm)
Hardness
(Kg/cm2)
Weight variation
(mg) (%devn.)
Friability
(%)
Drug content (%)
F1 3.120.18 6.330.25 3.520.21 0.820.06 97.830.41
F2 3.110.22 6.400.12 3.070.62 0.890.03 98.010.64
F3 3.050.18 6.050.11 3.450.23 0.800.06 98.830.88
F4 2.990.20 6.450.20 3.450.22 0.760.02 98.160.67
F5 3.050.18 6.370.18 3.460.17 0.750.08 99.00.18
F6 3.110.11 6.440.24 3.560.18 0.720.06 99.150.18
F7 3.250.24 6.510.31 3.450.22 0.450.04 99.520.75
F8 3.200.16 6.470.24 3.320.10 0.680.05 97.40.39
F9 3.060.20 6.230.23 3.350.13 0.670.04 98.120.64
F10 3.080.18 6.550.31 3.580.19 0.870.03 98.920.36
Physical characteristics of prepared matrix tablets)

18. Formula Code Initial weight (mg) Final weight (mg)
Swelling Index
(%)
F1 802.23 1149.44 65.8
F2 801.77 1173.43 67.6
F3 799.11 1146.12 65.9
F4 803.11 1143.61 65.4
F5 802.34 1178.76 69.4
F6 801.56 1207.23 79.9
F7 800.76 1288.22 92.6
F8 800.55 1268.76 68.5
F9 802.23 1257.65 68.7
F10 798.82 1285.37 76.6
Swelling indices of matrix tablets of Metformin Hydrochloride

19. In vitro drug release study:
Time(hrs)
Cumulative% drug release
F1 F2 F3 F4 F5
1 32.0 22.6 22.4 22.1 18.1
2 45.5 31.4 30.7 29.8 27.1
3 56.4 40.6 38.8 36.8 36.1
4 62.4 49.6 45.8 42.4 44.2
5 73.5 57.7 53.2 47.7 51.2
6 80.2 65.8 60.3 54.9 58.6
7 84.5 71.0 67.3 61.3 64.9
8 87.1 72.4 75.7 67.5 68.5
9 91.3 77.4 80.2 72.1 71.2
10 93.1 82.6 84.6 74.8 72.8
11 95.1 85.9 89.6 77.5 75.7
12 96.4 88.1 92.4 79.3 78.4
IN VITRO cumulative % release of drug from F1 to F10 Metformin Hydrochloride
matrix tablets
Time(hrs)
Cumulative% drug release
F6 F7 F8 F9 F10
1 20.1 27.1 21.3 23.6 21.4
2 31.98 42.4 28.6 30.6 29.4
3 42.6 57.5 35.8 39.8 40.7
4 51.7 67.9 41.8 48.8 48.7
5 61.7 83.7 45.8 52.7 57.7
6 73.5 88.8 54.6 65.3 66.6
7 81.5 92.1 58.6 71.7 72.8
8 85.9 95.5 64.6 71.6 72.5
9 89.0 96.5 75.4 76.5 76.6
10 91.2 97.9 79.5 81.3 81.2
11 93.5 99.3 78.9 84.6 84.5
12 94.1 99.8 82.5 86.6 91.6

20. FORMULA
TION
CODE
Coefficient of
Determination (R2)
Zero
Order
First
Order
Koresme
yer
-peppas
Higuchi
Square
root
F1 0.925 0.890 0.887 0.995
F2 0.937 0.890 0.921 0.988
F3 0.941 0.885 0.925 0.994
F4 0.953 0.884 0.931 0.979
F5 0.928 0.881 0.921 0.978
F6 0.931 0.882 0.931 0.995
F7 0.985 0.865 0.936 0.997
F8 0.981 0.872 0.922 0.977
F9 0.940 0.880 0.905 0.985
F10 0.964 0.882 0.920 0.998
coefficient of determinations for
prepared matrix tablets of Metformin
Hydrochloride
Formulat
ion Code
Correla
tion
coeffici
ent
( R2)
Release
exponen
t
(n)
Kinetic
constant
(k)
(mg/hr)
T50%
(hr)
T70%
(hr)
F1 0.9871 0.651 6.198 8.5 16.6
F2 0.9830 0.688 5.859 6.8 20.8
F3 0.9788 0.697 5.701 7.7 21.4
F4 0.991 0.684 5.415 9.6 18.8
F5 0.9942 0.713 5.583 7.8 18.9
F6 0.9966 0.662 6.198 9.6 11.40
F7 0.9682 0.647 6.302 11.4 16.20
F8 0.9799 0.621 7.321 13.9 16.19
F9 0.9674 0.675 5.585 12.9 18.99
F10 0.9915 0.655 6.209 7.75 20.81
Dissolution parameters of Metformin
Hydrochloride matrix tablets

21. Plot of Cumulative % drug release from F1 to
F5 Metformin Hydrochloride matrix tablets
Plot of Cumulative % drug release from F6
to F10 Metformin hydrochloride matrix
tablets
Plot of First order kinetic treatment from F1
to F5 Metformin hydrochloride matrix
tablets
Plot of First order kinetic treatment from F6 to
F10 Metformin hydrochloride matrix tablets

22. Plot of Higuchi treatment from F1 to F5
Metformin hydrochloride matrix tablets
Plot of Higuchi treatment from F6 to F10
Metformin hydrochloride matrix tablets
Plot of koresmeyer-peppas treatment for F1-F5
Metformin Hydrochloride matrix tablets
Plot of koresmeyer-peppas treatment for F6-F10
Metformin Hydrochloride matrix tabletst

23. Drug-excipients interaction study
This was established by using FTIR Spectroscopy method. Binary physical
mixtures of drug with individual excipients was pressed into pallets and
scanned. Not a single excipient was interacted with the drug. Spectra of FTIR
for drug -excipients are shown in Table
FT IR spectra of Carbapol934
GROUP WAVE NUMBER
O=H str 3000 CM-1
C=O str 1750-1700 CM-1
FTIR interpretation of Carbapol934)

24. FT IR spectra of HPMC K100M
GROUP WAVE NUMBER
N-H str 3420 cm-1
C-H str 2922.59 cm-1
C=O str 1058.73 cm-1
FTIR interpretation of HPMC K100M
FT IR spectra of Optimised
formulation F7
GROUP WAVE
NUMBER
C=N str 1689 cm-1
O=H str 2981 cm-1
C=O str 1634 cm-1
FTIR interpretation of Optimised
formulation F7

25. Differential scanning calorimetry
it shows endothermic peak at about 232.460C
Differential scanning calorimetry of
Metformin Hydrochloride
Differential scanning calorimetry of
Optimized formulation F7

26. Results of stability studies
The results of the accelerated stability studies are given in the following tables. I
shows that a slight reduction in %drug content at the end of 3 months.
Time (hour)
%CDR
Initial 1 month 2 month 3 month
0 0 0 0 0
1 3.18 3.15 3.05 3.03
2 5.81 5.45 5.33 5.25
3 16.48 16.36 16.15 16.09
4 28.30 28.15 27.95 27.65
5 36.19 36.08 35.95 35.87
6 42.88 42.75 42.59 42.35
7 59.27 59.05 58.85 58.49
8 62.38 62.16 63.93 63.85
9 77.95 77.71 77.55 77.39
10 88.39 88.05 87.88 87.47
11 94.21 93.89 93.65 93.25
12 99.58 99.13 98.93 98.85
Plot of Cumulative % drug
release vs Time for selected
formulation F7 (Stability studies)

27. DISCUSSIONPREFORMULATION
In the pre formulation study, it was found that the estimation of Metformin
Hydrochloride by UV spectro photometric method at λmax 233.0 nm in PH 1.2
buffer had good reproducibility and this method was used in the study.
FLOW PROPERTIES:
The Carr’s Index (Compressibility) of the granules was in the range of 13.85 to
16.90. The angle of repose of the powders was in the range of to 27.55 to 29.67,
which indicates a good flow property of the granules.
The results were evaluated for 12 hours. As per the results of dissolution
study for the formulations F-1, F-2, F-3, F-4, F-5, F-6, F-7, F-8, F-9, F10. the
percentage of drug release was found to be 96.4%, 88.1%, 92.4%, 79.3%,
78.4%, 94.1%, 99.8%, 82.5%, 86.6%, 91.6% respectively release over a period
of 12 hours.

28. Among all the formulation, F-7 shows 99.8% of controlled drug release and tablet
was retained at the end of 12 hours. It was found that the cumulative percentage of
drug release decreases with increase in the polymer concentration and cumulative
percentage of drug release increase with increase in filler concentration.
FT-IR SPECTROSCOPY.
Drug polymer interaction was checked by comparing the IR spectra of the
formulations with the IR spectra of the pure drug. There was no significant change in
the functional groups between the IR spectrums of the pure drug and also no
additional peaks were seen in the selected formulations This confirms that no
interaction between drug and excipients.

29. STABILITY STUDY
Stability studies were carried out on selected formulation (F-7) as per ICH
guidelines. There was not much variation in matrix integrity of the tablets at all the
temperature conditions. There was no significant changes in drug content , physical
stability, hardness, friability and drug release (table 2) for the selected formulation F-
7 after 90 days at 25oC± 20C / 60% ± 5% RH, 300C ± 20C / 65% ±5% RH and 400C ±
20 / 75% ± 5% RH.
Therefore the main objective of the study to formulate and evaluate the matrix tablets
of a Metformin Hydrochloride by using HPMC K 100, carbopol 934, MCC, Talc,
Magnesium stearate as a release rate modifier were achieved.
The parameters; T50%, T70% was used for comparison of release profile among
formulated tablets of Metformin Hydrochloride. The T50% and T70% values of
formulations containing lower portion of Carbapol934 were found better and
optimum among all the formulated tablets.

30. CONCLUSION
From the above observations it was concluded that slow and controlled release of
Metformin Hydrochloride over a period of 12 hours was obtained from matrix tablets
(F-7). It was found that increase in the polymeric concentration in polymeric ratio
decreases the drug release.
All the tablet formulations showed acceptable quality control properties like
hardness, friability, thickness, weight variation, drug content uniformity etc. and
complied with in the specifications for tested parameters gave better drug release rate
over a period of 12 hours. Thus, formulation F-7 was found to be the most promising
formulation on the basis of acceptable tablet properties and in vitro drug release rate
of 99.8%.

31. The results of the kinetic study obtained permit us to conclude that an orally
sustained Metformin Hydrochloride matrix tablet delivers the drug through a complex
mixture of diffusion, swelling and erosion.
Based on the FT-IR studies, there appears to be no possibility of interaction
between Metformin Hydrochloride and polymers/ other excipients used in the tablets.
Stability studies were conducted for the optimized formulations as per ICH
guidelines for a period of 90 days which revealed that the formulations were stable.
The results suggest that the developed sustained-release tablets of Metformin
Hydrochloride could perform better than conventional dosage forms, leading to
improve efficacy and better patient compliance.

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