British Journal of Pharmaceutical Research

4(24): 2679-2693, 2014

ISSN: 2231-2919

SCIENCEDOMAIN international
www.sciencedomain.org

Preparation of Metformin Hydrochloride

Extended Release Matrix Tablets by Direct
Compression Method and Its In vitro Evaluation
Mohammad Raquibul Hasan1*, Md. Abul Hossen2, Aumit Roy1,
Tufikul Islam1 and Md. Saiful Islam Pathan2

1
Department of Pharmacy, Jahangirnagar University, Savar, Dhaka – 1342, Bangladesh.
2
Department of Pharmacy, State University of Bangladesh, Dhaka, Bangladesh.

Authors’ contributions

This work was carried out in collaboration among all authors. All authors contributed equally.
Author MSIP supervised the overall work. All authors read and approved the final
manuscript.

Article Information

DOI: 10.9734/BJPR/2014/14013
Editor(s):
(1) Dongdong Wang, Department of Pharmacogonosy, West China College of Pharmacy, Sichuan University,
China.
Reviewers:
(1) Ganesh Dakhale, Pharmacology, MUHS, Nashik, India.
(2) Anonymous, SKB College of Pharmacy, Kamptee, Nagpur, India.
Complete Peer review History: http://www.sciencedomain.org/review-history.php?iid=859&id=14&aid=7023

th
Received 15 September 2014
th
Original Research Article Accepted 27 October 2014
th
Published 19 November 2014

ABSTRACT

Aims: Metformin Hydrochloride, a biguanide, is an orally active antihyperglycemic agent,

used in the treatment of non-insulin dependent diabetes mellitus (NIDDM). It has relatively
short plasma half life, low absolute bioavailability. Extended release formulation of
Metformin Hydrochloride by direct compression method has significant challenges due to
its poor inherent compressibility and high dose. The aim of this study was to develop
extended release tablets of Metformin Hydrochloride by direct compression method and In
vitro evaluation.
____________________________________________________________________________________________

*Corresponding author: Email: [email protected];

 British Journal of Pharmaceutical Research, 4(24): 2679-2693, 2014

Study Design: Nine different formulations were made by varying drug-polymer ratio and
were subjected to different physical property tests of the powder blend as well as
prepared tablets, followed by dissolution test.
Place and Duration of Study: Department of Pharmacy, State University of Bangladesh,
Dhaka, Bangladesh, between January 2013 and July 2013.
Methodology: Nine formulations of Metformin Hydrochloride matrix tablets - F-1, F-2, F-
3, F-4, F-5, F-6, F-7, F-8 and F-9 - were prepared by direct compression method using
release retarding materials, Methocel K100 MCR Premium (derivative of hydroxypropyl
methylcellulose - HPMC) and Xanthan gum. The drug and polymer ratio were 1:0.41,
1:0.45, 1:0.49, 1:0.59, 1:0.63, 1:0.67, 1:0.77, 1:0.81 & 1:0.85 respectively. The
micromeritic behavior of the powder blends were evaluated for bulk density, angle of
repose, compressibility index along with post compressional attributes of the tablets such
as thickness, hardness, friability, weight variation and content of Metformin Hydrochloride
in the tablets. The in-vitro drug release study was carried out in 1000 mL phosphate buffer
medium (pH 6.8) at 37±0.5°C at 100 rpm for 10 hours using USP Apparatus Type-II
(paddle) method.
Results: FT-IR study showed drug-excipient compatibility and DSC analysis showed no
solid state interaction between components. The physical properties of the powder blend
and the tablets were within the acceptable limits. Maximum and minimum drug release
were found in formulation F-1 and F-9 respectively which indicate that release rate is
inversely proportional to the concentration of Methocel K100 MCR Premium and Xanthan
gum in combination. Dissolution study also showed that, formulations F-7, F-8 & F-9 do
not comply with drug release specification of USP and among the rest six formulations F-
3, F-4 & F-5 comply better with drug release specification of USP. After fitting the data to
Korsmeyer-Peppas equation we found that diffusion along with erosion could be the
mechanism of drug release.Considering the micromeritic behaviour of the powder blend,
physical attributes of the compressed tablets, and dissolution, formulation F-4 seemed
most suitable.
Conclusion: Extended release Metformin Hydrochloride tablets can be produced to
overcome frequent dosing related problems. However, Further study on formulation
optimization and scale up, stability and bioequivalence is needed to confirm the
appropriateness of these formulated extended release tablets.

Keywords: Extended release, matrix tablet, release retardant polymer, powder blend &
Metformin Hydrochloride.

1. INTRODUCTION

Diabetes mellitus is a worldwide public health challenge due to its high morbidity & mortality
rate. As of 2010, Metformin Hydrochloride is one of only two oral antidiabetics in the World
Health Organization Model List of Essential Medicines [1]. Metformin HCl, the only available
biguanide, is the first-line drug of choice for the treatment of type 2 diabetes especially in
overweight and obese patients. It mainly acts by decreasing hepatic glucose production
through inhibiting gluconeogenesis and glycogenolysis and in muscle, by increasing insulin
sensitivity, improving peripheral glucose uptake and utilization. The maximum recommended
daily dose of Metformin Hydrochloride immediate release tablet is 2550 mg in adults and
2000 mg in pediatric patients (10-16 years of age); the maximum recommended daily dose
of Metformin Hydrochloride extended release tablet in adults is 2000 mg. It is a highly water
soluble drug (BCS class-III), having the absolute bioavailability of 50-60% and relatively

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short biological half-life of 1.5 – 4.5 h [2,3]. Because of its shorter biological half-life it should
be repeatedly administered to maintain plasma drug concentration within therapeutic window
[4]. The extended release tablets of Metformin Hydrochloride are needed to avoid repeated
administration of immediate release products, to prolong its duration of action and to improve
patient compliance [3].

Matrix devices (monolithic devices) are possibly the most common of the devices for
controlling the release of drugs. They are relatively easy to fabricate, compared to reservoir
devices, and there is no danger of an accidental high dosage that could result from the
rupture of the membrane of a reservoir device. Incorporation of drug in the matrix of
hydrophilic and hydrophobic polymers have been successfully employed in the development
of sustained release delivery systems to provide the desired release profile [5].

Hydroxypropyl methylcellulose (HPMC) is a semi synthetic derivative of cellulose, a

hydrophilic polymer which is very suitable to use as a release retardant in sustained release
matrix tablets due to its rapid hydration, excellent compressibility and gelling characteristics,
ease of use & availability and less toxicity. It controls the release of drug by controlling
swelling & cross linking [6]. Xanthan gum is also used as a release retardant sustained
release carrier and considered as a nontoxic and non-irritant material [7]. In this study
Methocel K100 MCR Premium (derivative of HPMC & trademark of The Dow Chemical
Company) & Xanthan gum were used in different (w/w) combinations, to prepare extended
release tablet.

Oral extended release dosage forms by direct compression method is a simple approach of
drug delivery that proved to be rational in the pharmaceutical arena for its ease of
manufacturing, quality control, faster production, less stability problem during processing of
dosage forms [8]. Amongst the techniques used to prepare tablets, direct compression is the
most advanced technology. Because, it requires fewer unit operations, less machinery,
reduced number of personnel and considerably less processing time along with increased
product stability.

Due to its poor compressibility the manufacturing of Metformin Hydrochloride tablets by

direct compression is a big challenge for manufacturer. Therefore, the main objective of the
present work was to prepare extended release matrix tablets of Metformin Hydrochloride by
direct compression method to assure prolonged acting and well reproducible drug release
profiles. In order to elucidate release kinetics it is essential to fit drug release data into a
suitable kinetic model. The commonly adopted models for understanding the release of
drugs from matrices are zero-order equation, first-order equation, Higuchi equation [9],
Korsmeyer-Peppas equation [10] & Hixson- Crowell Model [11].

2. MATERIALS AND METHODS

2.1 Materials

Metformin Hydrochloride was obtained as a gift sample from Active Fine Chemicals Ltd,
Bangladesh. Methocel K100 MCR premium, Xanthan gum, Microcrystalline Cellulose,
Colloidal Silicon Dioxide and Magnesium Stearate were obtained as a gift sample from ACI
Ltd. All other ingredients used throughout the study were of analytical grades and were used
as received.

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2.2 Drug-excipients Compatibility Study

FT-IR spectrophotometer (IR-Prestige 21, Shimadzu, Japan) was used to obtain the spectra
of the pure Metformin Hydrochloride and the formulation F-9 (maximum release retardant
polymer concentration) by KBr disc method. The spectra were obtained for pure Metformin
Hydrochloride and the formulation F-9 which were compared to check compatibility of drug
with polymers. Polystyrene disc was used as scanning reference before measurement of
-1
samples by FT-IR spectrophotometer in the range of wave number 4000 and 400 cm . The
samples were prepared in a smooth agate mortar and compressed into a disc of 13 mm
diameter using hydraulic press.

DSC measurements were carried out on a differential scanning calorimeter (DSC60,

Shimadzu, Japan) in order to evaluate the drug-excipient compatibility and to verify the
absence of solid-state interactions. The thermal analysis was performed in a nitrogen
atmosphere at a heating rate of 10°C/min over a temperature range of 30–300°C.

2.3 Preparation of Metformin Hydrochloride Matrix Tablets

The active pharmaceutical ingredients and all other excipients were accurately weighed &
passed through 60 mesh sieve for 100 gram batch size according to the formulations
(Table 1). Metformin Hydrochloride, Methocel K100 MCR premium, Xanthan gum &
Microcrystalline cellulose were added into poly bag and mixed for 30 minutes. Magnesium
stearate and Colloidal silicon dioxide were finally added for lubrication & mixed for 10
minutes. Finally powder blend compressed into tablets using single punch tablet
compression machine. Before compression of each batch, the surfaces of the die and punch
were lubricated using Magnesium stearate as lubricant. All the batches were stored in
airtight containers with proper label at room temperature for further study.

Table 1. Composition of different formulations of Metformin Hydrochloride matrix

tablet (in mg)

Ingredients Formulation/batch code

F-1 F-2 F-3 F-4 F-5 F-6 F-7 F-8 F-9
Metformin 500 500 500 500 500 500 500 500 500
Hydrochloride
Methocel K100 80 100 120 140 160 180 200 220 240
MCR premium
Xanthan gum 125 125 125 155 155 155 185 185 185
Ratio 1:0.41 1:0.45 1:0.49 1:0.59 1:0.63 1:0.67 1:0.77 1:0.81 1:0.85
(Drug:Polymer)
Microcrystalline 285 265 245 195 175 155 105 105 65
cellulose
Colloidal silicon 7 7 7 7 7 7 7 7 7
dioxide
Magnesium 3 3 3 3 3 3 3 3 3
stearate
Total weight (mg) 1000 1000 1000 1000 1000 1000 1000 1000 1000

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2.4 Evalution of Powder Blends

The powder blends of different formulations (F-1 to F-9) were evaluated for Bulk density
(Untapped & Tapped), Compressibility index, Hausner ratio, Angle of repose & Loss on
drying.

2.5 Evalution of Matrix Tablets

The prepared matrix tablets were characterized immediately after preparation for hardness,
weight variation, thickness, friability and drug content. The weight variation of the tablets was
evaluated (n=10) using an electronic balance (Shimadzu ATY 224, Japan). The hardness of
the tablets (n=6) was tested using a Veego hardness tester (Veego, India). Friability (n=10)
was determined in a Veego friabilator (Veego, India) for 4 minutes at a speed of 25 rpm. The
thickness of the tablets (n=10) was measured by slide calipers. Drug content was analyzed
by measuring the absorbance of standard and samples at λmax = 232 nm using UV-Vis
spectrophotometer (Shimadzu UV 1700, Japan).

2.6 In-vitro Drug Release Studies

Drug release studies were conducted using USP Apparatus Type II (Paddle) method
(Shimadzu UV 1700, Japan) at a rotational speed of 100 rpm at 37±0.5°C. The dissolution
media used were 1000 mL of pH 6.8 phosphate buffer solution. It was run for 10 hours.
Samples (10 mL) were withdrawn at regular intervals (each hour) and the same volume of
preheated (37±0.5°C) fresh buffer medium was replaced to maintain the volume constant.
The samples withdrawn were filtered through a Double Ring filter paper and the drug content
in each sample was analyzed after suitable dilution (1mL into 50 mL) with a UV-Vis
spectrophotometer (Shimadzu UV 1700, Japan) at λmax = 232 nm by using phosphate
buffer solution as blank. The absorbance of each sample was taken three times. The percent
release of Metformin Hydrochloride in dissolution medium after every hour was calculated,
using the following equation. Drug dissolved at specified time periods was plotted as
cumulative percent release versus time curve.

Absorbance of sample × Weight of Standard (mg) × Y

% release of Metformin Hydrochloride = ---------------------------------------------------------------
Absorbance of Standard × 20

Here, Y = Potency of working Standard.

2.7 Release Kinetics

The in vitro release data obtained from various formulations of Metformin Hydrochloride
extended release tablet were fitted to various kinetic models such as Zero order, First Order,
Higuchi model, Korsmeyer-Peppas model & Hixson- Crowell Model. In case of zero order (Qt
= Q0 + K0t) the graph was plotted as cumulative percent drug release vs time, and in first
order release kinetics (ln Q = ln Q0 – K1t) the graph was plotted in log cumulative percent of
½
drug remaining vs time. For Higuchi model Kinetics (Qt = K2 t ) the graph was plotted in
cumulative percent of drug released vs square root of time and for Korsmeyer-Peppas Model
n
(Q/Q0 = Kt ) the graph was plotted in log cumulative percent of drug release vs log time. For
1/3 1/3
Hixson- Crowell Model (Qt = Q0 - kt) the graph was plotted Cubic root cumulative percent
of drug remaining vs time.

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3. RESULTS AND DISCUSSION

3.1 Drug-excipient Compatibility Study

FT-IR studies revealed that Metformin Hydrochloride showed two typical bands at 3369 and
–1 –1
3296 cm due to N-H primary stretching vibration and a band at 3170 cm due to N-H
–1
secondary stretching and characteristics bands at 1626 and 1567 cm assigned to C=N
stretching. No significant shifts of reduction in intensity of the FT-IR bands of pure Metformin
Hydrochloride & the formulation F-9 were observed as shown in (Figs. 1 and 2.) respectively.
It indicated instead of excipient-drug were compatibility.

Fig. 1. FT-IR spectra of pure Metformin Hydrochloride

Fig. 2. FTIR spectra of formulation F-9

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DSC analysis was performed in order to evaluate possible solid state interaction between
the components to assess the actual drug-excipient compatibility. The thermal curves of
pure Metformin Hydrochloride and formulation F-9 were performed which are shown in
(Figs. 3 and 4). The DSC thermogram of pure Metformin Hydrochloride exhibited an initially
flat profile, followed by a single sharp endothermic peak representing the melting of the
substance in the range 223–237°C. DSC curves of formulation F-9 exhibited a flat thermal
profile. The thermal curves of formulation F-9 (Fig. 4), obtained by simple blending
corresponded to the superimposition of the single component (Fig. 3), indicating the absence
of solid-state interactions and allowing assessment of drug–excipient compatibility in the
examined formulation.

Fig. 3. DSC Thermogram of pure Metformin Hydrochloride

Fig. 4. DSC Thermogramof formulation F-9

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3.2 Evalution of Powder Blend

The results are shown in (Table 2). The bulk density, untapped and tapped, of all the
3 3
batches, varied from 0.53 to 0.59 gm/cm and 0.63 to 0.69 gm/cm respectively. Maximum
3
bulk density (tapped) was found in formulation F-9 (0.70 gm/cm ) which may be due to
highest concentration of dissolution retarding polymer. The results of Carr’s index or
compressibility index of all the batches ranged from 14.49% to 20.5% which reveals that flow
property of all the batches is good to fair; F-4 is excellent [12]. Hausner ratio of the
formulations ranged from 1.169 to 1.259, which is indicative of good flow property, F-4 has
the best value of all [13]. The values of angle of repose were found to be in the range of
25.78° to 29.25° which revealed excellent inherent flow property of the powder blend [13].
Lowest angle of repose was found in formulation F-5 (25.78°) and highest angle of repose
found in formulation F-1 (29.25°). Loss on Drying of all the batches ranged from 2.96% to
3.49%. The residual moisture content found to be appropriate for good tableting properties
and for good stability of compressed tablets.

Table 2. Physical properties of Metformin Hydrochloride powder blend (F-1 to F-9)

Formulation Bulk density Compressibility Hausner Angle of Loss on

Untapped Tapped (%) ratio repose (º) drying (%)
F-1 0.54 0.66 18.18 1.222 29.25 3.24
F-2 0.54 0.65 16.9 1.203 26.17 3.13
F-3 0.56 0.69 18.8 1.232 27.02 3.49
F-4 0.59 0.69 14.49 1.169 26.58 3.04
F-5 0.58 0.69 15.9 1.189 25.78 3.41
F-6 0.55 0.67 17.9 1.218 27.59 2.96
F-7 0.57 0.68 16.1 1.192 27.98 3.09
F-8 0.53 0.63 15.8 1.188 26.50 2.97
F-9 0.55 0.70 20.5 1.259 27.32 2.98

3.3 Evaluation of Matrix Tablets

The tablets were evaluated for diameter, thickness, weight variation, hardness, friability &
drug content and the results are shown in (Table 3).

3.3.1 Uniformity of weight (Weight variation test)

All the tablets passed the uniformity of weight test, i.e., percentage weight variation was
found within the official test limits of ±5%. (Table 3)

3.3.2 Hardness

Hardness or crushing strength of the tablets of all the batches was found to be ranging from
2
7.9 to 11.8 kg/cm (Table 3). The low standard deviation values indicated that the hardness
of all the formulations was almost uniform and the tablets possess good mechanical strength
2
with sufficient hardness. Maximum and minimum hardness were found 11.8 kg/cm and 7.9
2
kg/cm in formulation F-1 and F-9 respectively which reveals that hardness is directly
proportional to the content of microcrystalline cellulose in the formulation.

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Table 3. Physical properties of Metformin Hydrochloride extended release matrix

tablet (F-1 to F-9)

Formulation Thickness Hardness Friability Weight Assay of

2
code (mm) ± SD (kg/cm ) ± (%) (n=10) variation Metformin
(n=10) SD (n=6) (mg) ± SD Hydrochloride
(n=10) (%)
F-1 6.21±0.04 11.8±0.25 0.68 1001±5.02 98.51
F-2 6.25±0.03 11.4±0.36 0.69 1001±5.02 97.96
F-3 6.24±0.06 10.5±0.58 0.69 1001±5.02 98.79
F-4 6.25±0.04 9.2±0.36 0.70 1001±5.02 97.10
F-5 6.27±0.03 8.5±0.78 0.79 1001±4.10 97.90
F-6 6.27±0.04 8.2±0.56 0.80 1000±3.50 98.14
F-7 6.26±0.05 8.1±0.74 0.82 1002±4.05 98.89
F-8 6.25±0.06 8.1±0.59 0.83 1001±4.01 98.70
F-9 6.26±0.04 7.9±0.46 0.85 1002±3.05 98.37

3.3.3 Friability

Friability values of all the batches were in the range of 0.68% to 0.85% (Table 3). The
obtained results were found to be well within the approved range (<1%) in all the designed
formulations. That indicated tablets possess good mechanical strength. Maximum (0.85%)
and minimum (0.68%) friability were found in formulation F-9 & F-1 respectively which
represented that the tablet hardness has good role in friability.

3.3.4 Drug content

The assay of Metformin Hydrochloride matrix tablet was carried out by UV-Vis spectroscopy
method. Metformin Hydrochloride content of all the batches was found to be between
97.10% to 98.89% (Table 3) indicating high degree of drug uniformity.

3.4 In vitro Drug Release Study

The in vitro dissolution studies were carried out for the prepared tablets using USP
apparatus type II (paddle) method. Impact of polymers on drug release from different
combinations of hydrophilic matrices was characterized by variation of drug release. The
release profile of formulation (F-1 to F-9) of Metformin Hydrochloride extended release
tablets are shown in (Figs. 5 and 6), which also represents zero order kinetic graph. At
higher polymer concentration, gel matrix viscosity is increased that results a decrease in the
effective diffusion coefficient of the drug [14] consequently drug diffusion and erosion. The
release rate decreased as the concentration of Methocel K100 MCR Premium and Xanthan
gum increased. It indicates that drug-polymer ratio is crucial factor affecting the rate of drug
release from polymeric matrices. Initially 20.5% w/w combined polymer concentration was
selected to keep the amount of the polymer matrix to a minimum. Formulation F-1, F-2, F-3,
F-4 and F-5 containing drug polymer ratio of 1:0.41, 1:0.45, 1:0.49, 1:0.59, 1:0.63 showed
st
drug release 41.71%, 41.3%, 38.61%, 35.93%, 34.57% respectively after 1 hour, meeting
the desired specification [15]. And, 98.37%, 97.19%, 95.53%, 91.54% & 88.94% respectively
after 10 hours, meeting desired rate [16] (Fig. 5). Among these five batches the drug release
rate was slightly retarded as polymer concentration increased gradually.

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Fig. 5. In vitro cumulative release of Metformin Hydrochloride from batches F-1 to F-5

Formulation F-6, F-7, F-8 and F-9 containing drug polymer ratio of 1:0.67, 1:0.77, 1:0.81,
st
1:0.85 showed drug release 33.65%, 30.89%, 28.69%, 27.89% respectively after 1 hour
and 6.91%, 83.98%, 80.92% & 79.85% respectively after 10 hours which is shown in
(Fig. 6).

Fig. 6. In vitro cumulative release of Metformin Hydrochloride from batches F-6 to F-9

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It is quite evident from above discussion that the release rate gradually decreased with
gradual increase of the concentration of Methocel K100 MCR Premium and Xanthan gum.
Among all the formulations F-7, F-8 & F-9 do not comply with drug release specification of
USP and among the rest six formulations F-3, F-4 & F-5 comply better with drug release
specification of USP. Considering the micromeritic behavior of the powder blend and the
physico-chemical attributes of the compressed tablets, formulation F-4 is most suitable.

3.5 Interpretation of r2 Values for Different Release Kinetics

To describe the kinetics of drug release from matrix tablets, release data was analyzed
according to different kinetic equations, shown in (Table 4).

The dissolution curves of the First order, Higuchi, Korsmeyer-Peppas and Hixson-Crowell
release model of metformin HCl are shown in (Figs. 7, 8, 9 and 10), respectively.

Fig. 7. First order release model of Metformin Hydrochloride extended release

formulation
2
Table 4. r values for different release kinetics of formulations of Metformin
Hydrochloride extended release matrix tablets

Formulation Zero order First order Higuchi Korsmeye Hixson- Best

code r-Peppas Crowell fitted
2 2 2 2 2
r r r r r
F-1 0.846 0.964 0.846 0.901 0.986 Hixson-
Crowell
F-2 0.86 0.974 0.86 0.914 0.988 Hixson-
Crowell
F-3 0.876 0.976 0.876 0.922 0.985 Hixson-
Crowell
F-4 0.859 0.977 0.859 0.895 0.964 First order
F-5 0.86 0.984 0.86 0.891 0.964 First order
F-6 0.875 0.984 0.875 0.920 0.968 First order
F-7 0.883 0.983 0.883 0.910 0.966 First order
F-8 0.888 0.980 0.888 0.900 0.964 First order
F-9 0.909 0.978 0.909 0.935 0.97 First order

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Fig. 8. Higuchi release model of Metformin Hydrochloride extended release

formulation

Fig. 9. Korsmeyer-Peppas release model of Metformin Hydrochloride extended release

formulation

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Fig. 10. Hixson-Crowell release model of metformin HCl extended release formulation

Considering the overall data of release kinetics, it can be stated that the formulations follows
2
Hixson-Crowell release kinetics, showing high linearity in this model (r = 0.964 – 0.988).
From this, we can infer that in the formulations, as dissolution progresses, the surface area
and diameter of the drug matrix change with time [17].

4. CONCLUSION

Metformin Hydrocholoride is a poorly compressible active pharmaceutical ingredient that

presents huge challenge to manufacture tablets by direct compression method. In the
present study sustained released matrix tablets of Metformin Hydrochloride were
successfully prepared using hydrophilic polymers, Methocel K100 MCR Premium and
Xanthan gum, as the release retarding materials, by direct compression method. Higher
amount of polymer decreased the drug release. Among the prepared formulations, F-4 was
deemed as most suitable. An extended release formulation of Metformin Hydrocholoride not
only will increase the efficacy of the treatment of diabetes patients, but will also improve
patient convenience by lowering the dosage frequency to once a day. Further study on
formulation optimization & scale up, stability study and bioequivalence study is needed to
confirm the appropriateness of these formulated extended release tablets.

CONSENT

Not applicable.

ETHICAL APPROVAL

Not applicable.

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COMPETING INTERESTS

Authors have declared that no competing interests exist.

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© 2014 Hasan et al.; This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

Peer-review history:
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http://www.sciencedomain.org/review-history.php?iid=859&id=14&aid=7023

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