Pharmacology & Pharmacy, 2012, 3, 468-473
http://dx.doi.org/10.4236/pp.2012.34064 Published Online October 2012 (http://www.SciRP.org/journal/pp)
1
Preparation and in Vitro Drug Release Evaluation of
Once-Daily Metformin Hydrochloride Sustained-Release
Tablets
Ling Zhao1, Yumeng Wei1*, Yong Mei2, Li Yang2, Yuan You2, Xufeng Yang2, Yanhong Jiang2
1Department of Pharmaceutics, School of Pharmacy, Luzhou Medical College, Luzhou, China; 2Chongqing Conquor Pharmaceutical
Co., Chongqing, China.
Received June 24th, 2012; revised July 25th, 2012; accepted August 11th, 2012
ABSTRACT
The objective of this study was to develop once-daily metformin hydrochloride sustained-release tablets (MHSRT) and
evaluate their in vitro release behavior. MHSRT were prepared by the film coating method. The in vitro drug release
rate of MHSRT and the commercial tablets Fortamet® made in the United States of America in water was fitted with
zero order kinetic equation, and Ritger-Peppas kinetic equation in 0.1 M HCl and pH 6.8-phosphate buffer, respectively.
The similarity factor f2 values of MHSRT in three different dissolution medium were 82, 80 and 74, respectively in
comparison with imported Fortamet®, which were all greater than 50. The results of storage-stability showed that
MHSRT were stable for at least 6 months under stress condition (40˚C ± 2˚C, RH 75% ± 5%). Therefore, in this study,
MHSRT were successfully prepared using optimized formulation technologies that meet mass produce. The in vitro
release behavior of MHSRT was almost similar to that of imported Fortamet®.
Keywords: Sustained-Release Tablets; Metformin Hydrochloride; In Vitro Release Rate; Similarity Factor; Kinetic
Model
1. Introduction
Metformin hydrochloride (MH) is a biguanide oral anti-
diabetic drug which is widely used to treat non-insulin
dependent diabetes mellitus (type 2 diabets). Its mode of
action is thought to be multifactoral and includes de-
layed uptake of glucose from the intestinal tract, in-
creased peripheral glucose utilisation mediated by in-
creased insulin sensitivity and decreased hepatic and renal
gluconeogenesis. In clinical treatment, there are many
advantages of MH such as the tendency to weight reduc-
tion and the ability to reduce blood glucose to normal
level without significant hypoglycaemia [1]. However,
because of its relative low bioavailability (40% - 60%)
and short biological half-life (0.9 - 2.6 h) [2-5], the im-
mediate release dosage forms of MH such as conven-
tional tablets and capsules, have to be administered three
times a day [3], which results in a significant fluctuation
in the plasma drug concentration and poor patient com-
pliance. In order to overcome these problems, sustained-
release drug delivery systems of MH including sustained-
release matrix tablets [2,6-8], sustained-release pellets
[3,9], sustained-release microparticles [10], prolonged
release microspheres [11], gastroretentive drug delivery
preparation [12], pH-controlled peroral delivery formula-
tion [13] have been developed in recent years. Though
sustained release formulations of MH have been reported to
prolong drug release, formulation and technologies used in
these studies were complicated and costly, which influence
industrial scale and market expansion. At present, MHSRT
produced by Bristol-Myers Squibb Company (USA)
capture a major market share in China. However, many
patients in our developing country could not accept it due to
its high cost. Therefore, development of sustained release
dosage form of MH that is similar to imported drug is to
save pharmacy cost and improve clinical outcomes.
Therefore, in this study, MHSRT were prepared using
optimized formulation technologies that meet mass pro-
duce. The in vitro drug release behavior of MHSRT was
studied in water, 0.1 M HCl and pH 6.8-phosphate buffer
as release medium and compared with the commercial
tablets Fortamet® made in the United States of America.
2. Materials and Methods
2.1. Materials
Metformin hydrochloride (purity: 99.86%) was purchased
*Corresponding autho
r
.

Preparation and in Vitro Drug Release Evaluation of Once-Daily Metformin Hydrochloride Sustained-Release Tablets 469
from Huainan Jiameng Pharmaceutical Co., Ltd (China).
Carboxymethyl cellulose sodium (CMC) and pregelati-
nized Starch was obtained from Anhui Shanhe Pharma-
ceutical Excipient Co., Ltd (China). Ethyl cellulose was
purchased from Shandong Heda Co., Ltd (China). PEG-
6000 was supplied by Liaoyang Aoke Nano Meterial Co.,
Ltd. (China). Hexadecanol was purchased from Hunan
Erkang Pharmaceutical Co., Ltd (China). Magnesium
stearate was purchased from Chongqing Chemical Re-
agent Co. Ltd. (China). Fortamet® (batch number: 4602094;
expiry date: 20121102) were obtained from Watson La-
boratories—Florida Ft. Lauderdale, FL 33314 (USA).
were obtained from the United States of America. All
chemicals and reagents used were of analytical grade.
Water used in this study was double distilled water.
2.2. Preparation of MHSRT
Firstly, MH core tablets were prepared by wet granula-
tion method. MH and CMC were mixed and the mixture
was passed through a 100-mesh sieve. Granulation was
done using water. The wet mass was passed through
fourteen meshes using the pendular granulator and the
wet granules were air dried for about 2 h. The granules
were then sized by fourteen mesh sieve and mixed with
pregelatinized starch and magnesium stearate. The core
tablets were compressed on a tablet compression ma-
chine equipped with 12 mm convex punches. Secondly,
the film coat suspension was prepared by dissolving and
dispersing EC, PEG-6000 and hexadecanol in 95 %
ethanol. In brief, the above core tablets were placed into
a fluid-bed spray coater and prewarmed to 35˚C - 40˚C
for 3 - 5 min. The coating solution was delivered using
peristaltic pump with a flow rate of 1.8 mL/min. Coating
was carried out at 50˚C inlet air temperature and 45˚C
outlet air temperature. The resulted MHSRT were dried
at 40˚C for 12 h and then were further performed quality
evaluation.
2.3. Determination of Drug Content
According to the Chinese Pharmacopoeia (2010 version)
about the determination of MH content, the samples (20
tablets) were taken and ground to fine powder. Then
about 20 mg powder was accurately weighed and placed
in a 100 mL volumetric flask containing 75 mL water.
After it was dissolved using ultrasonication at room
temperature for 20 min, this solution was diluted with
water to 100 mL and mixed well, then filtered through a
0.45 µm hydrophilic membrane. 2.5 mL of the solution
was accurately taken and transferred to a 100 mL volu-
metric flask, and then was diluted with water to 100 mL
and mixed well. The drug content was measured using
an UV-visible spectrophotometer at a wavelength of
233 nm.
2.4. Weight Variation Test
To study weight variation, 20 tablets of each batch sam-
ples were weighed using an electronic balance (BT214D,
Germany Sartorius), and the test was carried out ac-
cording to the Chinese Pharmacopoeia (2010 version)
method.
2.5. Hardness and Friability Test
For each batch of MHSRT, the hardness and friability of
12 tablets was determined using tablet with four measur-
ing instrument (78X-6A).
2.6. In Vitro Release Test
In vitro release studies of MHSRT was carried out by the
rotating basket methods of Chinese Pharmacopoeia
(2010 version) appendix XD No.1. Six tablets of each
batch of MHSRT were taken and placed in rotating bas-
ket, respectively. Then the rotating basket was introduced
into 900 mL of each dissolution medium (water, 0.1 M
HCl and pH 6.8 phosphate buffer) at 37˚C ± 0.5˚C with a
rotation speed of 100 rpm. 5 mL of sample solution was
collected at different time intervals (2, 4, 6, 8, 10, 12 h)
and filtered through a 0.45 µm hydrophilic membrane.
1.0 mL of subsequent filtrate was taken accurately to add
into a 100 mL volumetric flask and diluted with the cor-
responding dissolution medium to 100 mL and mixed
well. The amount of drug dissolved in the dissolution
medium was measured using an UV-visible spectropho-
tometer at 233 nm. The same volume of fresh dissolution
medium at the same temperature was added to replace
the amount withdrawn after each sampling.
The drug amount of cumulative release from the
MHSRT was calculated with a standard curve prepared
using bracketed concentration of MH each dissolution
medium solution in a range from 15 to 125% of a theo-
retical concentration of 5.5 µg/mL. The standard curve:
Y = 0.0746X − 0.0031 for distilled water; Y = 0.0758X −
0.0034 for 0.1 M HCl and Y = 0.0798X − 0.0037 for pH
6.8 phosphate buffer were obtained with coefficient of
correlation (r = 0.9999).
2.7. Data Analysis
In order to evaluate the drug release kinetic model of the
MHSRT, four kinetic models including the zero-order
release equation, first-order release equation, Higuchi’s
equation and Ritger-Peppas ((1)-(4), respectively) were
chosen to process the in vitro drug release data.
1
M
tktb

 (1)


Ln 1002
M
tktb


(2)

Preparation and in Vitr o Drug Release Evaluation of Once-Daily Metformin Hydrochloride Sustained-Release Tablets
470
In order to validate whether the optimized formulation
technologies of MHSRT can be suitable for mass pro-
duce, the three batches of MHSRT (100000 tablets/batch)
were produced by Chongqing Conquor Pharmaceutical
Co., Ltd. and the results were shown in Table 1 and
Figures 1-3. Drug content was found to be uniform
among the three batches of MHSRT and ranged from
97.85% ± 0.09% to 99.36% ± 0.07%. The mean percent-
age weight variation of 20 tablets of each batch was less
12
3
M
tkt b (3)
Ln 4Ln
M
tk tb (4)
where Mt is the cumulative release percentage at time t,
the k1, k2, k3 and k4 are the rate constant of the above
kinetic equation, respectively.
In order to compare the difference of in vitro drug re-
lease behavior between the MHSRT, the similarity factor
f2 is used in this study and defined by the following
equation (5).


0.5
2
250 log11100fn


 
 (5)
024681012
0
20
40
60
80
100
120
MH released (%)
Time (h)
111105
111106
111107
where n is the number of time point, Rt and Tt are the
mean cumulative percentage drug dissolved at each time
point, t. MHSRT developed in this study and imported
Fortamet® made in the United States of America were
chosen as test samples and reference preparation, respec-
tively.
2.8. Stability Test of MHSRT
The accelerate stability testing was carried out according
to the Technical Standard of Drug Stability Test of Chi-
nese Pharmacopoeia (2010 version). The MHSRT sam-
ples were stored at 40˚C ± 2˚C, RH 75% ± 5% for 6
months and the in vitro release was measured after 1, 2, 3
and 6 months of storage.
Figure 1. Drug release profiles of the three batches (111105,
111106, and 111107) of MHSRT in water as dissolution
medium.
3. Results and Discussion
024681012
0
20
40
60
80
100
120
MH released (%)
Time (h)
111105
111106
111107
3.1. Development of MHSRT
In the preliminary study, MH, CMC, pregelatinized
starch and magnesium stearate were chosen to prepare
the core tablets as formulation composition. In addition,
the film coating formulation was composed of EC,
PEG-6000 and hexadecanol. On the basis of single factor
experiments, we have confirmed the dosage range of the
formulation composition. Then an orthogonal array was
used to investigate the key influence on preparation. In
the current research, the optimal formation of the core
tablets was MH (500 g), CMC (40 g), pregelatinized
starch (30 g) and magnesium stearate (9 g), the optimal
formulation of the film coating was composed of EC (15
g), PEG-6000 (6 g) and hexadecanol (6 g) dissolved or
dispersed in 95% ethanol resulting in 300 mL coating
suspensions.
Figure 2. Drug release profiles of the three batches (111105,
111106, and 111107) of MHSRT in 0.1 M HCl as dissolution
medium.
Table 1. Properties of the three batches of MHSRT prepared in this study.
Batch Drug content (%) Deviation in weight variation (%) Hardness (kg/cm2) Friability (%)
111105 98.55 ± 0.05 3.26 ± 0.02 6.8 ± 0.22 0.72 ± 0.04
111106 99.36 ± 0.07 2.90 ± 0.04 6.1 ± 0.17 0.79 ± 0.05
111107 97.85 ± 0.09 3.86 ± 0.03 7.4 ± 0.26 0.55 ± 0.04

Preparation and in Vitro Drug Release Evaluation of Once-Daily Metformin Hydrochloride Sustained-Release Tablets 471
than 5.0%. The hardness and percentage friability of the
tablets of all batches ranged from 6.1 ± 0.17 kg/cm2 to
7.4 ± 0.26 kg/cm2 and 0.55% ± 0.04% to 0.79% ± 0.05%,
respectively. The in vitro drug release behaviors of the
three batches of MHSRT in three different dissolution
medium were almost similar. Therefore, the optimized for-
mulation technologies possess good reproduction, which
are suitable for mass produce.
3.2. Evaluation of in Vitro Drug Release
The dissolution profiles of MHSRT developed in this
study and imported Fortamet® made in the United States
of America in water, 0.1 M HCl and pH 6.8 phosphate
buffer as release medium are shown in Figure 4. It was
found from Figure 4 that the release rate of MHSRT was
similar to that of Fortamet®. In the first 2 h, the cumula-
tive release percentages of MHSRT and Fortamet® were
25% and 27% in water; 25% and 22% in 0.1 M HCl;
22% and 20% in pH 6.8 phosphate buffer, respectively.
After 6 h, the cumulative release percentages of MHSRT
and Fortamet® were 59% and 56% in water; 64% and
62% in 0.1 M HCl; 58% and 51% in pH 6.8 phosphate
buffer, respectively.
As we all know, the different release kinetic models
are assumed to reflect different release mechanisms [14].
Therefore, in this study, zero-order release equation,
first-order release equation, Higuchi’s equation and Rit-
ger-Peppas were used to analyze the in vitro released
data. Correlation coefficients of Zero-order, First-order,
Higuchi’s equation and Ritger-Peppas kinetic models
used in this study were shown in Tables 2-4. It can be
seen that the in vitro drug release rate of MHSRT and
Fortamet® in water showed a zero order approximately
kinetic model and could be described by the following
equation: Mt = 7.915t + 8.934 (R = 0.996) and Mt =
7.843t + 9.934 (R = 0.996). However, the release rate of
MHSRT and Fortamet® in 0.1 M HCl and pH 6.8 phos-
phate buffer was fitted with Ritger-Peppas kinetic models
024681012
0
20
40
60
80
100
120
MH released (%)
Time (h)
111105
111106
111107
Figure 3. Drug release profiles of the three batches (111105,
111106, and 111107) of MHSRT in pH 6.8 phosphate buffer
as dissolution medium.
024681012
0
20
40
60
80
100
120
MH released (%)
Time (h)
MHSRT in water
Fortamet(R)in water
MHSRT in 0.1 M HCl
Fortamet(R)in 0.1 M HCl
MHSRT in pH 6.8 phosphate buffer
Fortamet(R)in pH 6.8 phosphate buffer
Figure 4. Drug release profiles of MHSRT develope d in this
study and imported Fortamet® in water, 0. 1 M HCl and pH
6.8 phosphate buffer as dissolution medium.
Table 2. Correlation coefficients of kinetic models used for evaluate the in vitro release behavior of MHSRT and Fortamet® in
water as dissolution medium.
Sample Zero-order First-order Higuchi’s equation Ritger-peppas
MHSRT 0.996 0.893 0.991 0.993
Fortamet® 0.996 0.910 0.989 0.991
Table 3. Correlation coefficients of kinetic models used for evaluate the in vitro release behavior of MHSRT and Fortamet® in
0.1 M HCl as dissolution medium.
Sample Zero-order First-order Higuchi’s equation Ritger-peppas
MHSRT 0.987 0.853 0.996 0.998
Fortamet® 0.988 0.865 0.993 0.997

Preparation and in Vitr o Drug Release Evaluation of Once-Daily Metformin Hydrochloride Sustained-Release Tablets
472
Table 4. Correlation coefficients of kinetic models used for evaluate the in vitro release behavior of MHSRT and Fortamet® in
pH 6.8 phosphate buffer as dissolution medium.
Sample Zero-order First-order Higuchi’s equation Ritger-peppas
MHSRT 0.995 0.827 0.993 0.999
Fortamet® 0.994 0.834 0.982 0.996
and could be described by the following equation: LnMt =
0.801Lnt + 2.665 (R = 0.998) and LnMt = 0.857Lnt +
2.551 (R = 0.997); LnMt = 0.875Lnt + 2.471 (R = 0.999)
and LnMt = 0.922Lnt + 2.354 (R = 0.996), respectively,
which indicated that the drug release mechanisms of
MHSRT and Fortamet® were similar in gastrointestinal
tract. According the formulation composition MHSRT, it
was obvious that drug diffusion and erosion were the
main factor in controlling the drug release rate from
MHSRT. This was also evidenced by the value of the
release exponent n of 0.801 and 0.875, because when n
ranged from 0.45 to 0.89, indicating that drug is released
by the combination of diffusion and erosion mechanisms
[15-16].
On the other hand, the similarity factor f2 value be-
tween 50 and 100 shows that two release profiles are
similar [17]. Therefore, in order to evaluate the in vitro
release difference of MHSRT, when imported Fortamet®
were chosen as reference, f2 value was calculated. It was
found that the dissolution profile of only MHSRT pre-
pared in this study was similar to that of Fortamet®, be-
cause the f2 values in water, 0.1 M HCl and pH 6.8
phosphate buffer were 82, 80 and 74, respectively, which
were all greater than 50.
3.3. Test for Stability
It was known that the stability of preparation is an im-
portant factor to estimate the quality of pharmaceutical
formulation. Thus, the acceleration stability test was
performed to study the stability of MHSRT. It can be
seen from Figures 5-7 that good storage stability was ob-
served and the in vitro release profiles had little change.
And no significant difference in cumulative release per-
centage of drug in water, 0.1 M HCl and pH 6.8 phos-
phate buffer after 1, 2, 3 and 6 months was observed in
comparison with MHSRT samples before storage (n = 3;
P > 0.05). Therefore, MHSRT developed in this study
were stable at least for 6 months under stress conditions.
4. Conclusion
In this study, once-daily metformin hydrochloride sus-
tained-release tables (MHSRT) were successfully devel-
oped by the optimized formulation technologies that are
suitable for mass produce at Chongqing Conquor Phar-
maceutical Co., Ltd. The in vitro release behavior of
MHSRT was almost similar to that of imported For-
024681012
0
20
40
60
80
100
120
MH released (%)
Time (h)
0 month
1 month
2 month
3 month
6 month
Figure 5. Drug release profiles of MHSRT develope d in this
study in water before and after 1, 2, 3 and 6 months of
storage under stress conditions (40˚C ± 2˚C, RH 75% ±
5%).
024681012
0
20
40
60
80
100
120
MH
re
l
ease
d
(%)
Time (h)
0 month
1 month
2 month
3 month
6 month
Figure 6. Drug release profiles of MHSRT develope d in this
study in 0.1 M HCl before and after 1, 2, 3 and 6 months of
storage under stress conditions (40˚C ± 2˚C, RH 75% ±
5%).
tamet®. Furthermore, MHSRT developed in this study
were stable at least for 6 months under stress conditions.
5. Acknowledgements
This research was supported of by the National Natural
Science Foundation of China (81101678), the Key Pro-
gram of the Scientific Research Foundation of the Edu-

Preparation and in Vitro Drug Release Evaluation of Once-Daily Metformin Hydrochloride Sustained-Release Tablets 473
024681012
0
20
40
60
80
100
120
MH released (%)
Time (h)
0 month
1 month
2 month
3 month
6 month
Figure 7. Drug release profiles of MHSRT develope d in this
study in pH 6.8 phosphate buffer before and after 1, 2, 3
and 6 months of storage under stress conditions (40˚C ± 2˚C,
RH 75% ± 5%).
cation Department of Sichuan Province [09ZA049;
11ZZ024], the Scientific Research Foundation of the
Health Bureau of Sichuan Province [100215; 100214]and
the Key Program of the Scientific Research Foundation
of Bureau of Science and Technology of luzhou Munici-
pality [2011-S-32(1/4)].
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