Online - 2455-3891

Vol 11, Issue 3, 2018 Print - 0974-2441

Research Article

FORMULATION AND EVALUATION OF METFORMIN HYDROCHLORIDE SUSTAINED-RELEASE

ORAL MATRIX TABLETS

PADMAJA BOOKYA1*, RAMAKRISHNA RAPARLA1, HARIKISHAN PRASAD SRIRAMULA1, SUNITHA TARRIGOPULA2,

SRIDHAR VANGA2
1
Department of Pharmaceutics, Vaageswari Institute of Pharmaceutical Science, Karimnagar – 505 481, Telangana, India.
2
Department of Pharmaceutical Chemistry, Vaageswari Institute of Pharmaceutical Science, Karimnagar – 505 481, Telangana, India.
Email: bookyapadmaja@gmail.com
Received: 08 July 2017, Revised and Accepted: 11 December 2017

ABSTRACT

Objective: The aim of this investigation was to develop and optimize metformin hydrochloride matrix tablets for sustained release application.
The sustained release matrix tablet of metformin hydrochloride was prepared by wet granulation technique using chitosan, xanthan gum, and
hydroxypropyl methylcellulose at varying concentrations.

Material and Methods: Extended release of metformin hydrochloride matrix tablets was prepared by wet granulation method. The influence of
varying the polymer ratios was evaluated. The excipients used in this study did not alter physicochemical properties of the drug.

Results: All the batches were evaluated for thickness, weight variation, hardness, and drug content uniformity. The in vitro drug dissolution study was
carried out using USP apparatus Type II, paddle method, and the release mechanisms were explored. Mean dissolution time is used to characterize
drug release rate from a dosage form and indicates the drug release is retarding efficiency of the polymer. This study revealed that as the concentration
of matrix material increased, drug release from matrices decreased. This may be due to slower penetration of the dissolution medium into the matrices.

Conclusion: Formulation with chitosan MS1 drug release was 86%, xanthan gum MS489%, and finally MS7 with hydroxypropyl methyl cellulose
which exhibited the highest drug release retardation also had the lowest matrix concentration. Hence, lower concentration of polymers is suitable to
prepare metformin hydrochloride tablets compared to higher concentrations.

Keywords: Sustained release tablet, Metformin hydrochloride, Hydroxypropyl methyl cellulose, Xanthan gum, Chitosan.

© 2018 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4. 0/) DOI: http://dx.doi.org/10.22159/ajpcr.2018.v11i3.21211

INTRODUCTION induce hypoglycemic at any reasonable dose, and hence it is called as an

antihyperglycemic rather than a hypoglycemic drug. The compound has
Oral route of administration is considered as widely accepted route due
a relatively short plasma half-life of 1.5–4.5 h with low bioavailability of
to ease inconvenience by self-administration, compactness, and simple
50–60% so need for the administration of 2–3 times a day when larger
manufacturing process. It was observed that drugs administered
doses are required can decrease patient compliance [7]. The objective
by oral route produce 90% of systemic effects [1]. Tablets being
of the present study was to prepare oral sustained release matrix tablet
most popular oral formulations available in the market are widely
of metformin hydrochloride by wet granulation using polymers such
preferred by patients and physicians alike in long-term therapy for
as chitosan, xanthan gum, and hydroxypropyl methylcellulose and
the treatment of chronic conditions [2]. Conventional dosage form
to evaluate the effect of concentration of polymers for the release of
produces the wide range of fluctuation in drug concentration in
the drug. Such a sustained release formulation if achieved would be
bloodstream which leads to a loss in drug effectiveness or increases
substantially more affordable to the patient.
the incidence of side effects with subsequent undesirable toxicity
and poor efficiency. However, sustained or controlled drug delivery MATERIAL AND METHODS
systems can decrease the frequency of the dosing and also increases
effectiveness of the drug by localization at the site of action, reducing Materials
the dose required and providing uniform drug delivery [3]. Sustained Metformin hydrochloride was the gift sample from Aurobindo Pharma
release preparations are helpful to reduce the dosage frequency and Ltd., Hyderabad. All other ingredients used throughout the study were
side effects of drugs and improve patient’s convenience. Sustained of an analytical grade such as chitoson, hydroxypropyl methylcellulose,
release matrix tablet is relatively easy to fabricate by incorporating the and xanthan gum were received from Loba Chemicals, Mumbai.
drug in slowly dissolving or inert porous polymer materials [4]. Drug Isopropyl alcohol, talc, and magnesium stearate were procured from
release through matrix system is determined by water penetration, S.D. Fine Chemicals, Mumbai.
polymer swelling, drug dissolution, drug diffusion, and matrix erosion
that lead to a rapid formation of external layer, allowing drug release Nine different tablet formulations were prepared using wet granulation
modification [5]. The major therapeutic goals in subjects with Type II method. The composition of tablets was given in Table 1. Sustained-release
diabetes are to optimize blood glucose control, reduce overweight, and matrix tablets of metformin hydrochloride were prepared using different
elevated blood pressure. However, pharmacological treatment with polymer ratios. All ingredients were passed through a #80 sieve weighed
oral hypoglycemic agents or insulin is required [6]. An oral biguanide on a digital balance (Shimadzu, Japan) and blended. Tablets weighing
metformin hydrochloride used in the management of Type II diabetes, 750 mg were prepared containing 500 mg of metformin hydrochloride,
a common disease that combines defects of both insulin secretion and hydroxypropyl methylcellulose, xanthan gum, and chitosan. Required
insulin action. Unlike other antidiabetic drugs metformin Hcl does not quantities of drug, diluents, and polymers were mixed thoroughly by
 Bookya et al.
Asian J Pharm Clin Res, Vol 11, Issue 3, 2018, 342-345

adding a sufficient quantity of binding agent like isopropyl alcohol slowly. Thickness
After enough cohesiveness was obtained, the wet mass was sieved The thickness of all formulations was determined on screw gauge
through #16 mesh. The sifted granules were dried at 50°C for 1 h in hot (Pharma Labs, Ahmedabad, India). Standard deviation values indicate
air oven (BTI, Bio Technics, Mumbai). The dried granules were mixed all formulations were within the range [13].
with talc as a diluent and magnesium stearate as a lubricant for 5 min [8].
Finally, tablets were compressed by 10 mm punches on 16 Station Rotary Tablet hardness
tablet machine (Saimach Ltd., India). All tablets were stored in airtight Hardness of the tablets for shipping or breakage under conditions of
containers for further study. Before compression, the granules were storage, transportation, handling depends on hardness which was
evaluated for their flow and compressibility characteristics. determined using Monsanto hardness tester [14] (E 30, Dwaraka Mai,
Hyderabad).
EVALUATION OF POWDER BLENDS OF METFORMIN
HYDROCHLORIDE Friability
The Friability of five tablets was determined using Roche friabilator
The powder blends of metformin hydrochloride formulations were (Electrolab, Mumbai). This device subjects tablets to the combined
evaluated before compression to assess the flow properties of the effect of abrasions and shock in a plastic chamber revolving at 25 rpm
powder. and dropping the tablets at the height of 6 inches in each revolution.
Pre-weighed sample of tablets was placed in the friabilator and was
Bulk density subjected to 100 revolutions dedusted and reweighed [15]. The
Required amount of powder m was transferred into the measuring friability (F) is given by the formula:
cylinder, and apparent volume V0 was measured, bulk density in g per
ml is calculated by the formula. F = (1-W0/W)*100

Bulk density = m/V0. Where, W0 is the weight of the tablets before the test.
W is the weight of the tablet after the test.
Where m-mass of powder, V0 -apparent volume.
Drug content
Tapped density Five tablets were weighed accurately and powdered, powder
After determination of bulk density the measuring cylinder Va volume equivalent to 10 mg of drug was dissolved in phosphate buffer pH 7.4,
in ml was measured initially, later the same cylinder was set for 100 filtered using 0.2 um membrane filter [16]. The drug content was
tappings on tapped density apparatus and measure the tapped volume measured by ultraviolet (UV)-spectrophotometer (Shimadzu, Japan)
finally Vb. Calculate tapped density in g per ml by the formula [9]. at 233 nm.
Tapped density = Va/Vb. In vitro drug release
In vitro, drug release studies for the prepared tablets were conducted
Where Va - initial volume, Vb - final tapped volume.
using USP Type II paddle dissolution apparatus (Electrolab, Mumbai,
India) at 100 rpm. One matrix tablet was placed in each flask of
Carr’s index
dissolution apparatus the study was conducted in 900 ml 0.1 N Hcl
It is an indirect method of measuring powder flow from bulk densities to
37±0.5°C in first 2 h and later 900 ml of phosphate buffer pH 7.4 for
measure bridge strength and stability. Carr’s index of each formulation
remaining 12 h. 5 ml samples were withdrawn at regular intervals and
was calculated according to the equation.
same volume was replaced to maintain sink conditions [17]. The samples
were analyzed after suitable dilutions with UV-spectrophotometer
Carr’s index = (Tapped density - bulk density)/tapped density *100.
(Shimadzu, Japan) at 233 nm. All the experimental units were carried
in triplicates.
HAUSNER RATIO
It is essential to determine the compressibility strength of powder. It Kinetic analysis of dissolution data
was calculated according to equation [10]. The in vitro drug release data were fitted into zero-order, first-order,
and Higuchi by employing the method of least squares the mechanism
Hausner ratio = Tapped density/bulk density. of drug release was compared for all the formulations.

Lower Hausner’s ratio (<1.25) indicates better flow properties than Mt/M∞ = Ktn
higher ones (>1.25).
Mt/M∞ = b+k2t1/2
Angle of repose
Accurately weighed quantity of powder was transferred into a funnel Mt/M∞ = a+k3t
which was adjusted to a height of 2 cm in such a way that the tip of
funnel touches apex of a pile of powder heap [11]. Finally, the height In Peppas equation, Mt/M∞ is the fraction of drug released up to time t,
and radius of powder cone were measured using the following equation. K kinetic constant and n is the release exponent indicative of the release
mechanism. In Higuchi and zero-order release equations, k1, k2, and
tan θ = h/r. k3 are constants [18]. On the other hand, Higuchi equation expresses a
diffuse release mechanism.
Where θ = angle of repose, h = height of pile, r = radius of pile base.
RESULTS AND DISCUSSION
EVALUATION OF METFORMIN HYDROCHLORIDE SUSTAINED-
In the present work, sustained-release tablets of metformin
RELEASE MATRIX TABLETS
hydrochloride were prepared by wet granulation method as it was
Weight variation feasible and simple. Formulations were prepared by varying amount of
Ten tablets from each batch were selected randomly and weighed on polymers to see the effect of various polymer concentration on drug
a digital balance (Shimadzu, Japan) individual weights were compared release rate. The prepared mixed powder was physically evaluated with
with average weight. The percentage difference in the weight variation some parameters and was suggested to be suitable for compression
should be within the permissible limits [12]. into tablets.

343
 Bookya et al.
Asian J Pharm Clin Res, Vol 11, Issue 3, 2018, 342-345

Evaluation of powder blends of metformin hydrochloride of the tablets was in the range of 4.18–5.32 mm. The hardness of tablets
sustained-release tablets was determined and found in the range of 6.10–7.41 Kg/cm2. As the aim
The method employed for the preparation of metformin hydrochloride of the study is to release the drug slowly, hardness was kept in the high
sustained-release tablets was wet granulation method, mixture of range. The % of content uniformity in tablets was determined by UV
drug and excipients should possess good flow properties. The flow spectrophotometer (Shimadzu, Japan). All formulations are subjected
properties of powder blend metformin hydrochloride were checked to content uniformity and were in the range of 98.4–101%. It was
by studying the angle of repose, compressibility index, and Hausner’s observed that all the formulations were as per I.P. specification limits
ratio. The powder blends were found to be free flowing with good flow (90.0–110.0%). The % drug release data and plot which were obtained
properties as shown in Table 2. for the metformin hydrochloride sustained-release tablets in 0.1N Hcl
in first 2 h and phosphate buffer pH 7.4 up to 12 h at 233 nm was shown
Bulk density was found to be in the range of 0.500–0.640 (g/ml) and in Table 4 and Fig. 1, respectively.
tapped density between 0.623 and 0.647 (g/ml) for all the formulations.
The % compressibility index was calculated using the density data. The From the drug release it was observed that at low concentrations of
obtained values 11.15–15.91% which were found to be good flow and the polymers, the matrices of the tablets readily disintegrated during
Hausner’s ratio values were in the range of 1.131–1.189 for all powder dissolution test. This was not, however, the case when the content of the
blends. This was further supported by the angle of repose values matrix former was increased, thus indicating that a minimum level of
between 17.17 and 20.55°. As it was below 30° it indicated good flow the polymers is required to form a proper matrix that would not readily
properties of powder blend. disintegrate. This study revealed that as the concentration of matrix
material increased, drug release from matrices decreased. This may be
Preparation and evaluation of metformin hydrochloride sustained- due to slower penetration of the dissolution medium into the matrices.
release tablets Formulations with chitosan drug release were 86% for MS1, xanthan
The studies were carried to find the effect of different concentrations gum was 89% for MS4, and finally MS7with hydroxypropyl methyl
ranges of polymers. Evaluation data of metformin hydrochloride cellulose for 92% which exhibited highest drug release retardation
sustained-release tablets were shown in Table 3. with the lowest matrix concentration. Hence, a lower concentration
of polymers is suitable to prepare metformin hydrochloride tablets
All the tablets were having beveled edged flat surface in round compared to higher concentrations. The initial drug release may be
shape with white color. Average weight of tablets was in the range of attributed to “burst” release of the drug on the tablet surface. It has
740–769 mg and weight variation was according to the limits. Thickness stated that the drug particles present on the surface of a matrix system

Table 1: Formula of metformin hydrochloride sustained‑release tablets

Ingredients MS1 MS2 MS3 MS4 MS5 MS6 MS7 MS8 MS9
Metformin hydrochloride 500 500 500 500 500 500 500 500 500
Chitosan 100 150 200 ‑ ‑ ‑ ‑ ‑ ‑
Xanthan gum ‑ ‑ 100 150 200 ‑ ‑ ‑
HPMC ‑ ‑ ‑ ‑ ‑ ‑ 100 150 200
Magnesium stearate 10 10 10 10 10 10 10 10 10
Talc 140 90 40 140 90 40 140 90 40
Isopropyl alcohol Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S
Total weight (mg) 750 750 750 750 750 750 750 750 750
HPMC: Hydroxypropyl methylcellulose

Table 2: Evaluation of powder blend of sustained‑release tablets

Batch No Angle of repose (θ) Bulk density (g/ml) Tapped density (g/ml) Carr’s index (%) Hausner’s ratio
MS 1 19.03±0.11 0.562±0.02 0.636±0.02 11.62 (Good) 1.131 (Good)
MS 2 19.03±0.11 0.566±0.06 0.647±0.03 15.91 (Good) 1.189 (Good)
MS 3 17.17±0.11 0.540±0.06 0.642±0.06 15.85 (Good) 1.189 (Good)
MS 4 20.55±0.51 0.549±0.05 0.623±0.05 11.85 (Good) 1.134 (Good)
MS 5 19.03±0.11 0.500±0.06 0.647±0.03 15.91 (Good) 1.189 (Good)
MS 6 17.17±0.11 0.540±0.06 0.642±0.06 15.85 (Good) 1.189 (Good)
MS 7 20.55±0.51 0.549±0.05 0.623±0.05 11.85 (Good) 1.134 (Good)
MS 8 19.01±0.11 0.546±0.05 0.640±0.03 11.15 (Good) 1.189 (Good)
MS 9 17.17±0.11 0.640±0.06 0.642±0.06 15.85 (Good) 1.189 (Good)

Table 3: Evaluation data of metformin hydrochloride sustained‑release tablets

Batch No Weight variation (mg) a Thickness (mm) b Hardness (Kg/cm2) b Friability (%) c Content uniformity (%) c

MS 1 757±0.86 4.40±0.01 6.10±0.23 0.192±0.57 98.4±0.73
MS 2 741±1.16 4.59±0.05 6.85±0.25 0.198±0.12 101±1.61
MS 3 762±3.57 4.38±0.88 7.41±0.05 0.218±0.17 99.2±0.12
MS 4 759±0.88 4.38±0.07 7.22±0.15 0.236±0.27 99.1±0.40
MS 5 758±0.88 4.18±0.07 6.15±0.98 0.216±0.07 99.8±0.19
MS 6 769±0.12 5.32±0.07 6.15±0.83 0.226±0.21 99.1±0.14
MS 7 740±0.88 4.18±0.03 6.15±0.75 0.246±0.78 99.8±0.78
MS 8 743±1.11 4.38±1.12 6.35±0.14 0.219±0.45 99.6±0.69
MS 9 745±0.12 4.36±0.15 6.15±0.56 0.286±0.32 99.8±0.42
Each value is an average of ten determinationsa, each value is an average of three determinationsb, each value is an average of five determinationsc

344
 Bookya et al.
Asian J Pharm Clin Res, Vol 11, Issue 3, 2018, 342-345

Table 4: % drug release data of metformin hydrochloride Formulations with chitosan MS1 drug release are 86%, xanthan gum
sustained‑release tablets MS4 was 89%, and finally MS 7 with hydroxypropyl methylcellulose
was 92% which exhibited the highest drug release retardation, also
Time (H) MS1 MS2 MS3 MS4 MS5 MS6 MS7 MS8 MS9 had the lowest matrix concentration. Hence, a lower concentration of
0 0 0 0 0 0 0 0 0 0 polymer such as hydroxypropyl methylcellulose is optimized batch
1 14 17 19 13 16 14 12 15 11 suitable to prepare metformin hydrochloride tablets compared to
2 20 21 27 22 19 26 22 25 16 higher concentrations. On analyzing regression coefficient values of all
3 26 27 30 31 24 32 33 30 22 batches, it was found that tablets exhibited almost zero-order kinetics,
4 34 33 37 38 29 41 39 36 27 followed Higuchi model.
5 41 38 45 44 35 48 49 42 32
6 47 43 55 50 42 52 53 59 39 ACKNOWLEDGMENT
7 55 53 62 54 57 59 59 63 48
8 67 61 67 62 69 61 63 69 58 The authors express their sincere thanks to management Dr. G. Srinivas
9 73 67 71 68 72 65 70 71 61 Reddy, Karim Nagar, India, for providing required facilities to carry out
10 81 71 75 78 79 71 78 75 79 this research work.
11 83 80 82 82 76 79 86 82 83
12 86 82 85 89 83 85 92 89 87 REFERENCES
1. Hadi MA, Babu VL, Narottam P. Formulation and evaluation of
sustained release matrix tablets of glimepiride based on combination
of hydrophilic and hydrophobic polymers. J Appl Pharm Sci
2012;2:101-7.
2. Patil J, Sarode SM, Sathe B, Jain PV. Formulation and evaluation
of sustained release tablets of ritonavir. World J Pharm Pharm Sci
2014;3:857-69.
3. Sanjit KR, Sweet N, Subhasis K, Ketousetuo K. Formulation
and evaluation of sustained release bilayer tablets of propranolol
hydrochloride. Int J Pharm Pharm Sci 2015;7;264-9.
4. Shanmugam S, Chakrahari R, Sundaramoorthy K, Vetrichelvan T.
Formulation and evaluation of sustained release matrix tablets of
losartan potassium. Int J Pharm Tech Res 2011;3:526-34.
5. Bisht T, Rishiwer P, Kumar P. Review on matrix tablet. Indo Glob
Pharm Sci 2016;6:38-42.
6. Basavaraj K, Mhase SR, Manvi FV. Formulation of extended-
release metformin hydrochloride matrix tablets. Trop J Pharm Res
2011;10:375-83.
7. Dharmendra S, Kumar JS, Mahapatra S. Formulation and evaluation of
sustained release metformin hydrochloride matrix tablet using natural
Fig.1: Cumulative % drug release plot of sustained-release tablets
polysaccharide. Am J Pharm Tech Res 2014;4:492-503.
8. Wadher KJ, Kakde RB, Umekar MJ. Study on sustained-release
were initially released into the surrounding media generating many metformin hydrochloride from matrix tablet: Influence of
pores and cracks which facilitate further release of drug and also the hydrophilic polymers and in vitro evaluation. Int J of Pharm Inv
2011;1:157-63.
formation of channels within the matrix.
9. Krishnarajan D, Reddy CM, Sasikanth K, Kumar NS, Purushothaman M.
Formulation and evaluation of sustained release matrix tablets
To describe the kinetics of drug release from matrix tablets, release data of levofloxacin using natural polymer pharmacophore. Int Res J
were analyzed according to different kinetic equations. The data were 2013;4:146-57.
analyzed by the regression coefficient method and regression coefficient 10. Nagendrakumar D, Ganesh G, Ambarish GS. Sustained release matrix
values (r2) of all batches. On analyzing regression coefficient values of all tablets of furosemide. J Pharm Sci 2015;5:105-14.
batches, it was found that tablets exhibited almost zero-order kinetics, 11. Ch C, Kumar YG, Vishnu YV, Madhuri MM. Metoprolol succinate
followed Higuchi model. The in vitro release profiles of the drug from all sustained release matrix tablets-Formulation development and in vitro
these formulations could be best expressed by Higuchi’s equation as the evaluation. Int J Pharm Pharm Sci 2014;6:481-6.
12. Jyothshna K, Pavan B, Venkateswara B, Pichika M. Formulation and
plots showed the highest linearity (r2=0.98–0.99). To confirm diffusion
development of multilayer and monolithic extended release matrix
mechanism, the data were fitted into Korsmeyer-Peppas equation. tablets of alfuzosin Hcl”. Asian J Pharm Clin Res 2013;7:76-9.
13. Patel J, Shah N. Formulation and evaluation of sustained release tablets
CONCLUSIONS containing atomoxetine hydrochloride. J Pharm Sci and Biosci Res
2014;4:196-200.
The present investigation was carried out to develop the sustained
14. Usman M, Ali I, Bibi H, Iqbal J. Preparation and evaluation of controlled
delivery of metformin hydrochloride for an effective and safe therapy release tablets containing mefenamic acid. Clin Exp Pharmacol
using three polymers such as chitosan, hydroxypropyl methylcellulose, 2012;2:1-3.
and xanthan gum. 15. Shanmugam S, Babu R, Satheeshkumar S, Shanmugasundaram P.
Formulation and evaluation of sustained release matrix tablets
The term modified-release dosage form is used to describe products that of levosulpiride using natural polymer. Asian J Pharm Clin Res
alter the timing and rate of release of drug substance. A modified-release 2017;10:285-92.
dosage form is defined “as one for which the drug release characteristics 16. Kanti SM, Giriraj T, Suresh B. Development of sustained release
of time course and/or location are chosen to accomplish therapeutic or bilayered tablets of diclofenac sodium using natural hydrogel as matrix
material drug content. JchrDD 2013;4:53-64.
convenience objectives not offered by conventional dosage forms such
17. Ajinkya, U., Sanjay, K., Mangesh, B. Design and optimization of
as solutions, ointments, or promptly dissolving dosages forms.” sustained release matrix tablet of opipramol hcl by using quality by
design approach. Asian J Pharm Clin Res 2014;7:227-34.
It is an oral antidiabetic drug in the biguanide class. It is the first-line 18. Varma JN, Ch PK, Reddy AK, Raju PP. Evaluation of Moringa oleifera
drug of choice for the treatment of Type II diabetes in particular, in gum as a sustained release polymer in diclofenac sodium tablet
overweight and obese people and those with normal kidney function. formulation. Int J Res Pharm Chem 2014;4:687-93.

345