Use of Hydrophilic Natural Guar Gum in Formulation of Controlled-Release Matrix Tablets of Metformin Hydrochloride and Its Comparison with Marketed Product

Nikunj Patel, Ashok Kumar P*, Basavaraj, Tom Damien, Someshwara Rao B and Suresh V Kulkarni

epartment of Pharmaceutics, Sree Siddaganga College of Pharmacy, B.H. Road, Tumkur-572102, Karnataka, India.

ABSTRACT:

In the present investigation an attempt was made to formulate the oral controlled release metformin hydrochloride matrix tablets by using Guar gum as rate controlling polymer and to evaluate drug release parameters as per various release kinetic models. The tablets were prepared by wet granulation method. Granules were prepared and evaluated for loose bulk density, tapped density, compressibility index and angle of repose, shows satisfactory results. All the granules were lubricated and compressed using 12.8 mm flat faced punches. Compressed tablets were evaluated for uniformity of weight, content of active ingredient, friability, hardness, in vitro release studies and swelling index. All the formulations showed compliance with Pharmacopoeial standards. The in vitro dissolution study was carried out for 12 hours using paddle (USP type II) method in phosphate buffer (pH 6.8) as dissolution media. The prepared matrix tablets were shown 99.92%, 97.41%, 94.95%, 89.29%, 86.41% and 84.72% release over a period of 12 hours. Formulations F-1 and F-2 failed to sustain release beyond 9 hours and 11 hours, respectively. Among all the formulations, F-5 showed the controlled release of drug for 12 hours with 86.41% release and the release profile was close to the marketed sample of metformin hydrochloride (M-SR). Selected formulation (F-5) was subjected to stability studies for 3 months, which showed stability with respect to release pattern. The drug release follows first order kinetics and the mechanism was found to be diffusion coupled with erosion.

KEYWORDS: Metformin hydrochloride, Guar gum, Matrix tablets, Wet granulation, Controlled release

INTRODUCTION:

In recent years oral controlled delivery systems have gained increased importance and interest since it is necessary to improve the systemic absorption of the drugs and patient compliance. In addition, controlled delivery systems maintain uniform drug levels, reduce dose, side effects, and increase the safety margin. Matrix controlled release tablet formulations are the most fashionable and straightforward to formulate on a commercial scale. A wide variety of polymer matrix systems have been used in oral controlled drug delivery to obtain a desirable drug release profile, cost effectiveness, and broad regulatory acceptance.

Metformin HCl is an antihyperglycemic agent which improves glucose tolerance in patients with type-2 diabetes by lowering both basal and postprandial plasma glucose. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type-2 diabetes or normal subjects and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease. The low bioavailability and short half-life of metformin HCl make the development of controlled-release forms desirable.

However, drug absorption is limited to the upper gastrointestinal (GI) tract, thus requiring suitable systems providing complete release during stomach-to- jejunum transit (Corti et al., 2008).

Natural gums are biodegradable and nontoxic, which hydrate and swell on contact with aqueous media, and these have been used for the preparation of dosage form.¹Guar gum is alactomannan, obtained from the ground endosperm of the guar plant, Cyamopsis tetragonolobus. It has been investigated as controlled release carrier and regarded as nontoxic and nonirritant material.^2-4

In this study, matrix tablets containing different concentrations of guar gum were prepared by wet granulation method and subjected to in vitro drug release studies to find the utility of guar gum in providing controlled release.

MATERIALS AND METHODS:

Materials:

Metformin hydrochloride was obtained as gift sample from (Micro Labs, Bangalore). Guar gum and polyvinyl pyrrolidine (PVP-K-30) were procured from (Himedia laboratories Pvt. Ltd, Mumbai). Avicel pH 101 was purchased from (S.D. Fine Chemicals, Mumbai). Magnesium stearate and talc were obtained from (Loba Chemicals, Mumbai). All other ingredients used were of analytical grade.

Preparation of matrix tablets:

Matrix tablets were prepared by wet granulation method. The composition of various formulations is given in Table 1. Metformin hydrochloride, Guar gum and Avicel pH 101 were mixed in a polybag, and the mixture was passed through mesh (No.60). Granulation was done using a solution of PVP- K-30 in sufficient isopropyl alcohol. The wet mass passed though mesh No.16. The wet granules were air dried for 2 hours. The granules were then sized by mesh No.22 and mixed with magnesium stearate and talc. Tablets were compressed at 1000 mg weight on a 27-station rotary tableting machine (Cadmach, Ahmedabad) with 12.8 mm flat-shaped punches. Six different formulas, having different concentrations of guar gum (10%, 15%, 20%, 25%, 30% and 35%), were developed to evaluate the drug release and to study the effect of polymer concentration on drug release.

Table 1: Tablet composition (%w/w) of different formulations of metformin hydrochloride controlled release matrix tablets

Ingredients	Formulation code
	F1	F2	F3	F4	F5	F6
Metformin HCl	50	50	50	50	50	50
Guar gum	10	15	20	25	30	35
PVP- K-30	5	5	5	5	5	5
Avicel pH 101	32	27	22	17	12	7
Magnesium stearate	2	2	2	2	2	2
Talc	1	1	1	1	1	1

Evaluation of granules:

The angle of repose was measured by using funnel method⁵, which indicates the flowability of the granules. Loose bulk density (LBD) and tapped bulk density (TBD)⁶ were measured using the formula: LBD= weight of the powder / volume of the packing. TBD= weight of the powder / tapped volume of the packing. Compressibility index⁷ of the granules was determined by using the formula:

CI (%) = [(TBD-LBD/TBD)] ×100.The physical properties of granules were shown in Table 2.

Table 2: Release mechanism with variation of n^* values

n value	Mechanism	dmt/dt dependence
n<0.5	Quasi-Fickian diffusion	t^0.5
0.5	Fickian diffusion	t^0.5
0.5<n<1.0	Anomalous (non-Fickian) diffusion	t^n-1
1	Non-Fickian case II	Zero order
n>1.0	Non-Fickian super case II	t^n-1

^*The diffusional exponent is based on Korsmeyer-Peppas equation. M_t/M_t = ktⁿ

Evaluation of tablets:

All prepared matrix tablets were evaluated for its uniformity of weight, hardness, friability and thickness according to official methods⁸ shown in Table 3.

Drug content:

Five tablets were powdered in a mortar. An accurately weighed quantity of powdered tablets (100 mg) was extracted with pH 6.8 buffer and the solution was filtered through 0.45 µ membranes. The absorbance was measured at 232 nm after suitable dilution.

In-vitro drug release studies:

In-vitro drug release studies were carried out using USP XXII dissolution apparatus type II (Electrolab, Mumbai, India) at 50 rpm. The dissolution medium consisted of 900 ml of pH 6.8 phosphate buffer, maintained at 37+ 0.5⁰c. The drug release at different time intervals was measured using an ultraviolet visible spectrophotometer (Labindia, Mumbai, India) at 232 nm. The study was performed in triplicate.

Swelling behavior of controlled release matrix tablets:⁹

The extent of swelling was measured in terms of % weight gain by the tablet. The swelling behavior of formulation F-3, F-5 and F-6 was studied. One tablet from each formulation was kept in a petridish containing pH 6.8 phosphate buffer. At the end of 1 hour, the tablet was withdrawn, soaked with tissue paper, and weighed. Then for every 2 hours, weights of the tablet were noted, and the process was continued till the end of 12 hours. % weight gain by the tablet was calculated by formula; S.I = {(Mt-Mo) / Mo} X 100, where, S.I = swelling index, Mt = weight of tablet at time't' and Mo = weight of tablet at time t = 0.

RESULT AND DISCUSSION:

The supplied drug passed the various tests of identification and analysis. The pure drug metformin hydrochloride and the solid admixture of drug and various excipients used in the preparation of controlled release tablet formulations were characterized by FT-IR spectroscopy to know the compatibility. The FT-IR study did not show any possibility of interaction between metformin hydrochloride and guar gum/other excipients used in the matrix tablets, figure-1.

Table 3: Granule properties of the different formulations of metformin hydrochloride controlled release matrix tablets

Parameters	Formulation Code
	F1	F2	F3	F4	F5	F6
Angle of repose	26.28 ± 0.265	25.84 + 0.390	26.85 + 0.871	27.68 + 0.174	27.71 + 0.279	28.40 + 0.195
Loose bulk density(LBD) (g/ml)	0.2027 + 0.005	0.2093 + 0.007	0.2083 + 0.005	0.2091 + 0.002	0.2042 + 0.001	0.2038 + 0.004
Tapped bulk density (TBD) (g/ml)	0.2465 + 0.014	0.2405 + 0.013	0.2419 + 0.018	0.2428 + 0.014	0.2352 + 0.016	0.2428 + 0.015
Compressibility index (%)	17.76 + 0.62	14.90 + 0.69	13.83 + 0.93	13.87 + 0.83	13.18 + 1.05	16.06 + 0.89

The values represent mean + S.D; n=6.

Table 4: Tablet properties of the different formulations of metformin hydrochloride controlled release matrix tablets

Parameters	Formulation code
	F1	F2	F3	F4	F5	F6
Thickness(mm)	5.72 + 0.05	5.78 + 0.04	5.69 + 0.02	5.75 + 0.04	5.74 + 0.03	5.65 + 0.02
Hardness(kg/cm^2)	7.2 + 0.01	7.3 + 0.10	7.1 + 0.01	7.3 + 0.10	7.3 + 0.12	7.3 + 0.06
Friability(%)	0.117	0.124	0.109	0.120	0.126	0.153
Drug content(%)	98.95 + 0.41	99.83 + 0.48	100.03 + 0.30	99.51 + 0.34	99.88 + 0.53	99.39 + 0.25

The values represent mean + S.D; n=6.

Table 5: Kinetic values obtained from different plots of formulations, (F1 to F6)

Formulation code	Higuchi’s plots^1	Korsmeyer et al’s plots^2		First-order plots^3	Zero-order plots^4
	R^2	Slope(n)	R^2	R^2	R^2
F1	0.995	0.4664	0.990	0.920	0.910
F2	0.996	0.4722	0.994	0.949	0.911
F3	0.998	0.4952	0.996	0.970	0.912
F4	0.996	0.5300	0.995	0.997	0.915
F5	0.994	0.5609	0.995	0.996	0.922
F6	0.996	0.5683	0.994	0.996	0.926
M-SR	0.995	0.4972	0.993	0.945	0.922

¹Higuchi equation, Q = Kt½.

²Korsmeyer et al’s equation, Mt/ M∞=Ktⁿ.

³First order equation, Log C = log C₀ - Kt/2.303.

⁴Zero order equation, C=K₀ t.

Figure 1. Comparison of In-vitro release profile of metformin hydrochloride from formulations F-1 to F-6 with marketed sample

Granulation is the key process in the production of many dosage forms. To ensure good content uniformity and avoid flow related intertablet weight variation problems, wet granulation is preferred in routine commercial production. Wet granulation was thus used in the present study. Physical properties of granules such as specific surface area, shape, hardness, surface characteristics and size can significantly affect the rate of dissolution of drug contained in a formulation. The granules of the different formulations were evaluated for angle of repose, loose bulk density, tapped bulk density, and compressibility index. The results of angle of repose and compressibility index (%) ranged from (25.84 + 0.390 to 28.40 + 0.195) and (13.18 + 1.05 to 17.76 + 0.62), respectively. The results of loose bulk density and tapped bulk density ranged from (0.2027 + 0.005 to 0.2093 + 0.007 and 0.2352 + 0.016 to 0.2465 + 0.014), respectively. The results of angle of repose (<30) indicate good flow properties of granules.^10,11 This was further supported by lower compressibility index values¹⁰ (Table 3). The physical properties of different batches of developed matrix tablets are given in (Table 4). The thickness of the tablets ranged from (5.65 + 0.02 to 5.78 + 0.04) mm. All the batches showed uniform thickness. The average percentage deviation of 20 tablets of each formulation was less than (5%), and hence all formulations passed the test for uniformity of weight as per official requirements (Pharmacopoeia of India 1996). The hardness of the tablets of all the formulations ranged from (7.1 + 0.01 to 7.3 + 0.12)kg/cm². Tablets hardness is, however, not an absolute indicator of strength. The percentage friability of the tablets of all the formulations ranged from (0.109% to 0.153%). In the present study, the percentage friability for all for formulations was below 1% w/w, indicating that the friability is within the prescribed limits (Banker and Anderson 1987). Drug content was found to be uniform among different formulations of the tablets and ranged from (98.95 + 0.41 to 100.03 + 0.30).

Figure 2. Fourier transform infrared spectra of A: Pure metformin hydrochloride, B: Guar gum, C: Metformin hydrochloride with guar gum, D: Formulation F-5. (From top to bottom)

The results of the dissolution studies for formulations F-1, F-2, F-3, F-4, F-5, F-6 and marketed SR tablets of glycomet-500 SR, USV Limited, Mumbai (M-SR) are shown in the figure-2. Formulations F-1 and F-2 released 99.92% and 97.41% of drug at the end of 9 hours and11 hours, respectively. Marketed SR tablets (M-SR) released 96.85% of drug at the end of 8 hours. Marketed SR tablets (M-SR) failed to sustain release beyond 8 hours. Formulations F-3, F-4, F-5 and F-6 exhibited slow and controlled release of drug and at the end of 12 hours, the drug release was 94.95%, 89.29%, 86.41% and 84.72%. It is reported in the literature that more than 30% release of drug in the first hour of the dissolution indicates the chances of dose dumping. The release of metformin hydrochloride containing low concentration of guar gum (formulations F-1 and F-2) showed initial burst release during the first hour (37.12% + 1.2% and 33.15% + 1.4%, respectively, for formulations F-1 and F-2). However, the release of metformin hydrochloride contained high concentration of guar gum formulations (F-3, F-4, F-5 and F-6) exhibited a well controlled effect and no burst release was observed. It was found that the cumulative percentage of drug release decreases with increase in the polymer concentration.

Figure 3: Relationship between swelling index and time.

Relationship between swelling index and time of formulation F-3 (-◊-), F-5 (-■-) and F-6(-▲-)

The swelling index was calculated with respect to time (figure-3). As time increases, the swelling index was increased, because weight gain by tablet was increased proportionally with rate of hydration up to 7 hours and 9 hours from formulations F-3, F-5 and F-6, respectively. Later on, it decreases gradually due to dissolution of outermost gelled layer of tablet into dissolution medium. The direct relationship was observed between swelling index and gum concentration, and as gum concentration increases, swelling index was increased. It has been observed that the cumulative percent drug release decreases with increasing concentration of gum and swelling index. The reason attributed to this fact is slow erosion of the gelled layer from the tablets containing higher amount of guar gum.

The inverse relationship was noted between amount of gum and release rate of metformin hydrochloride. Increasing the amount of gum in the formulation from 10% w/w to 35% w/w, resulted in slower rate, and decreased amount of drug release from the tablet Figure 2. This slow release is because of the formation of a thick gel structure that delays drug release from tablet matrix, where hydration of individual guar gum particles results in extensive swelling. Thus, maintain the integrity of the tablets, and retarding further penetration of the dissolution medium, prolonged the drug release.³

The release data was fitted to various mathematical models to evaluate the kinetics and mechanism of the drug release (Table 5). The regression coefficient obtained from first-order kinetics were found to be higher (R² : 0.920 to 0.996) when compared with those of zero-order kinetics (R² : 0.910 to 0.926), indicating that the drug release from all the formulations followed first-order kinetics. In this experiment, the in vitro release profiles of drug from all these formulation could be best expressed by Higuchi’s equation as the plots showed highest linearity (R² : 0.995 to 0.996) indicates that the drug release follows diffusion mechanism. To confirm the diffusion mechanism, the data were fitted into Korsmeyer–Peppas equation. The formulations F-1, F-2 and F-3 showed good linearity (R² : 0.990, 0.994 and 0.996) with slope(n) values ranging from 0.4664 to 0.4952 indicating that diffusion was the predominant mechanism of drug release from these formulations. When plotted according to Korsmeyer-Peppas equation, the formulations F-4 to F-6 showed high linearity (R² : 0.994 to 0.995) with a comparatively high slope (n) values of > 0.5 which appears to indicate a coupling of diffusion and erosion mechanism so called anomalous (non-Fickian) diffusion. Hence, diffusion coupled with erosion might be the mechanism for the drug release from guar gum based controlled release matrix tablets.

CONCLUSION:

From the above observations it is concluded that slow and controlled release of metformin hydrochloride over a period of 12 hours was obtained from matrix tablets (F-3 to F-6). Use of natural hydrophilic polymer like guar gum was successful in the formation of matrix and at the same time it is effective in retarding the drug release. The formulation F-5 shows the release profile close to that of marketed sample of metformin hydrochloride. The cumulative percentage drug release was decreased by increase in polymer concentration. The drug release follows first order kinetics. The mechanism of drug release was diffusion coupled with erosion. Based on the FT-IR studies, there appears to be no possibility of interaction between metformin hydrochloride and guar gum / other excipients used in the tablets. The stability studies shown that there was no significant change in hardness, friability, and drug content of selected formulation F-5. Thus, the proposed formulation F-5 can be successfully used for the management of type-2 diabetes, can overcome the disadvantages associated with conventional tablet formulations of metformin hydrochloride.

ACKNOWLEDGEMENT:

The authors are thankful to the Management, Sree Siddaganga College of Pharmacy, for providing necessary facilities to carry out this work.

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Received on 01.02.2010

Accepted on 02.04.2010

© A&V Publication all right reserved

Research Journal of Pharmaceutical Dosage Forms and Technology. 2(2): March –April. 2010, 193-197