FORMULATION AND EVALUATION OF FLOATING TABLET OF METOPROLOL SUCCINATE WITH SYNTHETIC SUPERDISINTEGRANT

Received on 09 November, 2013; received in revised form, 14 December, 2013; accepted, 23 March, 2014; published 01 April, 2014

FORMULATION AND EVALUATION OF FLOATING TABLET OF METOPROLOL SUCCINATE WITH SYNTHETIC SUPERDISINTEGRANT

Pankaj Kumar Yadav* and Himansu Chopra

Faculty of Pharmacy, GRD (PG) IMT, 214-Rajpur Road, Dehradun, 248009, Uttarakhand, India

ABSTRACT: The present work was designed to formulate floating tablet of Metoprolol Succinate with synthetic superdisintegrant as swelling agent. Various formulations of Metoprolol Succinate were prepared by direct compression method using the different concentrations of superdisintegrant ranging from 10% to 15%. The selected batches were evaluated for various parameter like weight variation, thickness, diameter, friability, floating lag time, duration of floating, water uptake, content uniformity, in-vitro drug release and in-vitro drug release kinetics. Formulations with Crosspovidone had showed better results than the Kyron T-314. The data obtained from the in-vitro dissolution studies of optimized batch F5 was fitted in different models viz. zero order, first order, Korsemeyer-Peppas model, Higuchi model and Hixon-Crowell model. Drug release mechanism was found to be First order from optimized formulation. Further for getting the type of release mechanism the data was fitted as per the Korsemeyer-Peppas equation. The exponent value n was found in between 0.45 to 0.89. It indicates that the release of Metoprolol Succinate from developed floating tablets followed non-Fickian transport mechanism.

Metoprolol succinate, Floating tablet, Superdisintegrant, Swellable polymeric devices

INTRODUCTION:Among all route of administration, oral route is most important and preferable route of administration for solid dosage form. Tablets are the most common solid dosage form, administered orally.Oral sustained drug delivery may be complicated by limited gastric residence time. Rapid gastrointestinal transit can prevent complete drug release in the absorption zone and reduce the efficacy of administered dose since the majority of drugs are absorbed in the stomach or the upper part of the small intestine.

Dosage forms that can be retained in the stomach are called gastro retentive drug delivery systems (GRDDS) ¹.Gastro retentive floating drug delivery systems (GRFDDS) have a bulk density lower than that of gastric fluids and thus remain buoyant in the stomach without affecting gastric emptying rate for a prolonged period of time. While the system is floating on gastric contents, the drug is released slowly at a desired rate from the system ².

After release of drug; the residual system is emptied from the stomach. This results in an increased GRT and a better control of the fluctuations in plasma drug concentration. The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion, flotation,sedimentation, expansion modified shape systems or by the simultaneous administration of pharmacological agentthat delay gastric emptying time ^{3, 4}.

Approaches to increase the GRT include:

(i)     Bio-adhesive delivery systems-which adhere to mucosal surfaces ⁵;

(ii)   Swellable delivery systems-which increase in size after swelling and retard the passage through the pylorus and;

(iii)Density-controlled delivery systems-which either float or sink in gastric fluids.

Floating drug delivery is of particular interest for drugs which;

(a)    Act locally in the stomach;

(b)   Are primarily absorbed in the stomach;

(c)    Are poorly soluble at an alkaline pH;

(d)   Have a narrow window of absorption and;

(e)    Are unstable in the intestinal or colonic environment ⁶.

Metoprolol succinate which is used in the treatment of hypertension, angina and arrhythmia has an absorption window and is mainly absorbed from the upper parts of GIT ⁷ and good stability in the acidic environment of the stomach makes it a suitable candidate to formulate in a GRDF ⁸. More over its half-life of 3-7hrs, making repetitive dosing is necessary. Therefore a sustained drug delivery system that spends most of its time in acidic environment of stomach i.e., floating dosage form which improves the bioavailability is desirable ⁹.

The main objective of this study was to prepare floating drug delivery system of Metoprolol succinate by direct compression method. Superdisintegrant {Crosspovidone and Kyron T-314} having ranging from 10% to 15% are used as swelling inducers. Metoprolol succinate is water soluble drug. The various formulations were prepared with different concentration of swelling polymer and superdisintegrant. The various parameters like weight variation, thickness, diameter, friability, wetting time, water absorption ratio, content uniformity, in vitro dissolution drug release study, in vitro drug release kinetics of Floating tablet of Metoprolol succinate is investigated.

MATERIAL AND METHOD: Metoprolol succinate was a gift sample from MACLEOD’S Pharmaceutical limited Andheri (East) Mumbai, Carbopol P-971 and Kyron T-314 were gift sample from COREL Pharma Chem (Ahmedabad), NaHCO₃ was purchase from RANKEM (RFCL Limited, New Delhi), Magnesium Stearate was YARROW Chem product (Mumbai).

Formulation of Floating Tablet: Floating tablet of Metoprolol succinate was developed by direct compression method. The drug and excipient were weighed accurately for individual batch and passed through sieve no. 80. Drug, Crosspovidone, HPMC K-100, Carbopol 971-P, NaHCO_3, MCC and PVPk-30 were mixed in planetary mixture for about 10 min. The NaHCO₃ is previously heated at 105˚C for about 10min.The above mixture is the lubricated with talc and Magnesium stearate in a double cone blender for about 5min. Then tablet is compress in 16 station tablet compression machine using 10 mm bi-concave punches. The different compositions of various formulations were given in (Table 1, Figure 1)

TABLE 1: COMPOSITION OF VARIOUS FORMULATIONS

Formulation of Floating Tablet:

FIGURE 1: FORMULATED TABLET

Evaluation of Formulated Floating Tablet: The prepared tablets can be evaluated for various parameters like thickness, diameter, buoyancy studies, duration of floating, weight variation, friability, content uniformity, water uptake study, in vitro dissolution drug release study and in vitro drug release kinetics ^{10, 11}.

1. Thickness: The thickness of tablet is measured by electronic Vernier caliper. Tablet thickness should be controlled with in a ± 5% variation of a standard value. In addition, thickness must be controlled to facilitate packaging. The thickness in millimeters (mm) was measured individually for ten pre-weighed tablets using electronic Vernier caliper. The average thickness and standard deviation were reported.
2. Diameter: The diameter size and punch size of tablets depends on the die and punches selected for making the tablets. The diameter of tablet is measured by electronic Vernier caliper. The Diameter in millimeters (mm) was measured individually for ten pre-weighed tablets using electronic Vernier caliper. The average diameter and standard deviation were reported.

TABLE 2: THICKNESS AND DIAMETERS

3. Buoyancy Studies: In vitro buoyancy was determined by buoyancy lag time. The tablets were placed in a 100 ml beaker containing buffer. The time required for the tablet to rise to the surface and float was determined as floating lag time.
4. Duration of Floating: This can be determining by the maximum time for the tablet to float on surface.

Test for buoyancy was performed in SGF- Simulated Gastric Fluid maintained at 37^oC.The time for which the dosage form continuously floats on the media is termed as floating time.

5. Weight variation: Twenty tablets were randomly selected and average weight was determined. Then individual tablets were weighed and percent deviation from the average was calculated.
6. Friability: Friability of the tablets was determined using Roche Friabilator (Electrolab, India) that is set at 25 rpm for 4 minutes dropping the tablets at a distance of 6 inches with pre-weighed sample of 20 tablets. Tablets were dusted using a soft muslin cloth and reweighed. The friability (F %) is given by the formula ¹².

F % = (1-W₀ / W) ×100

Where, W₀ is weight of the tablets before the test and W is the weight of the tablets after test.

7. Content uniformity: 20 tablets were randomly selected and average weight was calculated and powdered in a glass mortar. Powder equivalent to 25mg of drug was weight and dissolved in 100ml of 0.1N HCl, filtered and drug content analyzed at spectrophotometrically at 224nm.

TABLE 3: FLOATING LAG TIME (BUOYANCY STUDIES) AND DURATION OF FLOATING

TABLE 4: WEIGHT VARIATIONS, FRIABILITY AND DRUG CONTENT OF FORMULATED TABLET

8. Water Uptake Study: The swelling of the polymers can be measured by their ability to absorb water and swell. The water uptake study of the tablet was done using USP dissolution apparatus II. The medium used was distilled water, 900 ml rotated at 50 rpm. The medium was maintained at 37±0.5⁰C throughout the study. After a selected time intervals, the tablets were withdrawn, blotted to remove excess water and weighed. Swelling characteristics of the tablets were expressed in terms of water uptake (WU) ¹³ as:

WU (%) = [(weight of the swollen tablet-initial weight of the tablet) / initial weight of the tablet] × 100

TABLE 5: WATER UPTAKE STUDY

FIGURE 2: GRAPH OF WATER UPTAKE STUDY OF DIFFERENT FORMULATION

9. In-vitro drug release study: In-vitro drug release of Metoprolol succinate floating tablets was determined using USP Dissolution Apparatus II (Paddle type) (VEEGO). The dissolution test was performed using 900 ml of 0.1N HCl at 37˚C ± 0.5˚C. The speed of rotation of paddle was set at 50 rpm. 5 ml samples were withdrawn at time points of 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 360 min and same volume was replaced with fresh buffer media. Absorbance of solution was checked by UV spectrophotometer (Shimadzu-1700) at a wavelength 224nm and drug release was determined by standard curve ¹⁴.

a)      In vitro dissolution drug release kinetics: In order to investigate the mechanism of release, the data were analyzed with the following mathematical models¹⁵: Zero order kinetic (1), first order kinetic (2), Higuchi Model (3).

Qt = Q⁰    + K⁰ t ……….. (1)

Log Qt   = log Q⁰ + K¹ t /2.303……….. (2)

Qt   = K H. t 1/2   ……….. (3)

The following plots were made: Qt vs. t (zero order kinetic model), log (Q⁰ −Qt) vs. t (first order kinetic model) and Qt vs. t1/2 (Higuchi model), where Qt is the percentage of drug released at time t, Q⁰ is the initial amount of drug present in the formulation and K⁰, K¹ and KH are the constants of the equations13. Further, to confirm the mechanism of drug release, the first 60% of drug release was fitted in Korsemeyer and Peppas Release Model (4)

Mt / M∞ = K. tn   ……….. (4)

Where Mt / M∞ are the fraction of the drug release at time t, K is the rate constant and “n” is the release exponent. The value of “n” is used to characterize different release mechanisms and is calculated from the slope of the plot of log of fraction of drug released (Mt / M∞) vs. log of time.

TABLE 6: IN-VITRO % DRUG RELEASE

FIGURE 3: IN-VITRO DRUG RELEASE OF FORMULATION FROM F1 TO F9

FIGURE 4: IN-VITRO DISSOLUTION EVIDENCES FROM FORMULATION F1 TO F9

TABLE 7: TABLE 7: INTERPRETATION OF DRUG RELEASE MECHANISM

TABLE 8: IN-VITRO DISSOLUTION DRUG RELEASE KINETICS

The dissolution data was plotted in accordance with Zero order, First order and Higuchi kinetic and the drug release mechanism was evaluated by potting the data in accordance with Peppas equation. The best fit model was evaluated based on correlation coefficient (R²) value for each formulation by using BIT-SOFT (software)  and T_50% (time taken for T_50% dissolution as per best fit model ) and T_80% (time taken for T_80% drug release as per best fit model) were obtained. The different models were showed in Table 8. The formulation F5 was selected as optimized formulation based on drug release data, floating lag time, duration of floating, friability, drug content and kinetic model fitting of drug release data.

The F5 formulation showed floating lag time of 4 sec (Table 3) and T_80% equivalent to 12.6 hrs (Table 8). Further it followed Korsemeyer Peppas- power law as show in table 8. The n- value was found to be 0.6595 which indicate non-Fickian diffusion type of release mechanism (Table 7).

FIGURE 5: % CUMULATIVE DURG RELEASE FROM F5 FLOATING TABLET

FIGURE 6: FLOATING EVIDENCES OF FORMULATED TABLET

RESULT AND DISCUSSION: All the formulations were found to maintain the physical integrity for desired time interval. Thickness was found to be in range of 5.02 ± 0.023 to 5.06 ± 0.053 mm and Diameter was found to be  10.01 ± 0.11 to 10.05 ± 0.054mm (Table 2: Thickness and Diameter). On set of floating was found to be 2 second to 8 second and duration of floating was found to be 12 hours for all formulations (Table 3: Floating lag time and Duration of floating and Figure 5 Floating evidences of formulated tablet). Formulations were evaluated for water uptake, the results revealed 199.17 ± 8.13 to 357.52 ± 5.51 % water uptakes (Table 5, Water Uptake Study and Figure 2: Graph of Water Uptake Study of Different Formulation).

The drug release study (Table 6: In-vitro % Drug Release and Figure 3 and 4, In-vitro drug release of formulation from F1 to F9 and Image Evidence) revealed that formulation F1, F2 and F3 where the concentration of swelling agent was increased from 17.5mg to 35mg, the drug release was decreased in F3 formulation as compared with F1 formulation at all the time points.

The F3 formulation showed 17.75% drug release in 2hr whereas F1 showed 21.86% drug released similarly F3, F2 and F3 formulation showed 52.34%, 91.05% and 46.99% drug release in 6 hrs. Further drug release from formulation F1 to F3 were also evaluated by applying one-way ANOVA Test (Kruskal-Watts one way Analysis of variance on point) which showed the difference in the mean value among the treatment groups are greater than would be expected by chance; there is a statistically significant difference (P=0.046). The decrease in the drug release in formulation F3 in comparison to F1 may be due to the increased in path length as the concentration of swelling agent became double in F3 as compared to F1. The increase in diffusion path length might decrease the drug release. The formulation F4 and F5 were designed to check the effect of HPMC K-100 on drug release in comparisons to formulation F1. As the concentration of HPMC K-100 increased in F4 and F5 the drug release was partially decreased. The one way ANOVA test was applied to find out the statistically significant difference in drug release data. The result of ANOVA test in drug release profile of F1, F4 and F5 revealed that the difference in the mean value among the treatment group are not great enough to exclude the possibility that the difference is due to random sampling variability; there is not a statistically significant difference (P=0.913).

Formulation F6 and F7 were designed with varying concentration of Carbopol 971P. The formulation F1 contained 75mg of Carbopol 971P whereas formulation F7 contained 100mg of Carbopol 971P. The drug release data formulation F1, F6 and F7 revealed that drug released in 2hr was 21.86%, 49.9% and 17.68% respectively whereas drug release was 52.34%, 78.01% and 48.74% respectively in 6hr. The comparative drug release data showed that the drug release was decreased as the concentration of Carbopol 971P increased further. One way ANOVA was applied on drug release profile of F1, F6 and F7, which revealed that the differences in the group are greater than would be expected by chance; there is a statistically significant difference (P=0.03).

The formulation F8 and F9 were designed to check the effect of concentration of NaHCO₃ on drug release. The formulation F1, F8 and F9 were contained 52.5mg (15% concentration of total weight of tablet), 35mg (10%) and 43.75mg (12.5%) of NaHCO₃ respectively. The formulation F1, F8 and F9 showed 21.86%, 18.87% and 21.62% drug released in first 2hr respectively whereas 52.34%, 47.87% and 52.33% drug released respectively in 6hr. Further one way ANOVA was applied on drug release profile of F1, F8 and F9, which revealed that the differences in the group are greater than would be expected by chance; there is no statistically significant difference (P=0.705). .

Since the dosage form was floating type, the matrix tablet was fixed to the sinker and used for dissolution.  During the dissolution process, the dosage forms were observed for its integrity.  Even after 12 hours of drug release, the tablet remained intact, though in the gel form (Figure 4, In-vitro Dissolution Evidences)

CONCLUSION: Metoprolol succinate is used popularly for management of hypertension. It belongs to class I category in BCS classification system freely soluble & highly permeable. On the basis of analysis of data gathered from different formulations designed in our work we concluded that crosspovidone may be used as swelling inducer in combined matrix of HPMC K 100M and Carbopol 971P which sufficiently lowered the floating lag time. Further in present work, we optimized the ratios and conditions for sustained delivery of Metoprolol Succinate from floating matrix tablet of HPMC K 100M and Carbopol 971P using Crosspovidone as swelling inducer and sodium bi carbonate as gas generating agent.

ACKNOWLEDGMENT: The author  are thankful to the authority of G.R.D. (PG) I.M.T for providing support to the study and the other necessary facility like internet surfing, library and other technical support to write a research article.

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    How to cite this article:

    Yadav PK and Chopra H: Formulation and evaluation of Floating Tablet of Metoprolol succinate with synthetic superdisintegrants.Int J Pharm Sci Res 2014; 5(4): 1440-48.doi: 10.13040/IJPSR.0975-8232.5(4).1440-48

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