INTRODUCTION:

Tablets are the most popular oral solid formulation present in the market and are present by patient and physicians like. The sustained release dosage form have been indicate to enhance the therapeutic efficacy by maintaining steady state drug plasma concentration. Metoprolol Succinate β1 selective adrenergic receptor, blocking agent used in the angina pectoris, myocardial infraction, hypertension, cardiacarrhythmias, heart failure, hyperthyroidism and in the treatment of migraine.¹

Metoprolol Succinate is absorbed throughout the GIT.The most common method used to prepared sustained release tablet by wet granulation method or direct compression method. The manufacturing of the tablet by direct compression method is cost saving simple process. The metoprolol succinate sustained release tablet use the different polymer like sodium carboxy methyl cellulose, xanthan gum, Eudragit RL-100.Metoprolol succinate are present in the market like tablet, capsules and injection. The sustained release tablet is available in market (Asoprol 25 mg, Zulip 500mg, Met XLT25). Generic present (Ag-metoprolol-L, Apo-Metoprolol)²

MATERIALS:

Metoprolol Succinate was procured as gift sample from Mylan Laboratories Ltd, Sinner and polymers like Xanthan gum, Sodium carboxy methyl cellulose, Eudragit RL-100 were procured from balaji drug suppliers and lactose, magnesium stearate, talc this ingredients use are of lab grade chemicals.3

METHODOLOGY:

Preformulation Studies Standardization of Metoprolol succinate by UV-Visible spectrophotometry in 0.1 N HCl Solution:

Preparation of stock solution

Stock solution 100µg/ml of Metoprolol succinate was prepared in 0.1N HCl solution. This solution was approximately diluted with 0.1N HCl to obtain a concentration of 10µg/ml. The resultant solution was scanned in range of 200- 400nm using UV double beam spectrophotometer (Lab India UV-3000+).⁴

Standard calibration of Metoprolol succinate in 0.1N HCl

100mg of Metoprolol succinate was accurately weighed and dissolved in100ml of 0.1N HCl to obtain a concentration of 1000µg/ml. From the above 10ml was withdrawn and diluted to 100ml to obtain a concentration of 100µg/ml. From this stock solution aliquots of 1ml, 2ml, 3ml, 4ml, 5ml up to 10ml were diluted in 10ml volumetric flask with phosphate buffer. Absorbance was measured at 275nm.⁵

In pH 6.8 Buffer

Preparation of stock solution

Stock solution 100µg/ml of Metoprolol succinate was prepared in phosphate buffer of pH 6.8. This solution was approximately diluted with phosphate buffer of pH 6.8 to obtain a concentration of 10µg/ml. The resultant solution was scanned in range of 200- 400nm using UV double beam spectrophotometer (Lab India UV3000+).^6,7

Standard calibration of Metoprolol succinate in phosphate buffer of pH 6.8:

100mg of Metoprolol succinate was accurately weighed and dissolved in100ml of pH 6.8 phosphate buffer to obtain a concentration of 1000µg/ml. From the above 10ml was withdrawn and diluted to 100ml to obtain a concentration of 100µg/ml. From this stock solution aliquots of 1ml, 2ml, 3ml, 4ml, 5ml up to 10ml were diluted in 10ml volumetric flask with phosphate buffer. Absorbance was measured at 235nm.⁸

Drug- Excipient Compatibility by FTIR studies:

In the preparation of SR tablet, drug and polymer may interact as they are in close contact with each other, which could lead to instability of drug. Preformulation studies regarding drug-polymer interactions are therefore very critical in selecting appropriate polymers. FT-IR spectroscopy (Agilent Technologies) was employed to ascertain the compatibility between Metoprolol succinate and selected polymers. The individual drug and drug with excipients were scanned separately.⁸

Stability Studies:

The stability study was carried out according to ICH guidelines at 25±2ºC/60±5%RH for one months by storing the sample in () stability chamber.

Angle of repose:

The angle of repose was determined by the funnel method. The accurately weighed powder was taken in a funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touched the apex of the heap of the powder. The powder was allowed to flow through the funnel freely onto the surface. The diameter of the powder cone was measured. The angle of repose was calculated using the following equation.

Tan Ѳ= h/r

Where ‘h’ and ‘r’ are the height and radius respectively of the powder cone

Carr’s compressibility index:

The Carr’s compressibility Index was calculated from Bulk density and tapped density of the blend. A quantity ofblend from each formulation, filled into a 10mL of measuring cylinder. Initial bulk volume was measured, and cylinder was allowed to tap from the height of 2.5cm. The tapped frequency was 25±2 per min to measure the tapped volume of the blend. The bulk density and tapped density were calculated by using the bulk volume and tapped volume.

Carr’s compressibility index was calculated by using following formula:

Tapped density-Bulk density

Carr’s compressibility index (%) =–––––––––––––X 100

Tapped density

Tapped bulk density (TBD)

An accurately weighed powder blend from each formula was lightly shaken to break any agglomerates formed and it was introduced into a measuring cylinder. The measuring cylinder was tapped until no further change in volume was noted which gave the tapped volume. The tapped bulk densities (TBD) of powder blends were determined using the following formula.¹⁰

Total weight of powder

TBD=–––––––––––––––––––––––––––––––

Total volume of tapped powder

Formulation of tablets

The sustained release tablets of metoprolol succinate were prepared by both wet granulation and direct compression methods. The tablets obtained from these methods are compared for their release characteristics.

By Wet Granulation Method:

Different tablet formulations containing unit dose of metoprolol succinate were prepared by wet granulation technique. Required quantities of drug and polymer were mixed thoroughly in a mortar, and a sufficient volume of granulating agent (Ethanolic solution of EC or Eudragit or PVP or IPA solution of PVP for hydrophilic gums) was added slowly. After obtaining the required cohesiveness, the mass was sieved through 18mesh. The granules were dried at 40°C for 2 hours. Once dried, talc and magnesium stearate were finally added as glidant and lubricant. The tablets were compressed using a 10-station tablet compression machine using 8 mm punches (Tablet punching machine D-Tooling).¹¹ The composition of each tablet is shown in Table 1 and 2.

Table 1: Formula for the sustained release tablets of metoprolol succinate for each tablet (F1-F4)

Ingredients	F1	F2	F3	F4
Metoprolol succinate	47.5	47.5	47.5	47.5
Ethyl Cellulose	7	-	-	-
Eudragit RL-100	-	7	-	-
PVP	-	-	7	7
HPMC	-	40	40	-
NA.CMC	40	-	-	40
Lactose	150	150	150	150
Talc	2.5	2.5	2.5	2.5
Mg. Stearate	3	3	3	3
Total	250	250	250	250

Table 2: Formula for the sustained release tablets of metoprolol succinate for each table (F5-F6)

Ingredients	F5	F6	F7	F8
Metoprolol Succinate	47.5	47.5	47.5	47.5
Guar Gum	60	72	-	-
Xanthan Gum	-	-	60	72
Lactose	128	116	128	116
PVP	7	7	7	7
Talc	5	5	5	5
Mg. Stearate	2.5	2.5	2.5	2.5
Total	250	250	250	250

By Direct Compression Method:

Different tablet formulations containing unit dose of metoprolol succinate were prepared by Direct Compression technique. Required quantities of drug and polymer were mixed thoroughly, and a sufficient volume of filling agent (Micro Crystalline Cellulose) and Aerosil were added and mixed properly. Talc and magnesium stearate were finally added as glidant and lubricant. The tablets were compressed using a 8-station tablet compression machine using 8 mm punches (Tablet compression machine D-tooling).¹² The composition of each tablet is shown in Table 3.

Table 3: Formula for the sustained release tablet of metoprolol succinate for each tablet (F9-F10)

Ingredients	F9	F10	F11	F12
Metoprolol Succinate	47.5	47.5	47.5	47.5
Ethyl cellulose	50	0	0	75
Eudragit RL-100	50	87.5	125	0
MCC	90	102.5	65	115
Aerosil	5	5	5	5
Talc	5	5	5	5
Mg. Stearate	2.5	2.5	2.5	2.5
Total	250	250	250	250

Evaluation of tablets:

Hardness

The hardness of the tablets was tested by diametric compression using a Monsanto Hardness Tester. A tablet hardness of about 2-4 kg/cm2 is considered adequate for mechanical stability.

Friability

The friability of the tablets was measured in a Roche friabilator (Veego). Tablets of a known weight (W0) or a sample of 10 tablets are dedusted in a drum for a fixed time (100 revolutions) and weighed (W) again. Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss should not be more than 1 %

Initial weight- Final weight

Friability (%) = ––––––––––––––––––––––––––––x 100

Initial weight

Thickness and Diameter:

Thickness of the all tablet formulations were measured using vernier calipers by placing tablet between two arms of the vernier calipers. The same procedure should be adapted for the measurement of Diameter.

In- Vitro Dissolution Study:

The In-vitro dissolution study for the Metoprolol Succinate sustained release tablets were carried out in USP type-II dissolution test apparatus(Paddle apparatus)using 900 ml of phosphate buffer 6.8 pH as dissolution medium at 50 rpm and temperature 37±0.5⁰c.At predetermined time intervals,5ml of the sample were withdrawn by means of a syringe fitted with a pre-filter, the volume withdrawn as each interval was replaced with same quantity of fresh dissolution medium.¹³ The resultant sample were analysed for the presence of the drug release by measuring the absorbance at 275 nm using UV Visible spectrophotometer after suitable dilutions. The determinations were performed in triplicate.^14,15

RESULTS AND DISCUSSION:

The present study was carried out to formulate and evaluate sustained release tablets of metoprolol succinate both by wet granulation and direct compression method. The tablets were prepared by using different hydrophilic and hydrophobic polymers viz. ethyl cellulose, Eudragit RL-100, poly vinyl pyrrolidone, and xanthan gum.

Preformulation characteristics:

The drug Metoprolol succinate was standardized by UV method in 0.1N HCl and pH 6.8 Buffer separately. The lambda max were 275nm and 235 nm in 0.1N HCl and pH 6.8 buffer respectively.

Fig1: ƛmax of Metoprolol Succinate in 0.1 N HCl (275nm)

Fig2: Calibration curve of Metoprolol Succinate in 0.1 N HCl

Drug: Excipient Compatibility studies:

FTIR Drug-Excipient compatibility studies by FTIR revealed no interaction between drug and the polymers used in the formulation thus showing compatibility.

Fig3: FTIR spectra of pure drug

Fig 4: FTIR spectra of pure drug and polymer

Fig 5: FTIR spectra of Eudragit RL100

Fig6: DSC of Metoprolol Succinate

Fig7: DSC of Metoprolol Succinate and polymer

Pre-compression parameters

Evaluation properties of granules

Granulation is an important step in the preparation of tablets as the physical properties of granules play a vital role in the release of drug from the sustained release tablets. The Metoprolol succinate granules were prepared by wet granulation method. The prepared granules of different batches were evaluated for their granule size, angle of repose, bulk density, tapped density, compressibility index and Hausner‟s ratio, and the results are shown

The bulk densities of the granules were found to be in the range of 0.38-0.46 gm/ml. The tapped densities were in the range of 0.42-0.52 gm/ml. The Carr‟s indexes were in the range of 5.33-14.29. Hausner’s ratio was found in the range of 1.06-1. The angle of repose varied from 30.78-37.30. The low values of angle of repose indicate free flowing nature of the granules. Hence, as they complies with pharmacopoeial standards with good flow properties and may be compressed into tablets.

Table.4. Pre-compression parameters of granules for formulation

Batch Code	Bulk Density (gm/ml)	Tapped Density (gm/ml)	Cars Index (%)	Hausner’s Ratio	Angle of Repose (%)
F1	0.38	0.45	14.67	1.17	31.76
F2	0.40	0.43	7.50	1.08	31.33
F3	0.43	0.50	14.29	1.17	37.30
F4	0.39	0.42	7.06	1.08	35.31
F5	0.44	0.47	6.67	1.07	34.82
F6	0.40	0.44	8.24	1.09	36.18
F7	0.43	0.48	11.43	1.13	36.03
F8	0.44	0.51	13.51	1.16	33.07
F9	0.43	0.48	9.72	1.11	36.43
F10	0.44	0.51	14.29	1.17	36.25
F11	0.42	0.49	14.29	1.17	34.00
F12	0.46	0.52	11.76	1.13	32.74

Table.5: Post-Compression parameters off all formulation F1-F12.

Batch code	Hardness (Kg/cm2)	Friability (%)	Wt. Variation (mg)	Drug content (%)
F1	3.5	0.33	250±1.73	96.698
F2	4.1	0.27	249±2.02	101.415
F3	3.8	0.88	249±1.10	94.34
F4	3.5	0.33	251±1.84	102.981
F5	4.3	0.40	250±2.02	101.415
F6	4.0	0.33	250±2.05	106.138
F7	3.8	0.40	249±2.35	94.34
F8	4.5	0.40	250±1.55	96.698
F9	5.1	0.47	249±1.70	99.05
F10	4.9	0.47	250±1.75	103.774
F11	3.7	0.68	250±2.26	94.43
F12	3.7	0.33	250±1.95	108.241

Post-compression parameters Evaluation of tablets:

The sustained release tablets of metoprolol succinate were prepared both by wet granulation and direct compression methods. The tablets were evaluated for their weight variation, hardness, friability, drug content uniformity and the results are tabulated in the Table. The weight variation was within the prescribed limits and it varied between 249±1.10 to 251±1.93 mg.

Hardness was in the range of 3.4 to 5.2 kg/cm2. Therefore, another measure of a tablet’s strength, its friability, is often measured. Friability was less than 1% (i.e. 0.20 to 0.61%) in all the batches, which indicates tablet ability to withstand shock during the time of transportation and handling. Drug content uniformity was in the range of 91.98 to 110.85%. All the physical characteristics of the formulated tablets were within acceptable limits.

Table.6. In Vitro release data for formulation F1-F4

Time(hrs)	% Drug Release
	F1	F2	F3	F4
1	18.21	23.77	21.04	28.87
4	56.44	50.97	55.80	49.32
8	82.41	92.90	86.40	91.89
20	101.56	102.67	103.54	101.78

Fig 8: Drug release data for formulations F1-F4

Table.7. In Vitro release data for formulation F5-F8

Time(hrs)	% Drug Release
	F5	F6	F7	F8
1	19.94	15.21	26.27	15.69
4	57.98	16.57	16.88	57.82
8	95.43	91.95	95.55	93.35
20	102.46	99.41	106.52	103.50

Fig.9.Drug release profile formulation F5-F8

Table. 8. In Vitro release data for formulation F9-F12

Time(hrs)	% Drug Release
	F9	F10	F11	F12
1	10.02	9.15	17.57	19.34
4	46.53	41.61	55.52	63.01
8	84.67	77.29	86.95	89.61
20	103.47	93.14	101.55	105.53

Fig.10. Drug release profile for formulation F9-F12

Kinetics and mechanism of drug release:

The drug release mechanism was studied by comparing the correlation coefficient for different release model. Kinetic result shown in table9.The kinetic result show that the correlation coefficient (R²) is higher for zero order plot than all other plots. From zero order plot value of the optimized formulation is0.980 show that the release mechanism of formulation.

Table.9. Correlation coefficient (R²) values of formulation containing Eudragit RL-100

Kinetic model	R²
Zero Order Plot	0.9808
First Order Plot	0.8641
Higuchi model	0.9371
Korsmeyer –Peppas model	0.9795

Fig.11. Kinetic plots for optimized formulation containing Eudragit RL-100

CONCLUSION:

Metoprolol succinate sustained release tablet were prepared successfully using different polymer. The formulated tablets were evaluated for different parameters like thickness, hardness, friability, weight variation, drug content and in vitro drug release studies. Among all this formulation F10 is optimized. This formulation containing 47.5 mg drug, 35% of Eudragit RL-100, 102.5mg MCC ,5 mg aerosol, 5mg talc,2.5 mg. Stearate showed 93.14% release of drug in 20 hrs.Therotical drug release profile and has the sustain action i.e. the release is for a long time and thus more availability The analysis of the release profiles of kinetic models (zero order, first order,higuchi model, korsmeyer peppas model conclusion that ,the drug release from Eudragit polymer korsmeyer–peppas kinetics and the mechanism of drug release was both diffusion and erosion.

ACKNOWLEDGEMENT:

The authors are grateful to the authorities of Loknete Dr. J. D. Pawar College of Pharmacy, Manur for the facilities.

CONFLICT OF INTREST:

The authors declare no conflict of interest.

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Received on 11.06.2021 Modified on 17.07.2021

Res. J. Pharma. Dosage Forms and Tech.2021; 13(4):269-275.

DOI: 10.52711/0975-4377.2021.00044