INTRODUCTION:

The present study show that, Metoprolol Succinate is considered as ideal drug for designing appropriate dosage form. Metoprolol Succinate is β blocker used in the treatment of hypertension cardiac arrhythmias. The biological half-life of Metoprolol Succinate is 3-7 hrs¹. The most important tool for the formulation of sustained release dosage form is use of polymer. Eudragit RL100 and xanthan gum are used as a sustained release polymer for prolong action. The present work is based upon the selection of drugs and excipients, preformulation study including identification of drugs like organoleptic properties such as color, odours and appearance, melting point determination, solubility of drug in various solvents, compatibility study of drug and excipients by using FT-IR². After the preformulation study formulate the different batches which are applied by Box Behnken design.

Then performed the evaluation parameters such as pre-compression and post-compression. The pre-compression parameter such as angle of repose, tapped density, bulk density, Hausner’s ratio, compressibility index was performed^3,4. The post-compression evaluations parameter such as hardness, friability. Weight variation, in-vitro dissolution study and stability study. The main objective, to formulate the Metoprolol Succinate sustained release tablet and study the different factors affecting on dissolution rate. Commercially and economically this dosage form is more convenient because less frequency of dosage form, we can take once a day and economically also affordable to every patient. Improve the patient compliance and make the drug administration more convenient⁵.

The oral route of administration is the most preferred route due to flexibility in dosage form, design and patient compliance. But here one has to take into consideration, the various pH that the dosage form would encounter during its transit, the gastrointestinal motility, the enzyme system and its influence on the drug and the dosage form. Most oral sustained release systems use diffusion, dissolution, or a mix of the two methods to produce gradual drug release to the gastrointestinal tract. Theoretically and ideally, a sustained release delivery system should release the medication through a zero-order mechanism, producing a blood-level time profile comparable to that following intravenous constant rate infusion. Plasma drug concentration profiles for three different formulations: a traditional tablet or capsule, a formulation with sustained release, and a formulation with zero order sustained release^6,7.

Figure1. Plasma Concentration-profiles Vs. Time (Sustained released formulation and zero order formulation)

MATERIALS AND METHODS:

Methods:

Direct compression:

Direct compression: 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)^8,9.

Weigh drug and excipients

Blended drug and excipients

Added other excipients likes lubricants and glidants

Compressed

Figure 2. Flow chart of tablet preparation method

Wet granulation technique:

Matrix drugs, Metoprolol Succinate had been prepared by way of a traditional non-aqueous wet granulation method. In each formulation, the amount of the active element is 100 mg and the total weight of a tablet is 250 mg. The ingredients were passedvia a 60-mesh sieve. All ingredients aside from the glidant and lubricant were combined, and special care was paid to guarantee proper blending and phase homogeneity. Granulation became executed manually with a solution of isopropyl alcohol. The wet masses were passed through a 26-mesh sieve and the wet granules produced had been first air dried for 10 min and after lubrication with magnesium stearate. Tablets have been prepared using 7.5mm punch of the tablet compression machine^9,10,11.

Pre-compression evaluation:

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 equation¹².

Tan θ = ------

Where, ‘h’ and ‘r’ are the height and radius respectively of the powder cone Different ranges of flowability in terms of angle of repose are given below¹³.

Bulk density:

Bulk density is defined as the mass of a powder, divided by the bulk volume. The bulk density of a powder depends primarily on particle size distribution, particle shape, and the tendency of the particles to adhere to one another. LBD and TBD were calculated using following formula¹⁴.

Mass

BD= ---------------------

Volume

Tapped density:

Mass

TD= ---------------------

Volume

Hausner’s ratio:

Hausner’s ratio is an indirect index of ease of power flow.

Tapped density

Hausner’s ration = ----------------------------

Bulk density

Lower Hausner’s ratio (1.25) indicates poor flow¹⁵.

Carr’s compressibility index:

The Carr’s compressibility Index was calculated from Bulk density and tapped density of the blend. A quantity of blend 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:

Carr’s compressibility index (%) = [(Tapped density-Bulk density) X100]/Tapped density^{16, 17}.

Post compression evaluation:

Evaluation of tablets:

The prepared tablet were evaluated for Hardness, Thickness, Friability, Weight variation, Drug content, Fourier transform infrared spectroscopy analysis, Differential scanning calorimetric analysis, In vitro drug released study, In vivo oral toxicity study, stability study¹⁸.

Hardness:

Using the Monsanto hardness tester, the hardness of six tablets was find out. The tablet was placed between the tester's two jaws while being held along its diametric axis. The measurement at this time should be 0 kg/cm2. After then, the knob was turned continuously until the tablet broke. The value was noted at this time.

Thickness:

A Dial caliper (Advance) was used to measure the thickness of the tablets. The average values of three tablets of each formulation type were calculated. It is expressed in mm.

Friability:

The tablet's friability was assessed using the Roche friabilator. 6 preweighed tablets were used as a sample, which was placed in the Roche friabilator and run for 100 revolutions i.e. 4 minutes. The tablets were then dusted and reweighed. A loss of less than 1 % in weight in generally considered acceptable. Percent friability (% F) was calculated as follows.

Initial weight – final weight

% Friabilily = ----------------------------------------- x 100

Initial weight

Wet variation test:

20 tablets of each type of formulation were weighed individually using an electronic balance to determine weight variation. The average weight was then calculated, and each tablet's weight was compared to the average value to determine the deviation in weight.

Uniformity of drug content:

A total of twenty tablets were crushed in a mortar and powder equivalent to 10 mg of Metoprolol Succinate was weighed and dissolved in 100 ml of phosphate buffer (pH 6.8). From this stock solution, 1 ml of sample was withdrawn and diluted to 10 ml with phosphate buffer. A double beam UV-Visible spectrophotometer was used to measure the absorbance at wavelength 222 nm. Content uniformity was calculated using the formula¹⁹.

Conc. of unkown

% Purity = -------------------------------------

Conc. of standered

Fourier transform infrared spectroscopy analysis:

In vitro drug release study:

The in-vitro drug release was determined using USP dissolution testing apparatus type-II (paddle type). The dissolution test was performed using 900mL of 0.1 N HCl for 2hrs. and then in phosphate buffer (pH 6.8), at 37ºC±0.5°C and 30rpm. Sample volume of 10mL was withdrawn at regular time intervals. The volume withdrawn was replaced by fresh volume of dissolution medium to maintain constant volume of medium. The filtered samples were analyzed spectrophotometrically at 222nm using 0.1 N HCl and phosphate buffer (pH 6.8) as a blank. Drug content in dissolution sample was determined by calibration curve. The release data were fitted to various mathematical models as under to know which model is best fitting the obtained release profile. Zero order release kinetics, Higuchi model²⁰.

Stability study:

The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. The ability of a pharmaceutical product to retain its chemical, physical, microbiological and biopharmaceutical properties within specified limits throughout its shelf life and recommended storage conditions²¹.

Post compression parameter:

The thickness of all batches was found to be 4.02 to 4.23 mm and the hardness of all batches was found to be 4.53 to 5.16kg/cm2.All the tablets showed % friability in the range of 0.299 to 0.843% which was within the limit. drug content uniformity were ranged from 97.18±1.31 % to 99.64±1.78%. No variations in weight of the tablets as all tablets were found to be within the range limit for weight variation²².

Drug and excipients compatibility study:

Fourier transform infrared spectroscopy (FTIR):

To assess compatibility study Metoprolol Succinate and excipients mixtures were placed at temperature 40ºC and 75% RH for one month in 1:1 proportion on the basis of FTIR spectra it seems there were no possible interaction of Metoprolol Succinate and excipients. The below FTIR spectrums showed the peaks of major functional groups of drug. These peaks are nearly unchanged as compared to spectrum of mixture of drug along with excipients and pure drug. Hence, it can be concluded that there was no interaction between drug, diluents and the polymer used in the formulation. The IR spectra of drug and mixture showed the following characteristic features; broad band at N-Hstretch (3500-3100), C-H Stretch (3000-2800), C=O Aldehyde (1740-1720), N-H bend (1640-1550), Aromatic C=Cstretching (1600-1475), C-O stretching of alkyl ether²³.

Zero order kinetics:

Drug dissolution from pharmaceutical dosage forms that do not disaggregate and release the drug slowly, assuming that the area does not change and no equilibrium conditions are obtained can be represented by the following equation²⁴.

𝑄𝑡 = 𝑄𝜊 + 𝐾օ

Where,

𝑄𝑡 = amount of drug dissolved in time t.

𝑄օ = initial amount of the drug in the solution

𝐾օ = zero order release constant.

First order kinetics:

To study the first order release rate kinetics, the release rate data were fitted to the following equation,

𝐿𝑜𝑔𝑄𝑡 = 𝑙𝑜𝑔𝑄օ + 𝐾1𝑡/2.303

Where,

𝑄𝑡 is the amount of drug released in time t,

𝑄օ is the initial amount of drug in the solution and

𝐾1 is the first order release constant.

Higuchi model:

To study the Higuchi release kinetics, the release rate data were fitted to the following equation,

F= 𝐾.𝑡1/2

Where,

F is the amount of drug release,

K is the release rate constant and

t is the release time.

When the data is plotted as a cumulative drug released versus square root of time, yields a straight line, indicating that the drug was released by diffusion mechanism²⁵. The slope is equal to ‘K’

CONCLUSION:

Metoprolol succinate are sustained released drug. They are used in heart failure, angina pectoris, and uses include supraventricular tachycardia and thyroid storm. There are immediate and sustained released preparation used. There is also conflicting evidence regarding to optimal choice of a particular β blocker.

ACKNOWLEDGMENTS:

The authors are grateful to the authorities of Shri Sai College of Pharmacy, Khandala for the facilities.

CONFLICT OF INTEREST:

The authors are declare no conflict of interest

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Received on 25.05.2023 Modified on 07.10.2023

Asian J. Pharm. Res. 2024; 14(1):62-66.

DOI: 10.52711/2231-5691.2024.00009