INTRODUCTION:

Tablets are defined as solid pharmaceutical dosage forms made by compression or moulding that contain pharmacological ingredients with or without appropriate diluents. Some tablets are dissolved or dispersed in water before to administration, some are chewed and ingested whole, and some are stored in the mouth where the active ingredient is fully released.¹

When it comes to treating people with essential hypertension, beta-blockers are an essential part of treatment. Bisoprolol is one of the cardio selective beta-blockers used to treat coronary heart disease, arrhythmias, angina, and hypertension. Research has shown that bisoprolol fumarate is superior to propranolol, atenolol, and metoprolol is more successful in lowering high blood pressure.

In reality, Because of hypertension near about 5.8% deaths are happened every year, which are significant indicators of risk for stroke and heart disease. Overall, among the five chronic illnesses along with behavioural disorders, Type 2 diabetes, and disease related to heart is hypertension. (Illness, breathing problems), that which account for the half of the costs incurred by the system of healthcare. 15-20% of adults in Western nations have hypertension, which is a prevalent complicated condition defined by WHO guidelines as increased blood pressure readings surpassing 140/90mmHg. Primary or secondary hypertension are the two categories. The former category refers to hypertension without a recognized disease. When there is no other explanation for elevated blood pressure, essential hypertension is diagnosed. In contrast, Pheochromocytoma, main hyperaldosteronism (Conn's syndrome), Cushing's syndrome (excess glucocorticoids), kidney failure, or drug-induced hypertension have been shown to cause secondary hypertension in 5% of cases.²

MATERIALS AND METHODS:

MATERIALS:

Ingredients: - Bisoprolol Fumarate was obtained as a gift sample from Stride Industries Vadodara (Gujarat). Lactose (diluent), Talc (Glidant), Magnesium Stearate (Lubricant), HPMC (Polymer) and Sodium Starch Glycolate (Super Disintegrant) are purchases from Modern Chemical Industries Sinnar. Crospovidone (Super Disintegrants) and Micro crystalline Cellulose (Binder) are purchases from Research- Lab fine chem industries, Mumbai. Guar Gum (Polymer) is purchase from Balaji Drugs Nashik.

EQUIPMENT’S:

There are various instruments used for research work, including a UV-visible spectrophotometer (Equiptronics, model EQ-826/EQ-824) and a tablet compression machine (Cemach Machineries Ltd. Model no. 8 station D tooling) and also used Fourier Transform Infrared Spectrophotometer (Bruker), Electronic precision balance (Wenser PGB220), Bulk Density and Tapped Density Apparatus (Electro Lab ETD-1020), Tablet Friability Test Apparatus (Veego VFT-1), Hardness Tester (Monsanto 31-1), Disintegration Apparatus (Electro Lab, India USP-TDT-081), Dissolution Apparatus (Electro Lab, India USP-ED-2L), DSC Apparatus.

METHODS:

Preparation of Bisoprolol Fumarate Immediate Release (Part I):

Direct compression was used to create the bisoprolol fumarate tablets. The ingredients for each tablet. The Bisoprolol fumarate, Mannitol, Lactose, and disintegrating agents are Cross povidone, SSG were sieved using sieve #40. The components mentioned above were completely mixed (in a poly-bag). After being passed through mesh #80 in a plastic bag, talc and magnesium stearate were added and combined with the initial mixture. The powders were weighted for individual quantities.³

Preparation of Bisoprolol Fumarate Sustained Release (Part II):

Sustained-release tablets of bisoprolol were prepared by the direct compression method according to the formula given. In this method, at first for each formulation batch, the required amount of API (bisoprolol) and excipients are weighed by the electronic weighing machine. Then bisoprolol is mixed with HPMC and consequently other excipients like MCC, lactose, guar gum, and Mg stearate are mixed gradually in dry and clean mortar. The blend was passed through sieve no. 60. The components mentioned above were completely mixed (in a poly-bag). The powders were weighted for individual quantities.

Preparation of Bisoprolol Fumarate for Immediate Release and Sustained Release Tablet (Bilayer tablet):

Bilayer tablets were compressed using 12 mm round punches on an 8-station rotary punch tableting machine (Cemach Machineries, Station, D tooling), using 12 mm circular punches and the same hardness for the required number of tablets. Bilayer tablets were compressed as one layer only for Immediate Release (Part I) and second layer for Sustained Release (Part II). Both powders were used in the tablet's compression to create a bilayer tablet. In order to ensure that the layer was dispersed properly, the die cavity was first filled with Bisoprolol (Part II) and lightly compressed. The final compression was then completed (Bilayer Tablet) after the addition of the powdered Bisoprolol (Part I).⁴

Design of Experiment:

The processing with the help of the experimental design, parameters were optimized. Response Surface Analysis (RSM) is a commonly used method for creating and refining delivery methods for drugs. The procedure, which is based on the design of experiments (DOE) concept, selects the most effective formulation(s) by using a range of experimental designs, creating polynomial equations, and mapping the response over the experimental domain. The process is significantly more efficient and less expensive than the traditional techniques of creating dosage forms since it involves the least amount of experimentation and time.⁵

Optimization of formulation using quality by design:

For the optimization of Bisoprolol Fumarate bilayer tablet 2- Level Factorial Design was employed using Design Expert 8.0.7.1 software. Total 8 experiments were designed by considering 3 independent variables i.e., HPMC, Guar Gum and Magnesium Stearate at two levels and effect was studied on one response i.e. %CDR and Friability.⁶

Table No.1. Factors and levels for Design of experiments

Sr. No	Independent Factor	Unit	Low (-1)	High (+1)
1	Guar Gum	mg	40	70
2	Magnesium Stearate	mg	12.5	25
3	HPMC	mg	30	60

Table No. 2. Formulation Table

Sr. No.	Ingredients	F1	F2	F3	F4	F5	F6	F7	F8
BISOPROLOL FUMARATE IMMEDIATE RELEASE LAYER
1.	Bisoprolol Fumarate	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5
2.	Mannitol	46.5	50.5	66.5	45.5	61.5	41.5	65.5	70.5
3.	Lactose	8	4	8	4	8	8	4	4
4.	Crospovidone	30	30	10	30	10	30	10	10
5.	Sodium Starch Glycolate	5	5	5	10	10	10	10	5
6.	Talc	4	4	4	4	4	4	4	4
7.	Magnesium Stearate	4	4	4	4	4	4	4	4
	Immediate Layer Weight	100	100	100	100	100	100	100	100
BISOPROLOL FUMARATE SUSTAINED RELEASE LAYER
1.	Bisoprolol Fumarate	5	5	5	5	5	5	5	5
2.	HPMC	30	30	30	60	60	600	30	60
3.	Guar Gum	40	40	70	70	40	40	70	70
4.	Mico Crystalline Cellulose	182.5	190	170	160	182.5	170	190	162.5
5.	Lactose	230	210	200	180	200	200	192.5	190
6.	Magnesium Stearate	12.5	25	25	25	12.5	25	12.5	12.5
	Sustained Layer Weight	500	500	500	500	500	500	500	500
	Total Bilayer Tablet Weight	600	600	600	600	600	600	600	600

All ingredients are weighted in mg

Weight per tablet: 600mg

Hardness of tablet: 5-7Kg/cm²

Thickness of tablet: 4.00-6.00mm

Friability: Not more than 1%

Punch size: 12.00mm

Evaluation:

Preformulation Study

The primarily stage of the rational creation of medication dosage forms is where pre-formulation studies begin. Preliminary study involves the process of improving medication delivery by identifying the physical and chemical properties of novel compounds that may impact drug effectiveness and the creation of effective, reliable, and secure dosage forms.

Identification of Drug

A. Organoleptic Properties of Drug:

The sample of Bisoprolol Fumarate has its organoleptic properties such as colour, Odor, and appearance examined.

i) Colour

ii) Odour

iii) Appearance

B. Melting Point:

Bisoprolol Fumarate melting point were determined using a melting point device, and the obtained value was compared to the value that had been reported.

C. Solubility:

The solubility of Bisoprolol Fumarate in freely soluble in water and in methyl alcohol and slightly soluble in acetone.

D. Ultra Violet Spectroscopy:

Determination of Analytical Wavelength (λmax):

A standard stock solution of Bisoprolol Fumarate was prepared by dissolving accurately weighed 10mg of Bisoprolol Fumarate in water in a 100ml volumetric flask and the volume was made up to 100ml with water to obtain a stock solution of 100µg/ml. From the standard stock solution, 2.5ml was pipetted into 10ml volumetric flask. The volume was made up to 10ml with water. The resulting solution containing 10µg/ml was scanned between 200 and 400nm.

Drug- Excipient Compatibility Study:

Physical Compatibility:

The physical mixture of Bisoprolol Fumarate, Lactose, Sodium Starch Glycolate, Crospovidone, HPMC, Guar Gum and all excipients were kept under compatibility study for the temperature 40⁰C±75 RH for period of 2 months. They were found to be without any significant physical changes. Therefore, it is confirmed that all the active and inactive excipients which were kept under compatibility study are compatible with each other all these ingredients were selected and used in present work.

Chemical Compatibility:

A. Fourier Transform Infrared Spectroscopy:

The IR spectrum of the Bisoprolol Fumarate was recorded by KBr (Potassium Bromide) disk method. The IR spectra of the pure Bisoprolol Fumarate show the functional group as per the structure. The interpretation of the peak obtained in the IR spectra along with their corresponding functional group are at frequency 1247.58 cm^-1 is C-O stretching, 2880.74 cm^-1 is Aliphatic C-H Stretching, 3076.05 cm^-1 is Aromatic C-H Stretching and 1714.73 cm^-1is carbonyl C=O stretching.

B. Differential Scanning Calorimetry of Drug and All Excipients:

The DSC curve of Bisoprolol Fumarate shows sharp endothermic peak at 106.55°C at 6.06min. and the DSC of Bisoprolol Fumarate and all Excipients shows the they are compatibles.⁵

Pre- Compression Evaluation of Bisoprolol Fumarate Tablet

Bulk density:

It is the ratio of total mass of powder to the bulk volume of powder. It was measured by pouring the weight powder (passed through standard sieve #20) into a measuring cylinder and initial weight was noted. This initial volume is called the bulk volume.

Bulk density BD = (M/V) g/cc

Tapped density:

It is the ratio of total mass of the powder to the tapped volume of the powder. Volume was measured by tapping the powder for 750 times and the tapped volume.

Tapped density Td = Mass/Tapped volume

Hausner’s ratio:

Hausner’s ratio is an index of ease of powder flow; it is calculated by following formula.

Hausner’s ratio = Tapped density/Bulk density

Carr’s Index:

Tapped and bulk density measurements can be used to estimate the Carr’s index of a material. Carr’s index was determined by,

C.I (%) = Tapped density – bulk density /Tapped density*100

1.5. Angle of repose:

It is defined as maximum angle possible between the surface of the pile of powder and the horizontal plane.

θ = tan ^-1 (h/r)

Post-Compression Evaluation of Bisoprolol Fumarate Bilayer Tablet

A. Weight Variation:

10 tablets were selected randomly from the lot and weighted individually to check for weight variation. The individual weighed is then compared with average weight for the weight variations. [Table-3]

B. Hardness:

The strength of tablet is expressed as tensile strength (kg/cm²). The tablet crushing load, which is the force required to break a tablet into pieces by compression. It was measured using a tablet hardness tester (Monsanto hardness tester). Three tablets from each formulation batch were tested randomly and the average readings were noted [table 3].

C. Friability:

Friability of the tablets was determined using Roche Friabilator. This device consists of a plastic chamber that is set to revolve around 25rpm for 4min dropping the tablets at a distance of 6 inches with each revolution. Pre weighed sample of 10 tablets was placed in the friabilator and were subjected to 100 revolutions and reweighed. The friability (F %) is given by the following formula

F (%) = (1 – W0 / W) × 100

Where, W0 is weight of the tablets before the test

W is the weight of the tablets after test.

D. Swelling studies:

One tablet from each formulation was weighed and kept in Petri dish containing 20 ml of phosphate buffer of pH 6.8. At the end of specified time intervals tablets were withdrawn from Petri dish and excess buffer blotted with tissue paper and weighed. The % weight gain by the tablet was calculated by following formula.

R = wa – wb/ wb × 100

Where, wa = weight of tablet after absorption

wb = weight of tablet before absorption.

E. In vitro dissolution studies:

The dissolution studies were carried out in pH 6.8 for next 12hrs at 37±0.50C at 100rpm using basket type tablet dissolution apparatus USP type-I. At regular time interval, 5 ml of sample was withdrawn from the dissolution medium and replaced with equal volume of fresh medium. The samples were analysed at 225nm for Bisoprolol Fumarate against blank using UV-Visible Spectrophotometer.

RESULT AND DISCUSSION:

In the present study, in the use of factorial design 8 formulations of bilayer tablets of Bisoprolol Fumarate were prepared, in them ingredients of the immediate layer were kept constant and the sustained release layer ingredients like guar gum, HPMC were used in different concentrations and in combinations.

Standard calibration curve of Bisoprolol Fumarate in distilled water:

Accurately weighed quantity of Bisoprolol Fumarate (10 mg) was dissolved in little quantity of distilled water and volume was made up to 100ml with the same (100 µg/ml). Then withdraw 0.5, 1, 1.5, 2, 2.5ml from the above solution in to separate 10ml volumetric flasks and made up the volume to 10ml to produce 1, 2, 3, 4, 5 µg/ml respectively. And the absorbances were taken at 225 nm. This procedure was performed in triplicate to validate the calibration curve.

Figure No. 1 Calibration curve of Bisoprolol Fumarate in distilled water

Fourier Transform Infrared Spectroscopy:

B. Differential Scanning Calorimetry of Drug and All Excipients:

The DSC curve of Bisoprolol Fumarate shows sharp endothermic peak at 106.55°C at 6.06 min. and the DSC of Bisoprolol Fumarate and all Excipients shows the they are compatibles.

Figure No.2: FTIR Study of Bisoprolol Fumarate

Figure No.2: Differential Scanning Calorimetry of Drug and All Excipients

Table No. 3. Preformulation parameters pre compressional blend

Formulation Batch	Bulk Density	Tapped Density	Angle of Repose (θ)	Carr’s Index (%)	Hausnar’s Ratio
F1	0.412	0.442	28.11	6.57	1.07
F2	0.416	0.446	26.21	6.72	1.07
F3	0.421	0.432	28.45	2.54	1.02
F4	0.412	0.432	25.12	4.62	1.04
F5	0.416	0.442	28.14	5.88	1.06
F6	0.411	0.445	28.26	7.64	1.08
F7	0.412	0.442	24.68	6.74	1.07
F8	0.426	0.446	23.21	5.60	1.05

Table No. 4. Post compressional parameters of bilayer tablets

Formulation Batch	Weight Variation	Hardness(kg/cm²)	Thickness(mm)	Friability (%)	Drug Content (%)
F1	603±0.2	5.86	5.3	0.32	94.32
F2	602±0.6	5.67	5.6	0.34	95.34
F3	599±0.5	5.41	6.1	0.61	94.75
F4	598±0.3	5.56	5.9	0.34	96.88
F5	601±0.2	5.41	5.8	0.62	95.99
F6	603±0.5	5.52	6.2	0.26	98.70
F7	600±0.5	5.88	6.4	0.24	98.16
F8	598±0.5	5.51	6.6	0.31	95.82

Table No. 5. In-Vivo Dissolution Studies

Time (Min)	F1	F2	F3	F4	F5	F6	F7	F8
Immediate Release
0	0	0	0	0	0	0	0	0
5	22.2	26.82	26.82	31.11	22.37	27.68	34.02	25.45
10	28.66	30.92	47.20	47.23	30.38	43.95	48.44	35.54
15	44.13	47.57	52.80	56.57	47.39	56.90	60.69	48.45
20	60.67	67.55	79.57	77.88	64.12	77.88	81.33	67.55
25	76.1	81.37	90.01	89.14	79.64	90.00	93.45	81.37
30	87.42	93.45	96.82	90.06	93.44	96.92	98.66	95.16
Sustained Release
0	0	0	0	0	0	0	0	0
60	18.58	22.51	20	20.5	20.06	23.48	23.61	21.22
120	30.87	32.83	38.62	34.75	36.04	39.29	45.74	37.34
240	43.84	47.08	54.85	53.54	52.26	56.79	61.99	50.98
360	56.82	60.71	71.72	65.26	67.19	73.02	78.21	67.83
480	71.73	74.98	84.72	78.23	81.47	86.01	90.56	82.76
600	84.72	87.96	95.76	91.20	91.22	95.76	98.37	92.52
720	95.76	97.06	99.04	96.44	97.08	98.72	99.70	98.38

Figure No. 3: Cumulative % drug Release in Immediate Release

Figure No. 4: Cumulative % drug Release in Sustained Release

Analysis of Data:

To investigate the influence of 3 factors, full factorial design was used; polynomial equation was deduced to study the impact of independent variables upon the responses i.e., % drug release and disintegration time. Inference on results is obtained by regression equations after considering the magnitude of the coefficient and the sign of coefficient indicates the type of response. Positive sign in the polynomial equation infers that the response increases with increase in the value and negative sign shows the decrease in response with increase in the value. The kind of response when two factors were changed simultaneously is given by interaction terms.

a) Full model for Y1 Dissolution (% drug release):

Drug release = +92.51+0.29* A+0.56* B+0.96* C+1.99 * A +1.29 A * C+2.31* B * C-0.81* A * B * C

It was observed that the independent variables viz. HPMC, Guar Gum, Magnesium Stearate had a positive effect on drug release.

Figure No. 5: Full model for Y1 Dissolution (% drug release)

b) 3D Response Surface Plot:

§ Effect of HPMC, Guar Gum and Magnesium Stearate on drug release Time of Bisoprolol Fumarate in 3D response surface plot confirmed. From the figure response curve of Y1 (%Drug release),

§ It is observed that as concentration of HPMC increases from 30mg to 60mg, Guar Gum increases from 40mg to 70mg and Magnesium Stearate increases from 12.5mg to 25mg drug release increases significantly.

Figure No. 6: 3D Response Surface Plot

c) Full model for Y2 (Friability)

Friability = +0.64-0.063 * A-0.038 * B+0.038 * C-0.29 * A * B+0.087* A * C-0.038 * B * C-0.14* A * B * C. It was observed that the independent variables viz. (C) magnesium Stearate has positive effect, (A) HPMC and (B) Guar Gum had a negative effect on Friability.

Figure No. 7: Full model for Y2 (Friability)

d) 3D Response Surface Plot of (Friability)

§ Curved Y2 (Friability) Effect of HPMC, Guar Gum and Magnesium Stearate on friability of Bisoprolol Fumarate in 3D response surface plot confirmed. From the figure response curve of Y2 (% Friability),

Figure No. 8: 3D Response Surface Plot of (Friability)

CONCLUSION:

· The drug Bisoprolol Fumarate can be formulated in bilayer tablet using direct compression method. Following conclusions may be drawn from the study.

· Pre formulation study was performed by DSC and FTIR that no any significant was observed between Bisoprolol Fumarate and excipients.

Finally, the purpose of this current study was to develop bilayer tablet of Bisoprolol Fumarate for SR and IR with the objective to increase therapeutic effectiveness by using various polymers at different ratios. Tablets of Bisoprolol Fumarate are prepared using different amounts of guar gum and HPMC. In comparison to all other formulations, HPMC (F7 Batch 99.7%) maintained the release for 12 hours and achieved the objectives for this project. HPMC > Guar Gum is the order of the utilised polymers' sustained release capabilities. Immediate release tablets made with different quantities of SSG and Crospovidone. The formulation of Sodium Starch Glycolate (SSG) (F7 Batch), which instantly releases the drug within 30 minutes, achieved the objectives for the present study. Sodium Starch Glycolate > Crospovidone are the utilized super disintegrants that have the potential to release.

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Received on 06.06.2024 Revised on 28.08.2024

Accepted on 03.10.2024 Published on 18.11.2024

Available online from December 19, 2024

Res. J. Pharma. Dosage Forms and Tech.2024; 16(4):309-316.

DOI: 10.52711/0975-4377.2024.00048