INTRODUCTION:

The concept of orodispersible tablet drug delivery system emerged from the desire to provide patients with conventional means of taking their medication. The orodispersible tablets have become a very popular dosage form as they disintegrate rapidly in the mouth and don’t need water for administration. This is due to the increased patient compliance, pleasant mouth feel, ease of administration and swallowing and rapid disintegration and dissolution.^1,2,6,9

Fenofibrate stimulated the oxidation of free fatty acids in the liver. This promotion of the β-oxidation of fatty acids reduced the availability of fatty acids for very-low density lipoprotein synthesis and secretion. Fenofibrate is used to treat primary hypercholesterolemia, mixed dyslipidemia, severe hypertriglyceridemia.

Fenofibrate is practically insoluble in water and bitter in taste so solvent evaporation method are used to reduce of unpleasant taste, improving patient compliance and better therapeutics efficacy.^8,12

Fig. 1: Structure of Fenofibrate

Advantages:

· Easy to Administration

· Accurate and measured dose

· Unit Dosage form

· Cheap to the patient

· Rapid absorption

· Easy to prepare with minimum amount of equipment and time.

· Technique is non invasive as is the case with parenterals.

· It can Increase in bioavailability

· It can reduce gastric irritation.

· It can improve onset of action.

· Improved patient compliance.

MATERIALS AND METHODS:

Fenofibrate was received Bioplus life science, Bangalore and methanol, ethanol, chloroform, lactose, citric acid, polyvinylpyrrolidone, sodium starch glycolate, crospovidone, croscarmellose, magnesium stearate and talc were purchase from Loba Chemie Pvt. Ltd. Mumbai.

Methodology:

Pre-formulation studies:

Standardization of ^Fenofibrate by UV–Vis spectrophotometer: Accurately weighed 10mg of drug was dissolved in 10ml of methanol in 10ml of volumetric flask. The resulted solution (1000µg/ml) was used to prepare the concentration 10μg/ml. The spectrum of this solution was recorded in 200-400 nm range using UV-Visible spectrophotometer. ^{After
the complete scan λ}max ^{of fenofibrate was found 294nm.8,12}

From stock solutions of Fenofibrate: 1ml was taken and diluted up to 10 ml. from this solution 0.5, 1.0, 1.5, 2.0 and 2.5ml solutions were transferred to 10ml volumetric flasks and make up the volume up to methanol gives standard drug solution of 5, 10, 15, 20 and 25μg/ ml concentration.

Preparation of calibration curve in pH 6.8 phosphate buffer: 10mg of fenofibrate dissolved in 10ml of 6.8pH phosphate buffer give the solution of 1000µg/ml solution. From stock solutions of fenofibrate 1ml was taken and diluted up to 10ml. from this solution 1.0, 2.0, 3.0, 4.0 and 5.0 ml solutions were transferred to 10ml volumetric flasks and make up the volume up to 6.8pH phosphate buffer, gives standard drug solution of 10, 20, 30, 40 and 50μg/ ml concentration. The UV spectrum of fenofibrate is shown in fig. 2.

Fig. 2: UV spectrum of Fenofibrate in phosphate buffer in pH 6.8

Table 1: Calibration curve of fenofibrate in 6.8 pH phosphate buffer

S. No.	Conc. (µg/ml)	Absorbance
1.	10	0.125
2.	20	0.241
3.	30	0.365
4.	40	0.478
5.	50	0.602

Fig. 3: Calibration Curve of fenofibrate in Phosphate buffer in pH 6.8

Precompression Evaluation:^1,2,6,9

Preformulation investigations are designed to identify those physicochemical properties and excipients that may influence the formulation design, method of manufacture and pharmacokinetic-biopharmaceutical properties of the resulting product. Followings studies performed for in the preformulation study.

1. Bulk density:

It is a measure used to describe a packing of particles or granules. A quantity of 2 gm of powder blend previously shaken to break any agglomerates formed was introduced in to 10 ml measuring cylinder. After that the initial volumes was noted and determine bulk density and result was reported in table 7.

Bulk density = Weight of powder / Bulk volume

2. Tapped density:

In this method powder is filled in measuring cylinder. After that it is mechanically tap 100 times on device and result was reported in table 7.

Tapped Density = Weight of powder / Tapped volume

3. Compressibility Index:

Compressibility is indirectly related to the relative flow rate, cohesiveness and particle Size distribution of the powder. Powders with compressibility values lesser than about 20% has been found to exhibit good flow properties. Tapped (TD) and Apparent Bulk density (BD) measurements can be used to estimate the compressibility of a material and result was reported in table 7.

Carr’s Index (%) = [(TD-BD) x100] / TD

4. Hausner’s Ratio: It is the ratio of bulk volume to tapped volume or tapped density to bulk density and result was reported in table 7.

Hausner Ratio = TD / BD

5. Angle of repose:

The angle of repose of powder blend was determined by the funnel method. The accurately weight powder blend were taken in the funnel. The height of the funnel was adjusted in such a way the tip of the funnel just touched the apex of the powder blend. The powder blend was allowed to flow through the funnel freely on to the surface. The diameter of the powder cone was measured and angle of repose was calculated using equation and result was reported in table 7.

tan θ = h/r

θ= Angle of repose, h = height of the powder cone, r = radius of the powder cone

Preparation of Fenofibrate by Solvent Evaporation Method:

In this method separately an alcoholic solution of fenofibrate and an aqueous solution of PEG 6000 (1:5 w/w) were prepared then mixing of both solutions to get molecular dispersion of fenofibrate and complexing agents finally evaporating the solvent under vacuum to obtain solid powdered inclusion compound. The solid powdered was dried and pulverized and passed through mesh (#) 80 and stored in desiccators for further study.^3,14

Preparation of Orodispersible Tablet of Fenofibrate:

By direct compression method: Orodispersible tablets of fenofibrate were be prepared by direct compression method. The drug with solid dispersion and diluents, superdisintegrants and sweetener was screened through 40 # and properly mixed together. Talc and magnesium stearate was screened through 80 # and blended with initial mixture. Powder thus obtained was compressed into tablets on single punch rotary tablet compression machine.^1,7,15

Table 2: Composition of Fenofibrate Orodispersible Tablets

Ingredients	F1 (mg)	F2 (mg)	F3 (mg)	F4 (mg)	F5 (mg)	F6 (mg)	F7 (mg)	F8 (mg)	F9 (mg)
Fenofibrate (Equivalent to 40 mg solid dispersion) Solid Dispersion	240	240	240	240	240	240	240	240	240
Sodium Starch Glycolate	6	12	18	-	-	-	-	-	-
Crospovidone	-	-	-	6	12	18
Croscarmellose Sodium	-	-	-	-	-	-	6	12	18
Talc	5	5	5	5	5	5	5	5	5
Mg. Stearate	5	5	5	5	5	5	5	5	5
Lactose	34	28	22	34	28	22	34	28	22
Citric Acid	5	5	5	5	5	5	5	5	5
Mannitol	5	5	5	5	5	5	5	5	5
Total wt.	300	300	300	300	300	300	300	300	300

Post Compression Evaluation:^1,7,15

1. Thickness: Thickness can be measured using a simple procedure. Five tablets were taken and their thickness was measured using Vernier calipers. The thickness was measured by placing tablet between two arms of the Vernier calipers and result was reported in table 7.

2. Hardness: Hardness or crushing strength of the tested orally disintegrating tablet formulations was measured using the dial hardness tester (Monsanto Hardness Tester) and result was reported in table 7.

3. Friability: The friability was carried out Roche friabilator. Pre-weighed 20 tablets were placed in a plastic chambered friabilator attached to a motor revolving at a speed of 25 rpm for 4 min. The tablets were then de-dusted, reweighed, and percentage weight loss (friability) was calculated by

% Friability = W₀ - W/ W₀×100

W_○ = initial weight of 20 tablets

W = weight of 20 tablets after 100 revolutions

4. Weight variation test:

For uniformity of tablet weight, 20 tablets were being taken randomly from each tablet formulation and will be weighed individually. The average weight of all tablets and percentage deviation from the mean for each tablet was determined and result was reported in table 7.

Table 3: % Deviation in Weight Variation

S. No.	Average weight of a tablet	% deviation
1.	130 mg or less	10
2.	More than 130 mg and less than 324 mg	7.5
3.	324 mg or more	5

5. Uniformity of Drug Content:

10 tablets were weighed and powdered. An amount of drug equivalent to 10 mg of drug dissolved in 10 ml phosphate buffer (pH 6.8) sonicate it for 20 min. till the entire drug leached out from complex, then the solution was filtered through whatman filter paper. From this Solution take 1 ml and diluted up to 100 ml with phosphate buffer (pH 6.8) and the drug content was determined UV- Visible spectrophotometer at 294nm and result was reported in table 7.

6. In vitro disintegration time:

Disintegration test was performed using a USP disintegration apparatus, with 900 ml distilled water at 37±2°C. Time required for complete disintegration of six tablets was recorded and result was reported in table 7.

7. In vitro % drug release:

In vitro release studies of fenofibrate were performed according to USP II Paddle apparatus. Paddle speed was maintained at 50rpm and 900mL of 6.8pH of phosphate buffer was used as the dissolution medium. Samples (10ml) were collected at predetermined time intervals and replaced with equal volume of fresh medium, filtered through a 0.45μm filter and analyzed with a UV-Visible spectrophotometer at λ=294nm. Drug concentration was calculated from a standard calibration plot and expressed as cumulative % drug release.^4,5,11

RESULT AND DISCUSSION:

In the present investigation poorly water soluble drug is one of the most important parameters of oral formulations sucessfully developed fenofibrate was using solvent evaporation method drug: PEG 6000 in (1:5 w/w). In table 4 shows that the formulation F7 that orodispersible tablets of fenofibrate shows 79.98% drug release within 15 min. Thus, it can be concluded that in vitro release of drugs is a direct function of its solubility in the dissolution medium. When the regression coefficient values of were compared, it was observed that ‘r²’ values of higuchi release kinetics was maximum i.e. 0.995 hence indicating drug release from formulations was found to follow higuchi release kinetics.^11,13,16

Table 4: In Vitro % drug release for Optimized batch F7

Time (min)	Square root of time	Log time	Cumulative % drug release	Log cumulative % drug release	Cumulative % drug remaining	Log cumulative % drug remaining
1	1	0	26.65	1.426	73.35	1.865
5	2.23607	0.6989	48.85	1.689	51.15	1.709
10	3.16228	1	69.98	1.845	30.02	1.477
15	3.87298	1.1761	79.98	1.903	20.02	1.301

Table 5: Regression analysis data

Batch

Zero order release kinetic

First order release kinetic

Higuchi release kinetic

Korsmeyer peppas release kinetic

r²

0.955

0.958

0.995

Fig. 4: Zero order release kinetics

Fig. 5: First order release kinetics

Fig. 6: Higuchi release kinetics

Fig. 7: Korsmeyer peppas release kinetics

Optimized Formula:

Table 6: Optimized formula of Fenofibrate Orodispersible Tablets

Ingredients (F7)	Each tablet quantity (mg)
Fenofibrate (Equivalent to 40mg solid dispersion)	240
Croscarmellose Sodium	6
Talc	5
Mg. Stearate	5
Lactose	34
Citric Acid	5
Mannitol	5
Total wt.	300

Table 7: Evaluation of precompression and post compression parameters for Optimized batch F7 Fenofibrate Orodispersible Tablets

Evaluation Parameters	Batch F7
Bulk Density(gm/cm³)	0.358
Tapped Density(gm/cm³)	0.465
Carr’s Index (%)	23.011
Hausner’s Ratio	1.299
Angle of Repose(º)	26.4
Thickness(mm)	2.4±0.3
Hardness(kg/cm²)	3.5±0.2
Friability (%)	0.785±0.036
Weight variation	301±6
Disintegrating Time (sec)	48±1
Drug Content (%)	99.85±0.32

CONCLUSION:

It can be concluded that developed poorly water soluble drug for orodispersible tablets prove to be were beneficial. The formulation batch of F7 was the optimized formula showed satisfactory results with various physicochemical evaluation parameters like disintegration time and In vitro % drug release. Thus, it was concluded that in vitro release of drugs is a direct function of its solubility in the dissolution medium and orodispersible tablets of fenofibrate can be successfully prepared.

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Received on 18.06.2021 Modified on 03.07.2021

Asian J. Pharm. Tech. 2021; 11(4):279-283.

DOI: 10.52711/2231-5713.2021.00046