“PREPRATION, OPTIMIZATION AND EVALUATION OF

FUROSEMIDE LOADED PELLETS”

ABSTRACT
This study explores the formulation and optimization of Furosemide-loaded pellets for
controlled drug release. Furosemide, a loop diuretic used for hypertension and edema, faces
challenges due to low solubility and bioavailability, necessitating an effective delivery
system.
Using extrusion-spheronization, pellets were produced with a blend of ethyl cellulose and
hydroxypropyl cellulose to ensure prolonged drug release. Various formulations were
evaluated for particle size, drug content uniformity, in-vitro dissolution, and stability.
Among the formulations, F-5 demonstrated the best release profile, achieving 97.03% release
within 24 hours per USP standards. The results indicate that pelletization with ethyl cellulose
effectively enhances Furosemide's sustained release, offering a promising approach for
improved therapeutic outcomes.
Key word:-
Furosemide , Pellets, Hypertension, Drug delivery system, Extrusion-spheronization,
Controlled release, Bioavailability, In-vitro drug release, FT-IR spectroscopy, Scanning
Electron Microscopy (SEM)

1. INTRODUCTION
1.1 Hypertension:
Hypertension is a major global health issue, linked to increased risks of heart disease, stroke,
and renal failure. Despite advancements in treatment, control rates have stagnated, with
around 1.2 billion affected worldwide by 2010, particularly in the Eastern Mediterranean
Region (26% prevalence). Even minor increases in blood pressure can significantly raise
cardiovascular risks, making early detection and proactive treatment, including lifestyle
changes and medication, crucial.
Diagnosis, Classification, and Risk Assessment
Hypertension is diagnosed through multiple blood pressure readings, classified from normal
(<120/80 mmHg) to stage 2 hypertension (≥140/90 mmHg). Both systolic and diastolic
pressures affect cardiovascular risk, with systolic pressure more closely linked to stroke and
diastolic pressure to coronary artery disease. In older adults, increased pulse pressure
indicates heart disease risk. Comprehensive patient assessments, including lab tests and
cardiovascular history, are vital for effective management.
Pathophysiology and Complications
Hypertension results from increased cardiac output, vascular resistance, or both, influenced
by factors like sympathetic nervous system activity and vascular rigidity. Chronic
hypertension can lead to complications such as left ventricular hypertrophy and coronary
artery disease.
1.2 Pellets
Pharmaceutical pellets are small, multi-particulate systems designed for drug delivery that
provide numerous benefits, such as controlled release, consistent drug distribution, and
enhanced patient adherence. They can be manufactured through various methods, including
extrusion-spheronization, layering, and spray drying, tailored to achieve specific drug release
characteristics and formulation needs. Often, pellets are coated with polymers to adjust the
drug release profile, allowing for sustained, delayed, or targeted delivery. Their uniformity in
size and shape improves bioavailability and minimizes dose variability. These adaptable drug
delivery systems are extensively utilized in oral formulations, offering flexibility in the
production of capsules and tablets while enhancing therapeutic effectiveness.
Advantages of Pellets in Drug Formulation
 Improved Drug Absorption: Due to their small size and uniform dispersion in the
gastrointestinal tract, pellets enhance drug absorption and bioavailability.
 Controlled and Sustained Release: Pellets allow for the modification of drug release
profiles, making them ideal for sustained or delayed-release formulations.
 Reduced Gastric Irritation: Unlike conventional tablets, pellets distribute evenly in
the stomach, preventing local irritation and reducing side effects.
 Dose Flexibility: Different drug-loaded pellets can be blended to achieve combination
therapy or customized dosing.
 Reduced Intra- and Inter-patient Variability: Pellets provide a more consistent
drug release pattern, minimizing fluctuations in plasma drug concentration.
1.2.1 Pelletization Methods
Several methods are used for pellet formulation, including:
1. Extrusion-Spheronization: A widely used technique where wet granules are
extruded and spheronized to form uniform pellets.
2. Solution and Suspension Layering: A process where a drug solution or suspension is
layered onto a core material.
3. Spray Drying and Spray Congealing: Techniques involving atomization of drug
solutions to produce spherical particles.
4. Cryopelletization and Hot Melt Extrusion: Novel techniques that enhance drug
stability and controlled release properties.
2. Furosemide
Furosemide is a potent loop diuretic used to manage fluid retention (edema) from conditions
like congestive heart failure, liver cirrhosis, and renal disease, as well as to control
hypertension. It works by inhibiting the sodium-potassium-chloride cotransporter in the
ascending loop of Henle, increasing urine production and reducing fluid overload. Available
in oral and intravenous forms, it acts quickly—within an hour for oral and minutes for
intravenous. Common side effects include dehydration, electrolyte imbalances, dizziness, and
hypotension. Long-term use or high doses can lead to ototoxicity and renal impairment,
necessitating close monitoring, especially in patients with renal issues or those on other
medications affecting electrolytes.
3. Material and Method
The formulation comprises Furosemide, obtained from Cadila Healthcare Limited, along with
a range of excipients from various suppliers. Ethyl cellulose (4cps), Talc, and Isopropyl
alcohol are sourced from Central Drug House (P) Ltd., while Sodium lauryl sulfate is
provided by Sunchem India. Hydroxy propyl cellulose is supplied by All India Drug Supply
Co., and Povidone-K30 is acquired from Advance Chemical Sales Corporation. Low
substituted Hydroxy propyl Cellulose is sourced from Shandong Liaocheng Ehua
Pharmaceutical Co., Ltd. Furthermore, Sugar spheres (500-600µm) are supplied by M.B.
Sugars & Pharmaceuticals Limited. Together, these materials play a vital role in the
formulation process.
3.1 Selection of Process
Palletization were done by Spheronization.
3.1.1 General procedure for formulation of Furosemide sustained-release pellets:
Preparation of drug layering solution:
 Hydroxypropyl Cellulose were added slowly under continuous stirring to dissolve
completely.
 Then Furosemide was added slowly under continuous stirring to get a uniform
dispersion.
 After attaining uniform dispersion talc was added immediately with continuous stirring
for not less than 30 min.
 The above dispersion was passed through #40 sieve and complete dispersion was passed.
 A radial plate spheronizer with a plate diameter of 45.0 cm was used. The friction plate
speed in the spheronizer was varied between 800–1000 rpm, respectively.
 The extrudate was spheronized for 10 min. The wet pellets were dried in a hot air oven at
40°C for 24 h and then stored in sealed bags.
 The talc was passed through #40 sieve and pellets were lubricated.
 Required quantity of isopropyl alcohol was taken into a suitable vessel and to it ethyl
cellulose 4cps added and stirred well to get clear solution. This process was done at room
temperature.
 Table:1: 3.1.2 Formulation chart of Furosemide pellets:
Quantity per unit (mg)
S. No. Ingredients
F-1 F-2 F-3 F-4 F-5 F-6
1 Furosemide 20 20 20 20 20 20
2 Ethyl cellulose (4cps) 5 5 5 7 5 5
3 Povidone K30 20 - - - - -
Hydroxypropyl Cellulose,
4 - 20 - - - -
Low-substituted
5 Hydroxypropyl Cellulose - - 20 18 20 20
6 Sodium lauryl sulfate 0.5 0.5 0.5 0.5 0.5 0.5
7 Talc 1 1 1 1 1 1
8 Sugar spheres (500-600 µm) 272.5 272.5 272.5 272.5 272.5 272.5
9 Isopropyl alcohol q.s q.s q.s q.s q.s q.s
10 Purified water q.s q.s q.s q.s q.s q.s

3.1.3 Evaluation of prepared pellets:

7.1.1 (i) Bulk density:

Weighed quantity of 20 gm pellets was transferred into a 100 ml measuring cylinder without
tapping, during transfer the volume occupied by pellets was measured. Bulk density was
measured by using formula.

Pi = m/Vo

Where,
Pi = Bulk density
m = Mass of the pellets,
Vo = Untapped Volume

7.4.1 (ii) Tapped Density:

Weighed quantity of 20 gm pellets was taken into graduated cylinder, volume occupied by
granules was noted down. Then cylinder was subjected to 500 taps in tapped density tester
(Electro Lab USP II), the % Volume variation was calculated by following formula.

Pt = m/Vi

Where,
Pt = Tapped density
m= Mass of the pellets,
Vi = Tapped volume
 7.4.2 Carr’s compressibility index:

Compressibility is the ability of pellets to decrease in volume under pressure. Using untapped
density and tapped density the percentage compressibility of pellets were determined, which
is given as Carr’s compressibility index.

CI=Vi-Vo / Vi × 100

Where,
CI = Compressibility index
Vo = Bulk density
Vi = Tapped density

Table No: 7 Compressibility index

Compressibility index (%) Flow characters

< 10 Excellent
11-15 Good
16-20 Fair
21-25 Passable
26-31 Poor
0 Very poor

Hausner´s ratio

It is measurement of frictional resistance of the drug. It was determined by the ratio of

tapped density and bulk density.

Hausner´s ratio = Vo/Vi

Where,
Vo = Bulk density
Vi = Tapped density

Table No: 8 Hausner´s ratio

Flow characters Hausner´s ratio

Excellent 1.11
Good 1.12 – 1.18
Fair 1.19 – 1.25
Passable 1.26 – 1.34
Poor 1.35 – 1.45
Very poor 1.46 – 1.59
Very very poor >1.60
 7.4.1 Procedure for content uniformity:

The content of one pellet was transferred into 200 ml volumetric flask, to it 100 ml equal
volume of methanol and phosphate buffer (pH 6.2) was added. Then the solution was
sonicated until then contents are dispersed and volume was made up with methanol and
phosphate buffer (pH 6.2) in 1:1 ratio. This solution contains about 25 µg/ml furosemide.
Concomitantly the absorbance was determined 319 nm, in spectrophotometer, using the
methanol and pH 6.2 phosphate buffer mixture as the blank.

By calculating the formula:

(TC/D)(AU/AS)

T = labeled quantity of furosemide in mg

C= concentration (µg per ml) in the standard solution D= concentration (µg per ml) in the test
solution Based upon the labeled quantity per capsule and the extent of dilution.
Au and As are the absorbance of the solution from the capsule contents and the standard
solution.

7.4.2 Weight variation:

Individual weights of 20 pellets were taken and the average weight was calculated by using
the following formula.

(Capsule weight -Average weight)

Weight variation = × 100
Average weight of capsules

Weight variation should not be more than 7.5 %.

7.4.3 Percentage yield:

The yield was determined by weighing the pellets and then finding out the percentage yield
with respect to the weight of the input materials.

The formula for calculation of percentage yield is

Weight of pellets
Percentage yield (%) = × 100
Weight of drug + Weight of polymers
 7.4.4 IN-VITRO DRUG RELEASE STUDIES:

In-vitro drug release studies of Furosemide were carried by using apparatus USP test-Ι
rotation basket method with a stirring speed 75 rpm at 37 ± 0.5°C in 750ml of 6.2 phosphate
buffer for 24 hours. 5 ml of sample, with drawn at interval of 1, 2, 4, 6, 12, 24 hours with the
replacement of equal volume of dissolution media.
Filtered the solution through Millipore HYLP filter and these filtrate was measured at 319 nm
by UV spectrophotometer (UV-1700 SHIMADZU).

The percentages of the labelled amount of Furosemide dissolved at the time specified
acceptance table.

Table No: 9

Time (hours) Amount dissolved

1 Between 10% and 25%
2 Between 20% and 40%
4 Between 35% and 55%
6 Between 45% and 65%
12 Between 60% and 80%
24 Not less then 80%

7.4.5 Comparison of Dissolution Profile with Marketed Product

The dissolution profile (in USP 6.2 phosphate buffer) of optimized formula was compared
with the dissolution profile of marketed product and the results were noted.

8. RESULTS AND DISCUSSION

8.1 Drug- Excipient compatibility study:

Drug-Excipients compatibility study was carried out using various Excipients mentioned
below table no.11. From the Preformulation studies, it was observed that mixtures shown
have no color change.

Table No: 11 Physical observation

25°C /60 % RH
S. No Composition details Initial Physical &
40°C/ 75 % RH
 Description 1st Week 2nd Week 3rd Week
Light yellowish
1 Furosemide NCC NCC NCC
Powder
Furosemide + Hydroxy White to light
2 NCC NCC NCC
propyl cellulose yellowish powder
Furosemide + povidone White to light
3 NCC NCC NCC
K30 yellowish powder
Furosemide + low
White to light
4 substitued hydroxy propyl NCC NCC NCC
yellowish powder
cellulose
Furosemide + Ethyl White to light
5 NCC NCC NCC
cellulose (4cps) yellowish powder
Furosemide + sodium Light yellowish
6 NCC NCC NCC
lauryl sulfate powder
Light yellowish
7 Furosemide + Talc NCC NCC NCC
powder
Furosemide + sugar White to light
8 NCC NCC NCC
spheres yellowish powder

NCC: NO COLOUR CHANGE

8.2. Spectroscopic studies:

8.2.1 UV spectroscopy (Determination of λmax)

Figure: Spectrum of furosemide for absorbance maxima (15μg/ml)

Figure: Overlay spectra of furosemide (5-25 μg/ml)

 The observed λmax was 277 nm.
 8.2.2 IR Spectra of drug

Interpretation of Furosemide

Frequency Groups Assigned

3397, 3349, 2990 N-H, (Ar-NH-CH2)
1668 C=O Stretching
1580, 1571 SO2NH2 Stretching
1260, 1240 C-O Stretching
1148 SO2 Stretching
Discussion:

When FT-IR Spectrum of furosemide (pure drug) was prformed, there was no major changes
in the position of the spectrum. So it indicates absence of physical and chemical interactions
of Furosemide extended release pellets.
8.3 Furosemide particle size

Figure No.12 Magnification of 400X

8.4 Evaluation of pellets of Furosemide

Table No: 12

Bulk density Tap density Carr’s Index Hausner´s

S. No
(g/cc) (g/cc) (%) ratio
F-1 0.829±0.008 0.889±0.010 6.019±1.57 1.069±0.017
F-2 0.832±0.011 0.884±0.015 6.013±0.72 1.052±0.013
F-3 0.825±0.012 0.878±0.019 5.969±0.84 1.064±0.011
F-4 0.835±0.010 0.884±0.017 5.700±0.28 1.068±0.001
F-5 0.841±0.019 0.890±0.011 6.225±0.65 1.059±0.021
F-6 0.876±0.016 0.920±0.012 6.886±0.78 1.046±0.019
*Average values of the three determinations are given as results
8.4.1 Bulk Density & Tap Density

Both bulk density and tapped bulk density results are shown in table no.12. The bulk density
and tapped bulk density for all formulation varied in range of 0.825±0.012 to 0.876±0.016
and 0.878±0.019 to 0.920±0.012. The value obtained lies within the acceptable range and
with no much difference found between bulk density and tapped bulk density. These results
may further influence the pellets dissolution.

8.4.2 Compressibility Index & Hausner’s Ratio

The percent compressibility of pellets was determined by Carr’s compressibility index as

shown in table no.12.The percent compressibility for all formulation lies within the range of
5.700±0.28 to 6.886±0.78. Hausner’s ratio was found to be in a range of 1.046±0.019 to
1.069±0.017 which shows good flow property.

8.4.3 Content uniformity:

The results for uniformity of dosage units are presented in the table given below. The results
were found to be within the limits (90 % to 110%). It shows that the drug was uniformly
distributed.

Table No: 13

Content uniformity of pellets in

S. No
(%)
 F-1 99.60 ± 0.96
F-2 98.36 ± 0.86
F-3 99.50 ± 0.79
F-4 101.83 ± 0.52
F-5 99.24 ± 0.67
F-6 98.55 ± 0.87

8.4.4 Loss on drying

The prepared pellets of all the batches were evaluated for their moisture content. It is
observed that the range around 1%.

Table No: 15

S. No Loss on drying (%)

F-1 1.20 ± 0.03
F-2 1.24 ± 0.03
F-3 1.15 ± 0.01
F-4 1.19 ± 0.02
F-5 1.23 ± 0.01
F-6 1.21 ± 0.03

*Average values of the three determinations are given as results

8.4.5 Extended-release formulation of Furosemide pellets:

The in-vitro release studies of F1-F6 formulations were carried out by UV method and
reported. The limits for Furosemide pellet as per USP are listed in the table

USP limits for drug release for furosemide extended-release pellet

Table No: 16

Time (hours) Amount dissolved

1 Between 10% and 25%
2 Between 20% and 40%
4 Between 35% and 55%
6 Between 45% and 65%
12 Between 60% and 80%
24 Not less than 80%