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ISSN: 2249-2135

Asian Journal of
Pharmaceutical Sciences
and Clinical Research

Asian Journal of Pharmaceutical Sciences and Clinical Research (AJPSCR) Vol. 1, Issue 2 (2011), 1-9



Anuradha Patel
*, Parixit Prajapati
, Rikisha Boghra
, Dipti Shah

Department of Pharmaceutics, Smt. B.N.B. Swaminarayan Pharmacy College, Vapi, Gujrat-India
Received 15 July 2011, Revised 19 August 2011, Accepted 09 September 2011

Furosemide is a high efficacy loop diuretic drug that is poorly soluble in water. The present
study describes the preparation of solid dispersion designed to increase the solubility. Solid
dispersion of Furosemide was prepared using different concentration of polyethylene glycol
4000 (PEG 4000). The effect of solvent method of preparation of different solid dispersion on
dissolution behavior was also investigated. The dissolution rate of Furosemide were
significantly increase with PEG 4000.physical mixture containing PEG 4000 also
showed dissolution of Furosemide as compared with that of pure drug, indicating the
solubility effect of PEG 4000. Solid dispersions containing Furosemide/PEG 4000(1:5) showed
92.415% increase in dissolution after 30 minutes in 0.1 N HCl as compared with pure drug.
Technique of solid dispersion tablet of Furosemide which can be scaled-up industrially is
promising approach for enhancing solubility and dissolution rate. This was due to an increase in
wetting properties and surface of drug available for dissolution.

Keywords: Furosemide, Solid dispersion, Dissolution rate

Oral bioavailability of a drug depends on its solubility and/or dissolution rate, and
dissolution may be rate determining step for appearance of medicinal effect, therefore
efforts to increase dissolution of drug with limited water solubility is often needed.

* Corresponding author. Tel: +919913051223
E-mail address: (Anuradha Patel)
© Pharmaboon. All rights reserved.

Patel Anuradha et al.: Asian Journal of Pharmaceutical Sciences and Clinical Research, Vol.1, Issue 2 (2011), 1–9

Asian Journal of Pharmaceutical Sciences and Clinical Research (AJPSCR) Vol. 1, Issue 2 (2011), 1-9

Many methods are available to improve these characteristics, including salt formation,
micronization and addition of solvent or surface active agents. Solid dispersion (SD) is
one of these methods, and involved a dispersion of one or more active ingredients in an
inner carrier or matrix in solid state prepared by melting, dissolution in solvent or
melting solvent method. Solid dispersion technique has been used for a wide variety of
poorly aqueous soluble drugs such as nimesulide, ketoprofen, tenoxicam, nifedipine,

Furosemide (FRMD) is 5-(aminosulphonyl)-4-chloro-2-[(2-fuanyl-methyl) amino]
benzoic acid, a potent high ceiling (loop) diuretic, mainly used in the treatment of
hypertension. The drug has been classified as class IV drug as per the
biopharmaceutical classification system (BCS) and having low solubility and
Permeability, one of the major causes of the low oral bioavailability of FRMD is its
PEG-4000 has been used for the preparation of solid dispersion as a
component of the binary system for various drugs such as tenoxicam, tacrolimus, and
indomethacin, ibuprofen, nilvadipine
The present work aims to evaluate the potential
of the solid dispersion technique for enhancing solubility of FRMD using PEG-4000 as
the hydrophilic carrier. Furthermore, their solid state characterization, by applying
analytical tools like FTIR, XRD and DSC, and attempts to see the possible mechanism
of improved dissolution rate.

Materials and methods:
Furosemide was received as a gift sample from Alkem Ltd., Mumbai. Microcrystalline
cellulose was procured from Kemphasol, Mumbai. PEG 4000
was purchased from Rankem Ltd.,Mumbai. Starch Maize
procured from JRS Pharma, Rosenberg, Germany. Methanol (Qualigens chemicals Ltd.,
Mumbai).Talc (Sd fine chemicals Ltd., Mumbai). Magnesium stearate (Sd finechemicals Ltd.,
Mumbai). The commercial products of Furosemide were procured from the local market. All
other chemicals/solvents used were of AR grade.

Solubility Determinations of Furosemide
Solubility determinations were performed by taking an excess amount of Furosemide in
a screw-cap glass vial in 10 mL of an aqueous and 0.1N HCl solution containing
various concentrations of PEG 4000. The samples were shaken at 37 ± 0.5 °C for 24 hrs
in an orbital Incubation shaker. After 24 hrs, the samples were filtered through a 0.45-
µm watt man filter paper. The filtrate was suitably diluted and analyzed
spectrophotometrically at 342 nm using a UV spectrophotometer.

Preparation of Furosemide-PEG-4000 by solid dispersion method
Dissolve both Furosemide and PEG-4000 in a common solvent and then evaporate the
solvent to produce a solid solution. In this method 1:5 ratio of Furosemide and PEG-
4000 were taken in glass beaker. Then add co-solvent acetone into this mixture and
stirred with glass rod about 10-15 minutes.

Patel Anuradha et al.: Asian Journal of Pharmaceutical Sciences and Clinical Research, Vol.1, Issue 2 (2011), 1–9

Asian Journal of Pharmaceutical Sciences and Clinical Research (AJPSCR) Vol. 1, Issue 2 (2011), 1-9

Then poured it into petriplate and then evaporated this solvent by putting it on magnetic
stirrer at temperature about 23-65
C.When all solvent evaporated the hardened mixture
was then powdered in a mortar, sieved through a 100-mesh screen, and stored in a
screw-cap vial at room temperature until use.

Physical mixtures having the same weight ratios as the SDs were prepared. Thoroughly
mixing the required amounts of Furosemide and PEG-4000 for 10 min in a mortar. The
resulting mixtures were sieved through a 100-mesh sieve. The mixtures were stored in
screw-cap vials at room temperature until use.

Formulation of Furosemide Tablets

Tablets containing an equivalent weight of 25 mg of Furosemide were compressed on 8-
station tablet minipress (Karnavati Pvt. Ltd., Mehsana) by direct compression
technique. Tablet formulations were code as F1, F2, F3, F4, and F5 contain 150 mg of
solid dispersion, Avicel PH102, Starch Maize and Talc. The tablets were evaluated for
hardness (Tablet hardness tester), friability (Roche Friabilator), weight variation, and
drug content. In vitro dissolution studies on F1, F2, F3, F4, F5, Pure drug
Furosemide(FRMD) and physical mixture(PM) were carried out in 900mL of 0.1 N HCl
as the dissolution media as described previously. The ratio optimization and selected
optimize formula for tablet preparation was given in table 1 and 2 respectively.

Evaluation of Furosemide Solid Dispersions

Solubility Studies
It shows that Furosemide having solubility in water found to be 0.62 µg/ml and in 0.1 N
HCl 0.81µg/ml. solubility of the drug is increase as the concentration of PEG-4000
increase, 1:5 ratio of the Furosemide and PEG-4000 found to be optimum. 1:5 ratios
show 18.18 µg/ml drugs in 0.1 N HCl. The Concentration of different ratio of FRMD
with PEG-4000 was given in table 3.

Drug content Estimation

The percentage drug content in physical mixtures and solvent evaporative dispersions was
estimated by dissolved 10 mg quantities of physical mixtures and solvent evaporative dispersions
in methanol, mixed thoroughly by shaking and the volume was madeup to the mark with solvent
(0.1N HCl). The solution was filtered and the filtrate was diluted suitably with 0.1N HCl (1.2
pH) and absorbance was measured at 342 nm using UV/Visible spectrophotometer.

Preformulation studies of Furosemide and optimized Solid Dispersions
Pre‐formulation studies such as angle of repose, bulk density, tapped density; Carr’s index and
Hausner’s ratio were performed.

Evaluation of Furosemide tablets:
Various physical parameters such as hardness, friability, disintegration time were evaluated.

Patel Anuradha et al.: Asian Journal of Pharmaceutical Sciences and Clinical Research, Vol.1, Issue 2 (2011), 1–9

Asian Journal of Pharmaceutical Sciences and Clinical Research (AJPSCR) Vol. 1, Issue 2 (2011), 1-9

Content of active ingredient
For drug content analysis, twenty tablets were accurately weighed and finely powdered. The
quantity of powder, equivalent to 150 mg of Furosemide was taken in a 100ml volumetric flask
and filtered the solution, 1ml of the filtrate was dissolved in 10ml of 0.1N HCl (1.2 pH) and
assayed for drug content at 342nm, using spectrophotometer.

Disintegration test
One tablet was placed in each tube of disintegration apparatus (Thermonic model) and the test
was carried out using distilled water as Disintegration medium at 25 0C. The time for
Disintegration was noted in each test product for six tablets.

In vitro dissolution study of Furosemide tablets
Dissolution studies of tablet which was made by using solid dispersion of Furosemide
and PEG-4000, and PM (Physical mixture)and pure drug were performed using USP
Apparatus 2 at a paddle rotation speed of 50 rpm in 900 mL 0.1 N HCl at 37 ± 0.5 °C.
SD or PM equivalent to 25 mg of Furosemide were use for the tablet preparation and
use for the dissolution test. At specified times (every 10 min for 1 h), 5 ml samples
were withdrawn using a 0.45-µm syringe, filter and the percentage of drug release was
measured by UV spectrophotometer at λmax 342 nm. Fresh medium (5 ml) that was
prewar med at 37 °C was added to the dissolution medium after each sampling to
maintain a constant volume throughout the test.

Result and Discussion

Preparation of Furosemide Solid Dispersions
Solid dispersions of Furosemide were prepared by physical mixing and solvent evaporation
method. The carriers like PEG-4000 were used in the preparation of solid dispersions. Various
ratios of drug and carrier such as 1:1, 1:2, 1:3, 1:4, and 1:5 were used in the preparation. All the
solid dispersions prepared were found to be fine free flowing powders.

Drug content and solubility
The percent drug content and solubility data of all solid dispersions are given in table. Low
standard deviation in the percent drug content values indicated uniformity of drug content in
each batch of solid dispersions. It was observed that as the concentration of carrier is increased
the solubility was increased and it was also noticed that at the same concentration of carrier, the
solid dispersions prepared with solvent evaporation method displayed greater solubility than that
of physical mixing method.

PreFormulation Studies
Angle of repose, bulk density, tapped density, carr’s index and Hasusner’s ratio were calculated
and were found to be in the range of 25.12‐31, 0.52‐0.63, 0.61‐0.74, 16.98‐18.75 and 1.07‐1.23
respectively and is shown in table 4.From the preformulation studies of the Irbesartan solid
dispersions, it is clear that all the Furosemide solid dispersions fulfilled the official
requirements for compression of tablets through direct compression method.

Patel Anuradha et al.: Asian Journal of Pharmaceutical Sciences and Clinical Research, Vol.1, Issue 2 (2011), 1–9

Asian Journal of Pharmaceutical Sciences and Clinical Research (AJPSCR) Vol. 1, Issue 2 (2011), 1-9

Table 1: Ratio optimization for tablet preparation

SD(mg) MCC(mg) Talc(mg) Starch
F1 150 38 5 7 200
F2 150 40 3 7 200
F3 150 42 3 5 200
F4 150 44 3 3 200
F5 150 42 5 3 200

Table 2: Optimize Formula (F3) for tablet preparation
Ingredients Qty. for 1 tablet Qty for 30 tablet
Solid dispersion 150 mg 4500 mg
MCC 42 mg 1260 mg
Talc 3 mg 90 mg
Starch Maize 5 mg 150 mg
Total 200 mg 6000 mg

Table 3: Concentration of different ratio of FRMD with PEG-4000

Evaluation of Furosemide tablets
Hardness was found to be in the range of 4‐4.5 kg/ with standard deviation not more than
0.7. Disintegration time was found to be 130, 120, 94 , 109 and117, seconds for formulation F1,
F2, F3, F4 and F5 respectively, the results of the disintegration test revealed that F3 has faster
disintegration and it disintegrates within two minutes (94sec). Friability was found to in between
0.22‐0.38 with standard deviation not more than 0.81.
Drug content was above 99% in all the formulations. All the parameters evaluated are shown in
table 5. From the physicomechanical parameters of the formulated tablets, it is clear that all the
tablets fulfilled the official requirements of the compressed tablets.

Fourier Transform Infrared (FTIR) Spectroscopy
FTIR spectra were recorded on samples prepared in potassium bromide (KBr) disks.

Patel Anuradha et al.: Asian Journal of Pharmaceutical Sciences and Clinical Research, Vol.1, Issue 2 (2011), 1–9
Ratio Absorbance Concentration(µg/ml)
1:1 0.081 5.27
1:2 0.102 7.18
1:3 0.150 11.54
1:4 0.198 15.90
1:5 0.223 18.18
1:6 0.230 18.81

Asian Journal of Pharmaceutical Sciences and Clinical Research (AJPSCR) Vol. 1, Issue 2 (2011), 1-9

Samples were prepared in KBr disks by means of a hydrostatic press at 6-8 tons
pressure. The scanning range was 500 to 4000 cm -1.
IR spectra of FRMD and its binary systems with PEG-4000 are presented in Figure.
Pure Furosemide spectra showed sharp characteristic peaks at 3400.27, 3122.54, 1665,
and 1560 cm–1. All the above characteristic peaks appear in the spectra of all binary
systems at same wave number indicating no modification or interaction between the
drug and carrier. The FTIR of FRMD, PM and SD (1:5) was given in figure 1.

Table 4: PreFormulation Studies of Furosemide alone and its Solid Dispersions

System Angles of repose
Bulk density Tapped density Carr’s index Hausner’s ratio

Furosemide 31 0.52 0.64 18.75 1.23

F1 28.4 0.61 0.72 18.03 1.18

F2 25.34 0.63 0.74 17.46

F3 25.21 0.62 0.62 16.98 1.16

F4 25.8 0.57 0.61 17.01 1.07
F5 25.12 0.55 0.59 18.12 1.18
∗ Indicates mean of three readings.

Table 5: Evaluation of Furosemide tablets

Hardness (kg/ Disintegration time (sec) Friability (%) Drug content


4.5±0.43 130±0.88 0.38±0.22 99.78

F2 4.3±0.67 120±0.80 0.34±0.12 99.87



94±0.89 0.22±0.15 99.40
F4 4.1±0.69 109±0.78 0.30±0.67

F5 3.9±0.01 117±0.86 0.29±0.81 98.51

Table 6.Dissolution data of different formulation of Furosemide, PM and pure FRMD (Mean ± SD), n=3
F1 F2 F3 F4 F5 FRMD PM
10 21.1±0.7 25.6±1.0 31.5±0.7 29.3±0.5 30.3±0.7 1.8±0.2 8.2±0.8
20 36.6±0.8 40.4±0.7 48.7±0.5 43.1±0.2 45.2±0.4 3.2±0.6 14.2±0.6
30 51.2±0.9 54.3±0.4 61.5±0.7 57.6±0.8 59.3±0.4 5.2±0.3 20.8±0.4
40 63.4±0.7 77.6±0.8 86.1±0.9 81.3±0.5 83.7±0.7 9.1±0.4 27.7±0.3
50 75.3±1.2 81.2±0.7 88.3±0.7 85.0±0.6 87.3±0.5 13.1±0.5 36.3±0.5
60 80.8±1.1 87.6±0.7 92.0±0.5 89.1±0.3 90.3±0.4 13.8±0.3 38.2±0.5

Patel Anuradha et al.: Asian Journal of Pharmaceutical Sciences and Clinical Research, Vol.1, Issue 2 (2011), 1–9

Asian Journal of Pharmaceutical Sciences and Clinical Research (AJPSCR) Vol. 1, Issue 2 (2011), 1-9

Figure 1.FTIR of FRMD, PM and SD (1:5)

Figure 2.Dissolution Profile of different formulation of Furosemide, pure FRMD and PM

In Vitro Dissolution Study of Furosemide
Dissolution of tablet prepared using SD was more rapid and higher when compared to
corresponding physical mixtures and pure drug.

Patel Anuradha et al.: Asian Journal of Pharmaceutical Sciences and Clinical Research, Vol.1, Issue 2 (2011), 1–9

Asian Journal of Pharmaceutical Sciences and Clinical Research (AJPSCR) Vol. 1, Issue 2 (2011), 1-9

Among all the formulations F3 having high dissolution rate. In the first 60 minutes,
percent drug dissolved from FRMD pure drug was 13.8%, from physical mixtures was
38.2% (PEG-4000+FRMD). Significant increase in dissolution rate of F3 formulation
prepared by Solvent evaporation method in weight ratio 1:5 was observed. Percent drug
dissolved in 30 minutes from PEG-4000+FRMD SD was 92.0%. This was due to the
effect of molecular dispersion of drug in PEG-4000, the decreased crystallinity of
FRMD existing in solid dispersions. It was reported that molecular dispersion is one of
the important roles of drug release from the polymer-drug system. The present work
shows that the dissolution rate of Furosemide from solid dispersions with PEG 4000
improved compare to the pure drug. Further, solid dispersions performed better than the
corresponding physical mixtures. The present study confirmed the advantage of
improved aqueous solubility of FRMD in its solid dispersions form, with better
dissolution characteristics. The dissolution data and dissolution profile of different
formulations of Furosemide, PM and pure FRMD was given table 6 & figure 2

PEG-4000 has great potential for enhancement of solubility and dissolution rate thereby
bioavailability of FRMD. Permeability of FRMD increases by MCC which increase the
absorption in stomach. The solvent evaporation method enhances the solubility of
FRMD by converting it in to amorphous form, reducing the particle size and increasing
wettability. The optimum ratio for solvent evaporation mixture was found to be 1:5 w/w
which shows higher dissolution as compared to that of FRMD. The co-solvent
evaporation method is the most effective method, to enhance the dissolution. Also the
easiest, cost effective, possible scale-up and industrial application, without requiring
addition of solvents or high temperature for its preparation.

The author would like to acknowledged Alkem Pharmaceutical, Halol (India) for
providing gift sample and the Rankem Ltd, Mumbai for providing PEG-4000,
Smt.BNBswaminarayan Pharmacy College, salvav, Vapi for financial support.

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