Vol 2 | Issue 2 | 2012 | 56-63.

e-ISSN 2249 – 7706

print-ISSN 2249– 7714

International Journal of
Advanced Pharmaceutics
www.ijapjournal.com

IMPROVEMENT OF DISSOLUTION CHARACTERISTICS AND

BIOAVAILABILITY OF TADALAFIL BY SOLID DISPERSION
TECHNIQUE USING WATER-SOLUBLE POLYMERS
V. Ravi Kumar*, M. Sevukarajan, Jayasri Vulava, A.G. Pavankumar, Y. Deepthi,
M. Manjunath, A. Anand
Department of Pharmaceutics, Sree Vidyanikethan College of Pharmacy, Tirupati, A.P. - 517102, India.

ABSTRACT
The enhancement of oral bioavailability of poorly water-soluble drugs remains one of the most challenging aspects of
drug development. Tadalafil a BCS class II drug is an impotence agent. It is indicated for the treatment of erectile dysfunction
and is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5).However,
insolubility and poor dissolution of this molecule, delays its rate of absorption and finally the onset of action. Solid dispersion
has been successfully utilized as dissolution enhancement technique using water soluble polymers for wide variety of poorly
water-soluble drugs. The present study aims at enhancement of dissolution profile of Tadalafil using PVP K30 and PEG 6000
as carriers by solid dispersion technique. Solid dispersion containing Tadalafil was further investigated by drug content, in-vitro
drug release, FTIR, DSC, XPRD and SEM analysis. Absence of significant drug‐carrier interaction was confirmed by IR and
DSC data. XPRD reveals that crystallinity nature of Tadalafil was decreased. From the study it was concluded that the in-vitro
dissolution of Tadalafil can be enhanced by solid dispersion technique.

Keywords: Poorly water-soluble drugs, Solid dispersion, Tadalafil, PVP K30, PEG6000, Melting, Solvent evaporation method,
Co-grinding method.

INTRODUCTION can be attributed to one or a combination of the following

Solubilization of poorly water-soluble drugs has
gained much interest in the pharmaceutical industry [1, 2].
Many approaches have been developed to improve
solubility and to enhance the dissolution rate of poorly
soluble drugs, including both modifications to the drug
substance itself and the creation of specific formulations.
Physical modifications often aim to increase the surface
area, solubility and wettability of the powder particles and
therefore typically focus on particle size reduction or
generation of amorphous states [3, 4]. Solid dispersions are
one of the most successful strategies to improve drug
release of poorly soluble drugs [5-7].
In general, solid dispersion (SD) is a molecular
mixture of drug in various hydrophilic carriers used to
enhance drug dissolution by changing drug crystallinity to
an amorphous form and reducing particle size for better
wettability [8,9]. The increase in dissolution rate from SDs
factors: reduction of particle size of the drug, solubilizing
effect on the drug by the water soluble carrier,
enhancement of the wettability and dispersibility of the
drug by the carrier material, and the possible formation of
a metastable dispersion that has a greater solubility
resulting in a faster dissolution rate [10, 11].
Sekiguchi and obi were the first to report an
improved dissolution of the drug from sulfamethazole-urea
solid dispersion. Among the popular carriers used in the
formation of SDs are polyethylene glycol (PEG) and
polyvinylpyrrolidone (PVP). Polyethylene glycol is freely
soluble in water and is available in various molecular
weights [12]. The molecular size of the polymer favors the
formation of interstitial solid solutions [13].
Tadalafil,(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-
methyl-6-(3,4-methylenedioxyphenyl)pyrazino [20,10:6,1]
pyrido[3,4-b]indole-1,4-dione, BCS class II drug, is an

Corresponding Author:- V. Ravi Kumar Email:- ravikumarchowdary99@gmail.com

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impotence agent. It is indicated for the treatment of erectile
dysfunction. It is a selective inhibitor of cyclic guanosine
monophosphate (cGMP)-specific phosphodiesterase type-5
(PDE-5).The absolute bioavailability of Tadalafil is 83%
following oral administration as compared to intravenous
infusion indicating that the permeability is not the problem
associated with this drug. The peak plasma concentration is
achieved after about 2 hrs following its oral administration.
Thus, its availability seems to be dissolution rate limited.
Among the various approaches to improve the
dissolution of sparingly soluble drugs various techniques
like pseudo-solid dispersion, solid dispersion and inclusion
complexation have often proven to be very successful.
Thus, in the present study these solid dispersion techniques
are adopted to improve the dissolution of Tadalafil.
The aim of the present study was to formulate and
evaluate the solid dispersions of Tadalafil in PVP K30 and
polyethylene glycol 6000 (PEG 6000). Dispersions were
prepared by melting method, solvent evaporation method
and co-grinding method. In order to characterize the
prepared dispersions, differential scanning calorimetry
(DSC), X-ray powder diffraction, Fourier–transform
infrared spectroscopy, as well as dissolution and solubility
studies were carried out.
MATERIALS AND METHODS
Tadalafil is procured by A-Z Pharmaceuticals
Ltd., Chennai, India, PVP K30, PEG 6000 and methanol is
procured by S.D. Fine Chem. Ltd, Mumbai, India.
Method of Preparation of Solid Dispersion
Solid dispersions were prepared by three different
methods and were compared with the pure TDF.
Co-grinding method
Solid dispersions were prepared by thoroughly
grinding accurately weighed quantities of TDF and each of
the carriers (PVP K30 and PEG 6000) in various ratios
(1:1, 1:3 and 1:5) for 20-30 minutes in glass mortar
individually. The dispersions were then sifted through
sieve #60 and stored in desiccators till further use.
Melting method [14]
Three solid-dispersion preparations containing
different weight ratios of Tadalafil in PEG 6000 (1:1, 1:3,
1:5, and denoted as MMPEG 1:1, 1:3, 1:5, respectively)
were prepared by the melting method. Tadalafil was added
to the melted PEG 6000 at 750C, and the resulting
homogeneous preparation was rapidly cooled in a freezing
mixture of ice and sodium chloride and stored in
desiccators for 24 h. Subsequently, the dispersion was
ground in a mortar and sieved through 100# sieve. The
resulted product was stored in desiccators until further
evaluation.
Solvent evaporation method [15-18]
Solvent evaporation method was used for the
preparation of solid dispersions. Briefly appropriate
amount of Tadalafil was taken in china dish and minimum
amount of solvent system (combination of methanol and
dichloromethane 1:1) was added to dissolve the drug.
Required amount of carrier (PEG 6000 and PVP) was
added to prepare required drug to carrier ratio for
formulations. Excess of solvent system was added if
required to dissolve drug and carriers. The solvent was
then removed by evaporation at 40°C under vacuum. The
solid dispersions prepared were pulverized and sifted (80#)
and stored in a desiccators. Solid dispersions were
prepared using compositions as given in Table No 1
EVALUATION OF SOLID DISPERSIONS
The prepared solid dispersions were evaluated for
solubility studies; percent drug content, dissolution
efficiency, in-vitro drug release and Fourier transform
infrared Spectroscopy (FTIR), Differential scanning
calorimetry (DSC), X-ray powder diffraction (XRPD), and
scanning electron microscopy (SEM).
FTIR spectroscopy
FT-IR spectra of Tadalafil, PVP K-30, PEG 6000
and their solid dispersions were recorded. Sample of about
2.5 mg mixed thoroughly with 100 mg of potassium
bromide IR powder and compacted under vacuum. The
resultant disc was mounted in a suitable holder in thermo-
electron IR spectrophotometer (Model Schimadzu 8400S)
and IR spectral was recorded from 4,000 to 400 cm‐1.
Differential scanning Calorimetry (DSC)
DSC curves of Tadalafil, PVP K-30, PEG 6000
and their solid dispersions were recorded using modulated
scanning calorimeter (Model TAG 1000). The analysis was
performed by heating the 2-3 mg samples on an aluminum
crimp pans at a rate of 10C min in a nitrogen atmosphere
(50 ml/ min).
Powder X-Ray Diffractometry (PXRD)
X-Ray diffraction spectra of Tadalafil, PVP K-30,
PEG 6000 and their solid dispersions were recorded on
SIEFERT XRD 3000 TT diffractometer using CuK a
radiation. The data were recorded at 2 range of 10 to 60C
at time of 0.5 seconds. The relative intensity I/I0 and the
interplanar distance (d) corresponding to the 2 value were
reported and compared.
Scanning Electron Microscopy (SEM)
The external morphology of solid dispersions was
analyzed by Scanning Electron Microscope (SEM). The
samples were examined under a scanning electron
microscope JSM 6100 JEOL JAPAN.
Drug Content
From each batch of prepared solid dispersions
four samples of 10 mg were taken and analyzed for drug
content. 10 mg of mixtures were weighed and transferred
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in 100 ml standard flasks and volume was made up to 100
ml with methanol. The solutions were filtered through a
0.45µ membrane filter and diluted. One ml from above the
solution was transferred into a 10 ml standard flasks and
volume made up to 10 ml with methanol. Absorbance of
the solutions was measured at 284 nm and the results were
tabulated in Table 3 [19-21].
Phase solubility studies
Phase-solubility studies were carried out by
adding excess of drug (60 mg) in 25 ml of aqueous
solution of different (1%, 2%, 3%, 4% and 5%) PVP K30
and PEG 6000 concentrations. The suspensions were
continuously stirred on an electromagnetic stirrer with a
hot plate at 37 0C and 300 rpm for 48 h (this duration was
previously tested to be sufficient to reach equilibrium). The
suspensions were filtered through a 0.22 µm nylon
membrane filter. The filtrates were suitably diluted and
analyzed, spectrophotometrically, for the dissolved drug at
284 nm. All assays were performed in triplicate. The Gibbs
free energy of transfer ( Gtr0) of Tadalafil from pure water
to the aqueous solution of carrier was calculated as
follows:
Where S0/SS is the ratio of molar solubility of
Tadalafil in aqueous solutions of carrier to that of the same
medium without carrier. 1:1 complex apparent stability
constant (Ka) was determined as follows:
Ka =
Where slope and intercept were obtained from the
graph of %w/v of Tadalafil vs. aqueous concentration of
carrier (PVP K30 and PEG-6000) in %w/v.
In-vitro dissolution studies [22]
The release of pure Tadalafil was determined
using USP dissolution testing apparatus-II (paddle
method). The dissolution studies were performed using 900
ml of 0.1 N HCL as dissolution media at 37 ± 0.5C with
100 rpm for 90 minutes. Samples of each preparation
equivalent to 10 mg of drug were added to dissolution
medium. A 5 ml aliquot was withdrawn at different time
intervals (5, 10, 15, 30, 45, 60 and 90) and filtered through
0.45µ nylon filter. Each sample was replaced with 5 ml of
fresh dissolution medium. The samples were analyzed for
its drug content spectrophotometrically by measuring the
absorbance against blank at 284.5 nm. Percent of Tadalafil
dissolved at various time intervals was calculated and
plotted against time and the results were shown in Fig 6.
RESULTS AND DISCUSSION
Fourier Transform Infrared Spectroscopy (FTIR)
The comparison of FT-IR of the solid dispersions
of PVP K30 and drug & PEG-6000 and drug with the FT-
IR of its individual components was done to observe any
interactions between drug and polymer. The FT-IR spectra
of Tadalafil, PVP K30, PEG-6000, and the corresponding
solid dispersions are shown in Fig No 1. The FT-IR of
various mixtures reveals all the peaks of the drug. As it can
be seen, a strong absorption peaks at 1676.53 and 3328.91
cm−1 occurs in the IR spectrum of Tadalafil. So there is no
significant shift in the peak corresponding to the drug or
the polymer was observed in the solid dispersions. The
results clears that there is no chemical interaction between
Tadalafil and excipients, only the physical entrapment is
observed which is further evaluated by DSC and SEM
studies.
Differential Scanning Calorimetry (DSC)
The DSC runs for Tadalafil, PVP K30, PEG-600
and solid dispersions (CMPVP3, CMPEG3) are shown in
Fig No.2. The DSC curve for Tadalafil showed a sharp
melting endotherm at 276.35 0C. The DSC curve for PEG-
6000 showed a sharp melting endotherm at 63.27 0C. The
DSC curve for PVP K30 showed glass transition peaks at
178.14 0C. The Solid dispersions CMPVP3 & CMPEG3
showed no shift in the melting endotherm for Tadalafil
indicating that there is no chemical interaction between the
Tadalafil and PVP K30 & PEG-6000 in the solid
dispersions.
X-ray diffraction (XRD) analysis
Powder XRD of pure TDF and its solid
dispersions with PVP K30 and PEG 6000 are shown in
Fig. 3. The presence of distinct peaks in the X-ray
diffraction spectrum indicates that TDF is present as a
crystalline material with characteristic diffraction peaks
appearing at a diffraction angle of 2h at 7.468, 10.826,
12.757, 14.733, 18.64, 21.872, 24.383 etc. Spectroscopy of
PVP K30 (Fig. 3b) was characterized by the complete
absence of any diffraction peak. SEMPVP3, CMPVP3,
SEMPEG3, MMPEG3, CMPEG3 (Fig. 3 D-H) showed the
same diffraction pattern with most of the diffraction peaks
corresponding to the drug indicating that TDF was in an
amorphous state. Moreover, no peaks other than those that
could be assigned to pure TDF and PVP K30 or PEG 6000
were detected in Fig. 3.
Scanning electron microscopy (SEM)
The SEM of pure Tadalafil, pure PVP K30 is
shown in Fig No.4 respectively. It was seen that Tadalafil
is highly crystalline material. PVPK30 was present in
globular form. It was found that the crystals of Tadalafil
were dispersed between the carriers in the CMPVP3
formulations as shown in Fig No.4 (D). The change in
crystalline nature of Tadalafil in solid dispersion can be
easily seen in SEM, which reveals that the drug is
completely dispersed in polymeric matrix. The SEM also
supports data obtained from IR, XRD and DSC.
Percent Practical Yield (PY)
Percentage practical yield were calculated to
know about percent yield or efficiency of any method, thus
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its help in selection of appropriate method of production.
Solid dispersions were collected and weighed to determine
practical yield (PY) from the following equation.
Percentage of practical yield = x 100
Percentage drug content of TDF in solid dispersions
Solid dispersions of TDF with PVP K30 and PEG
6000 were prepared by three methods. The percentage of
drug content of all the formulations was shown in the
Table No.2. This result indicates that there was uniform
distribution of the drug throughout the batch.
The drug content of solid dispersions was found
to be from 92.52 to 101.46, which is found to be within the
range of ±1 % of the theoretical claim, which shows the
uniformity and reproducibility of the obtained method. The
saturation solubility of pure drug, PM and SD was found to
be 0.014 mg/ml, 0.228 mg/ml to 0.711 mg/ml and 0.252
mg/ml to 0.894 mg/ml. The results were shown in Table 2.
Phase solubility Studies
Fig. 5 represents solubility of TDF in the presence
of PVP K30 and PEG 6000. The Gibbs free energy of
transfer ( G0tr) and apparent stability constants (Ka)
derived from Fig. 5 are shown in Table 3. The plots of drug
solubility against the polymer concentration (Fig. 5)
indicate a linear relationship (AL type of curve) in the
investigated polymer concentration range.
Table 3 shows that all values of ( G0tr) were
negative at all levels of carriers, demonstrating spontaneity
of drug Solubilization process. The values show a
declining trend with increase in the carrier concentration
too construing that the process is more favorable at higher
carrier levels. Table 3 also indicates that TDF-PVP K30
interaction has a higher Ka value. The higher Ka value
indicates that the binding affinity between TDF-PVP K30
is more than that of TDF-PEG 6000. The results show that
in both cases, the solubility of TDF increased with
increasing carrier concentration.

Table 1. Composition of TDF solid dispersions

Method Carrier Drug: Carrier Formulation Code
1:1 CMPVP1
PVP K30 1:3 CMPVP2
1:5 CMPVP3
Co-grinding Method
1:1 CMPEG1
PEG 6000 1:3 CMPEG2
1:5 CMPEG3
1:1 SEMPVP1
PVP K30 1:3 SEMPVP2
1:5 SEMPVP3
Solvent Evaporation Method
1:1 SEMPEG1
PEG 6000 1:3 SEMPEG2
1:5 SEMPEG3
1:1 MMPEG1
Melting Method PEG 6000 1:3 MMPEG2
1:5 MMPEG3
Table 2. Percent Drug Content of Tadalafil-PVP K-30 & Tadalafil-PEG-6000 Solid Dispersions
S.No Formulation code % Practical Yield±SD (n=3) %Drug Content±SD (n=3)
1 CMPVP1 96.54±0.84 97.02±0.86
2 CMPVP2 96.81±0.72 94.34±0.48
3 CMPVP3 98.30±0.46 98.26±0.19
4 CMPEG1 95.09±1.03 95.79±1.03
5 CMPEG2 99.39±0.49 92.52±1.13
6 CMPEG3 99.63±0.46 93.81±1.21
7 SEMPVP1 94.78±0.29 94.50±0.93
8 SEMPVP2 96.04±0.95 92.82±0.84
9 SEMPVP3 97.62±1.04 101.19±0.82
10 SEMPEG1 98.41±1.23 97.52±1.38
11 SEMPEG2 94.00±0.94 101.46±1.40
12 SEMPEG3 93.39±0.92 98.51±0.94
13 MMPEG1 92.72±0.67 93.81±0.78
14 MMPEG2 94.47±1.37 97.27±0.16
15 MMPEG3 95.78±0.24 95.54±0.56

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Table 3. Solubility of Tadalafil (µg/ml) in aqueous solutions of PVP K30 and PEG 6000 in water at 37 0C (n=3)
(kJ/mol)
Concentration (% w/v)
PVP K30 PEG 6000
1 -1740.28 -199.703
2 -2852.9 -610.52
3 -3121.07 -1061.27
4 -4102.47 -1574.80
5 -4353.52 -1900.03
Slope 15.03 5.558
Ka 103.72 16.65

Fig 1. FTIR spectra of (A) pure drug TDF (B) PVP K30 (C) PEG 6000 (D) SEMPVP3 (E) CMPVP3 and (F) SEMPEG3

Fig 2. DSC thermograms of (A) pure drug TDF (B) PVP K30 (C) PEG 6000 (D) SEMPVP3 (E) CMPVP3 (F) SEMPEG3
(G) MMPEG3 and (H) CMPEG3

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Fig 3. PXRD graphs of (A) pure drug TDF (B) PVP K30 (C) PEG 6000 (D) SEMPVP3 (E) CMPVP3 (F) SEMPEG3 (G)
MMPEG3 and (H) CMPEG3

Fig 4. SEM photographs, (A) Tadalafil (B) PVP K 30 (C) PEG 6000 (D) CM4VP3 (E) SEMPEG3 (F)MMPEG3

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Fig 5. Solubility of Tadalafil (µg/ml) in aqueous solutions of PVP K30 and PEG 6000 in water at 37 0C. (n=3)
Fig 6. Comparative dissolution profile
In-vitro Dissolution Studies of TDF and Its Solid
Dispersion
In-vitro dissolution test results indicate complete
dissolution of drug from all its solid dispersion within 90
min which is depicted in Fig No.6. Among the various
formulations of preparation of solid dispersion, TDF with
PVP K30 (1:5) was found to be most effective. The
formulation CMPVP3 showed faster dissolution rate (90
min). The enhanced dissolution may be due to enhanced
wettability and dispersibility of drug in dissolution
medium.
The graph for the comparison in-vitro cumulative
percent release profile of Tadalafil of PVP K30 and PEG-
6000 solid dispersions formulations P1, CMPVP1,
CMPVP2, CMPVP3, CMPEG1, CMPEG2, CMPEG3,
SEMPVP1, SEMPVP2, SEMPVP3, SEMPEG1,
SEMPEG2, SEMPEG3, MMPEG1, MMPEG2 and
MMPEG3 are shown in Fig No.6 .It was evident that less
dissolution was achieved for pure Tadalafil even after 90
min, under the specified dissolution conditions. The
hydrophobic property of the drug prevented its contact
with the dissolution medium causing it to float on the
surface, and consequently hindering its dissolution. In all
the cases, cumulative percent release was much greater
than pure Tadalafil.
CONCLUSION
The enhancement of dissolution of Tadalafil from
solid dispersions may be due to the reduction of crystalline
nature of the drug in solid dispersions. From this study, the
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increase in dissolution rates of TDF, when dispersed in
PVP K30 or PEG 6000, can be observed. Solubility studies
showed a solubilizing effect of both carriers on TDF. The
negative values of Gibbs free energy indicated spontaneity
of transfer. XRD, DSC and SEM studies of TDF-PVP K30
solid dispersions indicated that the drug was entrapped
within the carrier (PVP K30) matrix while in the case of
TDF–PEG 6000 mixtures the drug was adsorbed as fine
particles on the surface of carrier (PEG 6000). In these
systems no drug carrier interaction was shown with the use
of FTIR. The dissolution rates of solid dispersions were
higher than those of pure drug, which was possibly caused
by increased drug wettability. Solid dispersions of
Tadalafil with PVP K30 in ratio 1:5 (CMPVP3) were
found to be best formulation by releasing 91.18 % of drug
at the end of 90 min.

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