Physicochemical Characterization and Dissolution Study of Solid

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dx.doi.org/10.14227/DT150308P17
Physicochemical Characterization and
Dissolution Study of Solid Dispersions of
Furosemide with Polyethylene Glycol
6000 and Polyvinylpyrrolidone K30
e-mail: [email protected]
Rakesh P. Patel1, Dhaval J. Patel, Dipen B. Bhimani, and
Jayvadan K. Patel
Department of Pharmaceutics, S.K. Patel College of Pharmaceutical Education and Research,
Ganpat University, Ganpat vidyanagar, Kherva, Mehsana-Gozaria Highway, PIN-382 711,
Gujarat, India.
ABSTRACT
Solid dispersions traditionally have been used as effective methods to improve the dissolution properties and
bioavailability of poorly water-soluble drugs. The aim of the present study was to improve the solubility and dissolution
rate of a poorly water-soluble drug, furosemide, by a solid dispersion technique. Solid dispersions were prepared using
polyethylene glycol 6000 (PEG 6000) and polyvinylpyrrolidone K30 (PVP K30) in different drug-to-carrier ratios.
Dispersions with PEG 6000 were prepared by fusion-cooling and solvent evaporation, while dispersions containing PVP
K30 were prepared by solvent evaporation technique. These new formulations were characterized in the liquid state by
phase solubility studies and in the solid state by differential scanning calorimetry, powder X-ray diffraction, and
FTIR spectroscopy. The aqueous solubility of furosemide was favored by the presence of both polymers. Solid state
characterizations indicated that furosemide was present as an amorphous material and entrapped in polymer matrix. In
contrast to the very slow dissolution rate of pure furosemide, the dispersion of the drug in the polymers considerably
enhanced the dissolution rate. Solid dispersion prepared with PEG showed the most improvement in wettability and
dissolution rate of furosemide. Even physical mixtures of furosemide prepared with both polymers also showed better
dissolution profiles as compared with that of pure furosemide. Tablets prepared using solid dispersions showed
significant improvement in the release profile of furosemide as compared with conventional tablets prepared using
furosemide without PEG or PVP.
INTRODUCTION
he therapeutic efficacy of a drug product intended
to be administered by the oral route depends first
of all on its absorption by the gastro-intestinal tract.
It is well established that dissolution is frequently the
rate-limiting step in the gastrointestinal absorption of a
drug from a solid dosage form. The relationship between
solution rate and absorption is particularly distinct when
considering drugs of low aqueous solubility. Poorly soluble
drugs have been shown to be unpredictable and are
slowly absorbed as compared with drugs with higher
solubility. Several methods that have been employed to
improve the solubility of poorly water soluble drugs
include increasing the particle surface area available for
dissolution by milling (1), improving the wettability with
surfactants or doped crystals (2), decreasing crystallinity
by preparing a solid dispersion (3), use of inclusion
compounds such as cyclodextrin derivatives (4), use of
polymorphic forms or solvated compounds (5), and use of
salt forms.
Solid dispersions (SDs) represent a useful pharmaceutical technique for increasing the dissolution, absorption,
T
1
Corresponding author.
and therapeutic efficacy of drugs in dosage forms.
The term “solid dispersion” refers to the dispersion of one
or more active ingredients in an inert carrier or matrix in
the solid state prepared by the melting, solvent, or
melting solvent methods (6).
A solid dispersion technique has been used by various
researchers who have reported encouraging results with
different drugs (7).
The mechanisms for the enhancement of the
dissolution rate of SDs have been proposed by several
investigators. A molecular dispersion of drug in polymeric
carriers may lead to particle size reduction and surface
area enhancement, which result in improved dissolution
rates. Furthermore, no energy is required to break up the
crystal lattice of a drug during the dissolution process, and
there is an improvement in drug solubility and wettability
due to the surrounding hydrophilic carriers (8). Reduction
or absence of aggregation and agglomeration may also
contribute to increased dissolution.
The method of preparation and the type of the carrier
used are important influences on the properties of such
solid dispersions (9). The methods used to prepare SDs
include the melting method, the solvent method, and the
solvent wetting method (10).
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Among the carriers used in the formation of solid
dispersions, polyethylene glycol and polyvinylpyrrolidone
are the most commonly used. Both polymers show
excellent water solubility and vary significantly in
molecular weight, ranging from 200 to >300,000 for
polyethylene glycol and from 10,000 to 700,000 for
polyvinylpyrrolidone. The molecular size of both polymers
favors the formation of interstitial solid solutions (11).
Both polymers are often employed as vehicles due to
their low toxicity, low melting point, rapid solidification
rate, high aqueous solubility, availability in various
molecular weights, economic cost, and physiological
tolerance. These and other properties make them very
suitable vehicles in the formulation of dosage forms
(12–14).
Many methods are available for determining the
physical nature of an SD. Solid dispersions can be
characterized in the solid state by Fourier transform
infrared spectroscopy (FTIR), differential scanning
calorimetry (DSC), powder X-ray diffraction (PXRD), and so
forth (11, 15, 16).
Furosemide (FUR) is a potent loop diuretic, chemically
designated as 4-chloro-2-(2-furylmethylamino)-5sulfamoyl-benzoic acid. It is a white to slightly yellow,
odorless, crystalline powder, practically insoluble in water
(10 µg/mL), sparingly soluble in alcohol, freely soluble in
dilute alkali solutions and insoluble in dilute acids (17).
The rate of absorption and the extent of bioavailability for
such an insoluble hydrophobic drug are controlled by the
rate of dissolution in the gastrointestinal fluids.
Improvement of aqueous solubility in such a case is a
valuable aim to improve therapeutic efficacy. Hence,
attempts are being made to increase the rate of
dissolution of such poorly water soluble hydrophobic
drugs, to increase their effectiveness and simultaneously
reduce their doses and hence their toxic effects.
The present study was planned to improve the aqueous
solubility and dissolution rate of FUR by preparing the
SD with polyethylene glycol 6000 (PEG 6000) and
polyvinylpyrrolidone (PVP K30) employing various
methods such as solvent evaporation, melting, and
physical mixing. The study further aimed to characterize
the interaction of FUR with PEG 6000 and PVP K30 by
using FTIR, DSC, and PXRD techniques.
MATERIALS AND METHODS
Materials
The samples of FUR, PEG 6000, and PVP K30 (average
molecular weights of 6000 and 50,000, respectively) were
generous gifts from Maan Pharmaceuticals Ltd. (Mehsana,
India) and were used without further purification. Directly
compressible lactose, colloidal silicon dioxide, and
magnesium stearate were procured from S.D. Fine-Chem
Ltd., Mumbai. All chemicals and solvents used in this study
were of analytical reagent grade. Freshly distilled water
was used throughout the work.
18
Phase-Solubility Study
Phase-solubility studies were performed according to
the method reported by Higuchi and Connors (18). FUR, in
amounts that exceeded its solubility, were transferred to
screw-capped vials containing 25 mL aqueous PEG 6000
or PVP K30 solutions of different concentrations (0, 1,
5, and 10%). The contents were stirred on an
electromagnetic stirrer (Remi, India) at 25 °C and 37 °C for
72 h and 300 rpm. This duration was previously tested to
be sufficient to reach equilibrium, after which no
improvement in solubility was observed. After reaching
equilibrium, samples were filtered through a 0.22-µm
membrane filter, suitably diluted with 0.1 N NaOH, and
analyzed for drug content at the λmax of 274 nm (17) using
a spectrophotometer (Shimazdu-1601, UV–vis
spectrophotometer, Shimadzu Corp, Kyoto, Japan). All
assays were performed in triplicate.
Preparation of Solid Dispersion and Physical Mixture
Solid Dispersions Prepared by Solvent Evaporation
SDs of FUR in PEG 6000 or PVP K30 containing different
weight ratios (1:1, 1:5, 1:10 and denoted as SEPEG or
SEPVP 1/1, 1/5, 1/10, respectively) were prepared by the
solvent method (19) as follows.
To a solution of FUR in ethanol (10 mg/25 mL), an
appropriate amount of PEG 6000 or PVP K30 was added.
The solvent was evaporated under reduced pressure at 40
°C, and the resulting residue was dried under vacuum for 3
h, stored in a desiccator at least overnight, ground in a
mortar, and passed through a #100 sieve.
Solid Dispersions Prepared by Melting of the Carrier
Four SD preparations containing different weight ratios
of FUR in PEG 6000 (1:1, 1:5, 1:10 and denoted as MEPEG
1/1, 1/5, 1/10, respectively) were prepared by the melting
method (20). FUR was added to the melted PEG 6000 at
75 °C, and the resulting homogeneous preparation was
rapidly cooled in a freezing mixture of ice and sodium
chloride, and stored in a desiccator for 24 h. Subsequently,
the dispersion was ground in a mortar and sieved through
a #100 sieve.
Physical Mixtures
Physical mixtures (PMs) having the same weight ratios,
as described in the previous two methods, were prepared
by thoroughly mixing appropriate amounts of FUR and
PEG 6000 or PVP K30 in a mortar until a homogeneous
mixture was obtained. The resulting mixtures were sieved
through a #120 sieve and denoted as PMPVP or PMPEG,
respectively.
Characterization of Solid Dispersion
Infrared (IR) Spectroscopic Analysis
FTIR spectra of moisture-free powdered samples of FUR
and its PMs and SDs with PEG 6000 and PVP K30 were
obtained using a spectrophotometer (FTIR-8300,
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Shimadzu Co., Kyoto, Japan) by potassium bromide (KBr)
pellet method. The scanning range was 750–4000 cm−1,
and the resolution was 1 cm−1.
Powder X-ray Diffraction (PXRD) Analysis
The physical state of FUR in the various preparations
was evaluated by powder X-ray diffraction study. Powder
X-ray diffraction patterns of all samples were determined
using a Phillips PW 3710 scanner, IW 1830 generator with
a CuK α anode at 40 kV and 30 mA, and a scan rate of 1°
min−1 from 2θ range 1 to 40°.
Differential Scanning Calorimetry (DSC) Analysis
DSC scans of all powdered samples were recorded
using Shimadzu DSC-60 with TDA trend line software.
All samples were weighed (8–10 mg) and heated at a
scanning rate of 10 °C/min under dry nitrogen flow
(100 mL/min) between 50 and 300 °C. Aluminum pans and
lids were used for all samples. Pure water and indium as
primary standard were used to calibrate the DSC
temperature scale and enthalpic response.
Wettability and Dissolution Studies
A wettability study was performed using open tubes
containing FUR and its PMs and SDs with PEG 6000 and
PVP K30; these were placed with their lower capillary ends
dipped into colored water (0.01% eosin in water). The
upward migration of the colored front was registered as a
function of time (21).
Dissolution studies of FUR in powder form and its PMs
and SDs with PEG 6000 and PVP K30 were performed to
evaluate in vitro drug release profile. Dissolution studies
were performed using USP Apparatus 2 with 500 mL
dissolution medium (demineralized water containing
0.25% [w/v] of sodium lauryl sulfate [SLS]) at 37 ± 0.5 °C
and 50 rpm for 4 h. Samples of pure FUR and PMs and SDs
equivalent to 20 mg of the drug were added to the
dissolution medium. At fixed time intervals, 5-mL aliquots
were withdrawn, filtered through a 0.22-µm membrane
filter, suitably diluted, and assayed for FUR content by
measuring the absorbance at 274 nm using a spectrophotometer. Equal volume of fresh medium prewarmed at the
same temperature was replaced in the dissolution
medium after each sampling to maintain constant volume
throughout the test. Each test was performed in triplicate,
and release curves were plotted using calculated mean
values of cumulative drug release. Similarity factor (f2) and
mean dissolution time (MDT) values were calculated to
compare the extent of improvement in the dissolution
rate of FUR from different samples. Preliminary tests
demonstrated that there was no change in the λmax of FUR
due to the presence of PEG 6000 or PVP K30 dissolved in
the dissolution medium.
Formulation Studies
Formulation excipients were selected on the basis of
preliminary tests, which demonstrated no interference of
these excipients with the λmax of FUR. Tablets containing
20 mg of FUR were made by direct compression
using different formulation excipients such as directly
compressible lactose, colloidal silicon dioxide, and
magnesium stearate. Tablets containing SDs equivalent
to 20 mg FUR were made similarly. The blend was
compressed on an eight-station single rotary machine
(Cadmach, India) using round-shaped, flat punches to
obtain tablets of 3–6 kg/cm2 hardness and 3.8–4.0 mm
thickness. For the assay, three tablets were crushed, and a
blend equivalent to 10 mg of FUR was weighed and
dissolved in dissolution medium. The release profile of
drug from tablets was studied in triplicate using the same
dissolution media, conditions, and procedure as described
for in vitro dissolution studies.
Statistical Analysis
A model-independent mathematical approach
proposed by Moore and Flanner (22) for calculating a
similarity factor f2 was used for comparing dissolution
profiles of different samples. The similarity factor f2 is a
measure of similarity in the percentage dissolution
between two dissolution curves and is defined by
following equation:
 
f2 = 50 log  1+
 
()
1
n
2
n
∑ wt (Rt − Tt )
t =1



−0.5

x 100

[1]
where n is the number of withdrawal points, Rt is the
percentage dissolved of reference at the time point t, Tt is
the percentage dissolved of test at the time point t, and
Wt is optional weight at time t (for the entire study, the
value of Wt is assumed to be 1).
A value of 100% for the similarity factor (f2) suggests
that the test and reference profiles are identical. Values
between 50 and 100 indicate that the dissolution profiles
are similar, while lower f2 values imply an increase in
dissimilarity between release profiles (22).
MDT reflects the time for the drug to dissolve and is the
first statistical moment for the cumulative dissolution
process that provides an accurate drug release rate (23).
It is an accurate expression for drug release rate. A higher
MDT value indicates a greater drug retarding ability (24).
To understand the extent of improvement in dissolution
rate of FUR from its PMs and SDs with PEG and PVP, the
obtained dissolution data of all samples were fitted into
the equation
n
MDTin vitro =
∑t
mid
∆M
i =1
n
∑ ∆M
[2]
i =1
where i is the dissolution sample number, n is the number
of dissolution times, tmid is time at the midpoint between
times ti and ti-1, and ∆M is the amount of FUR dissolved
(µg) between times ti and ti-1.
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RESULTS AND DISCUSSION
Phase-Solubility Study
The solubility of FUR in water at 25 °C is 10 µg/mL;
therefore, FUR can be considered to be a water-insoluble
drug. The phase solubility curve of FUR in the presence of
PEG and PVP at 25 and 37 °C is shown in Figures 1A and
1B. (For ease in discussion, hereafter, PEG 6000 and PVP
K30 are abbreviated as PEG and PVP, respectively). From
this curve, it can be seen that the apparent solubility of
FUR increased with increasing temperature and carrier
concentrations. At the highest polymer concentration
(10% w/w), the solubility increased approximately 27-fold
and 23-fold for PEG and PVP, respectively, at 37 °C.
The same tendency was observed at 25 °C.
An indication of the process of transfer of FUR from
pure water to aqueous solution of PEG or PVP was
obtained from the values of Gibbs free energy change
(25). The Gibbs free energy of transfer (∆Gtr°) of FUR from
pure water to aqueous solutions of SDs was calculated
using the following equation:
Table 1. Thermodynamic Parameters for Solubilization Process
of FUR in Aqueous Solutions of PEG 6000 and PVP K30 at 25
and 37 °C
PEG 6000
Polymer
concentration
(%w/v)
∆Gt° (KJ/mol)
25 °C
37 °C
1
−2.7
−4.2
5
−5.2
10
Ka (m−1)
PVP K30
∆Ht°
∆Gt° (KJ/mol)
∆Ht°
25 °C
37 °C
−22.7
−2.6
−4.1
−29.4
−7.0
−29.3
−5.2
−6.7
−33.6
−7.6
−8.5
−36.4
−6.8
−8.1
−38.9
884.0
1240.0
631.1
1042.1
S 
∆Gtr o = −2.303RT log  c 
 So 
[3]
where Sc/So is the ratio of molar solubility of FUR in
aqueous solution of PEG or PVP to that of pure water.
The enthalpy of transfer (∆Ht°) can be calculated from a
modification of the van’t Hoff equation:
∆Ht o = −R
dln( Sc So )
d(1 T )
[4]
The obtained values of ∆Gtr°, ∆Ht°, and apparent
stability constants (Ka) are shown in Table 1. The ∆Gtr°
values show whether the reaction condition is favorable
or unfavorable for drug solubilization in the aqueous
carrier solution. Negative ∆Gtr° values indicate favorable
conditions. ∆Gtr° and ∆Ht° values were all negative for
both polymers at various concentrations, indicating
the spontaneous nature of FUR solubilization, and
decreased with an increase in PEG or PVP concentration,
demonstrating that the reaction became more favorable
as the concentration of PEG or PVP increased. These
values also indicated that the extent of improvement in
solubility was more with PEG as compared with PVP.
Figure 1. Solubility of FUR (g/100 mL) in aqueous solutions of (A) PEG 6000
and (B) PVP K30 in water at 25 and 37 °C (n=3).
20
Characterization of SDs
Fourier Transform Infrared (FTIR) Spectroscopic Analysis
FTIR has been used to assess the interaction between
carrier and guest molecules in the solid state. In the SD
preparations, there is a peak band shift in the absorption
spectrum of the guest. However, some of the changes are
very subtle requiring careful interpretation of the
spectrum.
The FTIR spectra of all samples are shown in Figure 2.
The spectrum of pure FUR presented characteristic peaks
at 3340 cm−1 (NH2 stretching vibration of Ar-NHCH2),
3260 cm−1 (stretching vibration of SO2NH2), 1665 cm−1
(bending vibration of amino group), 1560 cm−1
(asymmetric stretching vibration of the carboxyl group),
and 1318 cm−1 (asymmetric stretching vibration of the
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Figure 2. FTIR spectra of (A) FUR, (B) PEG 6000, (C) PMPEG 1/10, (D) MEPEG
1/10, (E) SEPEG 1/10, (F) PVP K30, (G) PMPVP 1/10, and (H) SEPVP 1/10.
Figure 3. Powder X-ray Diffractograms of (A) FUR, (B) PEG 6000, (C) PMPEG
1/10, (D) MEPEG 1/10, (E) SEPEG 1/10, (F) PVP K30, (G) PMPVP 1/10, and (H)
SEPVP 1/10.
sulfonyl group). Important vibrations detected in the
spectrum of PEG are the C–H stretching at 2890 cm−1 and
the C–O (ether) stretching at 1125 cm−1. The spectrum of
PVP showed important bands at 2925 cm−1 (C–H stretch)
and 1652 cm−1 (C=O). A very broad band was also visible
at 3300 cm−1, which was attributed to the presence of
water confirming the broad endotherm detected in the
DSC experiments.
The spectra of PMPEG 1/10 and PMPVP 1/10 can be
simply regarded as the superposition of those of FUR and
PEG or PVP. No difference was seen in the position of the
absorption bands of FUR and PEG or PVP.
In the spectra of SEPEG 1/10, MEPEG 1/10, and SEPVP
1/10, the characteristic peaks of PEG or PVP were present
at almost the same positions, whereas peaks due to FUR
were absent indicating trapping of FUR inside the PEG or
PVP matrix. Moreover, all the spectra showed no peaks
other than those assigned to FUR, PEG, and PVP, which
indicates the absence of any well-defined chemical
interactions. Although hydrogen bonding between the
hydrogen atom of the OH of the drug and oxygen atom in
PEG or PVP could be expected, this was not demonstrated.
distinct peaks in the PXRD spectrum indicate that FUR was
present as a crystalline material with major characteristic
diffraction peaks appearing at a diffraction angle of 2θ at
5.95, 11.98, 14.11, 18.05, 18.90, 20.36, 21.28, 22.82, 24.73,
27.48, and 29.17. PEG also exhibited a distinct pattern with
diffraction peaks at 2θ at 15.00, 18.75, 23.15, 26.60, and
29.35, but the spectrum of PVP was characterized by the
complete absence of any diffraction peak, which is
characteristic of an amorphous compound.
The diffraction patterns of all the samples of SDs show
peaks due to PEG or similar to PVP and an absence of
major diffraction peaks corresponding to FUR, with most
of the diffraction indicating FUR was present as
amorphous material inside the PEG or PVP matrix.
Moreover, no peaks other than those that could be
assigned to pure FUR and PEG or PVP were detected in the
SEPEG 1/10, MEPEG 1/10, and SEPVP 1/10, indicating no
chemical interaction in the solid state between the two
entities. In the case of physical mixing, diffractograms of
PMPEG 1/10 showed more resemblance to PEG, whereas
diffractograms of PMPVP 1/10 showed resemblance to
FUR due to presence of free drug.
Powder X-ray Diffraction (PXRD) Studies
Powder X-ray diffractograms of FUR, PEG, PVP, their PMs
and SDs are shown in Figure 3. The presence of numerous
Differential Scanning Calorimetry (DSC) Studies
DSC enables the quantitative detection of all processes
in which energy is required or produced (i.e., endothermic
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Figure 5. Wettability study of pure FUR, its PMs and SDs with PEG 6000 and
PVP K30 in water (n=3).
Figure 4. DSC thermograms of FUR (A), PEG 6000 (B), PMPEG 1/10 (C), MEPEG
1/10 (D), SEPEG 1/10(E), PVP K30 (F), PMPVP 1/10 (G), and SEPVP 1/10 (H).
or exothermic phase transformations). The thermal
behavior of the prepared solid dispersions of FUR with
PEG and PVP was studied by DSC.
The DSC thermograms for pure FUR, PEG, PVP, their PMs
and SDs are shown in Figure 4. The FUR showed a melting
peak at 225 °C with an enthalpy of fusion (∆H) of
302.22 mJ/g (26). The DSC scan of PVP showed a broad
endotherm ranging from 80 to 120 °C due to the presence
of residual moisture in PVP, whereas PEG showed a single
sharp endotherm at 58 °C due to melting.
DSC thermograms of PMPEG 1/10 and PMPVP 1/10
showed the melting peak of the drug at 225 °C, a sharp
endothermic peak at 58 °C due to melting of PEG, and the
broad endotherm due to the presence of water ranging
from 90 to 110 °C in PVP.
The DSC scans of SEPEG 1/10 and MEPEG 1/10 showed
only one peak at 58 °C due to melting point of PEG, and
the scan of SEPVP 1/10 showed one peak at 90–110 °C due
to loss of water from PVP. All samples of SDs showed
complete absence of drug peak at 225 °C. This complete
absence of the FUR peak indicates that FUR is amorphous
or is in a solid solution inside the PEG and PVP matrix. This
type of interaction was also observed in the FTIR and
PXRD studies.
22
Wettability and Dissolution Studies
The wettability of FUR was significantly improved by
preparing its solid dispersions with PEG and PVP
(Figure 5). The greatest improvement of wettability in
water was observed with SEPEG 1/10 and SEPVP 1/10
(58.7% and 49.9%, respectively after 60 min). A significant
improvement in the wettability of FUR was also observed
in PMPEG 1/10 and PMPVP 1/10 as compared with pure
FUR (20%) after 60 min.
It is generally accepted that dissolution media are not
completely representative of gastrointestinal (GI)
conditions, yet it is proposed in guidelines that a good
method will employ a dissolution medium that is
physiologically meaningful or closely mimics in vivo
conditions (27). It has been suggested that including
surface-active agents in dissolution media is important for
poorly soluble compounds, because the lack of a surface
tension lowering agent would result in poorer wetting
and in vitro dissolution rates that are not representative of
in vivo rates (28). The FDA has permitted the use of
surfactants in media for conducting dissolution studies of
poorly soluble compounds (29).
Dissolution of pure FUR and all other prepared systems
(SDs and PMs) were carried out in demineralized water
containing 0.25% (w/v) SLS. DP30 min values (percent drug
dissolved within 30 min), t50% (time to dissolve 50% drug),
and mean dissolution time (MDT) values for different
samples are reported in Table 2. In vitro dissolution
profiles of pure FUR, its PM and SDs with PEG and PVP
over a period of 4 h are shown in Figure 6.
From data presented in Table 2 and Figure 6, it is
evident that the dissolution rate of pure FUR is very low
(DP30 min 7.6%, t50% >> 4 h, and MDT of 58.3 min at 4 h). SDs
of FUR with PEG and PVP significantly enhance the
dissolution rate of FUR (80–95%, respectively) within 4 h
as compared with PM as well as pure FUR. PMs with PEG
and PVP also improved the dissolution rate of FUR. The
highest improvement was obtained in SDs prepared with
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Table 2. Percent Drug Dissolved within 30 min (DP30 min), Time to
Dissolve 50% Drug (t50%), and Mean Dissolution Time (MDT)
from Pure FUR, its PMs and SDs
Sample
FUR
DP30 min
7.5
T50%(min)
>240
MDT(min)
Table 3a. Similarity Factor (f2) for Release Profiles of FUR from
SDs and PMs with PEG 6000
Sample
FUR
PMPEG
(1/10)
MEPEG
(1/10)
SEPEG
(1/10)
58.4
FUR
---
41.5
26.0
23.9
PMPEG (1/10)
26.0
113.1
45.7
PMPEG(1/10)
---
---
40.3
36.2
MEPEG (1/10)
59.7
18.2
33.7
MEPEG(1/10)
---
---
---
66.1
SEPEG (1/10)
68.2
16.0
20.2
PMPVP (1/10)
22.5
170.0
43.6
SEPVP (1/10)
63.7
18.8
21.6
Table 3b. Similarity Factor (f2) for Release Profiles of FUR from
SDs and PMs with PVP K30
Sample
FUR
PMPVP (1/10)
SEPVP (1/10)
FUR
---
45.2
26.1
PMPVP (1/10)
---
---
34.5
were similar. Release of FUR from SDs with PEG and PVP
were also significantly different from PMs with PEG and
PVP at different concentration levels.
Figure 6. In vitro dissolution profiles of pure FUR, its PMs and SDs with PEG
6000 and PVP K30 (n=3).
PEG by solvent evaporation techniques. SEPEG 1/10 (97%)
has a higher dissolution rate as compared with SEPVP
1/10 (88%) at the end of 4 hrs.
The obtained values of MDT for all samples are
presented in Table 2. The MDT of pure FUR is very high
(58.3 min). This value decreased to a greater extent after
preparing its SDs and PM with PEG and PVP. SEPEG 1/10
showed the lowest MDT (20.2 min). MDT values of SDs
prepared with PEG were lower than that with PVP. The
same relationship was also observed with PM prepared
with PEG and PVP also.
Comparisons between the release profiles of FUR from
different samples were made by similarity factor f2.
Calculated f2 values are presented in Table 3a and 3b.
From this table, it is evident that the release profile of FUR
from all the samples (i.e., SDs and PMs of PEG and PVP)
and from pure FUR was dissimilar since f2 values for all
these comparisons were less than 50. Release profiles of
FUR from SEPEG and MEPEG at different concentrations
Formulation Studies
The physical properties of all samples were studied to
judge tabletting ability. In general, compressibility index
values up to 15% and an angle of repose between 25 and
30 results in good to excellent flow properties (30).
Percentage compressibility and the angle of repose of
samples are shown in Table 4. These values indicate good
compressibility and flow properties, making these
samples suitable for tabletting.
Release profiles of FUR from conventional tablets
containing FUR (without PEG or PVP) and tablets
containing SDs and PMs of FUR with PEG or PVP are
Table 4. Physical Properties of SDs and PMs of FUR with PEG
6000 and PVP K30
Sample
Physical
Property
FUR PMPEG MEPEG
(1/10)
(1/10)
SEPEG
(1/10)
PMPVP SEPVP
(1/10) (1/10)
%
Compressibility
10.11
12.84
12.04
14.92
12.07
13.69
Angle of repose
21.22°
25.74°
24.29°
27.35°
26.35°
26.12°
Hardness
(kg/cm2)
4.0
4.2
4.0
4.8
4.0
4.5
Friability (%)
1.0
0.9
0.6
0.6
0.8
0.7
Diameter (mm)
7.6
7.8
7.7
7.7
7.8
7.7
Thickness (mm)
3.8
3.8
3.7
3.8
3.8
3.7
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Solubility studies show a solubilizing effect of both
polymers on FUR at different temperatures. The negative
values of the Gibbs free energy and enthalpy of transfer
for FUR from water to an aqueous solution of both
polymers indicate the spontaneity of the transfer.
FTIR, DSC, and X-ray diffraction spectroscopic studies
indicate that in solid dispersions, drug was present as
amorphous form inside the polymeric matrix. The highest
improvement in solubility and in vitro drug release was
observed in solid dispersions prepared with PEG by the
solvent evaporation method. Solid dispersions and
physical mixtures prepared using PEG showed more
improvement in solubility and in vitro drug release than
those prepared using PVP. The solubility and in vitro drug
release from the physical mixture, when compared to that
of the solid dispersion, was improved to a lesser degree.
Figure 7. Release profiles of FUR from tablets containing pure FUR, its PMs
and SDs with PEG 6000 and PVP K30 (n=3).
shown in Figure 7. Release of FUR from tablets containing
SDs with PVP or PEG was faster and greater as compared
with conventional tablets containing FUR. This confirmed
the advantage of improved aqueous solubility of FUR in its
SD form, which can be formulated as tablets with better
dissolution characteristics.
DP30min, t50%, and MDT values for release of FUR from
tablets prepared using different samples are shown in
Table 5. DP30min values were higher for tablets prepared
using SDs and PMs as compared with those of
conventional tablets containing only FUR (2.9), whereas
t50% and MDT values of FUR from tablets containing
SDs and PMs were significantly lower than those of
conventional tablets containing only FUR and no PEG or
PVP (76.0 min and >4 h, respectively).
CONCLUSION
The solid dispersions of FUR with PEG 6000 and PVP K30
were prepared in different weight ratios using methods
like solvent evaporation, melting, and physical mixing.
Table 5. DP30min, t50%, and MDT Values for Release of FUR from
Tablets Prepared Using Different Samples
Samples
FUR
24
DP30 min
t50% (min)
MDT (min)
2.9
>240.0
76.0
PMPEG (1/10)
15.7
113.8
53.7
MEPEG (1/10)
27.8
38.1
41.3
SEPEG (1/10)
52.8
32.2
32.1
PMPVP (1/10)
19.4
195.3
55.2
SEPVP (1/10)
40.9
48.4
39.7
ACKNOWLEDGMENTS
We would like to thank Maan Pharmaceuticals Ltd. for
providing formulation excipients. We are thankful to
Torrent Research Center, India, for conducting PXRD
studies of the samples.
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