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Asian Journal of Pharmaceutical Sciences 2012, 7(1):40-49

Preparation and characterization of spironolactone


solid dispersions using hydrophilic carriers
Shreya Shah, Sachi Joshi, S. Lin, P. L. Madan*
St. Johns University, College of Pharmacy, Queens, New York, USA

Received 2 November 2011; Revised 28 November 2011; Accepted 23 December 2011

_____________________________________________________________________________________________________________

Abstract
This investigation was undertaken to improve dissolution of spironolactone which shows poor bioavailability due to its poor solubility
in the gastrointestinal fluids. Polyethylene glycol (PEG 6000), polyvinylpyrrolidone (PVP K30) and Poloxamer 407 were used as
hydrophilic carriers at various spironolactone:polymer ratios to prepare solid dispersions using solvent evaporation method. Physical
mixtures of corresponding ratios were also prepared for comparison. The order of dissolution enhancement was Poloxamer 407 >
PVP K30 > PEG 6000 in solid dispersions as well as in physical mixtures. Dissolution enhancement was significantly greater in solid
dispersions than in physical mixtures. Apparent equilibrium solubility studies of spironolactone in solid dispersions showed about 1.5-fold
increase in solubility of spironolactone containing PEG 6000, 3-fold increase containing PVP K30 and 9-fold increase containing
Poloxamer 407 dispersions at 1:7 drug: polymer ratio. At high polymer concentration, PVP K30 solid dispersions appeared as glass
solution while PEG 6000 and Poloxamer 407 solid dispersions show presence of some crystallinity. Detection of hydrogen bonding in
Poloxamer 407 and PVP K30 dispersions from FT-IR studies suggests formation of a molecular dispersion. PVP K30 was most effective
in achieving amorphization of spironolactone while Poloxamer 407 was most effective in improving dissolution of spironolactone
perhaps due to micellar solubilization.
Keywords:Spironolactone solid dispersions; Equilibrium solubility; Dissolution rate; Polyvinylpyrrolidone; Poloxamer 407
____________________________________________________________________________________________________________

1. Introduction

amorphous clusters or in microcrystalline particles within


the crystalline or amorphous matrix [2,3]. Solid dispersions
offer many advantages, including greater reduction in
the particle size compared to conventional mechanical
milling, improved wettability of the powder, generation
of particles with higher porosity, and presence of powder
in the amorphous state, all of which may contribute to
enhance dissolution rate and solubility of the poorly
soluble compound. Therefore, dissolution enhancement
from solid dispersions depends on the physical state and
distribution of the drug within the carrier molecules and
consequently on (i) the method of preparation of the solid
dispersion, (ii) drug and polymer interactions, as well as
(iii) physicochemical properties of the drug and carrier.
The availability of a limited number of marketed drug
products utilizing solid dispersion technology is the direct
implication of poor understanding regarding (a) solid state
structure of solid dispersion, (b) drug release mechanism
from solid dispersions, (c) stability of solid dispersion,
and (d) in-vitro: in-vivo correlation of drug release from
solid dispersions drug absorption from a solid dispersion
formulation [4].
The most popular polymeric carriers used for solid
dispersion formulation are polyethylene glycol (PEG)
and polyvinylpyrrolidone (PVP) due to their water
solubility and ability to form solid solution [5]. Recently,
Poloxamers have also shown promise to be excellent

The enhancement of oral bioavailability of poorly


soluble drugs remains one of the most challenging aspects
of drug product formulation especially in view of the fact
that of all the newly discovered drug entities; more than
40% are lipophilic in nature and fail to reach the market
due to their poor solubility. Several strategies have been
used to improve solubilization and dissolution rate of
poorly soluble substances. Most of these strategies fall
into one or more of the following three categories: (i)
change in the nature of solvent environment, e.g., use of
co-solvent systems, emulsification, micellization, etc., (ii)
change in the chemical identity of the dissolving solute, e.g.,
salt formation, complexation, and pro-drug approach, and (iii)
physical change of the drug substance, e.g., particle size
reduction and solid dispersion [1].
Preparation of a solid dispersion formulation has been
successfully used to increase solubility and dissolution
rate of poorly soluble drugs using hydrophilic carriers. A
drug in the solid dispersion can disperse molecularly in
__________
*Corresponding author. Address: St. Johns University, College
of Pharmacy, Queens, New York 11439, USA.
Tel: +1-718-9906242
E-mail:madanp@stjohns.edu

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Asian Journal of Pharmaceutical Sciences 2012, 7(1):40-49

carriers for the preparation of solid dispersions because


Poloxamers have the capability to alter physical properties
such as hydrophobicity, surface charge, flocculation/
dispersion, floatation and wetting properties [6,7].
Spironolactone is a potassium sparing diuretic and it is
used to treat primary hyperaldosteronism, hypokalemia, and
various edematous conditions. It possesses low aqueous
solubility in the gastrointestinal fluids which results in
variable dissolution rate and incomplete oral bioavailability
[8,9]. Micronization [10] and complexation with -cyclodextrin [11] have shown to increase spironolactone bioavailability by increasing its dissolution rate. Recently, solid
dispersions of spironolactone with porous silica [12] and
microparticles with gelucire 44/14, a surface active carrier
[13], were reported to improve dissolution characteristics
of spironolactone. An earlier investigation reported the
use of PEG as a hydrophilic carrier to prepare solid
dispersions of spironolactone [14]. Due to the advances of
the solid dispersion approach, the objective of the present
investigation was to examine solubility and dissolution
characteristics of spironolactone from solid dispersions
prepared with selected hydrophilic carriers such as PEG
6000, PVP K30, and Poloxamer 407. In addition, solid
dispersions were characterized in order to understand drugcarrier interactions and mode of incorporation of spironolactone within the selected water-soluble matrices. The
solid dispersions of spironolactone were then characterized
using differential scanning calorimetry (DSC), powder
X-ray diffraction (PXRD) and Fourier transform infrared
spectroscopy (FT-IR) in order to evaluate state of the drug
as well as drug and polymer interactions.

spironolactone was added. The vials were screw-capped


and shaken (40 strokes/min) at 25C in a wrist action
shaker with temperature controlled water bath (Model
75, Burell Scientific, PA, USA). After 48 h, samples
were filtered, suitably diluted with 0.1 M hydrochloric
acid and analyzed at 243 nm using a UV double beam
spectrophotometer (DU Series 700, Beckman Coulter,
Inc., Brea, CA, USA).
2.3. Preparation of solid dispersions
To prepare solid dispersions, appropriate quantities of
spironolactone and polymers at ratios of 1:1, 1:3 and 1:5,
respectively, were accurately weighed and mixed well
in a glass mortar for 5 min. Anhydrous ethanol (20 l
per mg of spironolactone) was added to this physical
mixture, and the mixture was heated on a hot plate at 75C
for 3 min. The mixture was immediately cooled on an ice
bath for 5 min. The precipitates were dried in a vacuum
desiccator for 48 h for removal of residual solvent and
then passed through a #30 sieve (600 m) before analysis.
For comparison purposes, physical mixtures having the
same ratios of spironolactone and polymer were prepared
by gently mixing spironolactone and the polymer in a
glass mortar, and the mixtures were then passed through a
#30 sieve. The composition of these formulations and their
corresponding codes are outlined in Table 1.
Table 1
Composition and codes of physical mixtures and solid
dispersions.

2. Materials and methods

Excipients

2.1. Materials
PEG 6000

Spironolactone was purchased from Santec Chemicals


Corp. (Fresh Meadows, NY, USA). Poloxamer 407 was
purchased from Spectrum Chemical Mfg. Corp. (Gardena,
CA, USA). Polyethylene glycol (PEG 6000) and
polyvinylpyrrolidone (PVP K30) were bought from Fluka
Chemicals Corp. (Milwakee, WI, USA) and anhydrous
ethanol was purchased from Alfa-Aesar (Ward Hill, MA,
USA). All chemicals were of analytical or technical grade
and were used as received without further treatment.

PVP K30

Poloxamer
407

2.2. Solubility studies

Physical
mixture

Solid
dispersion

Drug:polymer
ratio

PM PEG 1:1

SD PEG 1:1

1:1

PM PEG 1:3

SD PEG 1:3

1:3

PM PEG 1:5

SD PEG 1:5

1:5

PM PVP 1:1

SD PVP 1:1

1:1

PM PVP 1:3

SD PVP 1:3

1:3

PM PVP 1:5

SD PVP 1:5

1:5

PM P407 1:1

SD P407 1:1

1:1

PM P407 1:3

SD P407 1:3

1:3

PM P407 1:5

SD P407 1:5

1:5

2.4. In-vitro dissolution studies

Solubility studies were performed using the method of


Higuchi and Connors [15]. Solutions of polymers (PEG
6000, PVP K30, and Poloxamer 407) ranging in concentrations from 1 to 10% (w/v) (in 1% w/v increments) were
prepared in 0.1 M hydrochloric acid. To 10 ml of each of
these solutions contained in screw-capped vials, 10 mg of

All in-vitro dissolution studies were carried out using


1000 ml of 0.1 M hydrochloric acid at 371C as the
dissolution medium in a USP Dissolution Basket Apparatus
(Distek Model Evolution 6100, North Brunswick, NJ,
USA) at a stirring speed of 75 rpm. Accurately weighed
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Asian Journal of Pharmaceutical Sciences 2012, 7(1):40-49

2.6.2. Powder X-ray diffraction (PXRD)

solid dispersions and physical mixtures containing 40 mg


of spironolactone were used for dissolution studies. Sink
conditions were not maintained because the focus of this
investigation was to evaluate solubility of spironolactone.
Five milliliter samples of dissolution medium were
withdrawn at predetermined intervals and immediately
replaced with an equal volume of the dissolution medium
(maintained at 371C) in order to maintain constant
volume of dissolution medium. The withdrawn samples
were filtered and analyzed for spironolactone content
at 243 nm and cumulative percentage of spironolactone
dissolved was calculated. The amount of spironolactone
removed in each sample was compensated in the
calculations. All experiments were performed in triplicate.
From the dissolution profiles, dissolution efficiency (DE120)
of formulations was calculated as area under the curve of
dissolution profile between two time points expressed as
the percentage of curve at maximum possible dissolution
over the same time period [16]. In this study dissolution
efficiency from 0 to 120 min (expressed as %DE120)
denotes the percentage of the area of the rectangle
described by 100% dissolution in the same time. The
function Area below curve in SigmaPlot 10.0 software
was used to calculate area under the curve.

Shimadzu X-ray diffractometer (LabX XRD 6000,


Shimadsu Scientific Instruments, Columbia, MD, USA)
was used for the evaluation of type of the solid dispersion.
The samples were exposed to CuKa radiation under 30 mA
current and 40 kV voltage. The scanning angle ranged
from 5 to 40 of 2 and steps were 0.02 of 2/s.
2.6.3. Fourier transform infrared spectroscopy (FT-IR)
A Perkin-Elmer Spectrum One FT-IR Spectrometer (Perkin
Elmer, Norwak, CT, USA) with LiTaO3 detector was used
for infrared analysis. The potassium bromide discs were
prepared by mixing a small amount of the sample with
potassium bromide and powder mixture was compressed
to form the disc. Resolution of 4 cm-1 was used and
scanned over a frequency range of 4000450 cm-1. Perkin
Elmer Spectrum v5.3.1 (Perkin Elmer, Norwak, CT, USA)
was used for data analysis.
2.7. Statistical analysis
Statistical analysis among formulations was performed
by one way ANOVA followed by Tuckeys multiple
comparison test using GraphPad Prism software (GraphPad
Software Inc., La Jolla, CA, USA) and P<0.05 was used
as the criterion to assess statistical significance.

2.5. Apparent equilibrium solubility


Equilibrium solubility studies were carried out by
accurately weighing and adding solid dispersion formulations containing 40 mg of spironolactone to 10 ml of
0.1 M hydrochloric acid contained in screw capped vials.
The vials were shaken on a wrist action shaker in a
temperature controlled water bath at 25C. After 24 h,
samples were centrifuged (Model 228, Fisher Scientific,
Dubuque, IA, USA) at 3400 rpm for 15 min. The supernatant solution was filtered and the filtrate was analyzed.
Equilibrium solubility studies were also carried out for
spironolactone powder to serve as a control.

3. Results and discussion


3.1. Solubility studies
The solubility of spironolactone was determined at
25C and at 37C in purified water as well as in aqueous
buffer solutions at pH 1, pH 4, and pH 6.8. The solubility
of spironolactone in purified water at 25C was 27.4
1.2 g/ml, which is in agreement with the values published
in the literature [13]. The solubility of spironolactone in
purified water at 37C as well as in other acidic solutions
was very similar to the solubility in purified water at 25C
indicating that the solubility of spironolactone is not
influenced either by the change in temperature or by the
change in pH of the solution.
The solubility of spironolactone in aqueous solutions
of the three selected polymers at different concentrations
is shown in Fig. 1. The solubility increased linearly,
though marginally in the PEG 6000 solutions (R2 = 0.9932
and slope = 2.72) suggesting very weak interactions
between spironolactone and PEG 6000. Solutions of PVP
K30 exhibited linear and significantly greater increase
in the solubility of spironolactone as the concentration
of PVP K30 was increased (R2 = 0.9969, slope = 12.6)

2.6. Physical characterization


2.6.1. Differential scanning calorimetry (DSC)
DSC analysis of prepared solid dispersions was performed using Perkin-Elmer DiamondTM DSC (Perkin Elmer,
Norwalk, CT, USA) with an Intracooler 2P as a cooling
device. Samples were accurately weighed (23 mg) in
aluminum pans, sealed and thermograms were obtained at
the heating rate of 10C per min up to a temperature of 220C.
Ultrahigh purity nitrogen was used as the purge gas at a
flow rate of 20 ml/min. Indium was used as a reference
standard and Pyris software 2.04 (Perkin Elmer, Norwalk,
CT, USA) was used for the data analysis.

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Concentration of spironolactone (g/ml)

signifying approximately 5-fold greater solubility than


that obtained in the PEG 6000 solutions. This might be
attributed to improved wetting in the presence of PVP
K30 or association between the functional groups of
PVP K30 and spironolactone [17-19]. The solubility of
spironolactone was found to be highest in Poloxamer
407 solutions. The increase was linear in the Poloxamer
407 concentration range of 1%5% (w/v), with a slope of
16.22 which indicates approximately 6-fold enhancement
in the solubility of spironolactone compared to that of
PEG 6000. At Poloxamer 407 concentration greater than 5%
(w/v), the solubility increased enormously. Compared to
PEG 6000, the increase in solubility was about 9-fold at 7.5%
(w/v) and about 14-fold at 10% (w/v) Poloxamer 407
concentrations, respectively. This solubility enhancement
might be attributed to the surface active property of
Polaxamer 407 and formation of more soluble complex,
and possibly micellar solubilization [18].
The higher solubility of spironolactone in the solutions
of the carriers suggests greater miscibility of spironolactone into the carrier and thus higher probability of solid
solution formation during the formulation of the solid
dispersion.

300
PEG 6000
PVP K30
Poloxamer 407

250
200
150
100
50
0
0

10

Concentration of polymer (%, w/v)


Fig. 1. Solubility of spironolactone in aqueous solutions of PEG
6000, PVP K30, or Poloxamer 407 at 25C (data shown as mean
standard deviation, n=3).
C
2 MJ 1 1
ln

C2

URT r1

r2

3.2. In-vitro dissolution


The dissolution profiles of micronized spironolactone
powder, physical mixtures and solid dispersions of spironolactone in 0.1 M hydrochloric acid are shown in Fig. 2
and their dissolution efficiency as well as percentage of
spironolactone dissolved in 120 min are outlined in Table 2.
Micronized spironolactone powder showed only 15%
spironolactone dissolution and 9% dissolution efficiency
in 120 min. Results in Fig. 2 suggest that all physical
mixtures (open symbols) increased dissolution efficiency
significantly as compared to that of spironolactone in
powder form. As the concentration of polymer increased,
the dissolution efficiency also increased significantly
(P<0.001) due to enhanced wetting of spironolactone
particles in the presence of hydrophilic groups of polymers.
Furthermore, these results also suggest that all solid
dispersions of spironolactone (closed symbols) exhibited
increased dissolution efficiency significantly as compared
to their respective physical mixtures (open symbols). On
the other hand, as displayed in Fig. 2A, solid dispersions of
spironolactone using PEG 6000 (closed symbols) showed
increased initial dissolution rate compared to respective
physical mixtures (open symbols); but this extent of
dissolution of spironolactone was improved only marginally.
PVP K30 solid dispersions of spironolactone at 1:1 (closed
circle) and 1:3 (closed square) spironolactone:polymer ratios
exhibited greater dissolution efficiency compared to that
of spironolactone powder (Fig. 2B). However, dissolution
efficiency at higher ratio, e.g., 1:5 spironolactone:polymer

Fig. 2. Dissolution profiles of spironolactone from physical


mixtures and solid dispersions containing (A) PEG 6000; (B)
PVP K30; and (C) Poloxamer 407, in 0.1 M hydrochloric acid at
25C (data shown as mean standard deviation, n=3).

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Asian Journal of Pharmaceutical Sciences 2012, 7(1):40-49

ratio (closed triangle) did not exhibit further increase, but


it decreased. Also, physical mixture of spironolactone
(open triangle) with PVP K30 at 1:5 ratio did not show
further significant enhancement in the dissolution
efficiency as compared to that at 1:3 ratio (P>0.05). Both
Poloxamer 407 physical mixtures and solid dispersions
of spironolactone at all drug:polymer ratios evaluated
showed significant enhancement in dissolution efficiency
compared to that of the powder form of spironolactone
(Fig. 2C). It is interesting to note that increasing the
spironolactone:polymer ratios to higher levels, such
as 1:3 (square symbols) and 1:5 (triangle symbols),
the dissolution efficiency of both physical mixture and
solid dispersions of spironolactone did not show further
significant enhancement. Also, spironolactone dissolution
from all solid dispersions of spironolactone reached a
plateau at around 6075 min of dissolution and complete
spironolactone dissolution was not obtained in any
formulation at the end of the 120 min studies.
In order to compare the type of polymers used in the
current investigation, dissolution profiles showing optimal
dissolution of spironolactone were replotted and are shown
in Fig. 3. Poloxamer 407 physical mixtures and solid dispersions of spironolactone showed significant enhancement in dissolution efficiency compared to that of other
two polymers. The rank order of dissolution enhancement
was Poloxamer 407 > PVP K30 > PEG 6000.
The low dissolution efficiency of pure spironolactone
indicates its poor aqueous solubility and wetting. Enhanced
dissolution from physical mixtures of spironolactone may
be attributed to deaggregation and increased wetting of
spironolactone due to the presence of the polymer. The
hydrophilic polymer undergoes dissolution immediately
upon exposure to the dissolution medium and attains high
concentration in the diffusion layer of the drug [20,21]. The
dissolved polymer then increases dissolution of drug in
the diffusion layer and therefore increases dissolution rate
of spironolactone [22]. Increase in dissolution efficiency
in the formulations containing PEG 6000 appears to be
due to increased dissolution rate resulting from wetting
property attributed to its hydrophilic oxyethylene groups.
PVP K30 showed better dissolution than PEG 6000 suggesting greater spironolactone and polymer interactions and
miscibility compared to PEG 6000. However, dissolution
efficiency was decreased at higher PVP K30 concentrations suggesting built up of viscosity in the diffusion
layer around the dissolving spironolactone particles
that retarded further spironolactone dissolution [23].
Poloxamer 407 was able to enhance dissolution efficiency
significantly more than other two polymers due to the
surface active property of Poloxamers. Below critical
micelle concentration (CMC), it reduces surface tension
between spironolactone particles and aqueous medium and
above CMC (0.0076% w/v, at 37C), it forms micelles

and dissolves entrapped hydrophobic spironolactone


particles [7,17,24,25]. Significantly greater dissolution
efficiency of solid dispersions compared to that of physical
mixtures even at low spironolactone:polymer ratios can
be attributed to decrease in particle size of spironolactone,
formation of disordered structure as well as spironolactone
and polymer interactions [4,24,26]. Reduced dissolution
rate after 6075 min of dissolution suggests formation of
spironolactone rich layer around spironolactone particles
or reagglomeration of dissolved particles.
3.3. Apparent equilibrium solubility
As shown in Fig. 4, the equilibrium solubility of
spironolactone in 0.1 M hydrochloride acid at 25C
was found to be 28 g/ml. Solid dispersions exhibited

Fig. 3. Comparison of the optimal dissolution profiles of spironolactone from physical mixtures and solid dispersions of spironolactone incorporated using different type of polymer in 0.1 M
hydrochloric acid at 25C (data shown as mean standard
deviation, n=3).

Fig. 4. Apparent equilibrium solubility of spironolactone from


solid dispersions of spironolactone in 0.1 M hydrochloric acid at
25C (data shown as mean standard deviation, n=3).

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amorphous spironolactone. PVP K30 solid dispersions of


spironolactone showed presence of a single Tg suggesting
formation of solid solution.
Lowering and absence of spironolactone endotherm
suggest formation of solid dispersion with all three
polymers. Presence of single Tg in PVP dispersions suggests
formation of solid solution. Absence of spironolactone
endotherm in physical mixture of spironolactone suggests
dissolution of spironolactone microcrystals within the
molten polymer due to heating during analysis. Such
phenomenon has been reported previously and that is
the limitation of DSC analysis because it is an invasive
method, and heating the sample during analysis dissolves
crystals into the molten polymer [18,31].

Concentration of spironolactone (g/ml)

increase in apparent solubility of spironolactone with


increasing polymer ratios in all three polymers. The PEG
solid dispersions of spironolactone showed least enhancement 300
in the apparent solubility of spironolactone while
Poloxamer 407 solid
showed highest enhancePEGdispersions
6000
PVP K30 in equilibrium solubility from
ment.250
Marginal enhancement
Poloxameris407
the PEG solid dispersions
suggestive of the formation of
200
non-interacting
solid dispersion. The apparent solubility of
solid dispersions at 1:5 spironolactone:polymer ratio
150 6000, PVP K30 and Poloxamer 407 showed
of PEG
approximately 1.5-fold, 2.5-fold and 6-fold enhancement,
100
respectively,
than that of spironolactone powder, suggesting
greater solubility of spironolactone in a medium contain50
ing PEG 6000, PVP K30 or Poloxamer 407.
The average particle size of the micronized spirono0
lactone was 2.21 m and further reduction in particle
0
2
4
6
8
10
size (less than 12 m) in solid dispersion may have also
Concentration of polymer (%, w/v)
contributed in improving equilibrium solubility due to
high free energy per unit mass as described by OstwaldFreundlich equation [27,28].
ln

C1
C2

(A)
(B)
(C)

2 MJ 1 1
(  )
URT r1 r2

Heat flow

In this equation C1 and C2 represent solubility of


particles of radii r1 and r2, respectively, M is the molecular
weight, is surface energy of the solid, is density of the
solid, R is gas constant, and T is absolute temperature.
During the preparation of solid dispersions, spironolactone
powder is reduced to its molecular size, thus reducing
the particle size of powder spironolactone. Based on
the increase in solubility, this equation predicts that the
particle size of spironolactone was reduced to 1.17 m in
PEG solid dispersions, 0.732 m in PVP K30 dispersions,
and 0.446 m in Poloxamar dispersions. Similar results
(increase in solubility) were reported with nanoparticle
formulations [29,30].

(D)
(E)
(F)
(G)
20

60

100

140

180

220

Temperature (C)
Fig. 5. DSC thermograms of (A) spironolactone; spironolactone:
PEG 6000 solid dispersions at (B) 1:1; and (C) 1:3 levels;
spironolactone: PVP K30 solid dispersions at (D) 1:1; and (E) 1:3
levels; and spironolactone: Poloxamer 407 solid dispersions at (F)
1:1; and (G) 1:3 levels.

3.4. Differential scanning calorimetry

3.5. Powder X-ray diffraction

As shown in Fig. 5, the micronized spironolactone


powder exhibited a single sharp endothermic peak at
212.33C with fusion enthalpy of 45.74 J/g. PEG 6000 and
Poloxamer 407 showed endothermic peaks at 62.36C and
51.66C, respectively, while PVP K30 did not show any
endothermic peak because of its amorphous nature. PVP
K30 exhibited glass transition temperature at 175C. The
position of endothermic peaks of PEG 6000 and Poloxamer
407 was maintained in all solid dispersions of spironolactone. Solid dispersion of spironolactone containing
PEG 6000 showed the presence of spironolactone
endotherm at the 1:1 spironolactone:polymer ratio
with H value of 8.54 J/g which is significantly lower
compared to that of the spironolactone powder. All other
solid dispersions of spironolactone showed absence
of spironolactone endotherm suggesting formation of

Solid dispersions as well as physical mixtures of


spironolactone were analyzed for comparison and nullify
dilution effect. Powder X-ray diffraction patterns of pure
spironolactone, each polymer, physical mixtures and solid
dispersions of spironolactone are displayed in Fig. 6.
Spironolactone powder showed sharp and high intensity
peaks at 2 of 9, 11.2, 12, 13.3, 15.8, 16.2, 17,
18 and 20 indicating its highly crystalline state. PEG
6000 and Poloxamer 407 exhibited characteristic PXRD
peaks at 19 and 22.5 of 2 corresponding to crystalline
polyoxyethylene groups while PVP K30 exhibited halo
pattern characteristic of amorphous materials. The position
of characteristic peaks of crystalline polymers was not
changed in physical mixtures and solid dispersions of
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Spironolactone

PVP-K30

PEG-6000

Poloxamer-407

PM PEG 1:1

SD PEG 1:1

PM PEG 1:3

SD PEG 1:3
SD PEG 1:5

PM PEG 1:5

SD PVP 1:1

PM PVP 1:1

SD PVP 1:3

PM PVP 1:3

SD PVP 1:5

PM PVP 1:5

SD P407 1:1

PM P407 1:1

SD P407 1:3

PM P407 1:3

SD P407 1:5

PM P407 1:5
10

15

20

25

30

35

40

10

15

20

25

30

35

40

Diffraction angel 2T ()
Fig. 6. Powder X-ray diffraction patterns of physical mixtures and solid dispersions of spironolactone containing PEG 6000, PVP K30
and Poloxamer 407 at various concentrations.
Table 2
Dissolution efficiency and percent spironolactone dissolved from physical mixtures and solid dispersions at 120 min in 0.1 M
hydrochloric acid.
Formulation

Physical mixture

Solid dispersion

Dissolution efficiency

Percent dissolved

Dissolution efficiency

Percent dissolved

PM PEG 1:1

13.270.86

21.551.33

23.970.57

31.081.65

PM PEG 1:3

18.451.36

26.571.54

30.590.25

39.982.03c

PM PEG 1:5

21.671.00b

28.912.25c

32.960.92b

43.240.95c

PM PVP 1:1

20.180.27

29.591.53

29.750.52b

42.670.65d

PM PVP 1:3

27.690.38c

41.301.33c

40.870.56b

55.571.15

PM PVP 1:5

28.970.95

42.380.60

32.070.27

44.260.93d

PM P407 1:1

45.170.17b

52.651.29

57.210.78

67.610.54d

PM P407 1:3

49.480.31b

60.872.33c

62.451.64c

70.751.43

PM P407 1:5

50.330.24

59.621.72

63.541.40

74.082.39d

b
b

At 120 min in 0.1 M HCl. Data are presented as mean standard deviation, n=3. bANOVA indicated a significant difference
(P<0.05) among all three ratios. cANOVA indicated a significant difference among all three ratios and pair-wise comparisons
(Tuckey method) indicated no significant difference for 1:3 versus 1:5. dANOVA indicated a significant difference among all three
ratios and pair-wise comparisons (Tuckey method) indicated no significant difference for 1:1 versus 1:5.
a

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Asian Journal of Pharmaceutical Sciences 2012, 7(1):40-49

spironolactone which suggest absence of change in the


polymorph. All solid dispersions of spironolactone showed
reduced intensity and broadening of spironolactone peaks
suggesting conversion of crystalline spironolactone to
partially disordered spironolactone molecules. PVP solid
dispersions also showed elevation of baseline indicating
conversion of crystalline spironolactone to completely
amorphous form. Superimposable PXRD patterns of the
physical mixtures and solid dispersions and absence of
any new diffraction peak also ruled out the possibility of a
chemical interaction.
Reduced intensity of peaks of spironolactone in all solid
dispersions of spironolactone compared to their physical
mixtures suggests reduced crystallinity of spironolactone.
During the formulation of solid dispersions, solvent
evaporation causes supersaturation of drug which if
maintained by the polymer, inhibits drug crystallization
either by formation of drug-polymer complex or by
retardation of nucleation, the degree of which depends
upon polymer concentration and its molecular weight [20,
32-35]. If the polymer concentration is high enough to
inhibit crystallization of the drug during formulation, the
dispersion will contain completely amorphous drug entities
while at low polymer concentrations, crystallization will
not be inhibited and the dispersion would contain some
crystalline/partially disordered drug entities. Thus, with

increasing polymer concentration, the crystallinity of the


drug reduces further. Conversion to completely amorphous
state in PVP K30 solid dispersions of spironolactone
suggests greater miscibility of spironolactone in the
polymer and presence of some binding forces between
spironolactone and PVP K30 molecules.
3.6. Fourier transform infrared spectroscopy
Fourier transform infrared (FT-IR) spectra of spironolactone, polymers, physical mixture and solid dispersions
of spironolactone are shown in Fig. 7. FT-IR spectra of
spironolactone showed characteristic peaks at 1777, 1700,
1677 and 1619 cm-1 corresponding to C=O stretching of
lactone ring, C=O stretching of thioacetyl group, C=O
stretching of , -unsaturated ring and C=C stretching of
, -unsaturated ring. PEG 6000 exhibited characteristic
peaks at 2890 cm-1 due to C-H stretching, at 1116 cm-1
due to C-O stretching and at 3350 cm-1 due to O-H
stretching. PVP K30 showed O-H stretch at 3482 cm-1
due to moisture absorption by the polymer. PVP has two
potential hydrogen bonding sites; one is the nitrogen of
pyrrolidone moiety and another is the carbonyl group of
pyrrolidone moiety which exhibit characteristic peaks at
1288 cm-1 and 1682 cm-1, respectively.
FT-IR spectra of solid dispersions of spironolactone

Spironolactone

PM PEG 1:1
SD PEG 1:1

T (%)

PEG-6000

4000

3200

PVP K30

SD PEG 1:3

Poloxamer-407

SD PEG 1:5

2400

1800

1400

1000

600

4000

3200

SD PVP 1:1

1800

1000

600

1400

1000

600

SD P407 1:3

SD PVP 1:5
2400

1400

SD P407 1:1

SD PVP 1:3

3200

1800

PM 407 1:1

PM PVP 1:1

4000

2400

SD P407 1:5
1400

1000

600

4000

3200

2400

1800

Wavenumber (cm-1)
Fig. 7. FT-IR spectra of physical mixtures and solid dispersions of spironolactone containing various concentrations of PEG 6000, PVP
K30 and Poloxamer 407.

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Asian Journal of Pharmaceutical Sciences 2012, 7(1):40-49

References

showed decrease in the number of peaks due to overlapping of peaks corresponding to spironolactone and
polymer. In solid dispersions with PEG 6000, some of
the peaks corresponding to spironolactone disappeared
due to overlapping of FT-IR spectra. In the case of PVP
K30, due to steric constraints on nitrogen atom of PVP
K30, the carbonyl group is more favored for hydrogen
bonding. However, due to overlapping spectra of PVP
K30 and spironolactone, participation of carbonyl group
of PVP K30 in hydrogen bonding could not be confirmed.
Nevertheless, the peak corresponding to the carbonyl group
of thioacetyl group of spironolactone shifted to 1690 cm-1
from 1700 cm-1 suggesting formation of hydrogen bonding.
Also, the peak corresponding to O-H stretch of PVP K30
shifted to significantly lower wavelengths. In Poloxamer
407 solid dispersions, the characteristic peaks were found
at 2890, 1343 and 1107 cm-1 due to C-H stretch, in plane
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cm-1 to 1769-1770 cm-1, and from 1126 cm-1 to 1115 cm-1
which suggests the presence of strong hydrogen bonding.
The presence of hydrogen bonding in PVP K30 and
Poloxamer 407 solid dispersions suggest formation of
molecular dispersion rather than clusters of drug crystalline/
amorphous entities. The absence of generation of new
peak in any solid dispersion again confirmed absence of
strong chemical interaction [7].

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The dissolution efficiency of polymer solid dispersions of
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Acknowledgments
Abstracted in part from a thesis submitted by Shreya
Shah for partial fulfillment of the requirements for Masters
in Science degree. The authors acknowledge St. Johns
University for providing financial assistance and research
facilities to carry out this research.

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