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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
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1. Introduction
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Excipients
2.1. Materials
PEG 6000
PVP K30
Poloxamer
407
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
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1
300
PEG 6000
PVP K30
Poloxamer 407
250
200
150
100
50
0
0
10
C2
URT r1
r2
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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).
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C1
C2
(A)
(B)
(C)
2 MJ 1 1
( )
URT r1 r2
Heat flow
(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.
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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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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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
O-H bend and C-O stretch, respectively. The obtained
spectra showed peak corresponding to C=O stretching of
lactone carbonyl of spironolactone was shifted from 1777
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].
4. Conclusion
Solid dispersions of spironolactone with PEG 6000
improved dissolution profile while PVP K30 and Poloxamer
407 enhanced solubility as well as dissolution profile.
The dissolution efficiency of polymer solid dispersions of
spironolactone were ranked as follows: Poloxamer 407 >
PVP K30 > PEG 6000. The physical characterization by
DSC, PXRD and FT-IR studies revealed that dissolution
enhancement of spironolactone from solid dispersions
was due to the formation of disordered structures. FT-IR
studies revealed hydrogen bonding of spironolactone with
PVP K30 and Poloxamer 407 indicating formation of solid
solution resulting into greater dissolution efficiency than
that of PEG 6000 solid dispersions.
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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