Formulation and Evaluation of Simvastatin Solid Dispersions for Dissolution Rate
Enhancement
Nakkala Balaji *, V. Sai Kishore and Kasani
Hari Krishna Gouda
Department of Pharmaceutics, Bapatla College of Pharmacy, Bapatla,
Guntur (Dt), Andhra Pradesh,
India. 522101
ABSTRACT:
Simvastatin (SIM) is a lipid lowering agent derived
synthetically from a fermentation product of Aspergillus terreus. Simvastatin
reversibly inhibit HMG-CoA reductase,
which catalyzes a rate-limiting step in cholesterol biosynthesis.
One of the major problems with this drug
is its low solubility in biological fluids, which results into poor
bioavailability after oral administration. Therefore, solid dispersions (SDs)
of Simvastatin were prepared to increase its aqueous
solubility using carriers such as lactose, urea. Simvastatin
SDs was prepared in 1:1, 1:2, 1:3, 1:4 and 1:5 ratios
of the drug to carrier (w/w). Solid dispersions were prepared by employing
solvent evaporation and kneading methods. The prepared solid dispersion was
evaluated for drug content, in vitro
drug release studies and powder X- ray diffractometry.
In vitro drug release profiles of all
SDs were comparatively evaluated and also studied against pure Simvastatin. Faster dissolution was exhibited by solid
dispersion prepared by solvent evaporation containing 1:4 ratio of Simvastatin: Urea. It was observed that kneading method was
more effective than solvent evaporation. In
vitro drug release studies revealed that there was progressive improvement
in the drug release rate from solid dispersions systems compared to pure drug alone.
The rate of drug release was depended on the type, ratio of drug to carrier and
method of preparation of solid dispersions. The enhancement in dissolution rate
of the drug may be due to increase in wettability,
hydrophilic nature of the carrier and due to reduction in drug crystallinity.
KEYWORDS: Solid dispersions, simvastatin,
solubility, carrier, solvent evaporation, kneading method.
INTRODUCTION:
A number of pharmaceutical active ingredients suffer from
aqueous solubility problems. Although these molecules have potential pharmacodynamic property, they show low bioavailability due
to poor aqueous solubility, because of these problems they may fail to reach
the market. Thus, the enhancement of aqueous solubility, dissolution rate, and
thereby improving the bioavailability of drug is a challenging task in dosage
form development for these drugs.
Aqueous
solubility is one of the key properties of a therapeutically active substance,
which governs dissolution, absorption, and thus the in vivo efficacy1.
Various techniques have been employed to improve the dissolution and
bioavailability of poorly water-soluble drugs such as micronization2,
solubilization3, salt formation, complexation with polymers, change
in physical form, use of prodrug and drug derivatization, pH alteration, addition of surfactants, and
others4.
.
Simvastatin (SIM) is a cholesterol lowering agent,
which is a white, nonhygroscopic, crystalline powder
having poor aqueous solubility and bioavailability. Simvastatin
is a potential inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. It catalyzes the
conversion of HMG-CoA to mevalonate;
this conversion is an early and rate-limiting step in the biosynthesis of
cholesterol5. Being a BCS Class
II drug, it often shows dissolution rate-limited oral absorption and high
variability in pharmacological effects. Therefore, need to improve its
solubility and dissolution rate thereby enhancing bioavailability6.
In
the present study, solid dispersions were prepared by a solvent evaporation and
kneading method using two different carriers at different drug–carrier ratios
(lactose and urea) and evaluated for different parameters like drug content, in vitro drug release studies.
MATERIALS AND
METHODS:
Materials:
Simvastatin
was procured from Dr. Reddy’s Laboratories, Hyderabad, India as a gift sample.
Lactose and urea were obtained from S.D. Fine
Chemicals, Mumbai, India. All other reagents used were of AR grade and
procured locally.
Preparation of Solid Dispersions:7
Solid
dispersions of simvastatin were prepared by employing
solvent evaporation and kneading methods.
Solvent evaporation:
Simvastatin
and carriers (lactose and urea) in various proportions viz. 1:1,1:2,1:3,1:4 and 1:5 (drug: carrier) were prepared by
solvent evaporation method as follows. To the solution of simvastatin
in ethanol, the aqueous solution of carrier
(lactose or urea) was added. Then allowed to evaporate the solvent by placing
it in vacuum drier for 3 hours at a temperature of 40 ºC and the dried sample
was stored in a desiccator for overnight. Then the dried sample was ground in a
mortar and passed through an 80 # sieve.
Kneading method:
Simvastatin
and carriers (lactose and urea) in proportions viz. 1:1,1:2,1:3,1:4 and 1:5 (drug: carrier) were prepared by
kneading method as follows. To the mixture of drug and carrier, small amount of
ethanol was added until paste like mass was obtained, later it was kneaded for 10 minutes. It is dried under reduced pressure
at 40ºC. Dried mass was ground in a mortar, and
passed through an 80 # sieve.
Evaluation of Solid Dispersions:
The
formulated solid dispersions were evaluated for following parameters:
Analysis of simvastatin
using a UV- Visible spectrophotometer:8,
9
1000 μg/ml stock solution of simvastatin was prepared in methanol and further dilutions
were made with Phosphate buffer PH 7 containing 0.5% SLS. The
concentrations of 2-10 μg/ml were prepared. The
calibration curve was obtained by analyzed spectrophotometrically at 238nm by
UV-Visible spectrophotometer. Calibration curve was plotted by taking
concentration (μg/ml) on x-axis and absorbance
on y-axis.
Drug content:9,
10
Solid
dispersions equivalent to 10 mg of simvastatin were
accurately weighed and dissolved in the ethanol. The solution was filtered,
suitably diluted and analyzed spectrophotometrically at 238 nm by UV-Visible
spectrophotometer. The actual drug
content was calculated using the following formula.
Actual amount
present in solid dispersion
% Drug content ---------------------------------------------
= X100
Theoretical amount present
in solid dispersion
In
vitro drug release studies:
In vitro drug release
studies of pure drug as well as solid dispersions were performed using USP XXII
type 2 dissolution apparatus (Electro lab, Mumbai, India). Solid dispersion
equivalent to 10 mg of simvastatin was accurately
weighed and subjected for dissolution in 900 ml of Phosphate buffer pH
7containing 0.5% sodium lauryl sulphate
at a temperature of 37±0.5ºc and stirring speed of 50 rpm. Aliquot of 5ml was
withdrawn at regular intervals of time (i.e 5 min)
and replenished the same volume with fresh medium. The samples were analyzed
spectrophotometrically at 238 nm by UV-Visible spectrophotometer.
Powder X-Ray Diffractometry:
The
X-ray diffractograms were obtained using on X-Ray
diffraction instrument (Philips Analytical X’Pert
PRO) with Cu radiation, at a voltage of 40kV and current of 20mA.
Infra red spectrum:
IR
spectrums of simvastatin and solid dispersions were
carried out using FT-IR based on the KBr pellet
method. The spectra were scanned over a wave number range of 2000 to 400 cm–1.
Table1: List of Solid dispersions (Simvastatin- Lactose) formulated by different methods at
different ratios.
|
Formulation Code |
Method employed |
Simvastatin: Lactose |
|
F1 |
Solvent evaporation |
1:1 |
|
F2 |
Solvent evaporation |
1:2 |
|
F3 |
Solvent evaporation |
1:3 |
|
F4 |
Solvent evaporation |
1:4 |
|
F5 |
Solvent evaporation |
1:5 |
|
F6 |
Kneading method |
1:1 |
|
F7 |
Kneading method |
1:2 |
|
F8 |
Kneading method |
1:3 |
|
F9 |
Kneading method |
1:4 |
|
F10 |
Kneading method |
1:5 |
Table2: In vitro Dissolution parameters of Simvastatin-
lactose solid dispersions prepared by different methods at different weight
ratios.
|
Formulation code |
Method employed |
Simvastatin: Lactose |
Correlation coefficient |
D.E20 (%) |
K1 (Min-1) |
T50 (Min) |
T90 (Min) |
|
|
Zero order |
First order |
|||||||
|
|
|
Pure drug |
|
|
23.16 |
0.0168 |
41.2 |
137.0 |
|
F1 |
Solvent evaporation |
1:1 |
0.9520 |
0.9549 |
33.10 |
0.0778 |
8.9 |
29.6 |
|
F2 |
Solvent evaporation |
1:2 |
0.9446 |
0.9473 |
37.41 |
0.1007 |
6.9 |
22.9 |
|
F3 |
Solvent evaporation |
1:3 |
0.9246 |
0.9785 |
50.53 |
0.1231 |
5.6 |
18.7 |
|
F4 |
Solvent evaporation |
1:4 |
0.9594 |
0.9602 |
44.88 |
0.1091 |
6.4 |
21.1 |
|
F5 |
Solvent evaporation |
1:5 |
0.8690 |
0.9681 |
42.4 |
0.0907 |
7.6 |
25.4 |
|
F6 |
Kneading method |
1:1 |
0.9387 |
0.9437 |
37.24 |
0.0818 |
8.5 |
28.2 |
|
F7 |
Kneading method |
1:2 |
0.9357 |
0.9559 |
39.22 |
0.1014 |
6.8 |
22.7 |
|
F8 |
Kneading method |
1:3 |
0.8348 |
0.9731 |
54.04 |
0.1117 |
6.2 |
20.6 |
|
F9 |
Kneading method |
1:4 |
0.4009 |
0.9558 |
73.56 |
0.1443 |
4.8 |
16.0 |
|
F10 |
Kneading method |
1:5 |
0.7367 |
0.9286 |
55.78 |
0.0903 |
7.7 |
25.5 |
RESULTS AND
DISCUSSION:
Drug Content:
Drug
content for all solid dispersions were in the range of 96.1-99.4 %. Higher the drug content in solid dispersions
was shown that low standard deviations, indicates that the drug was uniformly
dispersed in the formulation. These results revealed that the method used in
this study appears to be reproducible for preparation of solid dispersion
In vitro drug release studies:
The
dissolution profiles of simvastatin pure drug and
solid dispersions with lactose and urea prepared by solvent evaporation and
kneading method were shown in the table2, table4, and figure1-4. It was evident that solid dispersions exhibit faster
dissolution than the free drug. The improvement in the dissolution rate varies
with the method of preparation, carrier ratio. The in vitro dissolution studies of the solid dispersion prepared by
kneading method with urea at 1:4 ratio showed 98.67% release in 20 minutes
whereas solid dispersion with lactose by kneading method at 1: 4 ratio showed
98.93% release in 30 minutes. Enhancement in dissolution rate was may be due to
improved wettability which can lower the interfacial
tension between poorly soluble drug and dissolution medium.
Figure1: In vitro dissolution profiles of pure drug and simvastatin-
lactose solid dispersions prepared by solvent evaporation method.
Figure2: In vitro dissolution profiles of pure drug and simvastatin-
lactose solid dispersions prepared by kneading method.
Figure3: In vitro dissolution profiles of pure drug and simvastatin-
urea solid dispersions prepared by solvent evaporation method.
Table3: List of Solid dispersions (Simvastatin- Urea) formulated by different methods at
different ratios.
|
Formulation Code |
Method employed |
Simvastatin:Urea |
|
F11 |
Solvent evaporation |
1:1 |
|
F12 |
Solvent evaporation |
1:2 |
|
F13 |
Solvent evaporation |
1:3 |
|
F14 |
Solvent evaporation |
1:4 |
|
F15 |
Solvent evaporation |
1:5 |
|
F16 |
Kneading method |
1:1 |
|
F17 |
Kneading method |
1:2 |
|
F18 |
Kneading method |
1:3 |
|
F19 |
Kneading method |
1:4 |
|
F20 |
Kneading method |
1:5 |
Table4: In vitro Dissolution parameters of Simvastatin-
urea solid dispersions prepared by different methods at different weight
ratios.
|
Formulation code |
Method employed |
Simvastatin: Urea |
Correlation coefficient |
D.E20 (%) |
K1 (Min-1) |
T50 (Min) |
T90 (Min) |
|
|
Zero order |
First order |
|||||||
|
|
|
Pure drug |
|
|
23.16 |
0.0168 |
41.2 |
137.0 |
|
F11 |
Solvent evaporation |
1:1 |
0.7418 |
0.8738 |
62.42 |
0.1588 |
4.4 |
14.5 |
|
F12 |
Solvent evaporation |
1:2 |
0.6673 |
0.9455 |
70.38 |
0.1735 |
4.0 |
13.3 |
|
F13 |
Solvent evaporation |
1:3 |
0.6355 |
0.9730 |
66.91 |
0.1181 |
4.0 |
13.1 |
|
F14 |
Solvent evaporation |
1:4 |
0.7054 |
0.9922 |
77.45 |
0.2119 |
3.3 |
10.9 |
|
F15 |
Solvent evaporation |
1:5 |
0.5625 |
0.8166 |
67.15 |
0.1495 |
4.6 |
15.4 |
|
F16 |
Kneading method |
1:1 |
0.6375 |
0.9290 |
65.09 |
0.1825 |
3.8 |
12.6 |
|
F17 |
Kneading method |
1:2 |
0.7359 |
0.9930 |
75.98 |
0.2081 |
3.3 |
11.1 |
|
F18 |
Kneading method |
1:3 |
0.7167 |
0.9346 |
72.44 |
0.1755 |
5.9 |
19.5 |
|
F19 |
Kneading method |
1:4 |
0.6567 |
0.9747 |
78.61 |
0.2151 |
3.2 |
10.7 |
|
F20 |
Kneading method |
1:5 |
0.5186 |
0.9544 |
67.41 |
0.1078 |
6.4 |
21.4 |
Figure4: In vitro dissolution profiles of pure drug and simvastatin-
urea solid dispersions prepared by kneading method.
Powder X-Ray Diffractometry:
X-Ray
Diffraction patterns of pure drug and solid dispersions were showed in the
figure 5 and 6 respectively. The peak position
(angle of diffraction) is an indication of crystal structure and the peak height
is the measure of simple crystallinity. The pure drug
shows a highly crystalline nature, indicated by numerous intense peaks. On the
other hand solid dispersion was shown decrease in crystallinity,
evidenced by the absence of several intense peaks.
Figure5: X- ray diffraction pattern of Simvastatin.
Figure6: X- ray diffraction pattern of simvastatin urea solid dispersion (1:4).
Figure7: IR spectra of simvastatin.
Figure8: IR spectra of Simvastatin: urea solid dispersion (1:4)
Infrared spectroscopy:
FTIR
spectroscopy was used to study the possible interactions between simvastatin and urea in the solid dispersion. There was no
significant difference in the FTIR spectra of pure drug and solid dispersion
(figure7 and 8). All major peaks of simvastatin observed at wave numbers 3551 cm-1 (free O–H
stretching vibrations); 2961 cm-1 (C–H
stretching vibrations); and 1704 cm-1 (stretching vibration of ester and lactone carbonyl functional groups) were also retained in
case of solid dispersion, which clearly indicate that there was no interaction
exists between pure drug and urea in solid dispersion.
CONCLUSION:
The
solid dispersions of simvastatin with two different
carriers (lactose, urea) prepared by a solvent evaporation and kneading method
showed significantly higher drug dissolution in comparison with pure drug. From
the in vitro dissolution studies of
the solid dispersions, the higher drug release was obtained from solid
dispersions prepared by kneading method and with a carrier urea (1:4). FTIR
studies showed no evidence of interaction between the drug and carrier. PXRD
study confirmed amorphization of drug. The present
work concluded that solid dispersion technology can be used successfully to
enhance the dissolution rate of poorly soluble drug Simvastatin.
ACKNOWLEDGEMENTS:
The
authors thankful to the Dr.Reddy’s Laboratories,
Hyderabad, India for providing drug sample and Bapatla
College of pharmacy for providing necessary requirements
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Received on 17.05.2011
Accepted
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A&V Publication all right reserved
Research Journal of Pharmaceutical Dosage Forms and
Technology. 3(4): July-Aug. 2011,
152-156