X-Ray diffractometry: In order to investigate the physical nature of the encapsulated drug,

the powder X-ray diffraction technique was used. Crystalline state is another factor influencing
the dissolution and stability behavior of a compound. The crystalline state of the samples was
evaluated to prove the effect of stirring. Upon X-ray examinations, it was observed that the
specific peaks for simvastatin at specified 2 value in X-RD graph at 10, 15, 17, 20 were not
observed for SNS. This suggested that the crystallinity of simvastatin was not preserved in the
SNS formulation, indicating that the crystalline state of simvastatin was altered following
stirring. The absence of major peaks of simvastatin in case of SNS confirmed formation of
amorphous product which might leads to enhanced solubility of the drug in case of SNS.
Nanoparticles reduced its crystallinity. This is evident from the disappearance of most peaks in
the nanoparticles compared to the drug. X-Ray diffractometry graphs are shown in Fig. 14.

2468 Int J Pharm Sci Nanotech Vol 7; Issue 2 April-June 2014

Fig. 10. In vitro dissolution profile of plain drug and SNS batches in pH 7.4 phosphate buffer.
Fig. 11. In vitro dissolution profile of plain drug and SNS batch-7 in pH 1. 2 acidic buffer.

Shid et al:
Formulation a
nd Evaluation o
of Nanosuspen
nsion Delivery S
System for Sim
mvastatin
vitro Fig. 12. In vi
dissolution drug, physic
al mixture and powder in dis
stilled water.
24
profile of plain d SNS batch-7
469

2470
Fig. 13. DS SNS (Simv
Fig. 14. X Batch-7 SN In vivo st successfu the serum with stan to differe
SC spectra of (A) astatin Nanosus
X-Ray Diffractom NS Powder. study: Injectio ully induced hm TC, TG, LD ndard drug (S ent
degrees. I
) Simvastatin ph spension) (D) Sim
metry of (A) pla
on of Triton X yperlipidemia DL-c and VLD Simvastatin) In animals th
hysical mixture ( mvastatin (1), Sp
ain Simvastatin
X-100 (400 mg a in rats by in DL levels. Tr altered this e hat were trea
(Simvastatin,Poy pray dried Simva
n drug (B)
g/kg) has ncreasing reatment elevation ated with
T s re nh le st 2 in si w 6 L co le S te 4 te 2 ch gne th tr in th np
Int J Pharm
yvinylPyroidine astatin (2), phys
Triton X-100, erum, while t eceived stan nanosized sim had shown sig evel up to 78 tandard grou
2.307 mg/dL in ntraperitonea ignificantly u with standard 6.049 mg/dL ( LDL-c level i
ompared to evels found i Similarly, seru est group an 43.191 1.654
est and stand 2.586 mg/dL a hange in lipid group of sim nanosuspensio
micactivity. T he elevated riglyceride le ncreased HDL he above va nanosuspensio profile than
th
Sci Nanotech
K-30, Sodium L sical mixture (3).
the total li the increase w ndard drug. mvastatin pow gnificant decr 8.28 1.088 up (plain dru
n rats treated ally, decreas up to 191.56 d group (plain (p < 0.001). in test grou standard gro in
standard um VLDL-c l nd in standar 4 mg/dL. The H dard were 35 and 46.743. d levels in test
mvastatin tre
on powder de The simvasta total choles evel more si Lc level than alue it was on powder sh he
plaindrug. I

Vol 7; Issue 2
Luaryl Sulphate,
.
ipid level w was prevented Oral admini wder equivale
ease (p < 0.00 mg/dL when g) that show d only with tr se in seru 2.103 mg/dL n drug) having
Same dose d up 67.50 1 oup (plain dr group 85.86 level 32.43 rd group it w
HDL-c levels 5.08 1.023
239 mg/dL rt groups was ated rats. T emonstrated atin nanosusp sterol, LDL-c gnificantly (p
plain simvas found that ows greater d It is shown in
2 April-June 2
, Poloxamer-188)
as increased d in animals t istration of ent to 20 mg 001) in serum n compared w wed TC 101.0
riton (400 mg/ um TG le L when compa g value 225.4 decreased ser 1.008 mg/dL rug). The LD
1.383 mg/ 1.205 mg/dL was found to found in cont mg/dL, 51.9 respectively. T comparable w
The simvasta anti-hyperlip pension redu c, VLDL-c ap < 0.001) a tatin drug. Fr the simvasta
decrease in li n Fig. 15.
2014
) (C)
in that the g/kg TC with 7 /kg) evel ared 44 rum as DL-c /dL. L in be trol, 1 The with atin
ped- uced and and rom atin ipid

Shid et al: Formulation and Evaluation of Nanosuspension Delivery System for Simvastatin
2471
TABLE 6 Biochemical analysis of blood sample after induction of hyperlipidemia.
Bioanalytical Test
Normal Group Mean SEM
Control Group Mean SEM
SNS Powder Group Mean SEM
Plain drug Group Mean SEM TC 75.10 3. 2 113.43 3.115*** 114.83 3.234*** 113.47
2.822*** TG 130.20 1. 095 301.38 8.155*** 300.48 6.370*** 289.01 9.147*** LDL
82.84 2. 315 133.26 1.744*** 133.76 2.438*** 133.18 2.479*** VLDL 28.66 1. 918
62.32 2.462*** 64.25 1.968*** 62.57 3.070***
HDL 34.39 1. 415 34.24 1.828 34.84 2.088 38.15 1.559
TC-Total Cholesterol, TG-Triglyceride, LDL-Low Density Lipoprotein, VLDL- Very Low
Density Lipoprotein, HDL-High Density Lipoprotein, SNS-Simvastatin Nanosuspension, Plain
drug (Simvastatin), * = Normal vs, ***=Extremely Significant (P < 0.001)
TABLE 7 Biochemical analysis of blood sample after drug and SNS powder dosing (after 24
hr)/Pharmacodynamic study after 24 hr (after dosing).
Test
Normal Group Mean SEM
Control Group Mean SEM
SNS Powder Group Mean SEM
Plain drug Group Mean SEM TC 77.00 1.020 112.17 2.801*** 78.28 1.088### 101.07
2.307***##@@@ TG 134.99 1.773 282.27 8.279*** 191.56 2.103***### 225.44
6.049***###@@@ LDL 65.61 1.344 134.71 1.492*** 67.50 1.008### 85.86
1.383***##@@@ VLDL 25.78 1.100 55.59 1.479*** 32.43 1.205*### 43.191
1.654***###@@@
HDL 34.47 1.085 35.08 1.023 51.91 2.586***### 46.74 3.239**##
Results are expressed as mean SEM. Comparison between the groups was made by one way
analysis of variance (ANOVA) followed by Tukey's test TC-Total Cholesterol, TG-Triglyceride,
LDL-Low Density Lipoprotein, VLDL-Very Low Density Lipoprotein, HDL-High Density
Lipoprotein, SNS-Simvastatin Nanosuspension, Plain drug (Simvastatin), * = Normal vs, *** =
Extremely Significant (P < 0.001),** = Highly Significant (P < 0.01), * = Non Significant (P > 0.
05), # = Control vs, ### = Extremely Significant (P < 0.001), ## = Highly Significant (P < 0.01),
# = Non Significant (P > 0.05), @ = SNS Powder vs Plain drug, @@@ = Extremely Significant
(P < 0.001), @@ = Highly Significant (P < 0.01), @ = Non Significant (P > 0.05)

(A)
(B)
Fig. 15. (A) Pharmacodynamic parameter study after induction of hyperipidemia. (B)
Pharmacodynamic parameter study after dosing of plain simvastatin drug and batch-7 SNS
powder. TC-Total cholesterol, TG-Triglyceride, LDL-Low density lipoprotein, VLDL-Very low
density lipoprotein, HDL-High density lipoprotein.

2472 Int J Pharm Sci Nanotech Vol 7; Issue 2 April-June 2014

Stability study: The stability studies were carried out on optimized formulations. The samples
were stored at 40 2oC and 75% 5% RH for 3 months to access their stability. After 1,2,3
months samples were withdrawn and rested for entrapment efficiency and total drug content. The
optimized formulation did not show any significant difference in both parameters. It indicates
that this formulation was able to retain its stability up to 3 months.
TABLE 8 Stability data of optimized formulation of nanosuspension.
Time period Entrapment efficiency Total drug content Initial 92.78% 95.74% After storage 1
month 92.53% 95.49% 2 month 91.87% 94.91% 3 month 91.30% 93.65%
Experimental data analysis: A three factor, two level full factorial designs was adopted for
optimization employing the amount of SLS, amount of PVPK-30 and Poloxamer-188 as
independent variables. Total drug content (%) and polydispersity index as dependent variables.
Experimental trials were performed at all 8 possible combinations. Y1 is indicating total drug
content (%) whereas Y2 is polydispersity index. X1= amount of SLS, X2 = amount of PVPK-30
and X3 = amount of Poloxamer- 188. Each batch contains 20 mg of simvastatin.
In order to investigate the factors systematically, a 23 factorial design was employed; a
statistical model
incorporating interactive and polynomial terms was used to evaluate the responses. Total Drug
Content (TDC), the results of multiple linear regression analysis showed that the coefficients b1
bear a negative sign and coefficients b2 and b3 bear positive sign (R2 = 0.9395). 3-D Response
surface plot of total drug content was shown in Fig. 16(A).
TDC = +93.181.62 A+0.29 B+0.59 C Final Equation in Terms of Actual Factors:
TDC = +95.38750 0.80875 SLS+0.023200 PVPK 30 + 0. 078667 Polo-188 It can be
concluded from the equation (2) that when the concentration of X2 and X3 was increase with
decrease in the concentration of X1 then desired total drug content could be obtained and its
controlling the stabilization to the nanoparticles for coalescence and high total drug content was
observed intheformulation Batch-7.
Final Equation in Terms of Coded Factors:
PI = +0.46 0. 054 A-0.079 B-0.041 C Final Equation in Terms of Actual Factors:
PI = +98250 0.026875 SLS 6.30000E 003 PVPK - 30-5.5000E 003 Polo - 188 The
coefficients b1, b2, and b3 were found to be significantat P < 0.05. Concerning polydispersity
index, the results showed that the coefficients b1, b2 and b3 bear a negative sign (R2 = 0.9061)
3-D Response surface plot of polydispersity index was shown in Fig. 16(B).
TABLE 9 Design matrix of independent and dependent variable as per 23 factorial design
Run
X1 (SLS)

X2 (PVPK-30)
X3 (Polo-188)
Y1 (TDC%)
*Partical size (m) B1 4 25 15 94.11% 0.689 58.33% 1916.7 0.3-0.5 B2 8 25 15 90.01% 0.496
67.87% 1117.4 0.5-0.6 B3 4 50 15 94.45% 0.431 70.83% 653.8 0.2-0.3 B4 8 50 15 91.77%
0.414 74.62% 903.9 0.3-0.5 B5 4 25 30 94.87% 0.578 87.87% 624.2 0.2-0.6 B6 8 25 30 92.55%
0.420 89.5% 548.8 0.2-0.3 B7 4 50 30 95.74% 0.381 92.78% 258.3 0. 2 B8 8 50 30 91.9% 0.310
88.8% 604.7 0.2-0.3 *Not considered for factorial design. SLS-sodium lauryl sulphate, PVPK30-polyvinyl pyrolidine k-30, Polo-188-poloxamer-188, TDC-total drug content, PIpolydispersity index, EE -entrapment efficiency, MPD-mean partical diameter, nm-nanometer,
m-micron meter.
TABLE 10 ANOVA for Response Surface Linear Model: Response-1 (Total Drug Content).
Analysis of variance table partial sum of squares-Type III Source Sum of squares df Mean
squares F value P-value Probe > F Model 24.39 3 8.13 20.69 0.0067 significant A-SLS 20.93 1
20.93 53.27 0.0019 B-PVPK-30 0.67 1 0.67 1.71 0.2608 C-Polo-188 2.78 1 2.78 7.09 0.0563
Residual 1.57 4 0.39 Cor Total 25.96 7
Std. Dev. 0.63 R-Squared 0.9395 Mean 93.17 Adj R-Squared 0.8941 C. V% 0.67 Pred RSquared 0.7578 PRESS 6.29 Adeq Precisior 11.270
Y2(PI) *%E. E *MPD(nm)

Shid et al: Formulation and Evaluation of Nanosuspension Delivery System for Simvastatin
2473
TABLE 11 ANOVA for Response Surface Linear Model: Response-2 (Polydispersity Index).
Analysis of variance table partial sum of squares-Type III
Source Sum of squares df Mean squares F value P-valueProbe > F Model 0.086 3 0.029 12.86
0.0160 Significant A-SLS 0.023 1 0.023 10.33 0.0325 B-PVPK-30 0.050 1 0.050 22.17 0.0092
C-Polo-188 0.014 1 0.014 6.08 0.0692 Residual 8.950E-003 4 2.238E-003 Cor Total 0.095 7
Std. Dev. 0.047 R-Squared 0.9061 Mean 0.46 Adj R-Squared 0.8356 C. V% 10.26 Pred RSquared 0.6243 PRESS 0.036 AdeqPrecisior 10.389
Conclusions
Emulsification Solvent Diffusion method was employed to producing nanosuspension of
simvastatin, a poorly water-soluble drug, for the improvement of solubility and dissolution
velocity. In this process, the particle size of simvastatin can be obtained in the nano- size ranges,
by adjusting the operation parameters, such as the stabilizer concentration. The best
nanosuspension of simvastatin can be obtained by 4 mg
SLS, 50 mg PVPK-30, and 30 mg Poloxamer-188 using emulsification solvent diffusion
technique at laboratory scale. The dissolution of nanosized simvastatin is significantly enhanced
compare with the pure simvastatin suspension. From the In-vivo study value it was found that the
simvastatin nanosuspension powder shows greater decrease in lipid profile than the plaindrug.
Means the bioavailability of simvastatin nanosuspension is greater than the plain simvastatin
drug due to the decrease in particle size. Emulsification
Fig. 16. (A) 3-DResponse surface plot of total drug content (B) 3-D Response surface plot of
polydispersity index (PI).

2474 Int J Pharm Sci Nanotech Vol 7; Issue 2 April-June 2014

solvent diffusion canthus be a simple and effective approach to produce submicron particles of
poorly water- soluble drugs.
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