DESIGN AND CHARACTERIZATION OF VALSARTAN NANO SUSPENSION

Inter. J. of Pharmacotherapy / 2(2), 2012, 70-81.

70

DESIGN AND CHARACTERIZATION OF VALSARTAN

NANO SUSPENSION

Rajalakshmi. R1, Thanda Venkataramudu

*1, R. Arun Kumar

1, K. Divya Sree

2,

M. Deepti Kiranmayi3

Dept. of Pharmaceutics, 1Sree Vidyanikethan College of Pharmacy, Tirupati, A.P, 517102, India. 2SV University, Tirupati, A.P, 517102, India.

3AMR Memorial College of Pharmacy, Narasaraopet, Guntur, A.P, 522601, India.

INTRODUCTION

Various formulation parameters that play a

crucial role in the successful formulation of drugs are

aqueous solubility, stability at ambient temperature and

humidity, photostability, compatibility with solvent and

excipient. Among this aqueous solubility became a hurdle

for the formulation of new molecular entities. More than

40% of the new chemical entities being generated through

drug discovery programmes are poorly water‐soluble or

lipophilic compounds [1]. Formulating a poorly water

soluble drug has always been a challenging problem

confronted by the pharmaceutical scientist. The

formulation of nano‐sized particles can be implemented to

all drug compounds belonging to biopharmaceutical

classification system (BCS) classes II and IV to increase

their solubility and hence partition into gastrointestinal

barrier [2]. Micronization is used for class II drugs of

(BCS), i.e. drugs having a good permeability and poor

solubility [3‐5]. There are many conventional methods for

increasing the solubility of poorly soluble drugs, which

include micronization [6], solubilisation using co‐solvents

[7], salt form [8], surfactant dispersions [9], precipitation

technique [10‐11], and oily solution. Other techniques are

like liposomes [12], emulsions [13‐14], microemulsion

[15‐16], solid dispersion [17‐18] and inclusion

complexation using cyclodextrins [19‐21] show sensible

achiever, but they lack in universal applicability to all

drugs. These techniques are not applicable for those drugs

which are not soluble in aqueous and organic solvents.

Nanotechnology can be used to solve the problems

associated with these conventional approaches for

solubility and bioavailability enhancement.

Nanosuspension is favoured for compounds that are

Corresponding Author:- Thanda Venkataramudu Email: [email protected]

International Journal of Pharmacotherapy

www.ijopjournal.com

ISSN 2249 - 7765

Print ISSN 2249 - 7773

ABSTRACT

Low oral bioavailability of poorly water soluble drugs poses a great challenge during drug development. Poorly

water soluble compounds are difficult to develop as drug products and conventional formulation techniques are frequently

abandoned early in discovery. The aim of the present study was to improve the dissolution rate of a poorly water soluble

drug, valsartan, by a high pressure homogenization technique. Six different formulations were prepared by optimizing

various parameters using different polymers like polaxamer, soyalecithin, PVP and PVA. Formulations are evaluated for

pure drug identification, FTIR, DSC, %yield, drug content, %EE, SEM, In vitro drug release study. Polymer

concentrations have greater effect on retention of nanosuspension and control the drug release for longer period. From the

results of all the formulations F3 exhibited optimum characters.

Key words: Bioavailability, Poor solubility, Valsartan, Polaxamer, Soyalecithin, PVP, PVA, Nano suspension.

http://www.ijopjournal.com/


71

insoluble in water (but are soluble in oil) with high log P

value, high melting point and high doses. Nanosuspension

technology can also be used for drugs which are insoluble

in both water and organic solvents eg. Naproxen [22],

clofazomine [23], bupravaquone [24] etc.

Oral administration is the most convenient and

widely utilized and preferred route of drug delivery for

systemic action. The dissolution behavior of a drug is key

determinant to its oral bioavailability. An improved oral

bioavailability of poor water soluble drugs remains one of

the most challenging aspects of drug development.

Nanosuspensions are colloidal dispersions of

nanosized drug particles stabilized by surfactants. They

can also be defined as a biphasic system consisting of

pure drug particles dispersed in an aqueous vehicle in

which the diameter of the suspended particle is less than

1µm in size. Reduction of drug particles to nanometer

range leads to an enhanced dissolution rate not only

because of increased surface area but also because of

saturation solubility [25]. The increase in the saturation

solubility and solution velocity of nanoparticle is due to

increase of vapour pressure of the particles.

Nanosuspension have disclosed the problems associated

with the delivery of poorly water ‐soluble and poorly

water‐and lipid soluble drugs and are unequalled because

of their simplicity and rewards they confer over other

strategies.

Preparation of nanosuspension There are two methods for preparation of

nanosuspension. They are ‘Bottom up technology’ and

‘Top down technology’[26‐27] of nanoparticles in Bottom

up technology the drug is dissolved in a solvent, which is

then added to non‐solvent that causes precipitation of the

fine drug particles[28‐29]. All‐Trans retinoic acid

nanosuspensions were prepared with a precipitation

method[30]. Use of simple and low cost equipment and

also benefit for higher saturation solubility is the

advantage for precipitation technique compared to other

methods of nanosuspension preparation. Precipitation

technique is not applicable to drugs which are poorly

soluble in aqueous and non-aqueous media. In this

technique, the drug needs to be soluble in atleast one

solvent which is miscible with nonsolvent. The major

challenge is to avoid crystal growth due to Ostwald

ripening being caused by different saturation solubilities

in the vicinity of differently sized particles. The top down

technologies include (a) media milling [31‐32] (b) high

pressure homogenizer [33], emulsion diffusion method,

(d) supercritical fluid method.

Valsartan is a nonpeptide, orally active and

specific angiotensin II antagonist acting on the AT1

receptor sub type. It is widely prescribed therapeutic drug

for hypertension. The bioavailability ofter oral

administration is low (10-35%) with a higher variability.

In recent years much attention has been focused on drug

nanosuspension for the improvement of bioavailability of

water insoluble drugs [30-32].

The present study was aimed at developing

nanosuspension of valsartan in order to improve the

stability, bioavailability and efficacy in treatment of

hypertension. The stabilizers are used to maintain the

stability of the product.

MATERIALS AND METHOD

Valsartan was obtained as a gift sample from

Hetero Laboratory Ltd. Polaxamer was a gift sample from

Reddy’s Laboratory Ltd. Soyalecithin and PVA were

procured from Sigma-Aldrich, USA. Tween 80 was

purchased from Qualikems fine chemicals Ltd, New

Delhi. All excipients and solvents were of laboratory

grade and double distilled deionized water was used for

the research work.

Standard Plot for Valsartan

a) In Methanol:

100mg of valsartan was weighed and transferred

to a 100ml standard flask. Volume was made up to 100ml

with Methanol. 1ml from above stock solution was

transferred into 100ml standard flask and volume was

made with Methanol. Pipette out 2ml, 4ml, 6ml, 8ml and

10ml from the above solution and transferred into 10ml

standard flask and the volume was made with Methanol

b) In Phosphate Buffer (pH 7.4):

100mg of valsartan was weighed and transferred to a

100ml standard flask. The volume was made up to 100ml

with Phosphate buffer. 1ml from above stock solution was

pipetted and transferred into 100ml standard flask and

volume was made up to 100ml with Phosphate buffer.

Pipetted out 2ml, 4ml, 6ml, 8ml and 10ml from the above

solution transferred in 10ml standard flask and made the

volume up to 10ml with Phosphate buffer.

Table 1. Formulation of valsartan nanosuspension

Ingredients F1 F2 F3 F4 Pure

drug

Valsartan (mg) 40 40 40 40 40

Soya lecithin (%w/v) 0.5 1 1 - -

Poloxamer (%w/v) 1 - - 1 -

Tween 80 (%v/v) - - 0.5 0.3 -

Aqueous solvent (ml) 20 20 20 20 20

Preparation of Valsartan Nanosuspension

To prepare nanosuspension of Valsartan, it is

preferred to start with a very fine powder. First the

surfactants in different concentrations were dissolved in

water. The drug powder was dispersed in the aqueous

surfactant solution using high speed ultra sound

homogenizer for 30 min at high rpm to obtain


72

nanosuspension. Composition of different valsartan

nanosuspensions are presented in Table 1.

Particle size analysis and zeta potential measurement

The particle size of the produced nanosuspension

was analyzed by photon correlation spectroscopy using a

zetasizer 5000 (Malvern Instruments Ltd, UK). Sample

was measured appropriately after diluted with bidistilled

water. The nanoparticle surface appearance and shape

were analyzed by scanning electron microscopy (SE The

mean particle size for the formulations was determined by

a Zeta sizer Nano ZS-90 (Malvern Instruments Ltd., UK)

equipped with the DTS software. The reading was carried

out at a 900 angle with respect to the incident beam. The

zeta potential was measured by a laser doppler

anemometer coupled with the same instrument. A

potential of ± 150 mV was set in the instrument.

Disposable cuvettes of 0.75 mL capacity were used for all

measurements. Statistical 91 analysis of the data were

performed via one way analysis of variance (ANOVA)

followed by Tucky test using Minitab software version

15. Thumb rule describes the relation between zeta

potential determination responses of the suspension being

tested, particularly hydrophobic colloids. The prepared

nanoparticles suspensions were characterized with respect

to zeta potential by using zeta potential analyzer (Malvern

Zeta sizer).

Scanning Electron Microscopy

In order to examine the particle surface

morphology and shape, Scanning Electron Microscopy

(SEM) was used. A concentrated aqueous suspension was

spread over a slab and dried under vacuum. The sample

was shadowed in a cathodic evaporator with a gold layer

20 nm thick. Photographs were taken using a JSM-5200

Scanning Electron Microscope (Tokyo, Japan) operated at

10 kV.

Fourier Transform Infrared Spectroscopy

The Fourier transform infrared analysis was

conducted to verify the possibility of interaction of

chemical bonds between drug and polymer. The FTIR

spectrum was performed by using a PerkinElmer 1600

spectrophotometer with a resolution of 2 cm-1

. The

samples were scanned in the spectral region between 4000

and 400 cm-1

by taking an average of 8 scans per sample.

Solid powder samples were oven dried at around 300C,

finely crushed, mixed with potassium bromide (1:10 ratio

by weight) and pressed at 15000 psig (using a Carver

Laboratory Press, Model C, Fred S. carver Inc., WIS

53051) to make disc. The detector was purged carefully

by clean dry nitrogen gas to increase the signal level and

reduce moisture. For the analysis of the data, the spectrum

GX series model software was used.

Differential Scanning Colorimetry

Thermal characteristics of the pure materials, the

physical mixtures and nano-solid suspension were

determined by an automatic thermal analyzer system.

Accurately weighed samples were placed in

nonhermetically aluminum pans and heated against an

empty aluminium pan as a reference. Heating rate was 5 0C/min and nitrogen purge 20 ml/min.

Determination of valsartan solubility

Valsartan solubility studies were performed in

triplicate by adding excess amounts of valsartan to water

and buffer solutions having different pH (1.2 and 7.4)

buffers. The solutions containing flasks were kept on a

rotary shaker for 24 h. After 24 h, solutions were analyzed

using UV spectrophotometer at 248 nm, which was the

absorption maxima determined earlier and drug

concentrations were calculated.

Determination of Nanosuspension Process Yield

The nanosuspension production yield was

calculated by gravimetry. Fixed volumes of nanoparticles

suspension were centrifuged (16,000×g, 30 min, 15ºC)

and sediments were dried.

The percentage process yield (% P.Y.) was calculated as

follows:

Nanoparticles weight

% P.Y. = ---------------------------------------- x100

Total solids weight

Determination of % Entrapment Efficiency

The Nanosuspension with known amount of drug

(1.5mg/1ml) incorporated was centrifuged at 5000 rpm

for 15 minutes. The supernatant solution was separated.

5ml of supernatant was distributed with 100 ml of 2% w/v

tween 80 solutions and the absorbance was measured

using UV spectrophotometer at 248 nm using 2% w/v

tween 80 as blank. The amount of drug unentrapped in the

supernatant was calculated. The amount of drug entrapped

and percentage entrapment was determined from drug

unentrapped. Standard deviation was determined for 3

trials.

In vitro drug release study

The diffusion medium used was phosphate

buffer pH 7.4. Assembly of diffusion cell for in-vitro

diffusion studies the oral diffusion cell was designed as

per the dimension given. The diffusion cell was placed on

the magnatic stirrer.Receptor compartment was filled with

buffer solution. Then the prepared egg membrane was

mounted on the cell carefully so as to avoid the

entrapment of of air bubbles under the membrane.

Intimate contact of egg membrane was ensured with

receptor fluid by placing it tightly with clamp. The speed

of the stirring was kept throughout the experiment. With

the help of pipette 5ml of sample was withdrawn at a time


73

intervals of one hour from sampling port of receptor

compartment and same volume was the replaced with

receptor fluid solution in order to maintain sink condition.

The samples were withdrawn and the amount of drug

released was assessed by measuring the absorbance at 248

nm using a single beam UV spectrophotometer.

Stability studies

Stability is defined as extent to which a product

remains within specified limits throughout its period of

storage and use. A drug formulation is said to be stable if

it fulfills the following requirements.

It should contain at least 90 % of the stated active

ingredient.

It should contain effective concentration of added

preservatives, if any

It should neither exhibit discoloration or

precipitation, nor develops foul odour.

It should not develop irritation or toxicity.

Procedure

Formulation was divided into 3 sets of samples

and stored at:

4ºC in refrigerator

Room Temperature (29ºC)

45ºC ± 2ºC, 75ºC % RH ± 5 % in humidity control

ovens

After 30 days drug contents of all samples were

determined by the method as in entrapment efficiency.

RESULTS AND DISCUSSION

Solubility

The solubility of pure drug was carried out and it

was found to be as given in table 2.

Table 2. Solubility data of Valsartan in various

solvents.

S. No. Solvent Solubility

1. Distilled water 0.105 mg/ml

2. pH 1.2 Buffer 0.242 mg/ml

3. pH 7.4 Buffer 0.494 mg/ml

Calibration curve of Valsartan

Figure 1. Standard plot of Valsartan in Methanol

Figure 2. Standard plot of Valsartan in pH 7.4 buffer

0

0.078

0.172

0.261

0.351

0.435

y = 0.0435x R² = 0.9993

0

0.1

0.2

0.3

0.4

0.5

0 2 4 6 8 10 12

Ab

sorb

an

ce (

nm

)

Concentration (µg/ml)

Standard plot of Valsartan in Methanol

0

0.078

0.172

0.261

0.351

0.435

y = 0.0435x R² = 0.9993

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

0 2 4 6 8 10 12

Ab

sorb

an

ce (

nm

)

Concentration (µg/ml)

Standard plot of Valsartan in phosphate pH 7.4 buffer


74

Figure 3. FT-IR spectra of A) Valsartan, B) physical mixture of Valsartan and polaxamer, C) physical mixture of

Valsartan and Soyalecithin

C

B

A

Figure 4. DSC thermogram of (A) Valsartan, (B) Poloxamer 188, (C) Physical mixture

E:\Pharmaceutics\Adil\Tramadol-HCl+Carbopol.0 Tramadol-HCl+Carbopol SOLID 23/09/2010

3772.66

3696.13

3639.90

3452.69

3302.00

3012.50

2930.23

2859.02

2594.10

2478.60

1922.25

1838.72

1708.39

1581.17

1471.80

1288.46

1241.21

1173.49

1048.82

982.41

869.52

781.40

703.82

646.65

100015002000250030003500

Wavenumber cm-1

9697

9899

Transmitt

ance [%]

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3706.76

3637.74

3302.29

3010.31

2930.25

2851.58

2597.49

2475.49

1924.24

1838.16

1755.91

1580.70

1470.42

1287.04

1240.24

1173.89

1048.20

983.49 870.50 781.59 704.57

100015002000250030003500

Wavenumber cm-1

97.598.0

98.599.0

99.5100.0

Transmittance

[%]

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3852.26

3637.30

3506.17

3301.92

3006.36

2930.15

2858.88

2606.31

2477.07

2116.98

1921.43

1839.21

1754.00

1682.15

1580.63

1473.49

1431.19

1288.84

1242.25

1173.91

1048.95

984.95

869.88

781.60

704.41

641.30

100015002000250030003500

Wavenumber cm-1

97.097.5

98.098.5

99.099.5

100.0

Transmitt

ance [%]

Page 1/1

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3852.2

6

3637.3

0

3506.1

7

3301.9

2

3006.3

6

2930.1

5

2858.8

8

2606.3

1

2477.0

7

2116.9

8

1921.4

3

1839.2

1

1754.0

0

1682.1

5

1580.6

3

1473.4

91431.1

9

1288.8

41242.2

5

1173.9

1

1048.9

5

984.9

5

869.8

8

781.6

0

704.4

1

641.3

0

100015002000250030003500

Wavenumber cm-1

97.0

97.5

98.0

98.5

99.0

99.5

100.0

Tra

nsm

itta

nce [

%]

Page 1/1


75

Figure 5. Particle size of formulation F3

Figure 6. Size distribution of Formulation F3

Figure 7. SEM photograph of pure drug


76

Figure 8. SEM photographs of nanosuspension

Table 3. Percentage drug content, Drug entrapment efficiency and percentage yield of Nanosuspension

Formulation batches % drug content Entrapment efficiency % Yield

F1 96.24 82.52 78.50

F2 94.64 74.96 69.51

F3 97.24 83.17 82.12

F4 89.92 79.26 70.24

In vitro drug release studies

Table 4. Drug release from all the formulations

S. No. Time

(hours)

% drug release

F1 F2 F3 F4 PURE DRUG

1. 0 0 0 0 0 0

2. 1 26.74 22.57 22.51 23.28 16.67

3. 2 37.4 33.4 32.79 36.3 19.13

4. 3 69.86 58.01 56.24 55.44 24.72

5. 4 81.26 76.66 66.72 73.35 26.51

6. 5 94.36 89.45 79.24 85.29 27.12

7. 6 98.08 95.98 84.91 91.08 32.72

Figure 9. Cumalative drug release from all formulatins

0

20

40

60

80

100

120

0 2 4 6 8CU

MA

LATI

VE

% D

RU

G R

ELEA

SE

TIME (HOURS)

F1

F2

F3

F4

PURE DRUG


77

Figure 10. Zero order plot for formulation F3

Figure 11. Highuchi release model plot for formulation F3

Figure 12. First order release model plot for formulation F3

y = 14.361x + 5.8314 R² = 0.9729

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7

%dru

g r

ele

ase

time (H)

zero order kinetics

y = 36.581x - 7.6894 R² = 0.9556

-20

0

20

40

60

80

100

0 0.5 1 1.5 2 2.5 3

% d

rug

re

lea

se

square root of time

Higuchi release model

y = -14.101x + 93.735 R² = 0.9656

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7

% d

rug r

em

ain

ed

time(H)

first order kinetics


78

Figure 13. Korsmeyer release model plot for formulation F3

Figure 14. Hixson crowell release model plot for formulation F3

Fig: 15. Stability Study: Comparison of % Drug Content of Formulation F3 at 4ºC, Room temperature (29ºC) and 45

ºC

y = 1.6856x + 0.7791 R² = 0.6229

0

0.5

1

1.5

2

2.5

0 0.2 0.4 0.6 0.8 1

log %

dru

g r

ele

ased

log time

korsmeyer release model

y = -0.0564x + 4.6007 R² = 0.9661

4.24.25

4.34.35

4.44.45

4.54.55

4.64.65

4.7

0 1 2 3 4 5 6 7

cubth

root of %

dru

g r

em

ain

ed

time(H)

Hixson crowell model

0

50

100

4ºC RT45ºC

STABILITY STUDY

4ºC

RT

45ºC


79

FTIR studies

IR spectroscopic studies were conducted to

determine possible interactions between drug and carrier.

IR spectra of pure drug valsartan with Soya lecithin and

polaxamer were obtained. Which shows no chemical

interaction between Valsartan and excipients. The result

of IR study shown in Figure 3.

DSC studies The DSC thermograms of Pure drug and

optimized nanosuspension formulation were taken

between 30–200°C at a heating rate of 20°C/min. Pure

drug showed melting point at 117°C corresponding to its

melting point, whereas in the thermograph pattern of

formulation no such peak was observed. So it can be

concluded that the drug particles were absolutely bound

by the surfactant molecules. In the DSC of formulation

sharp transitions at 54.72°C was observed which

correspond to the melting points of poloxamer. From

thermograms, it was concluded that the drug and the

surfactant do not interact with each other. The data was

represented in figure 4.

Particle size analysis and zeta potential measurement

The effect of the drug to polymer ratio and the

effect of surfactant on size of the nanoparticles were

studied using six different ratios of polymer and

surfactant. The study was carried out in the range of 10-

40% drug incorporation in the formulation. The mean

particle size (Z-average diameter) for formulations varied

in the narrow range from 1200 nm to 190 nm. It could be

inferred from the results that there was significant impact

of the drug to polymer ratio on the mean particle size of

the drug loaded nanosuspension and the addition of the

surfactant also showed a significant change in particle

size. The mean particle sizes of the F3 formulation their

size distribution graph was shown in figure 5 and 6.

SEM analysis

SEM micrographs clearly showed great

differences between pure Valsartan (Figure. 7) and

optimized nanosuspension formulation (Figure 8) The

particles of Valsartan were found to be large and

especially irregular (Figure. 7). However after

formulation, particles disappeared and drug became small

and uniform. This might be due to the surfactant which

was used to stabillize the drug particles could be adsorbed

to crystal surface by hydrophobic interaction. So we can

say the method adopted to enhance the solubility is

appropriate.

Percentage drug content, Drug entrapment efficiency

and percentage yield In nanosuspension formulation the drug particles

were reduced to nano sized. During the formulation

process there was not any drug loss step involved, so

theoretically the formulation was considered as being

100% drug content. The Percentage drug content, drug

entrapment efficiency and percentage yield of all the

formulations were calculated and the results were

tabulated in table (3). Of all the formulations, formulation

F3 gave the highest percentage drug content with 97.24%

and least percentage content was found in F4 that is

89.92%. The drug entrapment efficiency of F3 was high

when compared to other formulations. This may be due to

the presence of optimum polymer and optimum tween 80

concentrations, comparing the formulations F1, F2 and

F4, it is clear that increase in polymer concentration

increased the drug entrapment efficiency. Considering

the formulations F1, F2, tween80 is in not used and the

drug cannot be reduced to lower particle size and high

polymer ratios causing the capture of drug molecules.

The percentage yield of formulation F3 leads the

race with 82.12% followed by F1, F2 and F4. This

indicates that F3 can be considered as best formulation,

where the polymer concentration is optimum and tween

concentration is to sufficient limit.

KINETICS

Different models like Zero order, First order,

Higuchi’s, and Peppa’s plots were drawn. The regression

coefficient (R2) value of Zero order, Higuchi’s, First

order, Korsmeyer and Hixson crowell plots (Figure 10-

14) for formulation F3 were found to be 0.972, 0.955,

0.965, 0.622 and 0.966. The optimized formulations F3

(0.972) follows Zero order plot since the regression

coefficient is found to be linear. The regression

coefficient (R2) values of zero order in the optimized

formulation F3 was greater than the R2 values of kinetics

model. Thus, the drug release follows zero order kinetics.

Stability studies

The stability studies of formulation F3 had been

performed and the results were shown in figure 15. The

formulation showed a good stability at 40C , at room

temperature and 450C.

CONCLUSION

A high pressure homogenization method was

developed to prepare Valsartan nanosuspension using

poloxamer and soyalecithin as stabilizers. From the

results of this study it may be concluded that

nanosuspensions of poorly soluble drugs such as

Valsartan are easy to prepare and represent a promising

new drug formulation for oral controlled drug delivery for

treatment of Hypertension. In vitro study in pH 7.4

phosphate buffer shows that nanosuspension formulation

gives higher drug release compared to the pure drug. The

optimized formulation F3 follows zero order plot since

the regression coefficient is 0.984 and plot was also found


80

to be linear. The regression coefficient (R2) values of zero

order in the optimized formulation F3 was greater than

the R2 values of First order. Thus, the drug release follows

zero order kinetics. The formulation showed a good

stability at 40c, room temperature and 45 ºC.

Consequently nanosuspensions represent a promising

alternative to current delivery systems aiming to improve

the biopharmaceutical performance of drugs with low

water solubility.

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DESIGN AND CHARACTERIZATION OF VALSARTAN NANO SUSPENSION

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