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Chaudhary Subash Kumar et al. UJPBS 2016, 04 (02): 1-19

Unique Journal of Pharmaceutical and Biological Sciences, 04(02), March-April 2016 11

UNIQUE JOURNAL OF PHARMACEUTICAL AND BIOLOGICAL SCIENCES

Available online: www.ujconline.net

Research Article

ISSN 2347-3614

ACECLOFENAC NANOSUSPENSION: FORMULATION AND EVALUATION

Chaudhary Subash Kumar1*

, Nina Mahmoudi2

, Rao Prakash B1, Chakraborty Joydeep

1

1Department of Pharmaceutical Technology, Karnataka College of Pharmacy, Bangalore, Karnataka, India 2Department of Pharmaceutics, Karnataka College of Pharmacy, Bangalore, Karnataka, India

Received 11-02-2016; Revised 09-03-2016; Accepted 07-04-2016

*Corresponding Author: Subash Kumar Chaudhary

Department of Pharmaceutical Technology, Karnataka College of Pharmacy, Bangalore, Karnataka, India

ABSTRACT

The purpose of this work is to formulate nanosuspension to improve solubility of poorly water soluble drug, Aceclofenac (AC).

Solubility of Aceclofenac was carried out in different solvents. Solubility in relatively non-toxic solvent is ethanol.Nanosuspension was

prepared by sonoprecipitation method for oral delivery. Nanosuspension was prepared in eight different formulations with hydroxy

propyl methyl cellulose (HPMC) and sodium lauryl sulphate (SLS) as stabilizers and evaluated for particle size analysis, zeta

potential, scanning electron microscopy, In-vitro dissolution studies, drug content, DSC and XRD. FT-IR study had confirmed no

interaction between drug and polymer. An enhancement of In-vitro dissolution in different eight formulations F-1 to F-8 like 40.67%,

38.35%, 41.08%, 42.82%, 37.7%, 43.52%, 41.1% and 38.68% respectively from the pure drug release of 19.8% in 60 mins. The

shape of nanosuspension was found to be relatively spherical, using scanning electron microscopy studies. On keeping the optimized

formula for stability studies for 3 months shows no considerable change in the formulation.

Keywords: Nanosuspension, Aceclofenac, Stabilizer, sonoprecipitationmethod, Dissolution rate.

INTRODUCTION

Mostly we are having problems with poor bioavailability of

the poor aqueous soluble drugs through oral route. So we have

challenge to improve bioavailability of the drugs. The uses of

more excipients and more organic chemicals is limited in

developing of the pharmaceutical formulation due to toxic

compounds. For last twenty year, development of novel drug

delivery system (NDDS) has been taken in consideration. The

control drug delivery is to modified the pharmacokinetics

and pharmacodynamic of drug substance in order to

enhance the safety and therapeutic efficacy through novel drug

delivery system1.

Non-steroidal anti-inflammatory drugs (NSAIDS) are a class

of analgesic medication that reduces pain, fever and

inflammation2

.Aceclofenac is an orally effective non-steroidal

anti-inflammatory drug (NSAID) of phenyl acetic acid group,

which possesses anti-inflammatory, analgesic properties. It is

well-tolerated among the NSAIDS, with a lower incidence of

gastrointestinal adverse effects. Unfortunately, it has low

aqueous solubility (0.058μg/ml), leading to poor dissolution

and insufficient oral bioavailability. It is an example of

biopharmaceutical classification system (BCS) class II

compound and its oral bioavailability is determined by

dissolution rate in the gastrointestinal tract. Therefore, the

improvement of Aceclofenac dissolution is an important issue

for enhancing its bioavailability and therapeutic efficacy2

.

Aceclofenac is used extensively in the treatment of

rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.

Aceclofenac provides symptomatic relief in a variety of

painful conditions. Aceclofenac is a newer derivative of

diclofenac having less gastrointestinal complication which

acts by blocking the action of Cyclo-oxygenase, which is

produced by prostaglandins. The usual therapeutic dose and

dosing frequency of conventional Aceclofenac tablets is high

(100 mg twice daily), because of the short biological half-life

of the drug (3-4 h); makes it an ideal candidate for modified

release dosage forms3

.

Non-steroidal anti-inflammatory drugs (NSAIDS) are

currently the most widely prescribed medication. During the

formulation of NSAIDS, it is strategically important to solve

their solubility problems, which can lead to decreases in the

drug quantity, applied and unwanted side effects, together

with an improvement of their bioavailability. A number of

advanced technological methods are available with which to

modify the physico-chemical properties and increase the rate

of dissolution of NSAIDS. The most common technologies are

particle size reduction, co-crystallization, the use of inert

water-soluble drug carriers in solid solutions or dispersions,

the production of a suspension by a solvent evaporation

method and the preparation of nanocrystalline4

.

The remedy of the poor water soluble drug is needed for

developing the nanosuspension technique an emerging method

in Pharma field. Nanosuspension is the alternative method to

Chaudhary Subash Kumar et al. UJPBS 2016, 04 (02): Page 11-19


enhance the bioavailability of poor water soluble drugs.

Nanotechnology can be used to resolve the problems

associated with these conventional approaches.

Nanotechnology is defined as the science and engineering

carried out in the nanoscale that is 10−9

m. The drug micro

particles/micronized drug powder is transformed to drug

nanoparticles by techniques like bottom-up technology (the

drug is dissolved in a solvent, which is then added to non-

solvent to precipitate the crystals) and top-down technology

(the drug is disintegrated to Nano-size)5

.

MATERIALS AND METHODS

Aceclofenac (Karnataka Antibiotics Pharmaceutical Limited,

Bangalore, India) and all other chemicals used were

A.R.Grade (Merck, Limited, Mumbai, India).Aceclofenacwere

obtained as gift sample. Hydroxy propyl methyl cellulose,

sodium lauryl sulphate and ethanol were obtained as gift

sample from Karnataka fine Chem., Bangalore, India.HPLC

grade water (Merck Limited, Mumbai, India).

Preformulation Studies

Solubility Studies: Excess of drug was taken and added to

10mL of Selected Solvents and mixed vigorously until it gets

dissolved and continue to add the drug to solvent until

Saturation is reached. Note down the range of quantity of drug

added. If required Filter and check the absorbance of the

solution under UV instrument and measure the maximum

absorbance to determine the solubility of various solvents6.

Compatibility Studies: FT-IR spectroscopy was carried out

to check the compatibility between drug and polymer.The FT-

IR spectra of drug with polymers were compared with the

standard FT-IR spectrum of the pure drug7.

Preparation Methods of AceclofenacNanosuspension

Aceclofenacnanosuspensions were prepared by

sonoprecipitation method. Aceclofenac was dissolved in 6ml

of ethanol solvent at room temperature. This organic solution

was poured into previously prepared aqueous solution

containing different ratio of stabilizers in a drop wise manner

and subsequently stirred at 6,000 – 10000 rpm using ultra-

turrax mixer for 1 hour to obtain milk-like nanosuspension.

The prepared formulation was allowed for slow stirring for an

hour to allow the volatile solvent to evaporate.Trial

formulation chart for Aceclofenacnanosuspension is shown in

Table 14

.

EVALUATION OF NANOSUSPENSION

Invitro Drug Release

Powder dissolution study was carried out by using USP

apparatus II (Paddle-Type) (Model: TDT-08L, Make: Electro

lab, India), dissolution media was 900 ml of Water at a

temperature of 37±0.5 °C at 50 rpm. 5ml of dissolution

medium was withdrawn at regular time intervals (10, 15, 30,

45, 60 minutes) and filtered and 1mL Filtered Sample was

diluted with Water. Absorbance of the resultant solution was

measured by ultra violet spectrophotometer (Model: UV- 1800

Make: Shimadzu) at 273nm using Water as a blank5.

Drug Content

Evaluation of the drug content in the Aceclofenac

nanosuspension formulation was carried out by centrifuging

10ml of the nanosuspension at 6000 RPM and the drug present

in the supernatant fluid was assessed by UV spectroscopic

method at 273nm5.

Optimization of Formulated Nanosuspension Using 23

Factorial Design

It is an experimental design, which uses dimensional factor

space at the corner of the design space. Factorial designs are

used in experiments where the effects of different factors or

conditions on experimental results are to be elucidated. These

are the design of choice for simultaneous determination of the

effect of several factors and their interaction. The two-factorial

design was applied where three factors each at two levels

obtained eight experiments which are situated at the corners of

an orthogonal cube in a 3-dimensional space.

The number of experiments is given by 2n, where ‘n’ is the

number of factors. 23 factorial design is one of the tools to

study the effect of different variables on the quality

determinant parameters of any formulation. Based on the

principle of design of experiments, this design was employed

to investigate the effect of three independent factors. A 23

factorial design for three factors at two levels each was

selected to optimize the varied response variables. The three

factors, amount of HPMC (X1), amount of SLS (X2) and

SPEED OF MIXING (RPM) (X3) were varied and the factor

levels were suitably coded. Drug release after one hour (R1),

Zeta Potential (R2) was taken as the response variables. In this

design, 3 factors are evaluated, each at 2 levels. Experimental

trials were performed at all 8 possible combinations variable

level of 23 Factorial Design for Aceclofenac nanosuspension is

shown in Table 2 and Formulation chart for Aceclofenac

nanosuspension is shown in Table 35.

CHARACTERIZATION OF NANOSUSPENSION

Scanning Electron Microscopy (SEM)

SEM photographs were taken for the prepared

nanosuspensions with a scanning electron microscope, Joel-

LV-5600, USA, at the required magnification in room

temperature. The photographs were observed for

morphological characteristics. Photographs were taken at the

magnifications of 75X, 200X, and 750X6, 7

.

Differential Scanning Calorimeter (DSC)

DSC is a technique in which the difference in heat flow

between the sample and a reference is recorded versus

temperature. DSC thermal analytical profile of a pure

chemical represents its product identity. By comparing the

DSC curves of a pure drug sample with that of formulation,

the presence of an impurity can be detected in a formulation.

The scanning temperature for reference pure drug and

formulation are the same when dynamic measurements are

performed, and hence the required heat energy for chemical

transformation is directly recorded on a heat flow versus

temperature graph. The energy is measured as Joules per

kilocalorie. All dynamic DSC studies were carried out on TA

instruments Q200 series. The instrument was calibrated using

high purity indium metal as standard. The dynamic scans were

taken in nitrogen atmosphere at the heating rate of

10ºC/min6,7

.

Powder X-Ray Diffraction Studies (XRD)

The powder XRD of the TEL, physical mixtures of drug and

polymers, their solid dispersions were recorded using an X-ray



diffractometer (Philips Analytical XRD). The scanning rate

was 5°C/min and diffraction angle was 0–70°8

.

Particle Size Analysis by Malvern Zeta Sizer

The particle sizes of nanosuspension, which were not visible

in the optical microscope, were measured by using Malvern

Particle Size Analyzer (Zeta Sizer, Nano series, S 90).

Samples were prepared by dispersing Nanoparticles with

sufficient amount of water to achieve obscuration around 5%.

The average particle size was determined from the particle

size distribution data9.

RESULTS

Solubility Studies

The solubility of Aceclofenac in various solvent was estimated

as shown in Table 4.

Compatibility Studies

Preformulation compatibility studies of pure drug Aceclofenac

with HPMC and SLS were carried out prior to the preparation

of Aceclofenac nanosuspension. FT-IR spectra of pure drug

Aceclofenac, HPMC and SLS combination of Drug and

Stabilizer were obtained, which are shown in Spectra

Fig.No.1.

Evaluation of AceclofenacNanosuspension

In-Vitro Drug Release

The in-vitro release profile obtained for all eight

formulations, F-1 to F-8, are shown in Table 5.

Drug Content

The drug content for formulation F1-F8 is shown in Table 6.

Characterization of Nanosuspension

X-Ray Diffraction To assess the physical state of Aceclofenac nanosuspension

XRD was performed as shown in the figure 5.

Differential Scanning Calorimetry

The DSC curves of Aceclofenac, Aceclofenac with the

mixture of HPMC and SLS were carried as shown in the

figure 6.

DISCUSSIONS

Solubility Studies

Among the various solvent, ethanol provides the highest

solubility of Aceclofenac so was selected for further study.

Compatibility Studies

From the obtained spectra it was observed that all the

characteristics peaks of Aceclofenac were present in the

combination spectra thus indicating the compatibility of the

drug with the stabilizer. It shows that there was no significant

change in the chemical integrity of the drug.

Evaluation of AceclofenacNanosuspension

In-Vitro Drug Release

The cumulative percent drug release after 60 min was found to

be 19.8% of Pure Aceclofenac where as Aceclofenac

nanosuspension was found to be 40.67%, 38.35%, 41.08%,

42.82%, 37.70%, 43.52%, 41.10% and 38.68% for F-1 to F-8

respectively, From the results it was observed that F-6

formulation produced highest release in 60 min time interval

which contain pure drug, HPMC & SLS in the formulation.

Drug Content

The drug content for formulation F1-F8 was found to be

92.9%, 94.3%, 97.7%, 96.9%, 94.8%, 99.5%, 98.3%, and

93.6% respectively. From the summarized results of drug

content F6 was found to have maximum drug concentration.

Factorial Models

Response: R1(% CDR at 60 min)

% CDR for all the formulation ranges from 38.35 to 43.52 %

(Table No.11). In this case, effect of HPMC, SLS and Speed

of Mixing can be explained by mathematical equation in terms

of coded factors:

%CDR at 60 min = + 40.49 + 1.54* C

The Model F-value of 9.38 implies the model is significant.

There is only a 2.21% chance that a "Model F-Value" this

large could occur due to noise. Values of "Prob > F" less than

0.0500 indicate model terms are significant. In this case

models are the Significant.

Response: R2(Zeta Potential)

Zeta Potential of all the formulation ranges from -22.8 to -38.6

mV (TABLE NO.12).In this case, effect of HPMC, SLS and

Speed of Mixing can be explained by mathematical equation

in terms of coded factors:

Zeta Potential = - 31.31 + 1.79 * C

The "Model F-value" of 0.17 implies the model is not

significant relative to the noise. There is a 91.23 % chance

that a "Model F-value" this large could occur due to noise.

Values of "Prob > F" less than 0.0500 indicate model terms

are significant. In this case there are no significant model

terms.

ANOVA for Selected Factorial Model

The result of ANOVA demonstrates that the model was

significant for % CDR at 60min and non-significant for Zeta

potential to all dependent variables. Regression analysis was

carried out to determine the regression coefficients. All the

independent variables (Factors) were found to be significant

for all R1 and non-significant for R2response variables. So,

above result indicate that the factors %CDR do play an

important role in the formulation of nanosuspension

containing Aceclofenac, whereas Zeta potential is not showing

any desirable effect. The data of factorial model, which can

provide a mean response and an estimate of design space.

Optimization

In the 23

Factorial model optimization technique, the

desirability approach was used to generate the optimum

settings for the formulation. For the optimized formulation,

Zeta potential and % CDR was kept at in range. The

composition of optimized formula is Aceclofenac (100mg),

HPMC (94.77mg), SLS (51.75mg), and Speed of Mixing

(7048.80rpm).

Characterization of Nanosuspension

X-Ray Diffraction The Diffraction pattern of Aceclofenac exhibits the typical

crystalline polymorphic substance and it is characterized by

the peak around 2θ and the optimized formulation consist of

Aceclofenac and mixture of HPMC and SLS obtained from

Sonoprecipitation method by using Ethanol, water and

predicted for the Aceclofenac nanosuspension showed

modification of diffraction pattern.X-RD graph shows that

the crystallisation of nanosuspension is reducing.

Chaudhary Subash Kumar

Unique Journal of Pharmaceutical and Biological Sciences

Differential Scanning Calorimetry

The DSC thermogram of Aceclofenac exhibit

exothermic peak near 155.37 °C, which is ind

melting temperature. The DSC thermogram of

with the mixture of HPMC and SLS

Nanoprecipitation method showed no significant d

Re-crystallization appeared which reveals no am

was produced during formulation.

CONCLUSION

In this study, Aceclofenac nanosuspension was prepared and

evaluated. The following conclusions are drawn from the

results obtained:

Figure 1: FT-IR Spectrum of Pure Aceclofenac

Subash Kumar et al. UJPBS 2016, 04 (02): Page 11

Unique Journal of Pharmaceutical and Biological Sciences, 04(02), March-

ited the sharp

ndicative of its

am of Aceclofenac

prepared by

nt differences.

morphous form

nanosuspension was prepared and

following conclusions are drawn from the

� This formulation approach can be used to improve

the therapeutic efficacy of poorly soluble drugs. The

changes in nanoparticles

affected by changes in stabilizer concentration.

� This formulation approach overcome problems

associated with delivery of poorly water soluble and

lipid soluble drugs.

� This formulation also enhances the physical and

chemical stability of Aceclofenac drug by providing

rapid onset of action.

� Among the prepared formulations, the in vitro release

profile and drug content of the formulations indicated

good result for formulation F6

IR Spectrum of Pure Aceclofenac (A), Aceclofenac + HPMC(B), Aceclofenac + SLS(C) and Aceclofenac + HPMC + SLS(D)

Figure 2: Zeta potential of Nanosuspension

11-19

-April 2016 14

This formulation approach can be used to improve

the therapeutic efficacy of poorly soluble drugs. The

changes in nanoparticles size and drug release were

affected by changes in stabilizer concentration.

This formulation approach overcome problems

associated with delivery of poorly water soluble and

This formulation also enhances the physical and

ility of Aceclofenac drug by providing

Among the prepared formulations, the in vitro release

profile and drug content of the formulations indicated

good result for formulation F6.

Aceclofenac + HPMC + SLS(D)



Figure3: 3-Dgraphshowing

Figure 4: 3-D graph s

Figure 5: Powder X-Ray Diffraction of pure Aceclofenacdrug(A) and

Figure 6: DSC for pure



geffect of HPMC andSpeedofMixing(rpm)onDrug release after One Hour

showing effect HPMC and Speed of Mixing (rpm) on Zeta Potential

Ray Diffraction of pure Aceclofenacdrug(A) and optimized nanosuspension formulation

Figure 6: DSC for pure Aceclofenac drug and optimized nanosuspension formulation

11-19

-April 2016 15

release after One Hour

optimized nanosuspension formulation (B)



Figure 7: Particle Size distribution Of Optimized Formulation

Table 1: Trial formulation chart for Aceclofenac

Sl.No. Aceclofenac (pure drug)

(mg)

TF-1 100

TF-2 100

TF-3 100

TF-4 100

TF-5 100

TF-6 100

Table 2: variable level of 2

Variablelevel

HPMC(mg)

SLS

SPEED OF MIXING(RPM)

Table 3: Formulation chart for Aceclofenac

Ingredients F1

Aceclofenac(mg) 100

HPMC (mg) 75

SLS (mg) 75

Ethanol (ml) 6

Water 10

Rpm 10000

Table 4: Solubility studies of Aceclofenac

Solvents

Acetone

Acetonitrile

Ethanol

Water



Figure 7: Particle Size distribution Of Optimized Formulation

Trial formulation chart for Aceclofenac nanosuspension

Stabilizers Ethanol

(mL) HPMC (mg) SLS (mg)

75 50 6

100 75 6

125 40 6

75 75 6

100 50 6

125 75 6

Table 2: variable level of 23 Factorial Design for Aceclofenac nanosuspension

-1(low)

75

50

6000

Table 3: Formulation chart for Aceclofenac nanosuspension

F2 F3 F4 F5 F6

100 100 100 100 100 100

125 75 125 125 125

75 50 75 50 50

6 6 6 6 6

10 10 10 10 10 10

10000 6000 6000 10000 6000 10000

Table 4: Solubility studies of Aceclofenac

Solubility of Drug

≥ 100mg/mL

67.04mg/mL

≥ 100mg/mL

8mg/mL

11-19

-April 2016 16

Distilled water (mL)

10

10

10

10

10

10

nanosuspension

+1 (high)

125

75

10000

F7 F8

100 100

75 75

50 75

6 6

10 10

10000 10000 6000

Solubility of Drug



Table 5: In-Vitro Drug Release Study

Time

(min)

Formulations

Water

Pure

Drug F-1 F-2 F-3 F-4 F-5 F-6 F-7 F-8

10 1.61 6.01 5.67 5.84 6.70 5.40 5.31 5.68 5.54

15 4.37 13.20 12.11 12.97 14.02 11.91 11.75 12.27 11.87

30 7.95 21.58 19.72 21.20 22.58 19.52 20.15 20.54 19.74

45 13.64 30.62 28.45 30.92 32.20 28.11 30.43 30.37 28.47

60 19.8 40.67 38.35 41.08 42.82 37.70 43.52 41.10 38.68

Table 6: Drug content

Formulation Drug Content (In %)

F1 92.9

F2 94.3

F3 97.7

F4 96.9

F5 94.8

F6 99.5

F7 98.3

F8 93.6

Table 7: Zeta Potential Distribution

Response: R1 (Drug release after One Hour)

Sl. No. Formulations Zeta potential (mV)

1. F-1 -34.5

2. F-2 -38.6

3. F-3 -38.2

4. F-4 -28.2

5. F-5 -32.8

6. F-6 -22.9

7. F-7 -32.5

8. F-8 -22.8

Table 8: Anova for Selected Factorial Model

Source Sum of

Squares Df

Mean

Square

F

Value

p-value

Prob> F Significant

Model 18.91 1 18.91 9.38 0.0221

C-RPM 18.91 1 18.91 9.38 0.0221

Residual 12.09 6 2.02 - -

Cor Total 31 7 - - -

Table 9: Estimated Regression Coefficients

Coefficient

Factor

Standard

Estimate

95% CI

Df

95% CI

Error Low High VIF

Intercept 40.49 1 0.5 39.26 41.72 -

C-RPM 1.54 1 0.5 0.31 2.77 1

Table10: Anova for Selected Factorial Model

Source Sum of

Squares Df

Mean

Square

F

Value

p-value

Prob> F

Model 25.56 1 25.56 0.63 0.456

not significant C-RPM 25.56 1 25.56 0.63 0.456

Residual 241.69 6 40.28 - -

Cor Total 267.25 7 - - -



Table11: Estimated Regression Coefficients

Coefficient

Factor

Standard

Estimate

95% CI

Df

95% CI

Error Low High VIF

Intercept -31.31 1 2.24 -36.8 -25.82 -

C-RPM 1.79 1 2.24 -3.7 7.28 1

Table 12: Optimized Formula

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Source of support: Nil, Conflict of interest: None Declared

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