Research Article

FORMULATION AND EVALUATION OF ACECLOFENAC LOADED SR MATRIX PELLETS: EXTRUSION SPHERONIZATION

PRASHANT K. PURANIK, FARHAN M. KHAN*

Government College of Pharmacy, Aurangabad 431005 (M.S.), India. Email: fmk3883@yahoo.com

Received: 28 Jun 2013, Revised and Accepted: 21 July 2013

ABSTRACT

Objective: The major objective of this study was to prepare and evaluate Once- Daily Sustained Release Matrix Pellets Formulation of Aceclofenac by using Extrusion-Spheronization technique.

Methods: The sustained release matrix pellets of Aceclofenac were prepared by industrially applied extrusion spheronization technique. The different formulations were prepared using HPMC K100M LVCR as hydrophilic matrix polymer , PEG 400 as potential plasticizer in different concentration, MCC PH101 as a spheronization aid and HPMC K4M (2% w/w) as binder. The prepared pellets were evaluated for parameters like Flow Properties, Morphological characteristics, Drug Content and In vitro drug release study in pH 6.8 phosphate buffer. Experimental design technique was used to select optimized formulation releasing drug for 24 hr.

Results: The Aceclofenac SR matrix pellets composed of HPMC K100M LVCR 11 % and PEG 400 3 % was selected as optimised. The evaluated parameters of optimised batch were found within the limits. Drug release of optimized batch (F3) at 2 hr was found to be less than 30 % (25.43 %) and at 24 hr more than 80 %( 98.32%).

Conclusion: The results from this study showed that combination of HPMC K100M LVCR as hydrophilic matrix polymer and PEG 400 as potential plasticizer is effective and useful for sustaining the Aceclofenac release. And hence Extrusion-Spheronization technique can be promising approach for the preparation of pellets which assure its applicability for large scale manufacturing.

Keywords: Aceclofenac, Extrusion-Spheronization, Hydroxypropyl Methylcellulose, Matrix Pellets.

INTRODUCTION

Aceclofenac is a new generation NSAID showing effective Anti-inflammatory and Analgesic properties and a good tolerability profile in a variety of painful conditions like Ankylosing spondylitis [1,2],

Rheumatoid Arthritis [3], and Osteoarthritis [4]. It directly blocks the prostaglandin’s synthesis and has less GI complications. It has a short biological half life of approx 4 h and a dosing frequency of 200 mg daily in two divided doses [5, 6]. This necessitates multiple daily dosing for maintenance of its plasma concentration within the therapeutic index. Hence, there is impetus for developing sustained release multiple-unit dosage form that maintains therapeutic plasma drug concentration for long period compared to conventional dosage forms. Several matrix based sustained release products of aceclofenac utilizing hydrophilic and hydrophobic polymers have been reported [7, 8]. Polymer matrix systems have the advantages of prolonging drug release and reducing adverse effects in patients. An attempt has been made in the present study to achieve desirable therapeutic profile of Aceclofenac by formulating its sustained release pellets using HPMC of various viscosity grades. Matrix pellets composed of drug and polymer as release retarding material offer the simplest approach in designing a sustained release system [9].

Multiple unit extended release dosage forms are becoming very popular dosage forms relative to single unit dosage forms because of their ability to spread uniformly in the gastrointestinal tract, thus minimizing the plasma level variability and reduced risk of local irritation [10, 11]. Pharmaceutical pellets may be defined as spherical, free-flowing granules with a relatively narrow size distribution (500-1500 μm) [12]. The ultimate dosage forms for pellets can be capsule or they may be compressed into disintegrating tablets. Interest in this area has been increasing continuously, since it offers some important pharmacological as well as technological advantages [13,14]. In the present study, Extrusion-Spheronization method was adopted for the preparation of sustained release pellets of Aceclofenac. Extrusion -Spheronization may be defined as a process in which a wet mass is extruded through a specific sieve with fixed diameter and subsequently spheronized into spherical particle called as spheroids, pellets or beads depending upon materials and process used for Extrusion –Spheronization [15].

MATERIAL AND METHODS

Aceclofenac was obtained as a gift sample from Flamingo Pharma Ltd (Mumbai, India). Hydroxypropyl Methylcellulose (Methocel® K4M, Methocel® K15M and Methocel® K100M) – Colorcon Asia Pvt. Ltd, (Mumbai, India ), Micro crystalline cellulose (Avicel® PH101& 102) - Signet chemical corporation, (Mumbai, India) and ), Polyethylene Glycol 400 (AR grade) were purchased from Merck (Mumbai, India). All other chemicals and reagents used were of AR grade.

Preliminary Studies

Selection of Spheronizing Aid for Pellets

The pellets of individual spheronizing aid like MCC PH101, MCC PH102 and lactose were prepared by extrusion Spheronization. The possibility of pelletization and appearance of pellets was observed as a response [16].

Selection of Binder and Binder Level Optimization

Pellets of microcrystalline cellulose PH101 were prepared incorporating various binder solutions such as water, HPMC (K4M, and K15M) solution (in water). The responses of consistency of extrudate were studied and pellets were observed for their appearance and strength [17, 18]. Pellets of MCC 101 were prepared with HPMC K4M in the concentration range of 1-3%w/v. The consistency of damp mass, pellet’s appearance and pellet’s strength were studied.

Optimization of Extrusion Spheronization Process

In an attempt to formulate pellets with desired characteristics (physical appearance and sphericity), the parameters like speed of spheronization and time of spheronization were varied in the range as mentioned below. Thus, 32 =9 formulations were prepared as per 32factorial model experimental design.

Speed of spheronization (X1) = 1000, 1200, 1400 rpm

Time of spheronization (X2) = 10, 15, 20 min

International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491 Vol 5, Suppl 3, 2013

AAccaaddeemmiicc SScciieenncceess

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Drug- Excipients Compatibility Study

Differential Scanning Calorimetry

Differential scanning Calorimetry was performed using DSC (DSC 60 Shimadzu, Japan) in order to investigate potential solid state

interactions between drug and excipients. Standard aluminium sample pans were used and a heating rate of 10 0C/min was employed in the range of 25–400 0C. DSC thermograph of Aceclofenac with the excipients HPMC K100M, K4M and MCC was recorded on Differential Scanning Calorimeter.

Table 1: Formulation compositions for different batches

Formulation F1 F2 F3 F4 F5 F6 F7 F8 F9 Aceclofenac % 30 30 30 30 30 30 30 30 30 HPMCK100 LVCR % 11 11 11 12.5 12.5 12.5 14 14 14 PEG 400 % 1 2 3 1 2 3 1 2 3 MCC PH 101 % 59 59 59 57.5 57.5 57.5 56 56 56 HPMC K4M (2%w/v solution in water)

(Approximate 19 gm)

Purified Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

Preparation of SR Matrix Pellets Formulation

The compositions for all the batches using 32 factorial design approach are given in Table 1. All the ingredients including drug and polymers were weighed accurately, sieved through 40 mesh sieve and mixed geometrically in a mixing bag. Powder blend was granulated with binder solution (2% HPMC K4M) and purified water to form wet mass. This wet mass was then extruded through roller extruder having 1 mm extruder screen. Extrudate was then spheronized using a Spheronizer; equipped with 4.2 mm friction plate at 1200 rpm for 20 min. as optimized earlier. (Extruder 20 and Spheronizer 250, Anish Pharma, India) Spheronized pellets were dried. These dried pellets were screened through 40 mesh and evaluated.

Evaluations of Prepared Pellets

Morphological Characteristics and Flow Properties of Pellets

All the batches were studied with regards to the morphological features i.e. roundness, aspect ratio, pellet size, and shape using photomicrograph. The prepared pellets were evaluated for the parameters bulk density, tapped density, compressibility index (Carr’s Index), angle of repose, and Hausner’s ratio [19].

Particle Size Analysis

Particle size of drug loaded formulations were measured by using optical microscope (Olympus CX 31, Japan) [20].

Friability

Accurately weighed quantity of pellets (3 gm) were taken from final batch of pellets and placed in a friabilator and tumbled for 100 revolutions at 25 RPM. Twelve steel balls (weighing 0.445 gm each) were used as an attrition agent. Subsequently, the pellets were sieved through sieve no. 20. The weight loss (%) is calculated as:

% F = (Wi-Wr/Wi) 100

Where, Wi is initial weight of pellets before friability testing, and Wr is the weight of pellets retained above the sieve after friability testing.

Drug Content

Accurately weighed pellets equivalent 200 mg drug were crushed in a dried mortar- pestle. Powder of the pellets was dissolved in upto 100 ml phosphate buffer pH 7.4. It was stirred for 15 min and filtered. Appropriate dilutions of solution were prepared subsequently from it and were analyzed by UV-VIS spectrophotometer (UV-1700, Pharmaspec, Shimadzu Ltd, Japan) at 275 nm.

In Vitro Drug Release Studies

The in vitro release of the drug from pellets of all formulation batches were performed using USP apparatus Type I (Basket) Electro lab, India. The dissolution medium consisted of 900 ml of phosphate buffer pH 6.8. Dissolution was performed at 37±0.5°C, with stirring speed of 50 rpm. 5 ml of aliquot was withdrawn at time

intervals of 1, 2, 4, 6, 8, 10, 12, 16, 24 Hrs. The medium was replenished with same amount of fresh dissolution media each time. The filtered samples were analyzed by UV-VIS spectrophotometer (UV-1700, Pharmaspec, Shimadzu Ltd, Japan) at 275 nm and absorbance were recorded [21].

Kinetics of Drug Release

The dissolution profile of all the formulations were fitted to zero order kinetics, first order kinetics, Higuchi, Hixson-Crowell, Korsmeyer and Peppas to ascertain the kinetic modeling of drug release by using a PCP Disso Version 2.08 software, and the model with the higher correlation coefficient was considered to be the best model [22, 23].

Scanning Electron Microscope (SEM)

Scanning electron microscopy was performed on pellets to assess the surface morphology like size and shape [24]. Sample was fixed on an aluminum stub with conductive double sided adhesive tape and coated with gold in an argon atmosphere (50 Pa) at 50mA for 50 s. The samples were scanned at a voltage of 5kV (Jeol-6380A, Japan electron optical laboratory)

Analysis of data by Design Expert Software

A 32 full factorial design was selected and the 2 factors i.e. concentration of HPMCK100M LVCR and PEG 400 plasticizer were evaluated at 3 levels. The statistical treatment and interpretation of data was done by Stat Ease Design Expert 8.0.7.1 software. The analysis of variance (ANOVA) is represented in table. The data were also subjected to 3-D response surface methodology to study the interaction of independent variables.

Optimization (Model validation)

Optimization was performed using Design Expert 8.0.7.1 software to obtain optimized batch. Comparison of drug release profile of desirable batches was done with the drug release profile responses predicted from the obtained model by software with results obtained by experimentation to obtain final optimized batch. The closer resemblance between observed and predicted response values indicates the validity of the generated model.

RESULT AND DISCUSSION

Selection of Spheronizing Aid for Pellets

The plasticity of primary damp mass and surface morphology of extrudate was considered as the key points for the selection of spheronizing aid. Extrudate prepared with lactose does not show proper plasticity (good extrusion ability) and good surface appearance. MCC have better spheronizing capacity and pellet forming capacity than lactose. But, the extrudates prepared with MCC PH102 shows cracks with granular surface which does not appears in the case of MCC PH101. Pelletability and aesthetic appeal was more with MCC PH101. So ultimately MCC PH 101 was selected for the further study.

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Selection of Binder for Preparation of Pellets

Pellets prepared without binder (i.e. only with water) & with binders i.e. HPMC K4M, HPMC K15M (in water) were observed for their consistency and strength. Among the binders used, HPMC K4M was chosen on the basis of good consistency of the mass to be extruded and spheronized. Mass of HPMC K15M did not get spheronized due to its relatively higher viscosity. The effect of binder on extrusion and spheronization ability is shown in Table 2.

Table 2: Selection of Binder

Binder (solvent)

Concentration (w/v)

Response

----- (Water) - No extrudability due to very low binding force

HPMC K4M (water)

1-3 % Good consistency and extrudate formed

HPMC K15M (water)

1-3 % Improper extrudates due to high viscosity,Not spheronizable

Binder Level Optimization (HPMC K4M)

Binder solution of HPMC K4M was prepared in the concentration range 1-3%. Response was analyzed for consistency of the damp mass and its ability to form proper extrudates and spherical pellets with smooth surface. HPMC K4 as a binder with concentration of 1% and 1.5% failed to extrude because of its poor binding capacity. At binder concentration of 2%, it was observed that the damp mass extruded and spheronized well to provide spherical pellets due to optimum binding capacity and plasticity. At concentration of 2.5%, it was found to give good extrudate but failed to spheronize because of its high viscosity. Concentration of 3% was unable to extrude due to stickiness and high viscosity. Hence, binder concentration of 2% was selected for further study. The effect of binder concentration is shown in Table 3.

Table 3: Binder Level Optimization (HPMC K4M)

Binder Concentration (% w/v) Response 1% Failed to extrudates 1.5% Improper extrudates 2% Good extrudates and

spheronizable 2.5% Good extrudates, unable to

spheronizer 3 % Sticky extrudates

Optimization of Extrusion Spheronization Process

In an attempt to formulate pellets with desired characteristics (physical appearance and sphericity), the parameters speed of spheronization and time of spheronization were varied. And formulations were prepared by following 32 factorial design approach. From this study the optimized parameter were selected.

Table 4: Optimized Parameters for Extrusion Spheronization

Parameter Value Extrusion speed 45 rpm Extrusion sieve 1 mm Spheronization plate 4.2 mm Spheronization speed 1200 rpm Spheronization time 20 min

Drug - Excipients Compatibility Study

The possible interactions between Aceclofenac and excipients and polymers were studied. There was no considerable change in DSC endothermic values on comparison of pure Aceclofenac’s with Aceclofenac added excipients and polymers. The peak value was obtained at 151.18 0C which complied with that of pure drug. There is no major shifting in this peak value. The presence of other excipients might have suppressed the peak height. Hence, it is concluded that there is no interaction of Aceclofenac with the excipients used i.e. they are compatible. The DSC thermogram is shown in figure 1.

Flow Properties of Pellets and Morphological Characteristics

The flow properties of all factorial batches are shown in Table 5. Angle of repose values ranges from 19.39±1.45 to 31.29±1.67. The value of bulk density and tapped density ranges from 0.65±0.07 to 0.87±0.031 (gm/cm3) and 0.74±0.009 to 0.95±0.05 (gm/cm3) respectively. The value of Carr’s index below 15% indicates a powder which usually gives rise to excellent flow characteristics whereas that above 25% indicates poor flow ability. Hausner’s Ratio (H) is an indirect index of ease of powder flow. The flow properties of the batch F3 and F5 was found to be excellent.

The comparative studies of photomicrograph of all batches are as shown below in Figure 2.

.

0.00 5.00 10.00

Time [min]

-10.00

-5.00

0.00

5.00

mW

DSC

100.00

200.00

300.00

C

Temp

151.18 x100COnset

160.54 x100CEndset

141.14 x100CStart

165.34 x100CEnd

155.63 x100CPeak

-386.41 x100mJ

-66.05 x100J/g

Heat

-17.01 x100mWHeight

File Name: Drug+Excipient.tadDetector: DSC60Acquisition Date 13/01/17Acquisition Time 13:35:36Sample Name: Drug+ExcipientSample Weight: 5.850[mg]Annotation:

[Temp Program]Start Temp 100.0Temp Rate Hold Temp Hold Time[C/min ] [ C ] [ min ]20.00 300.0 0

Thermal Analysis ResultDrug+Excipient.tadDrug+Excipient.tad

TempDSC

0.00 5.00 10.00

Time [min]

-30.00

-20.00

-10.00

0.00

mW

DSC

100.00

200.00

300.00

C

Temp

151.85 x100COnset

163.86 x100CEndset

147.47 x100CStart

168.98 x100CEnd

157.90 x100CPeak

-842.51 x100mJ

-110.13 x100J/g

Heat

-32.77 x100mWHeight

File Name: Drug.tadDetector: DSC60Acquisition Date 13/01/17Acquisition Time 13:15:34Sample Name: DrugSample Weight: 7.650[mg]Annotation:

[Temp Program]Start Temp 100.0Temp Rate Hold Temp Hold Time[C/min ] [ C ] [ min ]20.00 300.0 0

Thermal Analysis Result

Drug.tadDrug.tad

TempDSC

Fig. 1: DSC thermogram of Aceclofenac and Aceclofenac with formulation excipients

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Table 5: Flow Property of Pellets

Flow property Angle of Repose (θ) Bulk density (gm/cm3) Tapped density (gm/cm3) Carr’s Index (%) Hausner’s Ratio F1 30.95±2.51 0.75±0.048 0.85±0.04 7.40±0.7 1.08±0.02 F2 27.98±1.33 0.81±0.05 0.94±0.02 13.82±0.99 1.16±0.02 F3 29.90±1.17 0.83±0.04 0.91±0.01 8.79±0.12 1.09±0.03 F4 26.29±2.37 0.87±0.03 0.94±0.02 10.63±0.83 1.08±0.06 F5 21.72±1.06 0.67±0.01 0.79±0.02 15.18±0.25 1.17±0.04 F6 19.39±1.45 0.65±0.07 0.74±0.009 12.16±0.21 1.13±0.02 F7 31.29±1.67 0.82±0.01 0.95±0.05 13.68±0.42 1.15±0.07 F8 29.75±3.26 0.85±0.01 0.93±0.02 8.60±0.21 1.09±0.04 F9 28.2±2.62 0.76±0.02 0.80±0.05 5±0.02 1.05±0.02

All values expressed as mean± SD, n=3.

Fig. 2: Photo micrograph of all batches

Aspect ratio and roundness are the important parameters for the characterization of pellets. Aspect ratio nearer to 1 and roundness nearer to 100% shows spherical pellets. On the basis of aspect ratio and roundness, batches F3, F4, F5, showed good results with respect to HPMC K100 LVCR and plasticizer ratio. Batch F3 showed

minimum aspect ratio i.e. 1–1.07 and maximum roundness i.e. 98.80%. The morphological characteristics of all factorial batches are shown in Table 6. The Photomicrographic study also confirmed that batch F3 has more spherical and uniform pellets with smooth surface compared to other batches.

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Table 6: Morphological Characteristics of Pellets

Batches Shape Aspect ratio Roundness (%) F1 Cylindrical /Rod 1.224-2.69 69.276 - 76.778 F2 Cylindrical + Dumbbell 1.35-1.97 40.34 – 48.691 F3 Sphere 1 – 1.07 92.805-99.256 F4 Oval + Sphere 1.1-1.14 81.643 -85.152 F5 Oval + Sphere 1.13 – 1.16 86.672 – 97.57 F6 Dumbbell + Oval 1.08-1.12 87.128 - 93.135 F7 Dumbbell +Ellipsoid 1.19 - 1.39 41.987 - 48.787 F8 Cylindrical + Dumbbell 1.35-1.97 40.34 – 48.691 F9 Ellipsoid + Dumbbell 1.18 - 1.27 61.763 - 66.473 [

Particle size analysis

On the basis of aspect ratio and roundness, batches F3, F4 and F5 has shown good results with respect to HPMC K100 LVCR and plasticizer ratio, Particle size was determined by optical microscopy for drug loaded matrix pellets. Average particle size was found in the

range 943.87 mm to 1076.617mm. Average roundness of the pellets was found to be in the range 86.101 to 90.955 which is shown in Table 7. Amongst all batches, batch F3 showed larger particle size 998.102 mm and highest roundness 90.955 %. Hence, it is concluded that the pellets of batch F3 are more spherical relative to other. Particle size analysis parameters of pellets are shown in Table 7.

Table 7: Particle Size Analysis of Batches (F3, F4, F5)

Batch Length Width Area Asp.Ratio Roundness Shape Sphere volume F3 1093.103 998.102 914097.2 1.095 90.955 0.011 75755633 F4 1051.075 943.87 814375 1.114 86.101 0.012 63703467 F5 1193.557 1076.617 1009306 1.109 88.91 0.012 87894233

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Friability

The friability of the pellets tested with steel balls was found below 0.2%, and thus the pellets have desirable hardness and are of a good quality with respect to friability. Friability (%) of all the factorial batches is shown in Table 8.

Drug content

The drug loaded pellets of Aceclofenac prepared with the optimized formula exhibits drug loading capacity in range of 92.52±0.15% - 99.86±0.05%. Batch F3 showed maximum drug content i.e. 99.86%. Drug content of all the factorial batches are shown in Table 8.

Table 8: Friability (%) and Content Uniformity

Batch (%)Friability Drug content% F1 0.18±0.053 96.53±0.12 F2 0.15±0.03 99.37±0.02 F3 0.14±0.026 99.86±0.05 F4 0.15±0.01 92.52±0.15 F5 0.13±0.015 96.79±0.05 F6 0.18±0.053 95.65±0.13 F7 0.13±0.03 94.47±0.05 F8 0.14±0.026 96.47±0.02 F9 0.15±0.01 93.99±0.04

All values expressed as mean± SD, n=3.

In-Vitro Drug Release Study

In-vitro drug release study of all the formulation batches (F1-F9) were performed in triplicate using USP apparatus Type-I (Basket). The batches F4, F5, F6, F7, F8 and F9 shows drug release 68.25±0.28 %, 75.15±0.20%, 75.41±0.49%, 69.52±0.08%, 74.04±35% and 72.01±0.28% respectively in 16 hr, which can release the drug upto 24 hr but are unable to meet the criteria of 80% drug in release 16 hr probably due to more weight gain of HPMC K100MLVCR. F1 batch sustained the drug release only upto 78.97±0.56% in 16hr. The batches F2 and F3 showed drug release upto 82.2±0.12% and 85.38±0.016% in 16 hr, which meets the criteria of 80% drug release in 16 hr probably due to low weight gain of HPMC K100MLVC. Only the batches F2 and F3 showed desirable release profile suitable for sustained release systems. Batch F3 showed highest drug release as compared to the F2 batch in 24 hr i.e. 98.32±0.19%, although both batches contains the same concentration of HPMC K100MLVCR which may be due to the high concentration of PEG 400 in F3 batch. The PEG

400 increases the drug release on increasing it’s level from 1% to 3%. This increase in drug release may probably be due to PEG 400 as it is hydrophilic and a solubility enhancing agent. The results of cumulative drug release (%) of all the formulation batches are shown in Table 9 and Table 10.

The graphical representations of the dissolution profile of all factorial batches are shown in Figure 3, 4 and 5.

Kinetics of drug release

To describe the kinetics of the drug release from the matrix pellets, release data was evaluated by model-dependent (curve fitting) method using PCP Disso v3 software and the model with the highest correlation coefficient amongst them was considered to be the best model. The results shows that the factorial batches F1, F2 and F8 follows Korsmeyer Pappas order kinetics while the batches F3, F4, F5, F6, F7, F9 follows Matrix order kinetics. The observations are summarized in Table 11.

Table 9: Cumulative Drug Release (%) of F1 to F5

Time[Hr] F1 F2 F3 F4 F5 1 13.01±1.33 14.11±1.23 16.96±0.98 8.86±0.94 11.61±1.41 2 19.73±1.08 23.95±0.82 25.43±1.32 18.18±1.3 21.22±1.47 4 35±1.49 38.27±0.56 41.94±1.49 30.58±0.97 32.73±1.05 6 40.58±1.14 46.08±1.05 48.28±0.94 36.26±0.90 42.03±1.13 8 47.46±1.21 51.48±0.95 54.99±1.28 45.16±1.92 49.32±1.03 10 53.6±1.70 59.59±1.9 59.74±1.56 50.915±1.17 55.05±1.08 12 59.84±2.09 68.4±1.14 67.99±1.07 59.55±0.93 60.56±1.46 16 78.97±1.56 82.2±1.92 85.38±1.16 68.25±0.88 75.15±0.90 24 93.16±1.07 95.2±0.97 98.32±0.99 82.98±1.01 86.45±1.47

All values are expressed as mean± SD, n=3.

Table 10: Cumulative Drug Release (%) of F6 to F9

Time[Hr] F6 F7 F8 F9 1 13.68±1.42 10.97±1.04 11.13±0.91 10.7±1.32 2 22.325±1.61 18.615±1.36 16.10±1.31 21.31±0.95 4 33.29±0.97 28.58±0.98 31.57±0.87 32.17±0.90 6 46.52±1.68 41.36±1.49 38.66±1.36 42.14±1.06 8 50.25±1.28 43.53±1.63 49.37±1.01 48.2±1.21 10 60.21±0.97 49.4±0.93 52.52±0.99 55.73±2.03 12 63.12±1.53 58.68±1.42 56.30±1.39 61.84±2.24 16 75.41±0.99 69.52±1.08 74.04±1.05 72.01±0.98 24 90.15±2.32 79.51±1.73 85.51±1.59 89.28±1.97

All values are expressed as mean± SD, n=3.

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Fig. 3: Cumulative drug release of formulation batches F1-F3

Fig. 4: Cumulative drug release of formulation batches F4-F6

Fig. 5: Cumulative drug release of formulation batches F7-F9

Table 11: Drug Release Kinetics of All the Factorial Batches

Batch Code

r2 n K Zero order First order Matrix Korsmeyer peppas Hixon crowell

F1 0.629 0.529 0.943 0.969 0.729 0.424 0.027 F2 0.743 0.643 0.828 0.887 0.643 0.468 0.118 F3 0.653 0.634 0.990 0.886 0.634 0.352 0.219 F4 0.798 0.862 0.973 0.943 0.828 0.516 14.800 F5 0.810 0.869 0.984 0.945 0.837 0.430 12.718 F6 0.678 0.867 0.987 0.910 0.730 0.447 15.739 F7 0.607 0.917 0.965 0.924 0.867 0.424 16.934 F8 0.651 0.841 0.779 0.928 0.800 0.398 13.390 F9 0.649 0.843 0.952 0.904 0.901 0.387 18.349

Scanning Electron Microscopy

The scanning electron microscopic (SEM ) evaluation is important for determining the surface morphology, size, shape. Surface of

pellets as shown in SEM photograph was smooth and spherocity was also good and size of pellets was found to be 968 μm to 1003 μm and ratio of length to width (Aspect ratio) is 1.03 which indicates pellets are spherical in shape.

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Fig. 6: SEM analysis of optimized F3 batch

ANOVA Study

Evaluation and interpretation of research findings are of utmost importance and the p-value serves a valuable purpose in these findings. Table 12 and 13 shows ANOVA for the dependent variables Q2 and Q24 respectively. The coefficients of X1 and X2 were found to be significant at p<0.05 Hence, it confirms the significant effect of both the variables on the selected responses. Overall both the variables caused significant changes in the responses. ANOVA and Multiple regression analysis were done using Stat-Ease Design Expert 8.0.1 software.

Response surface plot

The Linear and Quadratic models obtained from the regression analysis was used to build a 3-D graphs in which the responses were represented by Sloped surface as a function of independent variables. The relationship between the response and independent variables can be directly visualized from the response surface plots. The response surface plots were generated using Design Expert 8.0.1 software presented in Fig 7 and 8 to observe the effects of independent variables on the response studied such as Q2 and Q24 respectively.

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Table12: Analysis of Variance for Q2

Source Sum of Squares Degrees of Freedom Mean Square F Value P Value Model Significant/Non significant Model 44.98208 2 22.49104 10.23441 0.0116 A-HPMC K100MLVCR 23.24602 1 23.24602 10.57796 0.0174 Significant B-PEG 400 21.73607 1 21.73607 9.890866 0.0199 Residual 13.18554 6 2.19759 Cor Total 58.16762 8

Table 131: Analysis of Variance for Q24

Source Sum of Squares Degrees of Freedom Mean Square F Value P Value Model Significant/Non significant Model 278.68 5 55.74 180.14 0.0006 A-HPMC K100MLVCR 172.48 1 172.48 557.47 0.0002 B-PEG 400 76.97 1 76.97 248.77 0.0006 AB 3.01 1 3.01 9.73 0.0525 Significant A^2 24.9 1 24.9 80.47 0.0029 B^2 1.32 1 1.32 4.26 0.131 Residual 0.93 3 0.31 Cor Total 279.61 8

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Fig. 7: Response Surface Plot for Q2

Design-Expert® SoftwareFactor Coding: ActualQ2

Design points above predicted valueDesign points below predicted value24.43

16.32

X1 = A: HPMC K100MLVCRX2 = B: PEG 400

1.00

1.50

2.00

2.50

3.00

11.00

11.60

12.20

12.80

13.40

14.00

16

18

20

22

24

26

Q

2

A: HPMC K100MLVCR B: PEG 400

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Fig. 8: Response Surface Plot for Q24

Optimization (Model validation)

The formulation OF3 was prepared for the model validation. The Q2 and Q24 were evaluated and found within the limits. The Solutions for the numerical optimization of Extrusion Spheronization process

are given in Table 14. The values of responses predicted from the obtained model are shown in Table 15 along with the results obtained by experimentation. The closer resemblance between observed and predicted response values indicates the validity of the generated model.

Table 14: Solutions for Numerical Optimization of Dissolution Study

S. No.

HPMC K100M LVCR (%)

PEG 400 (%)

Q2 (%) Q24 (%) Desirability

1 11.01 2.57 24.60 97.98 0.9431 Selected 2 11.51 1.74 20.24 95.57 0.8274 3 13.85 1.08 28.96 100.36 0.8151

Table 15: Comparison of Predicted and Experimental Values

Responses OF3 Predicted Experimental

Q2 (%) 24.60 25.45 Q16 (%) 82.89 85.38 Q24 (%) 97.98 98.32 [

CONCLUSION

A sustained released matrix pellets of Aceclofenac was formulated. The prepared pellets were optimized for parameters like Flow Properties, Morphological characteristics, Particle Size Analysis, Drug Content and Drug Released. The formulation having composition as HPMC K100M LVCR 11 % and PEG 400 3 % was selected as optimised. The evaluated parameters of optimised batch were found to be within the limits. Drug release of optimized batch (F3) at 2 hr was found to be less than 30 % (25.43 %) and at 24 hr more than 80 %( 98.32%). The results showed that combination of HPMC K100M LVCR as hydrophilic matrix polymer and PEG 400 as potential plasticizer is effective and useful for sustaining the Aceclofenac release and Extrusion-Spheronization technique was promising approach for the preparation of a sustained release Aceclofenac pellets which can be also used on large scale.

ACKNOWLEDGEMENT

The authors are grateful to Flamingo Pharmaceutical Ltd. (Mumbai, India) for kind gift sample of Aceclofenac. Further, we extend our thanks to Colorcon Asia Pvt. Ltd, (Mumbai, India) Signet chemical corporation, (Mumbai, India) and Merck (Mumbai, India) and AICTE for financial assistance.

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Design-Expert® SoftwareFactor Coding: ActualQ24

Design points above predicted valueDesign points below predicted value97.92

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X1 = A: HPMC K100MLVCRX2 = B: PEG 400

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B: PEG 400

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