Asian Journal of Pharmaceutics
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RESEARCH ARTICLE Table of Contents   
Year : 2008  |  Volume : 2  |  Issue : 2  |  Page : 110-115
Preparation and characterization of aceclofenac microspheres


1 Institute of Pharmacy, Bundelkhand University, Jhansi, Uttar Pradesh, India
2 SOS Pharmaceutical Sciences, Jiwaji University, Gwalior, Madhya Pradesh, India

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   Abstract 

The objective of the present study was to microencapsulate the anti-inflammatory drug (aceclofenac) to provide controlled release and minimizing or eliminating local side effect by avoiding the drug release in the upper gastrointestinal track. The drug was targeted to the colon and their aligned area for their local effect. Aceclofenac was microencapsulated with Eudragit (S 100, RL 100, and RS 100), using an O/W emulsion-solvent evaporation technique. Aceclofenac microspheres were subjected to micromeritic properties including angle of repose, bulk density, tapped density, Carr's index, Hausner's ratio, and particle size determination. Microspheres were subjected to drug loading, in vitro drug release as well as for scanning electron microscopy. The prepared microspheres were white, free-flowing, and almost spherical in shape. The drug-loaded microspheres show 60-82% drug entrapment, angle of repose was in the range of 16.13 0.621-24 0.590, bulk and tapped densities respectively were in the range of 0.311 0.006-0.562 0.012 and 0.373 0.01-0.735 0.02, Carr's index ranges from 14.04 0.026 to 27.25 1.405, Hausner's ratio was 1.14 0.026-1.37 0.03, and particle size was in the range of 79.7016-144.840 m. In vitro drug release studies were carried out up to 24 h in three different pH media, i.e., 0.1 N HCl (pH 1.2), phosphate buffer (pH 6.8), and phosphate buffer (pH 7.4). The drug-polymer concentration of dispersed phase influences the particle size and drug release properties. All the formulations at higher pH were followed by the Matrix-Higuchi model.

Keywords: Aceclofenac, Eudragit (S100, RL100, RS 100), microsphere, release kinetics, solvent evaporation

How to cite this article:
Trivedi P, Verma A, Garud N. Preparation and characterization of aceclofenac microspheres. Asian J Pharm 2008;2:110-5

How to cite this URL:
Trivedi P, Verma A, Garud N. Preparation and characterization of aceclofenac microspheres. Asian J Pharm [serial online] 2008 [cited 2014 Oct 23];2:110-5. Available from: http://www.asiapharmaceutics.info/text.asp?2008/2/2/110/42498



   Introduction Top


Aceclofenac is non-steroidal anti-inflammatory drug used extensively in the treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. Aceclofenac is one of the emerging NSAID molecules. [1],[2],[3] Aceclofenac is newer derivative of diclofenac and having less GIT complication, the short biological half-life 4 h, and dosing frequency more than are time make it an ideal candidate for modified release multiple unit preparation [1],[4],[5] To reduce the frequency of administrations and to improve patient compliances, aceclofenac is suitable for making sustain release dosage form. [1],[4],[5]

Microencapsulation is useful method for prolonging a drug release from dosage forms and reducing adverse effect [6],[7],[8] among various microencapsulation methods. The emulsion-solvent evaporation can be used to prepare microcapsules of water-insoluble drug with water-insoluble polymer [6],[7],[8] for sustained release system; the oral rate of drug administered has by for received the most attention as it is natural, uncomplicated, convenient, and safer route. [4],[7],[9]

In this present study aceclofenac microspheres were prepared by solvent evaporation technique using Eudragit (S100, RL 100, and RS100) as a release retarded material. [6],[7],[9],[10],[11],[12],[13] Poly vinyl alcohol, chloroform were used for the preparation of microsphere. The prepare microsphere were evaluated for drug content, [9],[10],[15] particle size, [16],[17],[18] micromeritic properties, [4],[11],[15],[18] SEM, [9] and for in vitro drug release studies. [6],[7],[9],[19]


   Materials and Methods Top


Materials

Aceclofenac (Ind-Swift Ltd., Chandigarh), Eudragit RS 100, Eudragit RL 100, Eudragit S100 (Ranbaxy Laboratories Ltd., New Delhi), sodium lauryl sulfate (SLS; CDH, New Delhi), disodium hydrogen phosphate (CDH, New Delhi), chloroform (Merck Ltd., Mumbai), potassium dihydrogen phosphate (CDH, New Delhi), NaOH (Merck Ltd., Mumbai), polyvinyl alcohol (MW = 12500; CDH, New Delhi), methanol (Merck Ltd., Mumbai), HCl (Merck Ltd., Mumbai), sodium chloride (Merck Ltd., Mumbai), and deionized water. All chemicals used in the experiment were of analytical grade and purchased from their respective commercial sources.

Methods

Aceclofenac microspheres were prepared by dissolving the drug in polymer, which was previously dissolved in the chloroform. The resulting solution was added to the aqueous phase containing 0.2% sodium of PVA as an emulsifying agent and the mixture was then agitated using a propeller with the rotation speed 500 rpm. The dispersed drug and Eudragit (S100, RS100, and RL100) were immediately transformed into fine droplets, which subsequently solidified into rigid microspheres due to solvent evaporation. The particles were collected by filtration, washed with dematerialized water, and desiccated at room temperature for 24 h. [4]

Determination of drug entrapments efficiency, drug loading, and yield

Microspheres (25 mg) were suspended in 25 ml of methanol. After 24 hrs, the solution was filtered and the filtrate was analyzed for drug content; this filtrate was diluted up to appropriate dilution; and for the determination of drug entrapment efficiency, the following formulas were used:



Drug loading, yield, and the drug encapsulation efficiency, for batch A1, A2, A3; B1, B2, B3; and C1, C2, C3, are respectively reported in [Table 1]. Each determination was performed in triplicate manner.

Particle size analysis

The particle size of microsphere was determined using optical microscopy method; [11] approximately 100 microspheres were counted for particle size using a calibrated optical microscope (Magnus MLX-DX). Particle size for each formulation ( n = 3) was reported in [Table 2] and [Figure 1].

Micromeritic properties

Angle of repose

Angle of repose of different formulations was measured according to fixed funnel standing method [11] ( n = 3) [Table 2].

θ = tan-1 h / r

where θ is the angle of repose, r is the radius, and h is the height.

Bulk density

Bulk and tapped densities were measured by using 10 ml of graduated cylinder. The sample poured in cylinder was tapped mechanically for 100 times, then tapped volume was noted down and bulk density and tapped density were calculated. Each experiment for micromeritic properties was performed in triplicate manner and reported in [Table 2].

Carr's index

Compressibility index (Ci) or Carr's index value of microparticles was computed according to the following equation:



Hausner's ratio

Hausner's ratio of microparticles was determined by comparing the tapped density to the bulk density using the equation:



Scanning electron microscopy

The microparticles were coated uniformly with gold-palladium by using Sputter coater (POLARON SC-76430), after fixing the sample in individual stabs. All samples were randomly examined for surface morphology of microspheres by using scanning electron microscope (SEM; LIO-430) [Figure 2] and [Figure 3].

In vitro dissolution analysis

In vitro dissolution studies were carried out on the microsphere at 37C (0.5C) at 100 rpm with USP dissolution apparatus II; 100-mg aceclofenac microsphere was place into the dissolution apparatus.

The in vitro dissolution studies were performed at three different pH values: (i) 1.2 pH, i.e., simulated gastric fluid pH; (ii) 6.8 pH, and (iii) 7.4 pH, which is simulated intestinal fluid pH. An accurately weight sample was responded in dissolution media consisting 900 ml of 0.1 N (pH 1.2) HCl containing 0.01% SLS and the dissolution was done for 2 h. At the end of 2 h, the 25.92 g of disodium hydrogen phosphate and 10.305 g potassium dihydrogen phosphate were added to make pH 6.8; the dissolution was done for 4 h. After the total 6 h, add 2.142 g disodium hydrogen phosphate and 0.171 g sodium chloride and change the pH up to 7.4 and after that the study was performed up to 24 h. The sample (5 ml) was withdrawn at each hour interval and replaced with the same volume of test medium and the withdrawn samples were diluted if required and then estimated for aceclofenac concentration at 275 mm spectrophotometrically (Shimadzu Pharmspec UV-1700 series, Japan). Finally, the drug content in all fluid was determined from the calibration curve of aceclofenac to determine the release pattern ( n = 3) [Table 3]; [Figure 4].

Kinetic parameters were also obtained by mathematical processing of drug release data. Evaluation of the influence of formulation variables on release rata constant k values, obtained for different groups of microsphere preparation, was determined by using the PCP Disso v2.08 (Program developed by - Anant Ketkar, Vinay Patil and A.R. Paradkar, Bhartiya Vidyapeeth Deemed University; Pune).


   Result and Discussion Top


Percentage yield, percentage loading, and encapsulation efficiency of aceclofenac microsphere

It was observed that as the polymer ratio in the formulation increases, the product yield also increases. The low percentage yield in some formulation may be due to microspheres lost during the washing process. Percentage yield of all formulations varies from 61% to 91%, the best one is C3 as given in [Table 1]. Theoretical concentration of drug in microsphere was evaluated to be 33.34%, 40%, 50% w/v, respectively in different formulations. Actual drug loading increases as the theoretical drug loading increases, which is shown in [Table 1]. The amount of drug remaining and available for encapsulation increased as the theoretical drug loading increased. Consequently, the actual drug loading increased. As the molecular weight of the polymer increased, its hydrophobicity increased, leading to better precipitation of polymer at the boundary phase of the droplets.

Morphology

The sustained release microspheres of aceclofenac prepared by solvent evaporation were found to be almost spherical, free-flowing, white or almost white in color.

SEM was performed on the prepared aceclofenac microspheres to access their surface and morphological characteristics as shown in [Figure 2] and [Figure 3]. The presence of uncovered drug crystal on the surface could be attributed to the formation of drug nucleus in the non-stirred layer surrounding the emulsified droplets during solvent evaporation.

Particle size

Here, keeping drug ratio constant and varied polymer ratio as the polymer concentration increases viscosity, which influences the interaction between disperse phase and dispersion medium that affects the size distribution of particle. If there was increase in the amount of polymer concentration, there was increase in relative viscosity so as a result increases in mean particle size [Table 2]; [Figure 1].

Micromeritic properties of aceclofenac microspheres

Angle of repose

All the formulations show angle of repose value in the range of 16.130-24.080, i.e., less than 30 ( n = 3), which shows free-flowing nature of the formed microspheres [Table 2].

Bulk density and tapped density

Bulk and tapped densities showed good packability of the microspheres [Table 2].

Carr's index (Ci)

Carr's index ranges from 14.04% to 27.25%, B2 had lowest Ci index, indicating excellent compressibility [Table 2].

Hausner's ratio

It was ranging from 1.14 to 1.37, i.e., all the preparation showed that they had good flow properties. Upon considering the micromeritic properties of all the formulations, B2 had the best flow property, as it had high angle of repose value (20.250), the lowest Carr's index (14.04%), and Hausner's ratio (1.14) [Table 2].

Drug release behavior

Aceclofenac release from the microsphere was studied for 24 h, i.e., in simulated gastric fluid (pH 1.2, 0.1 N HCl) containing 0.01% SLS for 2 h; in this duration, all the preparation showed negligible drug release. But changing the pH from 1.2 to 6.8 (mixed phosphate buffer), burst release was observed after 4 h. On further changing pH from 6.8 to 7.4 till 24 h, the drug released at constant rate in all these preparation and showed constant release from 12 h.

All the preparation having ratio 1:1 showed good release properties. As the amount of polymer increased, drug release was decreased. This is because smaller the particle size, larger the surface area available for drug release. The drug release from formulation containing Eudragit RS 100 was slow as compared from the formulation containing polymers Eudragit RL 100 and S 100. Eudragit RS 100 is less permeable, because it possesses less quaternary compound than Eudragit RL 100. Both Eudragit RL 100 and Eudragit RS 100 are pH-independent polymers, whereas Eudragit S 100 is pH-dependent polymer, which dissolves above pH 7, but the drug release from Eudragit S 100 was also found at pH 6.8 due to formation of pore and channels and due to swelling of polymer up to some extent [Table 3], [Figure 4].

Release kinetics

The release mechanism of aceclofenac from various formulations was determined by comparing their respective correlation coefficient. It was found that the mechanism of drug release from microspheres was diffusion controlled.

The release patterns of various formulations at pH 7.4:

C1>A1>B1>C2>A3>C3>B2>A2>B3

The drug release from all formulations at higher pH is described by the Matrix-Higuchi model.


   Conclusion Top


Aceclofenac microspheres were prepared successfully by using the solvent evaporation method. Polymer-drug ratio influences the particle size as well as drug release pattern of microsphere.

The yield was high and encapsulation efficiency was good for all the preparation, but was highest for C3 formulation. As the polymer concentration increases, the particle size increases.

The assessment of release kinetic showed that drug release from aceclofenac microspheres followed the Matrix-Higuchi model (diffusion-controlled drug release mechanism).

Initially at gastric medium (pH 1.2), very less release of drug (aceclofenac) from microspheres was found, but at pH 6.8 and pH 7.4, all formulations showed burst release initially and then tend to release at constant rate. As per our aim, formulation does not show release in gastric medium for desired period of time and releases the drug at pH 6.8 and 7.4, which is the pH of colon and their allied areas; the prepared microspheres proved to be good candidate for site-specific drug delivery.


   Acknowledgement Top


We are very thankful to Ind-Swift Ltd. (Chandigarh, India) and Ranbaxy Laboratories Ltd. (New Delhi, India) for generously providing the gift sample of drug aceclofenac and Eudragit polymers.

 
   References Top

1.An article on Aceclofenac 100 mg tables: High in efficacy, Higher in safety by Intas Pharmaceutical ltd.  Back to cited text no. 1    
2.Lay Summary of Aceclofenac 100 mg tablets by MHRA - PAR-PL 04416/0591.  Back to cited text no. 2    
3.Parfitt K. Analgesic Anti inflammatory and antipyretic. In : Reynolds JE, editor. Martindale: The complete drug reference. 32 nd ed. Massachusetts: 1999. p. 2-12.  Back to cited text no. 3    
4.Mutalik S, Naha A, Usha AN, Ranjith AK, Musmade P, Manoj K, et al . Preparations: In-vitro , Preclinical and clinical evaluation of once daily sustained release tablets of Aceclofenac. Arch Pharm Res 2007;30:222-34.  Back to cited text no. 4  [PUBMED]  
5.Yamazaki R, Kawai S, Mizushima Y, Matsuzaki T, Hashimoto S, Yokokura T, et al . A major metabolites of Aceclofenac, 4'-hydroxy Aceclofenac Suppress the production of interstitial pro-collagenase - pro MMP-1 and Pro-stromelysin-1 - Pro MMP-3 by human rheumatoid synovial cells. Inflamm Res 2000;49:133-8.   Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Bolourtchian N, Karimi K, Aboofazel R. Preparation and characterization of Ibuprofen microsphere. J Microencap 2005;22:529-38.  Back to cited text no. 6    
7.Obeidat WM, Price JC. Preparations and evaluation of eudragit S 100 microspheres as pH Sensitive release preparation for Piroxicam and Theophylline using the emulsion-solvent evaporation method. J Microencap 2006;23:195-202.  Back to cited text no. 7    
8.Perumal D, Dangor CM, Alcock RS, Hurbons N, Moopanar KR. Effect of formulation variables on in-vitro drug release and Micromeritic properties of modified release Ibuprofen microspheres. J Microencap 1996;16:475-87.  Back to cited text no. 8    
9.Jain SK, Rai G, Saraf DK, Agrawal GP. The preparation and evaluation of Albendazole microspheres for colonic delivery. Pharma Tech 2004;:66-71.  Back to cited text no. 9    
10.Sahoo SK, Mallick AA, Barik BB, Senapati PC. Formulation and in-vitro evaluation of eudragit microsphere of stavudine. Trop J Pharm Res 2005;4:369-75.  Back to cited text no. 10    
11.Ziyaur R, Kanchan K, Khar RK, Mushir A, Charoo NA, Shamsher AA. Characterization of 5-fluorouracil microsphere for colonic delivery. AAPS Pharm Sci Tech 2006;7:2.  Back to cited text no. 11    
12.Tamilvanan S. BSA effect of production variable on the physical characteristics of Ibuprofen loaded polystyrene microparticles. J Microencap 1999;16:411-8.  Back to cited text no. 12    
13.P formulate excipents - Aspartame Methacrylate - Based coating by Rohm. America, 1-2.  Back to cited text no. 13    
14.Jain D, Panda DK, Majumdar DK, Eudragit S. 100 entrapped insulin microspheres for oral delivery. AAPs Pharm Sci Tech 2005;6:E100-7.  Back to cited text no. 14    
15.Amal H, Kamel EL, AL-Shora DH, El Sayed YM. Formulation and pharmacodynamic evaluation of captopril sustain release microparticles. J Microencap 2006;23:389-404.  Back to cited text no. 15    
16.Patel JK, Patel RP, Amin AF, Patel MM. Formulation and evaluation of Mucoadhesive glipizide microsphere. AAPs Pharm Sci Tech 2005;6:165-78.  Back to cited text no. 16    
17.Milling EL. The theory and practice of industrial pharmacy. In : Lachman L, Liberman HA, editors. 3 rd ed. Mumbai India: Varghese Publishing House; 1991. p. 26-7.  Back to cited text no. 17    
18.Banker G, Anderson R. Tablet. In : Lachman L, Liberman H, Kanig J, editors. The theory and practice of industrial pharmacy. Philadelphia: Lea and Febiger; 1987. p. 317.  Back to cited text no. 18    
19.Liberman HA, Lachman L, Schwartz JB. Pharmaceutical dosage forms: Tablet, 2, New York: Marcel Dekker; 1990. p. 201-43.  Back to cited text no. 19    

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Correspondence Address:
Parul Trivedi
D/o Umesh Dutt Trivedi, 2/156 - Belamarg, Aligarh, Uttar Pradesh
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DOI: 10.4103/0973-8398.42498

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]

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