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FORMULATION AND EVALUATION OF SOLID DISPERSION OF ACECLOFENAC

MOHAMMED GULZAR AHMED*, KIRAN KUMAR GB, SATISH KUMAR BP and HARISH AR Dept of Pharmaceutics, Sri Adichunchanagiri College of Pharmacy, BG Nagar, India.

ABSTRACT The present study is aimed at improving the dissolution of poorly water-soluble drug, aceclofenac. It is very slightly soluble in water and hence orally administered drug is less bioavailable. In order to enhance the bioavailability it is necessary to improve its solubility, hence the solid dispersion technique was adopted to enhance solubility. The solid dispersions were prepared in different proportions using hydrophilic carriers like Urea and Mannitol. The dissolution rate studies were performed in both simulated gastric fluid and simulated intestinal fluid. It is observed that the dissolution was affected by the acidity of the medium. Solid dispersions gave faster dissolution rate when compared to corresponding physical mixture and pure drug. In vivo absorption and anti-inflammatory activity studies of solid dispersions also confirmed the above results. The FTIR and DSC studies revealed that there is no interaction between drug and carriers and the drug, aceclofenac is stable in solid dispersions. Key words: Aceclofenac, Anti-inflammatory, Carriers, Solid Dispersion, Dissolution

INTRODUCTION Aceclofenac is a new generational non-steroidal anti-inflammatory drug showing effective antiinflammatory and analgesic properties and a good tolerability profile in a variety of painful conditions like ankylosing spondylitis, osteoarthritis and rheumatoid arthritis. Aceclofenac is very slightly soluble in water and its bioavailability is also poor.
[1]

subjected to compatibility studies. In vitro dissolution rate studies were carried out and the results were reported. MATERIALS AND METHODS Aceclofenac was obtained as gift sample from IPCA Laboratories, Mumbai. Urea and Mannitol were of IP grade. All other chemicals were of analytical grade. Preparation of solid dispersions and physical mixtures: Solid dispersions of aceclofenac were prepared with carriers (urea and mannitol) in in1:0.5, 1:1 and 1:2 weight ratios by fusion method by the procedure given below
[3].

There are many

methods to enhance the bioavailability of poorly soluble drugs, in that Solid dispersion is also a unique technique
[2].

In solid dispersion method the drug is dispersed in

fine state in an inert water-soluble carrier in solid state. Many of the highly water soluble materials such as bile acids, citric acid, sterols etc., and polymers like Polyvinylpyrrolidone and Polyethylene glycols are used as carriers for solid dispersions[2]. The present investigation was carried out with a view to evaluate the feasibility of using urea and mannitol as hydrophilic carriers in the preparation of solid dispersions of aceclofenac. The prepared solid dispersions were

A weighed quantity of carriers (urea or

mannitol) and aceclofenac were mixed thoroughly and the mixture was subjected to thermal fusion with constant stirring. Then the melt was shock cooled on an ice cooled ceramic tile. The solid mass formed was powdered and kept in desiccator for 48 hours. It was then passed through sieve (No:100 ) and stored in airtight container for further studies [4].

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The physical mixtures were prepared by manually mixing pre-weighed amounts of sieved fractions of aceclofenac and carriers (urea, and mannitol) in1:0.5, 1:1 and 1:2 ratio. Four batches of aceclofenac: carriers (urea and mannitol) in different ratios as stated above were prepared in similar manner [4]. EVALUATION TESTS The physicochemical characterization, percentage yield and drug content were estimated. Compatibility of the drug and carriers was confirmed by comparing the IR spectra and DSC thermograms taken separately for the drug, carriers and solid dispersions. Drug content: Solid dispersion equivalent to 10mg of drug was accurately weighed and dissolved in 100ml methanol, from that 1ml of solution was diluted to 10ml and assayed for drug content by spectrophotometeric method[5]. Particle size analysis: The prepared formulations were evaluated for particle size distribution and average diameter by optical microcopy. Small quantity of the formulation was dispersed using liquid paraffin and spread into a thin film on a microscopic slide. Particles were observed under high power (45 ) and the size of randomly selected 150 particles from different locations were measured and average size of the particles was calculated [6].

Table 1: Characterization of Solid Dispersions Drug content ( g/ml) Carrier Drug: carrier 1:0.5 1:1 1:2 Mannitol 1:0.5 1:1 1:2 Theoretical value 10 10 10 10 10 10 Drug content 9.6 9.9 9.8 9.7 9.9 9.8 % Yield Average particle size ( m) 60 71 55 64 65 53 % Moisture absorption Ambient conditions (70% RH, 28 C) 4.3 8.7 19.8 0.8 0.3 0.9 Accelerated humidity conditions (99% RH, 28 C) 32.1 46.5 74.5 1.8 1.9 2.5

Urea

94.5 95.4 93.8 96.5 95.4 96.2

Moisture absorption studies The moisture absorption studies were carried out by drying solid dispersions under anhydrous calcium chloride and exposed to ambient atmospheric conditions and accelerated humidity condition (99%RH) for 2 days. The gain in their weight was determined and the percentage moisture absorbed was calculated [7]. The results of the above tests were given in table-1.

simulated gastric fluid (pH1.2) for 2 hours and simulated intestinal fluid (pH 7.4) for 2and 8 hours separately (50rpm at 37 0.5 C). Powdered samples (pure drug/ physical mixture/ solid dispersion) equivalent to 100 mg of aceclofenac were filled into a capsule and taken into the basket of the dissolution test apparatus. 5 ml samples were withdrawn at different time intervals, diluted appropriately and absorbance was measured at 275nm and the amount of aceclofenac was calculated [8]. The results are given in table-2 and 3 and fig-1 and 2.

In vitro dissolution study:

Dissolution studies were performed using USP XXI basket type dissolution test apparatus in 900ml of

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Table 2: Dissolution Studies of Solid Dispersions in Simulated Gastric fluid Carriers Drug : Carrier Pure drug 1:0 Urea 1:0.5 1:1 1:2 1:0 Mannitol 1:0.5 1:1 1:2 14.9 14.9 Percent release at 2hr. Physical mixture 15.20 17.10 18.21 16.19 19.29 23.67 Solid dispersion 18.32 29.43 34.33 23.92 32.81 44.13

50 45 40 Percent dru release 35 30 25 20 15 10 5 0 01:00 01:00.5 01:01 01:02

Pure drug Physical mixture(Urea) Solid dispersion(Urea)

Physical mixture (Mannitol) Solid dispersion (Mannitol)

Drug: Carrier ratio

Figure 1: Dissolution Profile of Solid Dispersions in Simulated Gastric fluid at 2 hours

In situ rat gut technique:

Comparison of extent of intestinal absorption of drug from a selected solid dispersion, which gave good in vitro release performance and pure drug, was performed using in situ rat gut technique. It was carried out by introducing a suspension of selected solid dispersion containing 100mg of drug and 100mg

of pure drug in 10ml of sodium CMC into the rat intestine. Samples of 0.1ml were withdrawn at predetermined intervals up to 8 hours
[9].

The collected

samples were analyzed spectrophotometrically at 275nm. The studies were performed in three trials and mean values were taken. The results obtained for pure drug and the solid dispersion were compared.

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45 40 Percent drug release 35 30 25 20 15 10 5 0 01:00 01:00.5 01:01 01:02 Physical mixture(Urea) Pure drug

Solid dispersion(Urea)
Physical mixture (Mannitol) Solid dispersion (Mannitol)

Drug:carrier ratio Figure 2: Dissolution Profile of Solid Dispersions in Simulated Intestinal fluid at 2 hours

Anti-inflammatory activity: Anti-inflammatory activity was studied by paw edema method8 using rats as test animals. The animals were divided into 3 groups, each containing 6 animals. First group was served as control for which 0.5% of sodium CMC suspensions, for second group, suspension of pure drug in 0.5% sodium CMC and for last group

the suspension of selected solid dispersion in 0.5% sodium CMC were administered orally. The inflammation was induced by administering 0.1% w/v carrageenan by sub plantar route. Percent reduction in the oedema produce in the paw of the rats in each group was determined for the evaluation of inflammatory activity[10]. anti-

Table 3: Dissolution Studies of Solid Dispersions in Simulated Intestinal Fluid Percentage release of drug Carriers Drug: Carrier Pure drug 1:0 1:0.5 Urea 1:1 1:2 1:0 1:0.5 Mannitol 1:1 1:2 10.9 10.9 2 hours Physical mixture 10.3 11.1 11.4 9.9 13.5 14.1 Solid dispersion 16.4 22.1 24.25 20.2 28.4 39.6 Pure drug 26.4 26.4 8hours Physical mixture 13.1 16.5 18.3 14.6 17.4 21.4 Solid dispersion 30.4 37.1 44.3 46.2 50.9 55.3

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60 50 Percent drug release 40 30 20 10 0 01:00 01:00.5 01:01 01:02 Physical mixture(Urea) Pure drug

Solid dispersion(Urea)
Physical mixture (Mannitol) Solid dispersion (Mannitol)

Drug:Carrier ratio Figure 3: Dissolution Profile of Solid Dispersions in Simulated Intestinal fluid at 8 hours

RESULTS AND DISCUSSIONS: IR spectra taken for pure drug, carriers and solid dispersions have not produced any extra peaks than that is characteristic for the compounds under study. These studies revealed that the drug is compatible with mannitol and urea. DSC thermograms produced the peaks corresponding to the melting point of the component present in the solid dispersions, confirms that the solid dispersions are stable and absence of any additional peaks indicates no interaction between the drug and carrier. All the solid dispersions were found to be free flowing under dry conditions. Percentage yield of solid dispersions with reference to the weight ranged between 95-98%. Percentage drug content in different batches of solid dispersions was found to be in confirmation with the theoretically calculated values, which indicate the reliability of the analytical method used. Low values of standard deviation in % drug content indicate the reproducibility of the method. The particle size of solid dispersions with urea and mannitol ranged from 5-150 and the average diameter was to 70 . The

solid dispersions prepared with urea as carrier as compared to mannitol (Table-1). Studies on Insitu rat-gut technique revealed that the extent of intestinal absorption was more in solid dispersions with mannitol as carrier in comparison to the pure drug. The first-order rate constant obtained for the pure drug was less (0.004min-1), as compared to that of solid dispersion with mannitol 1:2 (0.011min-1). Comparison of results obtained from dissolution studies for aceclofenac, physical mixture of aceclofenac and carriers and solid dispersions of aceclofenac with same carriers have shown that the dissolution rates are in the order solid dispersion > physical mixture > aceclofenac (Table 2 and 3). The increased solubility of solid dispersion is due to reduction in the particle size and/or the presence of drug in the form of solid solution in a water-soluble carrier in molecular form. Greater solubility of physical mixture than the pure drug can be attributed to the wetting of hydrophobic surface of aceclofenac due to solubilization of water-soluble carrier (Figure-1). In the above studies solid dispersions with 1:2 of drug carrier found to give higher dissolution rate than the others. Maximum release rate was found out with solid dispersions prepared with mannitol (1:2). The enhancement of dissolution rate

found out to be in the range of 50

hygroscopic studies revealed that the tendency of moisture absorption was found to be more with the

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may be due to increase in the effective surface area made available to the dissolution media. Further it may be attributed that the use of water-soluble carriers improves the wet ability of the drug particles and hence high dissolution rate (Figure 2 and 3). Stability of solid dispersions is also confirmed from the IR spectra obtained for solid dispersions of aceclofenac. The spectra have shown the characteristic peaks corresponding to the drug and carriers used. The in vivo performance of selected solid dispersions systems showed the higher intestinal absorption along with excellent anti-inflammatory The authors wish to thank IPCA Laboratories, Mumbai, for the gift sample of acecofenac and to Indian Institute of Sciences, Bangalore for the IR spectral analysis and thermal analysis. activity. Studies on anti-inflammatory activity revealed that the percentage inhibition of oedema with solid dispersions is more (43.2%) in comparison to the pure drug (31.5%).The enhanced biological activities of solid dispersions were due to its enhanced dissolution rate of drug from solid dispersion system. ACKNOWLEDGEMENT

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High Street, London SEI7JN,UK,570-571. 2. Chiou W.L . and Riegelman S. J 1971; 60: 1281-1302. 3. Swarbrick James, Boylan C. James, Encyclopedia of Pharmaceutical Technology, Vol. 3, Marcel Dekker INC, 270 Madison Avenue, New York, 1990, 337-338.

Pharm Sci.

ADDRESS FOR CORRESPONDENCE: mohammedgulzar@rediffmail.com

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