Formulation and In-Vitro evaluation of Aceclofenac Controlled release tablets by wet granulation method and solid dispersion technique
T. Venkateswara Rao, Dr. S. Vidyadhara and Dr. K.R.S. Sambasivarao
Department of Pharmaceutics, Bapatla College of Pharmacy, Bapatla, Guntur (Dt.), Andhra Pradesh.
Dept. of Pharmaceutics, Chebrolu Hanumaiah College of Pharmaceutical Sciences, Guntur , Andhra Pradesh.
Dept. of Biotechnology, Acharya Nagarjuna University, Guntur, Andhra Pradesh.
*Corresponding Author E-mail: tv_rao2@yahoo.com
ABSTRACT:
The objective of the present study was to develop controlled release matrix tablets of Aceclofenac by wet granulation method and solid dispersion technique using Eudragit RL100 as a rate controlled material. Drug-excipient computability studies were conducted by FT-IR and DSC, results showed no chemical interaction was observed between drug and excipient. The granules were evaluated found free flow properties. The tablets were subjected to thickness, hardness, friability weight variation and in-vitro drug release studies. Results of in vitro drug release studies revealed that drug release was controlled for 12hrs prepared by wet granulation method over the formulations by solid dispersion technique. The drug release pattern followed zero order kinetics and the mechanism of drug release was governed by peppas model. The ‘n’ values were found to be more than 1 (n>1) which indicated that the drug release was predominately controlled by super case II diffusion.
KEYWORDS: Aceclofenac, Eudragit RL100 (ERL), solid dispersion, wet granulation, controlled release tablets.
INTRODUCTION:
Aceclofenac is a Non-steroidal anti inflammatory drug useful in the treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondyltis1, 2. The maintenance of effective drug concentration level in the body for a constant and uniform supply of drug, it desired in the form of a controlled release tablets. It is rapidly and effectively absorbed after oral administration but has short biological half life of 4 hr.3
A controlled release dosage form may be formulated to provide drug for an immediate release as well as gradual and continuous release of remaining doses for extended period of time.4,5 The technique of solid dispersion in which a drug is incorporated into an inert carrier or matrix has been extensively used to enhance the dissolution of poorly water soluble drugs.
Hydrophobic polymers provide several advantages ranging from good stability at varying pH values and moisture levels to established safe applications. Eudragit RL100 is a hydrophobic polymer and is used extensively as a coating material and in the preparation of matrix type controlled release tablets.6
There are only a few reported on controlled released solid dispersion or matrix type wet granulated tablets that employ Eudragit RL100 as a rate controlling polymer.7, 8
In the present work a controlled release formulation of Aceclofenac formulated by solid dispersion technique and wet granulation method by using Eudragit RL 100 as rate controlling polymer. The effect of polymer concentration and effect of different manufacturing processes i.e. solid dispersion technique and wet granulation method were studied.
MATERIALS AND METHODS:
Materials:
Aceclofenac, Eudragit RL100 and Aerosil were gift samples from M/s Seeko Biotech Ltd, Vijayawada. Lactose (anhydrous), ethanol and magnesium stearate were purchased from S.D. Fine Chemicals, Mumbai.
Methods:
Preformulation studies:
Compatibility studies in between Aceclofenac and Eudragit RL 100 were studied by FT-IR and DSC.
FT-IR Spectroscopic studies:
Fourier-Transformed Infrared (FT –IR) spectra were obtained on a thermo Nicolet nexus 670 FT- IR system using the KBr disc method. The spectrum was recorded in the wavelength region of 4000 to 400cm-1 .
Differential Scanning Calorimetry:
Differential scanning calorimetric was performed for Aceclofenac, Eudragit RL 100 and its physical mixtures by using SIIO 6300-Japan.DSC Thermogram recorded at Heating rate 50o c /min over a temperature range of 0 to 350oC. The samples was hermetically sealed in a aluminum crucibles and heated. Nitrogen gas was purged at the rate of 100ml/min for maintaining inert atmosphere. The heat flows as a function of temperature was measured for the drug-polymer mixture.
Preparation of Tablets by Solid dispersions9:
Required quantity of Aceclofenac (55.55%w/w) and Eudragit RL100(3-9%w/w) were transferred into a beaker, ethanol was added to the beaker and stirred for 15min until dissolved. Lactose as diluent to maintain the total tablet weight was 360mg was then added and mixed for 10min. The beaker containing the dispersion was then incubated at 400c for complete evaporation of the solvent. After evaporation of the solvent, the mass was passed through sieve no.10. The obtained granules were then dried in an oven at 400c for 2hrs. The dried granules were passed through sieve no.12. Magnesium stearate (1%w/w)and Aerosil (1%w/w) were added to the above mass and blended for 2min. The final blend was then compressed into tablets by using a single punch tablet compression machine (Cad mach, Ahmadabad, India) using 9mm punches and dies.
Preparation of Tablets by Wet Granulation Method:
Required amount of Aceclofenac (55.55%w/w), Eudragit RL100 (3-9%w/w) and lactose as diluent to maintain the total tablet weight was 360mg were geometrically mixed. Sufficient quantity of ethanol was added to get uniform wet mass. sieve no.10 was used for granulation , obtained granules were kept for drying for 2 hrs in hot air oven at 400C. The dried granules were again passed through sieve No.12. To the obtained granules Magnesium stearate (1%w/w) and Aerosil (1%w/w) were added and subjected to compressed into tablets by single station compression machine (Cadmach, Ahmedabad, India) using 9mm punches and dies.
Evaluation of granules;
The granule parameters like angle of repose, bulk density (tapped and untapped), compressibility index and Hausner’s ratio were evaluated by the following:
Angle of Repose10:
The flow characteristics of different granules were studied by measuring the angle of repose employing fixed funnel method. The angle of repose was calculated by using the following formula.
Where, h = height of pile , cm
r = radius of the base of the pile, cm
θ = angle of repose.
Bulk Density11 :
Apparent bulk density (gm/ml) is determined by pouring granules in to a graduated cylinder and measured the volume , from weight and volume intial bulk density was calculated . Tapped bulk density was measured by placing a graduated cylinder on a mechanical tapper apparatus operated for 100 taps. The intial bulk and tapped bulk density calculated by the following equations.
Carr’s Index12 and Hausner’s ratio13;
Carr’s index and Hausner ratio were determined from the tapped and bulk densities of a known weight of samples using a bulk density apparatus. The following formulas were used for calculating Carr’s index and Hausner’s ratio:
Evaluation of tablets:
Thickness 14
The thickness of the tablets was determined by using Vernier calipers. Five tablets from each batch were used, and average values were calculated.
Hardness15
Hardness of the tablet was determined by using the Monsanto harness tester. The lower plunger was placed in constant with the tablet and zero reading was taken. The plunger was then forced against a spring by tuning a threaded bolt until the tablet fractured. As the spring was compressed a pointer rides along a gauge in the barrel to indicate the force.
Friability16
The Roche friability test apparatus was used to determine the friability of the tablets. 20 pre-weighed tablets were placed in the apparatus, operated for 100 revaluations. Then the tablets were reweighed, percentage friability was calculated according to the following formula.
Friability (%) =
Initial weight of tablets – final weight of tablets
-----------------------------------------------------X100
Initial weight of tablets
Table: 1 Evaluations of Granules Prepared by Wet Granulation Method and Solid Dispersions
|
Formulations code |
Angle of repose ( q) |
Loose bulk density (g/ml) |
Tapped bulk density (g/ml) |
Compressibility index (%) |
Hausner’s ratio |
|
F1 |
18.42±0.02 |
0.57±0.010 |
0.64±0.02 |
10.00±0.06 |
1.11±0.01 |
|
F2 |
21.35±0.03 |
0.58±0.016 |
0.65±0.01 |
10.09±0.05 |
1.11±0.02 |
|
F3 |
23.73±0.01 |
0.54±0.067 |
0.62±0.05 |
9.03±0.06 |
1.09±0.07 |
|
F4 |
25.18±0.01 |
0.55±0.071 |
0.62±0.06 |
8.29±0.08 |
1.09±0.07 |
|
F5 |
19.09±0.02 |
0.45±0.013 |
0.48±0.05 |
5.56±0.01 |
1.059±0.06 |
|
F6 |
23.74±0.01 |
0.46±0.014 |
0.49±0.07 |
5.48±0.01 |
1.058±0.05 |
|
F7 |
24.76±0.01 |
0.44±0.032 |
0.46±0.028 |
5.33±0.02 |
1.056±0.34 |
|
F8 |
26.55±0.01 |
0.43±0.034 |
0.45±0.018 |
5.20±0.02 |
1.055±0.04 |
All values are expressed as Mean± S.d, n=3.
Table: 2 Evaluations of Tablets Prepared by Wet Granulation Method and Solid Dispersions
|
Formulation code |
Thickness* (mm) |
Hardness* (kg/cm2) |
Friability** (%) |
Weight variation *** (%) |
Drug content* (%) |
|
F1 |
3.75±0.01 |
4.6 ±0.13 |
0.58 ±0.05 |
2.249±0.02 |
99.38±0.13 |
|
F2 |
3.71±0.01 |
4.8 ±0.21 |
0.64 ±0.06 |
2.950±0.02 |
98.38±0.08 |
|
F3 |
3.69±0.02 |
4.1 ±0.22 |
0.78 ±0.06 |
3.099±0.07 |
97.38±0.07 |
|
F4 |
3.66±0.01 |
4.3 ±0.24 |
0.69 ±0.04 |
3.234±0.01 |
95.44±0.12 |
|
F5 |
3.71±0.02 |
4.6 ±0.10 |
0.65±0.01 |
4.08±0.06 |
98.55±0.17 |
|
F6 |
3.69±0.04 |
4.1 ±0.22 |
0.73±0.02 |
4.16±0.08 |
97.62±0.12 |
|
F7 |
3.69±0.03 |
4.9 ±0.20 |
0.82±0.03 |
3.23±0.06 |
98.96±0.03 |
|
F8 |
3.68±0.02 |
4.2 ±0.13 |
0.61±0.03 |
2.22±0.02 |
99.12±0.14 |
All values are expressed as Mean± S.d; * n=3;
Fig 1: IR spectra of Aceclofenac
Fig 2: IR spectra of Eudragit RL 100
Fig 3: IR spectra of Aceclofenac-eudragit RL100 physical mixture
Fig 4: DSC Thermogram of Aceclofenac
Fig 5: DSC Thermogram of Aceclofenac-Eudragit RL 100 physical mixture
Weight Variation Test :
The formulated tablets were tested for weight uniformity, 20 tablets were weighed collectively and individually. From the collective weight, average weight was calculated. Each tablet weight was then compared with average weight to ascertain whether it is within permissible limits. The following formula was used to calculate % weight variation.
Average Weight–Individual weight
%Weight variation= ----------------------------------------X100
Intial weight of tablets
Fig6:Dissolution Profiles of Aceclofenac Tablets Prepared with Eudragit RL100 by Solid Dispersions
Fig7: Dissolution Profiles of Aceclofenac Tablets Prepared With Eudragit RL100 by Wet Granulation Method
Drug Content
Twenty tablets of each formulation were collected, weighed and powdered. Powder equivalent to 100mg of Aceclofenac was weighed dissolved in 5ml of methanol and diluted with 6.8 phosphate buffer. It was allowed to sonication for 15min. The solution was filtered and the absorbance was measured after serial dilutions by using Shimadzu UV spectrophotometer at 275nm.
In Vitro Dissolution Studies17:
The in vitro dissolution study was carried out by using USP Type II dissolution apparatus. The study was carried out in 900 ml of 2% w/v of SLS in 0.1N HCL for first 2 hours and next 3 to 12 hrs in 900 ml of phosphate buffer (pH 6.8). The dissolution medium was kept in thermostatically controlled water bath, maintained at 37±0.50C. The formulated tablet was then introduced into the dissolution jar and the paddle was rotated at 75 rpm. At different time intervals, 5 ml sample was withdrawn and 5 ml of fresh dissolution medium was replaced into the dissolution flask. The samples were collected for 12hr, analyzed by using spectrophotometer at 275 nm.
X -Ray diffraction studies:
X ray diffraction pattern of Aceclofenac, eudragit RL 100 and tablets were recorded by x ray diffract meter (Shimadzu, XRD- 7000 Maxima). The voltage at 45kv, current at 40mA were maintained the XG conditions, sample powder placed on the sample holder pack and smoothen its surface with a polished glass microscope slide, scanned in the 2θ angle range of 2.5000-50.0000(deg) under the following conditions. CU(1.54060 A),SLIT DS 1.00 degusted size 1.0170 discount time 0.51 sec ,RS 0.15mm and scan speed 2.0 deg/min.
RESULTS AND DISCUSSION:
IR spectrum of Aceclofenac, eudragit RL100and its physical mixtures were shown in fig 1,2 and 3. The following peaks were observed, 3366.16cm-1 (-OH stretching), 1711.51cm-1 (C=0 stretching), 1261.22 cm-1 acid peak (C-O stretching), 1152.26 cm-1 ester peak ( C-O stretching) and 851.14cm-1 (C-C1 stretching).
DSC thermo grams of Aceclofenac and Aceclofenac with eudragit RL100 were showed in fig 4&5. The DSC scan of Aceclofenac showed endothermic peak at 155.3ºc corresponding to its melting point. DSC Thermogram of Aceclofenac tablets formulated with Eudragit RL100 showed on endothermic peak at153.2ºc. and 155.5ºC. No changes were observed in the endothermic peaks of Aceclofenac mixed with eudragit RL100, when compared with Aceclofenac endothermic peaks. These interaction studies were further supported by FT-IR spectral analysis studies. Results showed that, no chemical interaction between the drug and polymers. Hence, these polymers were selected and developed as oral controlled release formulations of Aceclofenac tablets.
The results of evaluation parameters for granules shown in table-1. The results of angle of repose (between 20-30%) indicate good flow properties; this was further supported for lower compressibility index values and Hausner’s ratio. All these results indicated that the granules have free flowing nature. The formulations have uniform thickness and passed the test for uniformity of weight as per official requirements. Good uniformity in drug content was found among different formulations and was more than 98 %. The values of Hardness and friability of the tablets were found to be with in the limits of tablets stated in the I.P as reported in table-2
In-Vitro dissolution studies were carried out at different media: medium 0.1 N HCl with 2%w/v SLS for first 2hr and next 3-12 hr with phosphate buffer pH 6.8. The dissolution profiles for tablets were depicted in fig-6,7. Formulations (F7) made from wet granulation method controlled the release for 12hrs,further increasing the concentration from 7-9%w/w of eudragit RL100 the drug release rate was retarded..
Fig 8 : X-ray difracto gram of Aceclofenac
Fig 9: X-ray difractogram of Aceclofenac with Eudragit RL100 tablets
The formulations made by solid dispersion technique release the whole amount of drug with in 10 hrs. this would may be the entrapment of polymer in solid dispersions.
Drug release kinetics were investigated by fitting the dissolution data to a zero order, first order, matrix and Peppas. The release of drug from tablets obeyed zero order kinetics and Peppas mechanism. Diffusion exponent of release profiles (slope) has a value for n>1, which indicates drug release was predominately controlled by super case II transport diffusion. The result showed that tablets made by the wet granulation method requires lower amount of polymer than solid dispersion technique to produce a similar release profile.
XRD patterns of Aceclofenac and tablet with eudragit RL100 peak intensities of 142, 862, 134 at 8.48, 224, 121, 138 at 9.99, 2Ɵ scattered angles as fig8. Similarly XRD peaks of tablet prepared with Eudragit RL100 were also measured at 2Ɵ scattered angle and the corresponding linear counts were 180, 140, 150, 158, 116, 113 at 8.48, 9.99, 20.87 2Ɵ scattered angles as fig 9. X-ray diffraction patterns showed that the polymorphic transition does not occurred in final formulations.
CONCLUSION:
Eudragit RL 100 can be used successfully to formulate controlled release Aceclofenac tablets. Both methods i.e. wet granulation and solid dispersions were found relatively more efficient in preparing Aceclofenac controlled release tablets using Eudragit RL 100 as rate controlling polymer due to more efficient drug trapping in the tablet matrix.
ACKNOWLEDGEMENTS:
The authors thankful to the Dr. Reddy’s Laboratories, Hyderabad, India for providing drug sample and Bapatla College of Pharmacy for providing necessary requirements.
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Received on 10.01.2012 Modified on 10.02.2012
Accepted on 21.02.2012 © RJPT All right reserved
Research J. Pharm. and Tech. 5(4): April 2012; Page 505-512