Aceclofenac Extended Release Matrix Tablets: Formulation and In Vitro Evaluation

 

Suman Katteboina¹* and VSR Chandrasekhar P²

¹Dept. of Pharmaceutics, Bapatla College of Pharmacy, Bapatla, Guntur Dist, Andhra Pradesh, India – 522101.

²Dept. of Pharmaceutics, Hindu College of Pharmacy, Amaravathi road, Guntur, Andhra Pradesh, India – 522002.

*Corresponding Author E-mail:  sumankatteboina5@gmail.com

ABSTRACT:

The objective of the present study was to develop once-daily extended-release matrix tablets of aceclofenac, a non-steroidal anti-inflammatory drug (NSAID) has been indicated for various painful indications, and proved as effective as other NSAIDs with lower indications of gastro-intestinal adverse effects and thus, resulted in a greater compliance with treatment. Natural polymer, xanthan gum was used as matrix former, microcrystalline cellulose (Avicel PH101), dibasic calcium phosphate (DCP) were used as diluents. The matrix tablets were prepared by direct compression, and were subjected to physical characterization and in vitro release studies. The in vitro drug release was carried out using USP apparatus 2 at 100 rpm in 900 ml of 2% SLS acidic dissolution medium (pH 1.2) for 2 hrs, followed by 900 ml alkaline dissolution medium (pH 6.8) for 3-24 hrs. Formulation was optimised on the basis of acceptable tablet properties and in vitro drug release. The results of dissolution studies indicated that formulation F-II (drug to polymer (1:0.3), the most success of the study, exhibited drug release pattern very close to the marketed extended release profile. By applying exponential equation, optimised formula followed korsmeyer-peppas model with non-Fickian anomalous transport mechanism.

 

 

 

INTRODUCTION:

Aceclofenac, 2-[[2-[2-[(2, 6-dichlorophenyl) amino],phenyl] acetyl] oxy] acetic acid, a non-steroidal anti-inflammatory drug (NSAID) has been indicated for various painful indications, and proved as effective as other NSAIDs with lower indications of gastro-intestinal adverse effects and thus, resulted in a greater compliance with treatment.¹ The successful treatment of arthritis depends on the maintenance of effective drug concentration level in the body for which a constant and uniform supply of drug is desired.² Extended release dosage forms deliver the drug at a slow release rate over an extended period of time and achieve this objective. It’s short biological half life (4 hours) that calls for frequent daily dosing (3 to 4 times). The development of extended release formulations of aceclofenac is therefore therapeutic relevance and can be used to provide a consistent dosage through extending an appropriate level of the drug over time.³

 

Hydrophilic matrices are commonly used as oral drug delivery systems and being increasingly investigated for controlled-release applications because of their good compatibility.⁴

 

They are usually easy and economical to formulate & broad regulatory acceptance.⁵ Drug release from hydrophilic matrix tablets is controlled by the formation of a hydrated viscous layer around the tablet which acts as a barrier to drug release by opposing penetration of water into the tablet and also movement of dissolved solutes out of the matrix tablet.⁶ The hydration characteristics of the polymer and the subsequent physical properties of the hydrated gel layer may critically influence drug release, any change in the properties of the hydrated surface layer caused by a change in pH is likely to influence the performance of hydrophilic polymer as a extended release or controlled-release carrier.⁷

 

Xanthan gum is a high molecular weight extracellular polysaccharide, produced on commercial scale by the viscous fermentation of gram negative bacterium Xanthomonas campesteris. The molecule consists of a backbone identical to that of cellulose, with side chains attached to alternate glucose residues. It is a hydrophilic polymer, which until recently had been limited for use in thickening, suspending and emulsifying water based systems.⁸ It appears to be gaining appreciation for fabrication of matrices, as it not only retards drug release but also provides time-independent release kinetics with added advantages of biocompatibility and inertness. Xanthan gum has been evaluated as a hydrophilic matrix for CR (controlled release) preparation, using different model drugs including glipizide, buprenorphine HCl, diclofenac sodium.^9-11

The most convenient way to achieve controlled release of active agent involves physical blending of drug with polymer matrix, followed by direct compression, compression molding, injection molding, extrusion, or solvent casting which results either in monolithic device or in swellable hydrogel matrix. For any controlled-release dosage form it is very important to use minimum number of excipients with minimum processing steps in order to reduce the tablet-to-tablet and batch-to-batch variations, hence direct compression is the most suitable and easily up-scalable technique. When taken as an aggregate, directly compressed hydrophilic matrices are the demand of today's fast going era with both a scientific and economic appeal.¹²

 

MATERIALS AND METHODS:

Aceclofenac was kindly supplied by Aristo pharmaceuticals Ltd, Mumbai, India. Xanthan gum, microcrystalline cellulose (Avicel PH 101), dibasic calcium phosphate (DCP) were obtained from Aurobindo pharmaceuticals, Hyd. All other ingredients used were of pharmaceutical grade and used as supplied without further purification.

 

Preparation and characterization of matrix tablets:

Drug excipients interaction was investigated by IR studies. Before compression, the powder mixtures were checked for Hausner ratio, Carr’s compressibility index, and angle of repose.

 

Preliminary experiments were carried out by preparing matrix tablets by direct compression of several homogenous blends of polymer and excipients in different ratios in order to achieve desired drug release profile (Table 1). Briefly, weighed quantity of drug was physically mixed with all the auxiliary excipients by geometric addition using a glass mortar and pestle for about 10 min. Then magnesium stearate and talc were added as the lubricant/glidants and thoroughly blended for 2 min and were sieved through 100 mesh sieve. The homogeneous powder mixture for a single matrix was weighed, fed manually into the die of an automatic rotary tablet machine (Cadmach Machinery, Ahmedabad, India) equipped with flat faced die-punch set of 9 mm diameter, and compressed to a target weight (as per the composition of the matrix) and an average hardness of 6–8 kg/cm² for all the tablets. The obtained matrices were subjected to various physico-chemical investigations like, appearance, weight variation, thickness, hardness, drug content, and in vitro drug release.

 

Evaluation of Tablets:

The prepared matrix tablets were evaluated for hardness, weight variation, thickness, friability, and drug content. Hardness of the tablets was tested using a Monsanto hardness tester. Friability of the tablets was determined in a Roche fraibilator. The thickness of the tablets was measured by vernier calipers. Weight variation test was performed according to official method.¹³ Drug content of aceclofenac was carried out by measuring the absorbance of samples at 275 nm using UV/Visible spectrophotometer (Shimazdu) and comparing the content from a calibration curve prepared with standard aceclofenac in the same medium.

In Vitro Drug Release Studies:

The in vitro dissolution studies were carried out using USP apparatus type II (paddle) at 100 rpm.¹⁴ The dissolution medium consisted of 2% SLS in 0.1N Hcl for the first 2 hours and the phosphate buffer pH 6.8 from 3 to 24 hours (900 ml), maintained at 37°C ± 0.5°C. Five ml of samples were withdrawn and analysed spectrophotometrically at 275nm using a UV-visible spectrophotometer after suitable dilution of the samples. Fresh dissolution medium was replaced after each withdrawal.

 

Analysis of Release Data:

The mechanism of drug release from xanthan gum matrix tablets during dissolution tests in 2% SLS in 0.1 N Hcl and phosphate buffer pH 6.8 was determined using zero-order, first-order, and Higuchi equation. These models fail to explain drug release mechanism due to swelling (upon hydration) along with gradual erosion of the matrix. Therefore, the dissolution data were also fitted to the well-known exponential equation (Korsmeyer–Peppas equation), which is often used to describe the drug release behaviour from polymeric systems when the mechanism is not well-known or when more than one type of release phenomena is involved.

                               

Where k is a constant incorporating the structural and geometric characteristics of the matrix tablets, n is the release exponent, indicative of the drug release mechanism and Mt/Mf represents the drug dissolved fraction at time t. When determining the n exponent, only the portions of the release profile where Mt/Mf ≤0.6 were employed. To clarify the release exponent for different batches of matrices, the log value of the percentage drug released was plotted against log time for each batch according to Eq.

               

In case of Fickian release (diffusionally controlled release), the n have the limiting values of 0.45 for release from cylinders. Case II transport or relaxation controlled delivery; the exponent n is 0.89 for the release from cylinders. The non- Fickian release or anomalous transport of drug occurred when the n values fall between the limiting values of Fickian and Case II transport. The non-Fickian kinetics correspond to coupled diffusion/polymer relaxation. Occasionally, values of n > 0.89 for release from cylinders have been observed, which has been regarded as Super Case II kinetics. This mechanism could result from an increased plasticization at the relaxing boundary (gel layer).¹⁵

 

Stability Studies:

The optimized aceclofenac formulation was strip packed and subjected to accelerated stability studies as per ICH guidelines (40 °C±2 °C/75% RH±5% RH). The samples were withdrawn periodically (0, 15, 30, 60, 90, and 180 days) and evaluated for the different physico-chemical parameters viz. appearance, weight variation, thickness, hardness, drug content, and in vitro release studies.¹⁶

Table 1: Composition of aceclofenac matrix tablets

Batch  No	drug	Xanthan gum	Avicel  PH 101	DCP	Talc	Mg sterate
F-I	200	40	104.75	--	3.5	1.75
F-II	200	60	84.75	--	3.5	1.75
F-III	200	80	64.75	--	3.5	1.75
F-IV	200	40	--	104.75	3.5	1.75
F-V	200	60	--	84.75	3.5	1.75
F-VI	200	80	--	64.75	3.5	1.75

The drug: polymer ratios of F-I, F-II, F-III, F-IV, F-V and F-VI  are 1:0.2, 1:0.3, 1:0.4, 1:0.2, 1:0.3 and 1:0.4 respectively.

 

Table 2: Properties of Compressed Tablets

Batch no	Weight in mg ±SD(n=20)	Hardnesskg/cm2 ±SD (n=5)	Thickness ±SD(n=5)	Friability ±SD(n=5)	Drug content (%)± SD(n=5)
F-I	348.5	7.4±0.2	3.76	0.18±0.4	98.54±0.2
F-II	349.5	7.4±0.4	3.78	0.77±0.3	99.52±0.3
F-III	349.2	7.5±0.3	3.79	0.71±0.5	98.56±0.2
F-IV	348.3	7.4±0.5	3.81	0.80±0.2	100.5±0.4
F-V	349.5	7.3±0.2	3.79	0.65±0.3	98.5±0.2
F-VI	348.4	7.4±0.3	3.80	0.76±0.2	101.5±0.3

Note: All figures in the parentheses represent ±SD; n is specified in each column head

 

Table 3: Kinetic values obtained from different plots of formulations, F-I to F-VI and marketed.

Batch no	Release model
	Zero order K0              R0	First order K1          R1	Higuchi matrix KH        RH	Koresmeyer-peppas n             kk         rk	Hixson-crowell Ks            Rs
F-I	5.97     0.9680	-0.15     0.897	21.34  0.983	0.680   13.66  0.9983	-0.034      0.975
F-II	4.35     0.9883	-0.122     0.799	17.66   0.961	0.7155  9.63  0.9926	-0.02        0.933
F-III	3.33     0.9628	-0.05     0.990	13.65   0.980	0.59     10.37   0.988	-0.014      0.991
F-IV	5.95     0.9731	-0.14      0.912	21.23  0.980	0.68     13.26  0.9975	-0.03        0.978
F-V	4.82      0.9897	-              -	18.61  0.959	0.722    10.1   0.9929	-0.031      0.830
F-VI	3.58      0.9710	-0.05     0.9820	14.64    0.976	0.627    10.19   0.992	-0.016     0.9919
Marketed	4.43      0.9901	-              -	17.97  0.9570	0.7229  9.579  0.990	-0.03       0.8525

 

 

RESULTS AND DISCUSSION:

The aceclofenac matrix tablets of were prepared by using various concentrations of xanthan gum. The formulated matrix tablets were subjected to various evaluation tests such as thickness, uniformity of weight, drug content, hardness, friability, and in vitro dissolution. All the formulations showed uniform thickness. In a weight variation test, the pharmacopoeial limit for the percentage deviation for the tablets of more than 350 mg is ±5%. The average percentage deviation of all tablet formulations was found to be within the above limit, and hence all formulations passed the test for uniformity of weight as per official requirements. Drug content was found to be uniform among different batches of the tablets, and the percentage of the drug content was more than 95%. The formulation F-III showed a comparatively high hardness value of 7.5 kg/cm². Conventional compressed tablets that less than 1% of their weight are generally considered acceptable. In the present study the percentage friability for all the formulations was below 1% indicating that the friability is within the prescribed limits. All tablet formulations showed acceptable pharmacotechnical properties and complied with the in-house specifications for weight variation, drug content, hardness and friability (Table-2).

 

In vitro release studies demonstrated that the release of aceclofenac from all these formulated ER matrix tablets can generally be extended (fig.1). Xanthan gum exhibits pseudo plasticity (shear-reversible property) in aqueous solutions, which can be explained on the basis of its helical structure. Viscosity of xanthan gum increases due to the unwinding of the ordered conformation such as helix into a random coil with a consequent increase in resultant shape and size of the molecules. The presence of anionic side chains on the xanthan gum molecules enhances hydration and makes xanthan gum soluble in cold water. Six xanthan gum based formulations were screened to select those characterized by a minimal burst effect and a slow release of aceclofenac over 24 hrs. At lower xanthan gum content, rapid swelling of matrices, with less tight hydrogel structure resulted in higher initial drug release followed by complete release within 18 hrs. Conversely at the higher xanthan gum content, the initial drug release was diminished and drug diffuses slowly continuously for more than 24 hrs. As the amount of xanthan gum in the matrix increased, there would be a greater degree of hydration with simultaneous swelling which results in a lengthening of the drug diffusion pathway and reduction in drug release rate. It seems that, there is some threshold level for xanthan gum, within which the slight difference in its concentration can result in statistically significant different drug release profiles shown in figure 1. It may be concluded from the present study that slow, controlled and complete release of aceclofenac over a period of 24 hrs was obtained from matrix tablets (F-II) formulated employing drug polymer ratio of 1:0.3. Drug release from this formulation was also comparable to that of a commercially available ER tablet tested (fig 1). It is also evident from the results that formulation F-II is a better system for once-daily ER of aceclofenac.

Table 4: Stability studies

Parameter                                              strip pack at 45°c with 75%  RH
	initial tablets	15 days	30 days	60 days	90 days	180 days
Drug content( %) T50(h) T90(h)	99.52(0.3) 10.75 21.5	99.49(1.2) 10.70 21.48	99.45(1.3) 10.66 21.45	99.40(1.4) 10.62 21.41	99.30(1.0) 10.60 21.39	99.10(1.6) 10.55 21.35

 

Figure 1: In vitro release profiles of Aceclofenac from formulated matrix tablets Batch F-I, F-II, FIII, F-IV, F-V, F-VI, and marketed ER tablets.

 

 

The mechanism of drug release from all formulation was diffusion coupled with erosion (non-Fikian) (Table 3). According to ICH guidelines, six month accelerated stability study (45±2 °C/75±5% RH) for the optimized formulations showed negligible change over time for the parameters like appearance, weight variation, thickness, hardness, and drug content (shown in table 4).

 

CONCLUSION:

Overall, the findings of this study demonstrate that direct compression of drug release retardant xanthan gum with other rate controlling excipients effectively controls aceclofenac release throughout the course of 24 hrs. Since the process of manufacturing-direct compression involves minimum number of unit operations, it is easily up scalable without any sophisticated production facilities. Combining xanthan gum with microcrystalline cellulose, at particular proportions offered promising extended-release formulations (F-II). The optimized formulations were characterized by the absence of an initial burst and satisfactory extended-release properties. Furthermore, the in vitro release rate suggests that aceclofenac concentrations may be maintained at constant levels for 24 hrs.

 

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Received on 07.07.2009          Modified on 03.09.2009

Accepted on 10.10.2009         © RJPT All right reserved