DEVELOPMENT AND CHARACTERIZATION OF DIRECT COMPRESSED MATRIX MINI TABLETS OF NAPROXEN SODIUM

The present study was carried out to formulate and evaluate multiparticulate system containing mini-tablets of Naproxen sodium. Naproxen is a nonsteroidal anti-inflammatory drug (NSAIDs) with analgesic and antipyretic properties. Pre-formulation studies showed good ﬂow and compaction capacity, leading to the production of highquality mini-tablets. The drug-excipients compatibility studies were performed using FTIR techniques. Ten different matrix mini tablets were manufactured by direct compression using various polymers like HPMC K4M, PVP K30 in different ratio. The prepared mini tablets were subjected to pre and post compressional parameters and the values were within the prescribed limits. The in-vitro performance showed the desired biphasic behaviour. Drug release from matrix mini tablets was sustained over a period of 10 hours and release rate. Study concludes that Naproxen sodium can be successfully released in a controlled manner by the use of developed matrix mini-tablets.


MATERIALS AND METHODS Materials
Naproxen sodium was obtained from Adpharm Pharmaceuticals Limited, Lagos State, Nigeria. PVP K30 and Magnesium stearate were obtained from Afrab-Chem Limited, Lagos State, Nigeria. Aerosil was obtained from Agary Pharmaceutical Limited, Lagos State, Nigeria. Sodium lauryl Sulphate and Avicel were obtained from Biopharma Nigeria Limited, Lagos State, Nigeria. All other ingredients, chemicals and solvents used were of analytical grade.

PREFORMULATION STUDIES Fourier Transform Infrared (FTIR) spectral analysis
The compatibility for pure drug Naproxen, polymers andtheir physical mixtures used in this experimental procedure was evaluated by recording of spectra using FT-IR Spectrophotometer (Perkin Elmer, spectrum-100, Japan). The spectra were recorded by taking 5% of sample in potassium bromide (KBr) and after this mixture was grounded into a fine powder it was compressed into KBr pellets at 4000 Psi compaction pressure for a period of 2 min. The resolution was 1 cm1 and the range of scanning was 400-4000 cm -1

Angle of repose
The fixed funnel and free standing cone methods employ a funnel that is secured with its tip at a given height, h, which was kept 2 cm above graph paper that is placed on a flat horizontal surface. With r being the radius, of base of conical pile, angle of repose can be determined by following equation: = tan-1 (h/r) Where,  is the angle of repose, h is height of pile, r is radius of base of the pile. Bulk density and tapped density Both loose bulk density and tapped bulk density were determined.A quantity of 2gm of granules from each formula, previously light Shaken for the break of any agglomerates formed, was introduced into the 10ml of measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall down its own weight from the hard surface from a height of 2.5cm at 2 sec Intervals. The tapping was continued until no further change in the volume was noted LBD and TBD were calculated using the following formulas: Bulk Density=(Weight of sample (gm))/(Volume occupied by sample (ml)) Bulk Density=(Weight of powdered blend (gm))/(Tapped volume of the packing (ml)) Compressibility index The compressibility index of the granules was determined by Carr's Compressibility index. Compressibility Index=(Tapped Density-Bulk Density)/(Tapped Density) X100 Hausner's ratio Hausner's ratio can be determined by the following equation, Hausner Ratio=(Tapped Density)/(Bulk Density) large size poly bag by tumbling action. Finally, magnesium stearate was added and again mixed for 5 minutes so that particle surface was coated by lubricant evenly. The blend was then compressed into mini tablets weighing about 100 mg using 2.8 mm shallow biconcave punches in rotary tablet punching machine to a hardness of 5-6 kg/cm 2 . The prepared mini tablets were used for further evaluation studies.

EVALUATION OF NAPROXEN SODIUM MATRIX MINI TABLET Tablet thickness
The thickness of 20 Naproxen sodium matrix mini-tablets was determined using a Vernier caliper and the mean of these readings was taken as the mean tablet thickness. Tablet weight uniformity Ten Naproxen sodium matrix mini-tablets were weighedindividually on electric balance from which the mean was calculated and the percentage deviations determined. Friability A friability test was conducted on the tablets using an veego friabilator. Twenty Naproxen sodium matrix mini-tablets were selected from each batch and any loose dust was removed with the help of a soft brush. The tablets were initially weighed (W i ) and transferred into friabilator. The drum was rotated at 25 rpm for 4 minutes after which the tablets were removed. Any loose dust was removed from the tablets as before and the tablets were weighed again (W f ). The friability of tablets less than 1% is considered acceptable. The percentage friability was then calculated by, %F=(Wi-Wf)/Wi X100

Hardness
The Naproxen sodium matrix mini-tablets to be tested were held between a fixed and a moving jaw of hardness test apparatus (Monsanto) and reading of the indicator is adjusted to zero. The screw knob was moved forward until the tablet breaks and the force required breaking the tablet was noted.

Drug content
The drug content in each Naproxen sodium matrix mini-tablet was determined by triturating 20 tablets and powder equivalent to average weight was added in 100 ml pH 1.2 HCL, 7.4 and 6.8 pH phosphate buffer, followed by stirring. The solution was filtered through a 0.45μ membrane filter, diluted suitably and the absorbance of resultant solution was measured spectrophotometrically at 331 nm using pH 1.2 HCL and pH 7.4, 6.8 phosphatembuffers as blank.

In-vitro drug release study
In vitro release studies of Naproxen sodium matrix mini-tablets were carried out using a modified USP XXIII dissolution test apparatus. The dissolution study was conducted for all the formulations using paddle method. The dissolution test was performed using 900ml of buffer pH 7.4 at a speed of 50 rpm and the temperature of 37 o C was used in each test samples of dissolution(5ml) were withdrawn and absorbance was measured at 331 nm using analysis by UV spectroscopy. The dissolution data was fitted tomodels such as zero-order, first-order, Higuchi and Peppa's -Korsemeyer equations.        The release rate kinetic data for all formulations is shown inTable 5. When the data were plotted according to zero order, the formulations showed a high linearity with regression coefficient values (R 2 ) between 0.8664-0.9278. It showed that the drug release follows zero order. When the data were plotted according to first order, the formulations showed regression coefficient values (R 2 ) between 0.8478-0.9173. Diffusion is related to transport of drug from the matrix tablets into the dissolution medium depends upon the concentration. This is explained by Higuchi's equation. When the data were plotted according to Higuchi's equations, the regression co-efficient values (R 2 ) were between 0.7153-0.8951. By using Korsmeyer-Peppas model, the mechanism of drug release was determined. If n = < 0.45, it is Fickian diffusion and if n= 0.45 -0.89, it is non Fickian diffusion transport 12 . The results of all the formulations showed that the n values are between 0.6542-0.6937. It proved that all formulations followed non-Fickian transport mechanism19 bothdiffusion and erosion 9 .

RESULTS AND DISCUSSION
The granules of all the formulations were evaluated for angle of repose, bulk density, tapped density, compressibility index and Hausner ratio. The angle of repose was found to be in the range of 21.88 to 24.59 o . It indicates that granules have a good flow property. The bulk density and tapped density was found to be in the range of 0.521 ± 0.32 to 0.572 ± 0.31 g/cm 3 and 0.581 ± 0.09 to 0.633± 0.25 g/cm 3 respectively. The compressibility and Hausner ratio was found to be 9.47± 0.17 to 11.00± 0.20 and 1.10±0.16 to 1.11±0.09 indicating good flow characterof the granules (table 2). All the results are within the prescribed limits. The hardness of the tablets for all the formulations was in the range of 5-7 kg/cm2. The uniformity weight of twenty tablets of all the formulations was within 5% deviation. The friability of all the formulation was less than 1%. Drug content of all the formulations were found to be in the range of 96 to 99 % (table 3). All the results are within the prescribed limits. The FT-IR studies showed that the ingredients are compatible with the Naproxen sodium. The results of the in-vitro release study for all the 10 formulations are shown in Figure 3 and Figure 4. At the end of 10 hrs the maximum cumulative percentage drug release 84.725% was shown by the batch MT1 and minimum 55.42 was shown by batch MT8.
An increase in the compression force increases the hardness and the apparent density of the tablet, thereby reducing the matrix porosity in the tablet. As the compression force increases, release rate decreases 6 . The drug release was found to be faster at lower compression force than at higher ones because of the relatively larger matrix porosity of the tablet, which allowed greater penetration of dissolution fluid into the matrix, thus enhancing polymer disentanglement and drug dissolution 11 . The controlled drug release may also be due to increased proportion of polymer 15 .

CONCLUSION
The study was undertaken with the aim to formulation and evaluation of Naproxen sodium sustained-release matrix tablets using various concentrations of polymers. It was concluded that there was no interaction between the drug and polymer compatibility, which is analyzed by FTIR.Ten different formulations of matrix mini tablets were prepared successfully. The physicochemical evaluation studies like thickness, hardness, drug content, weight variation and friability were performed. From the obtained results, it is concluded that the formulation of sustained release tablet of Naproxen sodium of batch MT1is considered as ideal or optimized Therefore the study proves that Naproxen sodium can be successfully released in a controlled manner by the use of developed matrix mini-tablets.