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

Oyeniran Taiwo Opeyemi¹,  Obanewa opeyemi Adegbenro²

¹Department of Physiology, Faculty of Basic Medical Sciences, University of Ilorin, Nigeria. 

²Department of Physiology University of Ibadan, Nigeria.

DOI: https://doi.org/10.22270/ujpr.v3i5.205

ABSTRACT

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 ?ow and compaction capacity, leading to the production of high quality 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.

Keywords: HPMC K4M, in-vitro study, mini tablets, Naproxen sodium, NSAIDs, PVP K30.

INTRODUCTION

Oral tablets are the most widely used dosage form due to compactness, ease in manufacturing and convenience in terms of self-administration¹.  Matrix technologies are very popular among the oral controlled drug delivery technologies due to their simplicity, ease in manufacturing, high level of reproducibility, stability of the raw materials and dosage form and ease of scale-up and process validation^2,3,4. Matrix tablets are the “oral solid dosage forms in which the drug or active ingredient is homogeneously dispersed throughout the hydrophilic or hydrophobic matrices which serves as release rate retardants. Mini tablets are yet another category of solid oral formulation that offers analogous therapeutic benefits. Mini tablets have diameter typically equal to or smaller than 3.0 mm^5,6. Mini tablets can be prepared very easily by the means of direct compression method. These mini tablets can be filled into hard gelatine capsules, can be administered with a dose dispenser for individual dosing or can be compressed into larger tablets^7,8.  Matrix mini tablets as multiparticulate dosage forms score more advantages like uniformity of drug release, less tendency of dose dumping, greater patience compliance, improved mechanical strength, more dose loading capacity, and uniformity of size and shape⁹. Furthermore mini tablets can maintain their structure and shape in a more reproducible way than pellets or granules¹⁰.

The significant anatomical differences of the buccal cavity within paediatric and adult patients mean that children, particularly those under 5 years of age, encounter swallowing difficulties. Mini tablets are a potentially suitable dosage form for paediatric drug delivery^11,12. Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties that relieves pain, fever, swelling, and stiffness. It is commonly used as sodium salt¹³. Naproxen itself is rapidly and completely absorbed from the GI tract with an in-vivo bioavailability of 95%. Naproxen is extensively metabolized to 6-0-desmethyl naproxen and both parent and metabolites do not induce metabolizing enzymes¹⁴. The elimination half-life of Naproxen is approximately 15 hours. Most of the drug is excreted in the urine and a small amount (< 5%) of the drug is excreted in the faeces. Since Naproxen is extensively bound to plasma albumin, so it may be more efficient to deliver this drug in its sustained-release dosage form¹⁵.

The aim of present investigation is to design development and characterize the controlled release matrix mini tablets of Naproxen sodium with varying proportions of selective polymers. To release the drug for a prolong period of time within the GIT, thus to improve the patient compliance. By the means of controlled drug delivery systems danger of dose dumping and alteration in drug release profile can be avoided.

MATERIALS AND METHODS

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 and their 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 min¹⁶.

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 surface¹⁷. With r being the radius, of base of conical pile, angle of repose can be determined by following equation:

Where, q 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 intervals¹⁸. The tapping was continued until no further change in the volume was noted LBD and TBD were calculated using the following formulas:

Compressibility index

The compressibility index of the granules was determined by Carr’s Compressibility index.

Hausner’s ratio

Hausner’s ratio can be determined by the following equation,

Preparation of matrix mini tablet

Naproxen sodium matrix mini-tablets were prepared by direct compression technique¹⁹. Tablet ingredients were accurately weighed as mentioned in the Table 1. All ingredients were then passed through #20 mesh sieve. After screening, the powdered ingredients were blended in a 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/cm². The prepared mini tablets were used for further evaluation studies.

EVALUATION OF MINI TABLETS

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 weighed individually 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 acceptable²⁰. The percentage friability was then calculated by,

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 noted²¹.

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 phosphate buffers as blank²².

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^oC 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 to models such as zero-order, first-order, Higuchi and Peppa’s –Korsemeyer equations²³.

RESULTS AND DISCUSSION

Granules of all the ten formulations were subjected for various pre-compressional evaluations such as angle of repose, bulk and tapped density, compressibility index and Hausner’s ratio. Results of all the pre-compressional parameters performed on granules for formulations shown in Table 2. 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/cm³ and 0.581 ± 0.09 to 0.633± 0.25 g/cm³ 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 character of 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.  Another measure of a tablet's strength is friability. Conventional compressed tablets that lose less than 1% of their weight are generally considered acceptable. Results of friability test were also has been found within limit. 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 C-H stretching, C-O stretching, C-H bending, O-H deformation, C-H out of plane bending of pure Naproxen sodium and with  PVP K30 and HPMC K4M were almost in the same region of wave number ranging from 4000 cm^-1 to 400 cm^-1. It showed that there was no significant interaction between the drug and polymer and they are compatible with each other.

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 decreases⁶. 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 dissolution¹¹. The controlled drug release may also be due to increased proportion of polymer¹⁵. The release rate kinetic data for all formulations is shown in Table 5. When the data were plotted according to zero order, the formulations showed a high linearity with regression coefficient values (R²) 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 (R²) 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 (R²) 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 transport¹². 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 both diffusion and erosion⁹.

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 by direct compression technique. 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.

CONFLICT OF INTEREST

No conflict of interest is associated with this work.

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Figure 1: FTIR spectrum of Naproxen sodium

Figure 2: FTIR spectrum of mixture of Naproxen sodium, HPMC K4M and PVP K30. 

Table 1: Composition of Naproxen sodium matrix mini-tablets formulations (mg/mini tablet)

Table 2: Results of physical evaluation of pre-compression blend

Table 3: Results of physicochemical parameters of all formulations

Figure 3: In-vitro drug release profile of Naproxen sodium matrix mini-tablets of batch MT1 to MT5

Figure 4: In-vitro drug release profile of Naproxen sodium matrix mini-tablets of batch MT6 to MT10

Table 5: Drug release kinetics of different Naproxen sodium matrix mini-tablets

R²=Correlation coefficient value, n=slope