Development and Evaluation of Sustained Release Matrix Tablet of Naproxen Using Natural Polymer

The oral route is the most popular method for drug administration, primarily due to its ease of use and the gastrointestinal system's flexibility in dosage form design compared to other routes ^[1,2]. Sustained release refers to a drug delivery system or pharmaceutical formulation that is designed to release a drug slowly and steadily over an extended period of time. The objective of sustained release is to maintain a therapeutic drug concentration in the bloodstream or target tissue for a prolonged duration, often enabling less frequent dosing compared to immediate-release formulations. Typically, sustained-release dosage forms achieve slow drug release through mechanisms involving diffusion, dissolution, or a combination of both. Ideally, these formulations aim to release the drug at a predetermined rate, potentially mimicking a zero-order mechanism. Matrix tablets are regarded as commercially viable sustained-release dosage forms because they require minimal processing variables, utilize standard manufacturing facilities, and can incorporate large doses of medication^[3]. There is ongoing interest in developing new formulations for sustained drug release using readily available and inexpensive excipients through matrix-based formulation. Before formulating sustained-release dosage forms, several factors must be considered, including the pH variations in the gastrointestinal tract (GIT), gastrointestinal motility, enzyme systems affecting the dosage form and drug, among others. In recent years, the use of natural polymers has grown rapidly, continuing to play an important role in the creation of new controlled release formulations. Compared to synthetic polymers, natural polymers are much safer. They offer numerous applications in the development of new controlled release dosage forms, serving as binders, disintegrators, diluents, and release modifiers. Moringa oleifera gum, exuded from the bark, is primarily hydrophilic in nature and consists of polysaccharides  that exhibit anti-inflammatory, antioxidant, antimicrobial, and wound-healing properties^[4-6]. In pharmaceuticals, it serves as a natural binder, matrix-forming agent, and drug release modifier in sustained-release formulations^[7]. Naproxen  is  a powerful  NSAID belonging to the BCS class II drug with poor water solubility, is effective for managing pain and inflammation but can cause gastrointestinal side effects like ulcers at high doses^[8,9]. A sustained-release formulation of naproxen addresses these issues by providing controlled, steady drug release, reducing dosing frequency, minimizing side effects, and improving therapeutic efficacy. The objective of the present study is to develop a sustained release dosage form of naproxen using natural polymer that will help in releasing only small quantities of drug over a long period of time.

2. MATERIALS AND METHODS

Naproxen was obtained from Yarrow chem. Products, Mumbai. Moringa oleifera gum was naturally collected, HPMC K100 from Himedia, Microcrystalline cellulose obtained from Sd.Fine Chem. Limited, Magnesium stearate from Loba Fine Chemie PVT. LTD, Talc and PVP K 30  obtained from  Oxford Lab fine chem.

Experimental Method:

UV spectrophotometer analysis:

The identification of the drug, Naproxen was carried out by UV spectrophotometric method using Shimadzu UV-1800 Spectrophotometer (Shimadzu Corp., Japan). Approximately 100 mg of the drug was accurately weighed and transferred into a 100 ml volumetric flask and it was dissolved in a suitable amount of phosphate buffer (pH 6.8) and diluted to a final volume of 100 ml to form a stock solution with a concentration of 1000 µg/ml. From this stock, 10 ml was taken and further diluted to 100 ml using the same phosphate buffer (pH 6.8), resulting in a 100 µg/ml solution. This solution was scanned over the UV range of 200-400 nm, and the spectrum was recorded for analysis.

Preparation of calibration curve:

In a 100 ml volumetric flask, precisely 100 mg of naproxen was accurately weighed and then dissolved in 50 ml of phosphate buffer (pH 6.8). The volume was adjusted to 100 ml with  phosphate buffer (pH 6.8), resulting in a stock solution with a concentration of 1000 µg/ml.  From the above stock solution 10 ml was taken and diluted to 100 ml in phosphate buffer (pH 6.8) with a concentration of 100 µg/ml. Subsequent dilutions were prepared from the above solution by diluting with phosphate buffer (pH 6.8), covering a concentration range of 10-50 µg/ml. The absorbance of the resulting naproxen solutions were measured using a UV Visible spectrophotometer (Shimadzu-1800) at 329 nm against reagent blanks.

Melting point determination:

Melting point of the drug sample was determined by using a melting point appratus. Small quantity of drug sample was taken and placed into a sealed capillary tube. Then the capillary tube was placed in the melting point apparatus.The temperature was increased gradually in the apparatus and temperature was noted when the entire drug sample melted.

FT-IR Spectroscopic analysis:

To prepare the sample, 10 mg of naproxen was triturated with a small amount of  KBr. The mixture was then placed into a pellet die, and a thin pellet approximately 13 mm in diameter was formed by applying 8 tons of pressure under vacuum conditions. This pellet was subsequently mounted in a sample holder for analysis. Measurements were conducted using an FTIR spectrometer across the wavenumber range of 4000 to 500 cm?¹.

Solubility studies of drug:

The solubility of Naproxen was assessed in distilled water and various solvents, including phosphate buffers at pH levels 6.8, 7.0, and 7.4, as well as methanol, ethanol, and  HCl.The different types of solubility studies include qualitative solubility analysis and quantitative supersaturation solubility analysis.

a. Qualitative solubility study

A qualitative solubility analysis of Naproxen was performed in distilled water and various solvents, including phosphate buffer solutions at pH 6.8, 7.0, and 7.4, as well as methanol, ethanol, and hydrochloric acid (HCl). For this analysis, 10 mg of the drug was dissolved in 10 ml of each solvent in a conical flask. The solutions were shaken at 25°C for 24 hours to facilitate dissolution.These samples were examined for clarity and checked for any suspended or undissolved particles.

b. Quantitative solubility study

The quantitative solubility of Naproxen was determined in distilled water and various solvents, including phosphate buffer solutions at pH levels 6.8, 7.0, and 7.4, as well as methanol, ethanol, and hydrochloric acid (HCl). An excess amount of Naproxen was added to 10 ml of each selected solvent in a conical flask to achieve saturation. The mixtures were shaken at 25°C for 24 hours to reach equilibrium. Once equilibrium was established, the samples were filtered using Whatman filter paper. After appropriate dilution, the concentration of Naproxen dissolved in each solvent was analyzed using a UV-visible spectrophotometer.

Formulation of sustained release matrix tablets of Naproxen :

Nine formulations of Naproxen sustained release matrix tablets were prepared using wet granulation method, as outlined in Table 1. The process involved weighing Naproxen, polymers, diluents, binders, lubricants, and glidants, and passing them through a sieve no. 30-mesh to ensure uniform particle size. The sieved naproxen, polymers, diluents, and binders were then thoroughly mixed. A granulation solution was prepared by dissolving PVP K30 in distilled water, which was added slowly to the mixture to form enough cohesiveness mass in the stainless steel container by rotating the wet mass by stainless steel rod. The wet mass was passed through a sieve no. 16-mesh to produce wet granules, which were dried at 40°C for 30 minutes in a hot air oven. The dried granules were resized by sieving them again through a sieve no. 16-mesh. Talc and magnesium stearate were added as glidants and lubricants to the resized granules and mixed thoroughly. The prepared granules were then ready for compression into tablets. Prepared granules were compressed at 500 mg weight on a mini rotary tableting machine.

Bulk Density ^[10]:

A known amount of powder blend was transferred into a measuring cylinder and carefully level the powder blend without compacting and measuring the bulk volume. The bulk density was calculated by using the formula:

Bulk Density = Weight of sampleBulk volume

Tapped Density:

A known amount of powder blend was placed in a measuring cylinder and tapped 100 times using the apparatus. The tapped density was then calculated using the following formula:

Tapped Density = Weight of sampleTapped volume

Hausner’s ratio:

It is the measure of cohesiveness between particles, calculated as the ratio between tapped density and bulk density:

Hausner’s ratio =  Tap densityBulk density

Angle of Repose ^[11]:

It is the maximum angle which is formed between the surface of a pile of powder and the horizontal surface. The Angle of Repose is typically calculated using the following formula:

  θ  = tan?¹ hr  

Carr’s Index^[12]:

Carr's Index, also known as the Compressibility Index, is a measure used to assess the flowability of a powder by determining how much it compresses under pressure. It provides an indication of the cohesiveness between particles in a powder. Carr's Index calculated by using the following formula:

Carr’s index = Tap density - Bulk densityTap density  ×  100%

Evaluation Of Tablets

Thickness:

The thickness of the tablets from each formulation was determined using a Vernier caliper. Ten tablets were selected from each formulation for testing, and their average thickness was calculated.

Hardness:

The hardness of the tablets was determined using a Monsanto hardness tester.. Ten tablets were randomly selected from each formulation and their average hardness was calculated, the results expressed in kg/cm².

Weight variation^[13]:

Twenty tablets from each batch were weighed using electronic balance, and their average weight was calculated. The variation in tablet weight was then estimated using the following equation.

Weight variation = Individual  weight - Average weightAverage weight  ×  100%

Friability:

Friability measures how much weight a tablet loses when small particles break off its surface. This was tested using a Roche friabilator, which ran at 25 rpm for 100 revolution, with a drop height of 6 inches. The difference in the tablet's weight before and after the test was recorded, and the percentage of friability was calculated using the following formula^[14].

% Friability = Initial  weight - Final weightInitial  weight  ×  100

Drug Content:

Ten tablets were powdered, and a portion of the powder equivalent to 100 mg of Naproxen was weighed. This was dissolved in 50 ml of methanol and the volume was made up to 100 ml in a volumetric flask. The drug content was determined using a UV-Visible spectrophotometer (Shimadzu 1800) at 329 nm, with the corresponding blank as reference.

In-vitro dissolution study:

The in vitro dissolution study was carried out using a USP Type II (Paddle Apparatus) dissolution apparatus set to 50 rpm. The test ran for 12 hours, using 900 mL of pH 6.8 phosphate buffer as the medium, maintained at a temperature of 37 ± 0.5°C. Sampling was performed by withdrawing 5 ml at various time intervals and replacing them with an equivalent volume of fresh buffer. The drug release was analyzed with a UV-Visible spectrophotometer (Shimadzu-1800) at 329 nm, using the pH 6.8 buffer as a blank reference solution.

Stability Study:

The objective of stability testing is to demonstrate how the quality of a drug substance or product changes over time under the influence of various environmental conditions, such as temperature, humidity, and light. This testing helps determine appropriate storage conditions, re-test intervals, and shelf lives. Typically, observing how the product degrades at room temperature requires a prolonged period. To avoid this delay, accelerated stability studies are employed. The ICH guidelines outline the duration of the study and the necessary storage conditions.

3. RESULTS AND DISCUSSION

UV Spectroscopy:

The maximum absorbance (λmax) of Naproxen was observed at 329 nm, which is close to the standard reference value. The UV spectrum of the Naproxen drug  is shown in Figure 1.

The correlation coefficient for the calibration curve of Naproxen in phosphate buffer (pH 6.8) at 329 nm was determined to be 0.999. The linearity of the graph and the high correlation coefficient indicate that Beer-Lambert's law was followed within the drug concentration range of 10-50 µg/ml.The recorded data is presented in Table 2, and the graphical representation is depicted in Fig 2.

Melting point of the drug sample was determined by using a melting point appratus and was found to be in the range of 155ºC - 158ºC, which was found to be similar 154ºC - 157ºC as reported in Indian pharmacopoeia.The melting point of Naproxen is shown in Table 3.

Table 3: Melting point of Naproxen

FT-IR Spectroscopic analysis:

The FT-IR spectrum of naproxen exhibited peaks identical to those observed in the reference sample of naproxen as depicted below.

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250424143552-8.jpg" target="_blank">
            <img alt="FTIR Spectrum of Naproxen and Moringa Oleifera Gum.jpg" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250424143552-8.jpg" width="150">
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  Fig 4: FTIR Spectrum of Naproxen and Moringa Oleifera Gum

The qualitative and quantitative solubility of naproxen in various solvents was determined: with the results provided in Table 4.

The bulk density of the various formulations was observed to range between 0.40 to 0.47, while the tapped density ranged between 0.46 to 0.54. The Hausner ratio was found to lie between 1.13 to 1.18, and the Carr's Index varied between 11.76 to 15.38, indicating good compressibility of the formulations. Additionally, the angle of repose was measured between 24.37 to 27.53, signifying good flow properties. The results of the bulk density, tapped density, angle of repose, Carr’s Index, and Hausner ratio are presented in Table 5.

Evaluation of Sustained-Release Matrix Tablets of Naproxen:

The sustained-release matrix tablets of naproxen were assessed for parameters including thickness, hardness, weight variation, friability, and drug content. Thickness of all nine formulations were found  in the range of 4.62 - 4.91mm, hardness 5.3 - 6.5 kg/cm² indicates good tablet strength, in weight variation study % deviation of average weight of tablet was found under deviation limits of 5% as per IP 0.44 to 0.67% and % friability between 0.15 - 0.36% , drug content was found 97.7 to 99.1%. The results of these evaluations are displayed in the below Table 6 .

*All values are presented as mean ± standard deviation, n=3.

In- vitro dissolution release rate

The in-vitro dissolution study of nine formulations (F1–F9) over 12 hours shows that F5 and F3 achieve near-complete sustained release at 12 hours (98.69% and 97.8%, respectively). F1 exhibits rapid release (99.86% at 10 hours), F2 reaches 98.43% at 11 hours, while F4, F6, F7, and F9 range between 92.27% to 95.87%, and F8 achieves 86.11%,which indicates increased in polymer concentration in the formulation results in decreased drug released rates. Results are given below in Table 7 and Figure 10-12.

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250424143552-2.png" target="_blank">
            <img alt="Cumulative drug release of batch F1 - F3.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250424143552-2.png" width="150">
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Fig 10: % Cumulative drug release of batch F1 - F3

In this study, the selected formulation F3 underwent stability testing for up to 3 months under accelerated conditions (40°C ± 2°C at 75% RH ± 5%) to assess the effects of aging on hardness, drug content, and in vitro drug release. The optimized F3 formulation was stored at 40°C ± 2°C with 75% RH ± 5% for 3 months in tightly sealed aluminum foil. Samples were withdrawn after periods of 1, 2 , 3 months and analyzed for physical appearance. The observations are given below in Table 8.