Solubility Enhancement Of Naproxen Tablet Using Solid Dispersions Method.

Naproxen is a widely prescribed non-steroidal anti-inflammatory drug (NSAID) used for the management of pain, inflammation, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and various musculoskeletal disorders.[1] It exerts its pharmacological action by inhibiting cyclooxygenase (COX) enzymes, thereby reducing the synthesis of prostaglandins responsible for inflammation and pain.[2] Despite its therapeutic efficacy, Naproxen exhibits poor aqueous solubility, which limits its dissolution rate and oral bioavailability. [3] According to the Biopharmaceutical Classification System (BCS), Naproxen is categorized as a Class II drug, characterized by low solubility and high permeability. For such drugs, dissolution is the rate-limiting step in drug absorption, making solubility enhancement an essential aspect of formulation development. [4]

Poor water solubility remains one of the major challenges in pharmaceutical research and development. Drugs with low aqueous solubility often exhibit erratic gastrointestinal absorption, delayed onset of action, and variable bioavailability. [5] These limitations can affect therapeutic outcomes and may necessitate higher doses, potentially increasing the risk of adverse effects. Therefore, improving the solubility and dissolution characteristics of poorly soluble drugs has become a significant focus in modern pharmaceutical formulation science.[6]

Several approaches have been investigated to improve the solubility of poorly water-soluble drugs, including particle size reduction, salt formation, complexation, crystal engineering, self-emulsifying drug delivery systems, nanotechnology, and solid dispersion techniques.[7] Among these methods, solid dispersion technology has emerged as one of the most effective and widely accepted strategies.[8] Solid dispersions involve dispersing the drug in an inert hydrophilic carrier matrix, resulting in enhanced wettability, reduced particle size, improved porosity, and conversion of the crystalline drug into an amorphous form. These modifications significantly enhance the dissolution rate and apparent solubility of the drug.[9]

The concept of solid dispersion was first introduced by Sekiguchi and Obi in 1961, and since then, extensive research has demonstrated its potential in improving the bioavailability of poorly soluble drugs. [10] Hydrophilic carriers such as polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), and poloxamers are commonly employed in solid dispersion formulations. [11] These carriers facilitate rapid drug release by improving wettability and preventing drug aggregation during dissolution. The preparation methods for solid dispersions include solvent evaporation, fusion method, spray drying, hot-melt extrusion, and kneading techniques, each offering distinct advantages depending on the physicochemical properties of the drug and carrier. [12]

For Naproxen, enhancement of solubility through solid dispersion is particularly advantageous because its poor aqueous solubility can significantly limit therapeutic performance. Incorporation of Naproxen into hydrophilic polymer matrices may increase the drug's surface area available for dissolution, reduce crystallinity, and promote molecular-level dispersion. Consequently, improved dissolution behavior can lead to enhanced oral absorption and better therapeutic efficacy. [13]

The development of Naproxen tablets utilizing solid dispersion technology represents a promising approach to overcome solubility-related limitations. By integrating solid dispersions into tablet formulations, it is possible to achieve faster drug release, improved bioavailability, and enhanced patient compliance. Furthermore, solid dispersion-based tablets can offer manufacturing simplicity, cost-effectiveness, and scalability for commercial production. [14]

Therefore, the present study aims to formulate and evaluate Naproxen solid dispersions using suitable hydrophilic carriers and incorporate them into tablet dosage forms. The study focuses on improving the solubility and dissolution profile of Naproxen, thereby enhancing its pharmaceutical performance and therapeutic effectiveness. The developed formulation may provide an efficient and reliable oral delivery system for the treatment of inflammatory and painful conditions. [15]

MATERIALS

The materials used in the formulation and evaluation of Naproxen solid dispersion tablets were procured from reputed suppliers and were of laboratory reagent (LR) grade. Naproxen was used as the active pharmaceutical ingredient, while various polymers, excipients, and solvents were employed for the preparation of solid dispersions and tablet formulations. Hydroxypropyl Methylcellulose (HPMC K100 and HPMC K4) and Ethyl Cellulose were utilized as polymers for controlling drug release and enhancing the physicochemical properties of the formulation. Polyvinyl Pyrrolidone (PVP K30) was used as a hydrophilic carrier and binder to improve drug solubility and tablet integrity. Microcrystalline Cellulose served as a diluent, Magnesium Stearate as a lubricant, and Talc as a glidant to facilitate tablet manufacturing. Isopropyl Alcohol was used as a solvent during the preparation of solid dispersions. All materials were obtained from Research-Lab Fine Chem Industries, Mumbai, and were used without further purification.

INSTRUMENTS

The analytical instruments and equipment listed above were utilized for various stages of formulation development and evaluation. The UV-Visible Spectrophotometer was employed for quantitative estimation of Naproxen, while FTIR spectroscopy was used to investigate drug–excipient compatibility. Differential Scanning Calorimetry (DSC) was performed to study the thermal behavior and crystallinity of the drug and solid dispersions. The Dissolution Apparatus was used to evaluate in vitro drug release profiles, and the Bulk Density Apparatus was employed for pre-compression studies. Tablet quality attributes such as hardness, friability, thickness, and weight variation were assessed using the Hardness Tester, Friability Apparatus, Vernier Caliper, and precision balances. The Tablet Compression Machine was used for tablet manufacturing, whereas the Stability Chamber and Environmental Testing Chamber were employed for accelerated stability studies under controlled temperature and humidity conditions.

Formulation and Development of Naproxen Solid Dispersion Tablets

The formulation of Naproxen solid dispersion tablets was carried out to enhance the aqueous solubility and dissolution rate of Naproxen, a BCS Class II drug exhibiting poor water solubility. Solid dispersions were prepared using different hydrophilic and hydrophobic polymers, namely HPMC K100M, HPMC K15, and Ethyl Cellulose, at varying drug-to-polymer ratios. The solvent evaporation method was employed using Isopropyl Alcohol as the solvent. The prepared solid dispersions were subsequently blended with suitable excipients and compressed into tablets by direct compression.

Six trial formulations (T1–T6) were prepared to evaluate the influence of polymer type and concentration on the physicochemical characteristics and dissolution behavior of Naproxen. Each formulation contained 50 mg of Naproxen, while the polymer concentration was varied between 40 mg and 90 mg. PVP K30 was incorporated as a hydrophilic carrier and binder to improve drug dispersion and tablet integrity. Magnesium stearate and talc were used as lubricant and glidant, respectively, whereas Microcrystalline Cellulose (MCC) was used as a diluent to adjust the final tablet weight to 250 mg.

Preparation of Solid Dispersion by Solvent Evaporation Method

The solid dispersions of Naproxen were prepared by the solvent evaporation technique using different polymers such as HPMC K100M, HPMC K15, and Ethyl Cellulose. The accurately weighed quantity of Naproxen and the selected polymer were dissolved in a sufficient quantity of Isopropyl Alcohol (IPA) under continuous magnetic stirring to obtain a clear and homogeneous solution. The resulting solution was subjected to solvent evaporation using a rotary evaporator maintained at 40°C under reduced pressure until complete removal of the solvent was achieved.

The obtained solid mass was further dried under vacuum over silica gel for 12 hours at room temperature to ensure complete removal of residual solvent. The dried solid dispersion was then pulverized gently and passed through a 250 µm sieve to obtain a uniform particle size distribution. The prepared solid dispersion powder was stored in a desiccator until further use.

For tablet preparation, the solid dispersion equivalent to the required dose of Naproxen was blended with Microcrystalline Cellulose (MCC), PVP K30, talc, and magnesium stearate. The final blend was mixed uniformly and compressed into tablets using the direct compression method.

Preparation of Tablets by Direct Compression

The prepared solid dispersions were blended uniformly with the required quantity of tablet base. The resulting powder mixture was evaluated for pre-compression parameters and subsequently compressed into tablets by the direct compression method using a six-station tablet punching machine. The compressed tablets were collected and stored in airtight containers for further characterization and evaluation studies.

Pre-formulation Study –

Solubility Study

The ability to dissolve of Naproxen has been investigated in a variety of solvents, including pH 6.8 phosphate buffer, 0.1N HCL, methanol, and ethanol.

Melting Point

Using a melting point device and the capillary technique, the melting temperature of Naproxen was determined. Values seen and reported are compared.

UV Analysis of Drug (API) Sample

A 100 ml volumetric flask containing precisely weighed 10 mg of Naproxen was filled with 0.1N HCl to create a standard stock solution with a concentration of 100 μg/ml. This is the typical stock remedy.

FTIR Study (Drug Excipients Study)

Infrared spectroscopy is useful analytical technique to the characterization of drug. Therefore, infrared spectroscopy is used.

EVALUATION OF PREPARED SOLID DISPERSION

Determination of Naproxen in Solid Dispersion:

Solid Dispersions equivalent to 10 mg of Naproxen was accurately weighed and transfer to 100 mL volumetric flask. The solution was diluted up to the mark with methanol. Suitably diluted solution was measured spectrophotometrically at 280 nm.

Fourier Transform Infrared (FTIR) spectroscopy-

FT-IR spectroscopy was carried out on an FTIR Spectrophotometer (Alpha, Bruker, Germany). The spectrum was reported. The spectra obtained for drug, polymer, physical mixture and optimized solid dispersion were compared.

Differential Scanning Calorimetry (DSC)-

The thermal behaviour of the samples was studied by Differential Scanning calorimeter (DSC-PYRIS-1, perkin elmer). DSC scan was carried out in an atmosphere of dry nitrogen within the measuring range of -2 mW to 20 mW. The samples were heated at a rate of 10°C min−1 from room temperature to the melting point using reference of an empty aluminium pan.

In vitro Dissolution Study-

The United States Pharmacopoeia (USP) - type II dissolution equipment was used to conduct the in vitro drug release investigation. To simulate the GIT conditions, 900 ml of 0.1 N HCl (pH 1.2) release medium. The experiment was conducted with a paddle rotating at a speed of 50 rpm at 37â—¦C ±0.5â—¦C. After the 10 ml sample withdrawn and filtered through the 0.45-micron Syringe filter. To preserve the sink conditions, at the same time, an refinish the 10ml volume dissolution medium was added in vessels.

PRECOMPRESSION STUDY

The angle of Repose (Ø)

The frictional force in a loose powder or granules can be measured by the angle of repose. The angle of repose is defined as the maximum angle possible between the surface of a pile of the powder and horizontal plane

Tan Ø= H/r

Were,

Ø= angle of repose is the height of the cone, R= radius of the base of the cone

Different ranges of flow ability in terms of angle of repose are given in the below table.

Bulk Density & Tap Density:

Loose bulk density (LBD) and tapped bulk density (TBD) of dose form and the dosage form blends were determined using bulk density apparatus. The pure drug was passed through the #18 sieve to break the clumps if any. Accurately weighed 5 g of the drug or 25 g of polymers was placed in a 100 ml graduated measuring cylinder.

The initial volume was observed. The cylinder was tapped initially 100 times from a distance of 14 ± 2 mm. The tapped volume was measured to the nearest graduated unit. The tapping was repeated additional 100 times. Again, the tapped volume was measured to the nearest graduated unit. The same thing was done for powder blends of the dosage form. The LBD and TBD were calculated in g per ml using the following.

Bulk Density = weight of the powder/volume of the packing

Tab Density = weight of the powder / tapped volume of the packing

Hausner ratio:

The Hausner ratio of the powder was determined by the following equation.

Hausner ratio = TBD / LBD

The lower Hausner ratio (<1.25) indicates better flow properties than higher ones (>1.25).

POST-COMPRESSION PARAMETERS STUDY

Weight Variation & Content Uniformity:

The weight variation statistical quality control test is used to confirm uniformity of the dosage unit and therefore also to support product safety, identity and quality. In the production of food and beverages, checking the weight of packages provides fast confirmation that fills quantities meet legal requirements.

Thickness:

Thickness of tablets indicates the strength to withstand compression force applied during manufacturing process. Thickness of tablets was measured by digital caliper.

Hardness:

Test Hardness (diametric crushing strength) is the force required to break a tablet across the diameter. The hardness of a tablet is an indication of its strength. The tablets should be stable to mechanical stress during handling and transportation. The degree of hardness varies with the different manufacturers and with the different types of tablets. The hardness was tested using Monsanto tester. “Hardness factor”, the average of the six determinations, was determined and reported. The force was measured in kilograms per centimeter square.

Friability:

Test Friability is the loss of weight of tablet in the container/package, due to removal of fine particles from the surface. This in process quality control test is performed to ensure the ability of tablets to withstand the shocks during processing, handling, transportation, and shipment. Permitted friability limit is 1.0 %. Roche friabilator (Electrolab, Mumbai) was used to measure the friability of the tablets. Ten tablets were weighed collectively and placed in the chamber of the friabilator. In the friabilator, the tablets were exposed to rolling, resulting free fall of tablets (6 inches) within the chamber of the friability. It was rotated at a rate of 25 rpm. After 100 rotations (4 minutes), the tablets were taken out from the friability and intact tablets were again weighed collectively

% Friability = W1 – W2 /W1 × 100

Where, W1 is weight of the tablet before the test & W2 is weight of the tablet after test.

Disintegration study:

Complete decomposition is defined as a state where no residue, except for fragments of the tablet shell or undissolved tablet shell, remains on the display of the test apparatus or adheres to the bottom surface of the dish if the disc is used; if there is still another residue then it is soft mass without a core material.

The mean disintegration time of tablets containing microcrystalline cellulose or dicalcium phosphate dihydrate was 37 min and 44 min, respectively. Tablets containing corn starch or sodium carboxy-methylcellulose break down very slowly and adhere firmly to the gastric mucosa. In the project, we have to do the disintegration test in two different gastric media i.e., acidic & basic media.

In vitro study:

Dissolution studies-

In Vitro dissolution studies for all the prepared tablets and the marketed available tablets were carried out using the USP paddle method at 50 rpm in 900 ml of buffer solution 0.1N HCL as dissolution media, maintained at 37 + 0.5°. 5 ml of sample was withdrawn from the dissolution medium at the specified regular intervals, filtered through Whatman filter paper, and assayed spectrophotometric at 280nm.

An equal volume of pre-warmed (37°C) fresh medium was replaced with the dissolution medium after each sampling, to maintain the constant volume throughout the test. Then the cumulative percentage of drug release was calculated and represented graphically.

RESULTS AND DISCISSION

PRE-FORMULATIONS

Solubility:

S. No.	Medium	Observation
1	Water	Practically insoluble
2	0.1 N HCl	Slightly soluble
3	Methanol	Freely soluble
4	Ethanol	Soluble
5	pH 6.8 Phosphate Buffer	Sparingly soluble to moderately soluble

Table No. 1: The Table contains the Solubility of API

Sr. no.	Concentration (In ppm)	Absorbance
1	5	0.286
2	10	0.586
3	15	0.859
4	20	1.122
5	25	1.412

Table No. 2: Concentration and Absorbance in 0.1 N HCL

Figure No. 1: Calibration curve of Naproxen in 0.1N HCl

Sr. No	Concentration (In ppm)	Absorbance
1	5	0.300
2	10	0.589
3	15	0.796
4	20	1.026
5	25	1.217

Table No. 3: Concentration and Absorbance in Phosphate buffer 6.8

Figure No. 2: Calibration curve of Naproxen in Phosphate buffer 6.8

Sr. No	Concentration (In ppm)	Absorbance
1	5	0.249
2	10	0.405
3	15	0.514
4	20	0.605
5	25	0.796

Table No. 4: Concentration and Absorbance in Methanol

Figure No. 3: Calibration curve of Naproxen in Methanol

Figure No. 4: FTIR Spectra of Naproxen

Figure No. 5: Differential Scanning Calorimetry of Naproxen

Figure No. 6: FTIR Spectra of Naproxen + HPMC K100.

Figure No. 7: FTIR Spectra of Naproxen + HPMC K15.

Figure No. 8: FTIR Spectra of Naproxen + Ethyl cellulose

Figure No. 9: Overlay FTIR Spectra of Naproxen + All Excipients.

Figure No. 10: % Drug content of SD tablet of Naproxen

Time (min)	F1	F2	F3	F4	F5	F6	F7	F8
0	0	0	0	0	0	0	0	0
10	60.32	54.90	61.90	54.36	66.39	58.24	40.87	43.78
15	79.34	69.30	65.01	60.63	72.40	71.80	57.23	57.98
30	85.72	76.84	70.38	68.34	74.29	89.57	69.01	76.43

Table No. 13: Characterization of swelling index

Figure No. 11: Characterization of swelling index

Time (Min)	F1	F2	F3	F4	F5	F6	F7	F8
0	0	0	0	0	0	0	0	0
5	45.23	48.59	59.03	38.69	57.41	47.99	55.29	56.98
10	52.87	58.45	66.30	47.40	75.90	62.33	60.43	64.02
15	66.12	65.96	79.00	67.00	85.42	68.66	68.85	70.05
30	92.65	97.30	87.01	89.18	96.41	98.96	92.32	96.12

Table No. 14: % Drug Release of Naproxen in 0.1N HCl

Figure No. 12: % Drug Release of Naproxen in 0.1N HCl

Sr. No.	Parameter	Result
1.	Weight Variation (mg)	251
2.	Diameter (mm)	8.00
3.	Thickness (mm)	4.23
4.	Hardness (kg/cm2)	6.26
5.	Friability (%)	0.48
7.	% Drug Release	98.96 (30 min)

Table No. 15: Evaluation parameter of optimized Batch (F6)

CONCLUSION

Naproxen solid dispersion tablets were successfully formulated and evaluated using various polymer combinations. All formulations exhibited acceptable pre-compression and post-compression properties. Drug content ranged from 79.67% to 98.50%, indicating satisfactory drug distribution within the formulations. The swelling index of tablets increased with time, confirming the hydrophilic nature of the polymers used. Dissolution studies demonstrated enhanced drug release from all formulations, with cumulative drug release ranging from 87.01% to 98.96% at 30 minutes. Among all batches, formulation F6 showed the highest drug content (98.50%) and maximum drug release (98.96%). Stability studies confirmed the formulation remained stable without significant changes in physical appearance, drug content, swelling behavior, or dissolution characteristics.

The solid dispersion technique proved to be an effective strategy for improving the dissolution performance of Naproxen. All formulations complied with acceptable pharmaceutical quality parameters; however, formulation F6 demonstrated superior performance with the highest drug content, excellent tablet characteristics, and maximum cumulative drug release of 98.96% in 30 minutes. Stability studies further confirmed the robustness of the optimized formulation. Therefore, formulation F6 can be considered the optimized formulation for enhancing the dissolution and potential bioavailability of Naproxen.

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