Formulation And Evaluation of Ibuprofen Tablets Using Hydrotropic Solid Dispersion Technique

Abstract

Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), belongs to Class II of the Biopharmaceutical Classification System, characterized by low aqueous solubility and high permeability, which limits its dissolution and oral bioavailability. This study aims to enhance the solubility of Ibuprofen through hydrotropy-based solid dispersion and evaluate its tablet formulations. Various hydrotropes were screened for solubility enhancement, with sodium benzoate demonstrating the highest solubility of 18.73 mol/L. A solid dispersion of Ibuprofen was prepared using a drug-to-hydrotrope ratio of 1:3 via the solvent evaporation technique. Four formulations (F1, F2, F3, and F4) were developed and analyzed for pre-compression parameters, followed by characterization through FT-IR and Powder XRD studies. The solid dispersion was then compressed into tablets using direct compression and evaluated for post-compression parameters, including dissolution rate studies. FT-IR analysis confirmed the absence of chemical interactions, while Powder XRD studies provided insights into crystal structure and powder orientation. Among all formulations, F2 exhibited the highest drug release of 82.2% with a rapid disintegration time of 3.15 minutes. The findings indicate that sodium benzoate effectively enhanced Ibuprofen solubility, and the formulated tablets demonstrated superior drug release compared to pure Ibuprofen tablets.

Keywords

Introduction

Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID) derived from propionic acid, belongs to Class II of the Biopharmaceutics Classification System (BCS). It is widely used for its analgesic and antipyretic properties. Like other NSAIDs, its therapeutic effect is primarily attributed to the inhibition of prostaglandin synthesis. Despite its widespread use, comprehensive physicochemical data on properties such as solubility and molar volume remain limited. ^[1] Due to its high membrane permeability, Ibuprofen is almost completely absorbed, with an absorption extent approaching 100%. As a result, dissolution becomes the rate-limiting step for its absorption, making rapid release in the gastrointestinal tract following oral administration highly desirable. To enhance its solubility and bioavailability, various formulations have been developed, including prodrugs, inclusion complexes, and microcapsules. ^[2] Solubility plays a crucial role in achieving the desired drug concentration in systemic circulation to elicit the necessary pharmacological response. Hydrophobic drugs often require high doses and frequent administration to attain therapeutic plasma levels. Poor aqueous solubility remains a significant challenge in the formulation and development of both New Chemical Entities (NCEs) and generic drugs. For orally administered drugs, solubility is a key rate-limiting factor influencing their ability to reach optimal systemic concentrations for effective therapeutic action. ^[3] To increase the solubility of poorly water-soluble drug different solubilization technique have been used which are- Solid Dispersion, Nanonization, Eutectic mixtures, Hydrotropic solubilization, Solvent deposition, Spray freeze drying Micronization etc.^[4] Hydrotropy is a solubility enhancement technique that involves the addition of a large quantity of a second solute to increase the aqueous solubility of a poorly soluble substance. This second solute is typically an ionic organic salt, often an alkali metal salt of an organic acid. ^[5] Commonly used hydrotropes: Urea, Sodium benzoate, Nicotinamide, Potassium citrate, Potassium acetate, Benzo sulfonate, Polyethylene glycol 400 (PEG 400), Propylene glycol (PG), Caffeine, Sodium accurate, Sodium p-benzoate, Sodium acetate, Sodium salicylate, Sodium citrate, Piperazine, Resorcinol, etc.^[6] Hydrotropes are water-soluble, surface-active compounds that enhance the solubility of organic solutes such as esters, alcohols, aldehydes, ketones, hydrocarbons, and lipids. They are non-reactive, non-toxic, and do not induce any temperature changes upon dissolution in water. Key characteristics of hydrotropes include pH-independent solvent behavior, high selectivity, and the ability to improve solubility without causing emulsification. ^[7] Solid dispersion technology is a widely used approach to enhance the dissolution rate of poorly water-soluble drugs, thereby improving both the rate and extent of drug absorption. A common method for preparing solid dispersions is solvent evaporation, where a volatile organic solvent dissolves the hydrophobic drug, followed by solvent removal through evaporation to yield the solid dispersion. A more recent advancement, hydrotropic solid dispersion (HSD) technology, eliminates the need for organic solvents. This method utilizes a water-soluble hydrotropic agent as a carrier, while the drug itself remains insoluble in water. In the presence of a high concentration of the hydrotropic agent, the drug undergoes solubilization through the hydrotropic solubilization phenomenon. The solid dispersion is then obtained by evaporating water, resulting in HSDs. ^[8]

This study aims to develop and evaluate an Ibuprofen tablet formulation using hydrotropic-based solid dispersion and to compare its in vitro dissolution rate with that of pure Ibuprofen. Since Ibuprofen has poor aqueous solubility, its dissolution rate is a limiting factor in drug absorption. The use of a hydrotropic agent in this experimental approach offers an alternative strategy to enhance the release of poorly soluble drugs in aqueous solutions. The proposed hydrotropic solid dispersion method has the potential to significantly improve the dissolution rate and bioavailability of Ibuprofen.

MATERIALS AND METHODOLOGY

The Active Pharmaceutical Ingredient, Ibuprofen was purchased from Empree medicaments Pvt Ltd, Belagavi. Other chemicals- Sodium benzoate, Sodium citrate, Sodium acetate, Lactose, Magnesium stearate, Talc and Microcrystalline cellulose (102) were acquired from Burgoyne Burblidges & Co., India. All the chemicals and solvents used were of analytical grade.

Preparation of standard calibration curve of Ibuprofen: ^[9]

Preparation of Stock Solution: A standard curve was generated by dissolving 100 mg of Ibuprofen in phosphate buffer (pH 7.2) and adjusting the volume to 100 mL. This stock solution was then further diluted to obtain a concentration range of 0–25 µg/mL. The absorbance values were recorded at 221 nm.

Preparation of Working Standard Solutions: From the second stock solution (SS-II), aliquots of 0.5, 1, 1.5, 2, and 2.5 mL were transferred into 100 mL volumetric flasks. The volume was adjusted with phosphate buffer (pH 7.2) to achieve final concentrations of 5, 10, 15, 20, and 25 µg/mL, respectively. The absorbance of each solution was measured at 221 nm.

Selection of Hydrotrope for poorly aqueous soluble drug: ^[10]

The required amounts of sodium acetate, sodium benzoate, sodium citrate, and water were separately added to 0.1 g of Ibuprofen in aqueous solution. Each mixture was mechanically shaken and sonicated for 30 minutes. The resulting solutions were filtered using Whatman filter paper, and the filtrates were analyzed spectrophotometrically. The absorbance values were extrapolated from the calibration curve to determine the unknown concentration, and the solubility of each sample was calculated. The selected Hydrotrope was then combined with the drug (0.1 g) in varying Drug: Hydrotrope ratios (1:1, 1:2, 1:3), and the process was repeated. The ratio yielding the highest solubility was chosen for formulation, as illustrated in table 2 and 3.

Preparation of Ibuprofen HSD (Hydrotropic Solid Dispersion):

Ibuprofen (0.1 g) was added to a minimal quantity of aqueous medium maintained at a controlled temperature, containing an adequate amount of the selected Hydrotrope in its dissolved state. The mixture was stirred until a semisolid mass was formed. Following evaporation, the mass was spread to facilitate faster drying at 60–65ºC. The dried mass was then pulverized, ground, and subjected to repeat drying in an oven. The final dried powder was sieved using a #60 mesh sieve and stored in an air-tight desiccator to maintain stability. ^[10]

Figure 1: Preparation of IBU HSD powder

Physical characteristics of Ibuprofen HSD:

Fourier-Transform Infrared Spectroscopy: FT-IR spectroscopy was conducted to assess the compatibility between the drug and the polymer. The FT-IR spectra of Ibuprofen with polymers were compared with the standard FT-IR spectrum of the pure drug. For analysis, 2–3 mg of Ibuprofen and the prepared formulations were separately mixed with 400 mg of dry potassium bromide (KBr) powder, compressed into transparent discs, and their IR spectra were recorded in the wavelength range of 4000–400 cm?¹. ^{[12, 13]}

Powder X-ray Diffraction (PXRD): Powder X-ray diffraction (PXRD) was conducted to assess the physical characteristics of Ibuprofen in the samples using an XRD2 micro-diffractometer. The diffraction patterns were recorded on a quartz plate at a tube voltage of 56 kV and a current of 182 mA. A scan rate of 2º/min was applied over an angular range of 0–180º 2θ to analyze the crystalline or amorphous nature of the drug. ^[14]

Preparation of HSD Ibuprofen tablets:

Four different formulations were prepared, including tablets of pure Ibuprofen (F1) and Ibuprofen hydrotropic solid dispersion (HSD) formulations (F2, F3, F4), using the direct compression method as illustrated in table 1. Each ingredient was accurately weighed and sifted through a #40 mesh. The active pharmaceutical ingredient (API) was gently mixed with different formulations of lactose and microcrystalline cellulose (MCC 102) in a glass mortar using a pestle. The blend was then lubricated with magnesium stearate and talc. Before compression, the punch surfaces were lubricated with a 2% w/v magnesium stearate solution in acetone. The powder blend was directly compressed into tablets using a 10 mm round concave-faced punch on an eight-station rotary tablet machine, ensuring uniform hardness and thickness across all batches. The compression force was maintained constant for all formulations. The tablets were ejected and stored in screw-capped bottles for 24 hours to assess potential hardening and elastic recovery. In-process and finished product evaluation tests were conducted immediately after ejection and again after a 24-hour relaxation period. All four formulations were evaluated for both pre-compression and post-compression parameters to ensure quality and consistency. ^[15-26]

*Formulation F1 contains pure drug Ibuprofen

Table 2: Standard Calibration of Ibu In 7.2 pH Phosphate Buffer

Sr. No	Concentration (µg/ml)	Trail 1	Trail 2	Trail 3	Standard deviation (n =3)
1	0	0	0	0	0.000
2	05	0.213	0.213	0.214	0.213±0.004
3	10	0.468	0.469	0.467	0.467±0.002
4	15	0.661	0.663	0.662	0.661±0.001
5	20	0.854	0.851	0.852	0.852±0.002
6	25	1.055	1.054	1.055	1.055±0.002

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 2: Standard calibration curve of Ibuprofen

Table 3: Selection Of Hydrotrope for Poorly Aqueous Soluble Drug

Hydrotrope	Absorbance (nm)	Solubility (mol/l)
Sodium benzoate (SB)	0.801	18.73
Sodium citrate (SC)	0.265	5.97
Sodium acetate (SA)	0.223	4.975
Water	0.195	4.30

Table 4: Solubility Of Ibuprofen In Different Drug: Hydrotrope Ratio

(IBU: SB) ratio	Absorbance (nm)	Solubility (mol/l)
1:1	0.801	18.73
1:2	1.018	23.79
1:3	1.446	34.095

Hydrotropes, including sodium benzoate, sodium citrate, and sodium acetate, were evaluated for their solubility enhancement potential in an aqueous medium. Among them, sodium benzoate exhibited the highest solubility of 18.73 mol/L as depicted in table 2. Subsequently, sodium benzoate was combined with Ibuprofen in different Drug: Hydrotrope ratios (1:1, 1:2, 1:3) to determine the optimal ratio for solubility enhancement. The highest drug solubility of 34.095 mol/L was observed at a 1:3 Drug: Hydrotrope ratio as illustrated in table 3, which was selected for further formulation development.

Figure 3: FT-IR spectra of pure Ibuprofen

Figure 4: FT-IR spectra of Ibuprofen HSD

The results of FT-IR showed that there was no interaction between the drug and excipients. Hence, by performing FT-IR, it was observed that the drug was compatible with the excipients. Depicted in Figure 3 and 4.

Figure 5: PXRD of pure Ibuprofen

Figure 6: PXRD of Ibuprofen HSD

The X-ray diffraction (XRD) analysis of pure Ibuprofen exhibited multiple sharp diffraction peaks, confirming its crystalline nature. In contrast, the physical mixture of Ibuprofen hydrotropic solid dispersion (HSD) powder displayed only a few peaks with weaker intensities, indicating a significant reduction in crystallinity and a more amorphous nature as depicted in figure 5 and 6. This transformation suggests improved solubility and dissolution potential of Ibuprofen in the HSD formulation.

Formulation code	Evaluation parameters
	Physical appearance	Angle of repose (θ )	Bulk density (g/cm³)	Tapped density (g/cm³)	Carr’s index (%)	Hausner’s ratio
F1	White, crystalline	34.99	0.46	0.74	36.11	1.54
F2	White, crystalline	25.17	0.69	0.8	13.75	1.15
F3	White, crystalline	28.96	0.65	0.79	17.72	1.21
F4	White, crystalline	32.34	0.51	0.78	34.6	1.52

Table 5: Pre-Compression Studies Of The Formulated Powders

Figure 7: Bar graph representation of bulk density, tapped density and carr’s index

The bulk density of all formulations ranged between 0.4 to 0.6 g/cm³, while the tapped density was within 0.7 to 0.8 g/cm³. A smaller difference between bulk and tapped density indicates good flow properties, whereas a larger difference suggests poor flow. F2 and F3 showed a bulk-tapped density difference of 0.11 and 0.14, respectively, indicating good flow properties. F1 and F4, with differences of 0.28 and 0.27, respectively, exhibited poor flow due to stronger inter particle interactions. Carr’s Index, which reflects powder flowability, was lower for F2 and F3, confirming better flow. In contrast, F1 and F4 had higher Carr’s Index values, suggesting poor flowability. The angle of repose, another key indicator of powder flow, further supported these findings: F2 (25.17º) and F3 (28.96º) had good flow. Whereas, F1 (34.99º) and F4 (32.24º) showed poor flowability. Hausner’s Ratio, which should ideally be ≤1.25 for good flow; F2 (1.15) and F3 (1.21), confirming good flow properties. Whereas, F1 (1.54) and F4 (1.52), indicating poor flowability as values exceeded 1.5.

All tablets were successfully formulated using the direct compression method and exhibited a white, round, uniform appearance with a smooth texture and shiny surface. The thickness of all formulations ranged between 3.11 mm and 3.16 mm. The average hardness of the four formulations was recorded between 6.4 and 6.8 kg/cm², while the average tablet weight remained consistent at 500-501 mg. A weight reduction of no more than 1% is generally considered acceptable. The friability results, ranging from 0.1% to 0.3%, were well within the permissible limit of less than 1% for uncoated tablets. Additionally, all formulations demonstrated drug content uniformity exceeding 97%.

Figure 8: Bar graph representation of disintegration test

The disintegration time for uncoated tablets remained within the acceptable 15-minute limit, ensuring that all batches met this requirement and confirming that the tablets effectively crumble, allowing the medicine to dissolve. Excipients play a crucial role in disintegration. MCC (102) is highly compressible and possesses disintegrant properties but lacks sufficient flowability for high-speed tablet production with uniform weight. In contrast, certain forms of lactose exhibit excellent flowability but are only moderately compressible and do not possess disintegrant properties. However, when combined, these two excipients complement each other, creating an optimized formulation with balanced flow and compressibility characteristics. The disintegration times varied among the formulations, with F2 disintegrating in 3.15 minutes, F3 in 10.12 minutes, F4 in 8.56 minutes, and F1 taking the longest at 14.38 minutes.

Figure 9: In vitro drug release profile (%CDR v/s Time)

The rate of dissolution plays a crucial role in determining how quickly and efficiently a drug is absorbed, directly influencing its therapeutic effectiveness. According to the USP, the acceptable tolerance limit requires that at least 80% of the labeled amount of Ibuprofen be dissolved within 60 minutes. In this study, the F2 formulation met this criterion, demonstrating a drug release of 82.2%. In contrast, F3 and F4 exhibited drug release rates of 73.75% and 77.2%, respectively, while F1 showed the lowest release at 50.8% within the same timeframe. F2, identified as the best-performing formulation, was subjected to stability studies over one month. The results confirmed that F2 remained stable, with minimal variation in its physical and chemical properties, ensuring its reliability and effectiveness over time.

CONCLUSION

In conclusion, this study demonstrates that the solubility of Ibuprofen was significantly enhanced through the addition of hydrotropes. Among the hydrotropes tested, Sodium benzoate in a 1:3 ratio (drug: Hydrotrope) showed the most notable improvement in solubility. Based on this analysis, the selected Hydrotrope was incorporated into directly compressed tablet formulations, which exhibited a superior drug release profile compared to pure Ibuprofen tablets. Dissolution studies confirmed that HSD IBU tablets achieved the highest cumulative drug release (% CDR) at 60 minutes. These findings suggest that the proposed Hydrotropic Solubilization approach can be effectively utilized for quantitative analysis, dissolution studies, and potential enhancement of bioavailability. This method highlights the role of hydrotropes in improving the solubilization dynamics of Ibuprofen.

ACKNOWLEDGEMENT

The authors are thankful to Rani Chennamma College of Pharmacy, Belagavi for providing facilities for carrying out the research work. Authors would also acknowledge KLE College of Pharmacy, Belagavi for doing FT-IR analysis of samples and Rani Chennamma University, Belagavi, for performing PXRD of samples.

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