Solubility Enhancement of Ketoprofen and Ibuprofen Using Hydrotropic Solubilization Method

Abstract

Poor aqueous solubility is a major limitation affecting the oral bioavailability of many non-steroidal anti-inflammatory drugs (NSAIDs), particularly ketoprofen and ibuprofen, which belong to the Biopharmaceutics Classification System (BCS) Class II. The present study investigates hydrotropic solubilization as a simple, economical, and scalable approach to enhance the solubility of these poorly water-soluble drugs. Hydrotropic agents such as sodium benzoate, sodium salicylate, and urea were evaluated at varying concentrations (10–40% w/v) using the shake-flask method. Quantitative analysis was performed using UV spectrophotometry, and calibration curves exhibited good linearity, confirming method reliability. Significant enhancement in solubility was observed in hydrotropic solutions compared to distilled water, with higher concentrations producing greater effects. The systems showed good clarity, stability, and drug content within acceptable limits (98–102%), indicating no degradation. The study demonstrates that hydrotropic solubilization is an effective and industrially feasible technique for improving the solubility of ketoprofen and ibuprofen, offering a promising alternative to conventional solubility enhancement methods

Introduction

Hydrotropic Solubilization of Ketoprofen and Ibuprofen (Summary)

Poor aqueous solubility is a major limitation in oral drug delivery, especially for BCS Class II drugs like ketoprofen and ibuprofen, leading to variable absorption and delayed therapeutic action. These drugs are weak acids with high lipophilicity and exist mainly in unionized form in gastric conditions, resulting in very low solubility.

Problem & Need

Conventional solubility enhancement techniques (micronization, co-solvency, cyclodextrins, nanoparticles) have drawbacks such as toxicity, cost, complexity, and stability issues. Hence, hydrotropic solubilization is explored as a simpler, safer, and scalable alternative.

Hydrotropic Solubilization Concept

Hydrotropes (e.g., sodium benzoate, sodium salicylate, urea) increase solubility by forming non-micellar aggregates that improve drug–water interactions through hydrogen bonding and hydrophobic shielding. This method avoids organic solvents and is compatible with pharmaceutical manufacturing.

Methodology

• Excess drug added to hydrotropic solutions (10–40% w/v)
• Shaken for 24 hours (shake-flask method)
• Filtered and analyzed using UV spectrophotometry
• Solubility compared with distilled water
• Calculated using calibration curves and SER (Solubility Enhancement Ratio)

Key Findings

• Solubility increases significantly with hydrotrope concentration.
• Ketoprofen: Best enhancement with sodium salicylate (SER ~16.17 at 40%)
• Ibuprofen: Highest enhancement with sodium benzoate (SER ~32.85 at 40%)
• Drug content remained within 98–102%, confirming stability and uniformity.
• Calibration curves followed Beer–Lambert law, ensuring reliable quantification.

Conclusion

The present study successfully demonstrates that hydrotropic solubilization is an efficient and practical strategy for enhancing the aqueous solubility of the poorly soluble NSAIDs ketoprofen and ibuprofen. The selected hydrotropic agents particularly sodium benzoate (for ibuprofen) and sodium salicylate (for ketoprofen) produced substantial, concentration-dependent solubility enhancement, as evidenced by SER values of up to 32.85 and 16.17, respectively. The UV spectrophotometric analytical methods demonstrated excellent linearity, precision, and reliability. Drug content analysis confirmed formulation uniformity and the absence of degradation. Clarity and stability studies indicated that optimized hydrotropic systems remained physically and chemically stable over the 7-day evaluation period. Overall, hydrotropic solubilization offers several manufacturing advantages: simplicity of preparation, avoidance of organic solvents, cost-effectiveness, and straightforward scale-up. The technique holds strong potential for developing liquid and solid dosage forms with improved bioavailability. The current study was limited to three hydrotropic agents and short-term (7-day) stability under ambient conditions. Future work should include extended stability studies (3–6 months), evaluation of additional hydrotropes such as nicotinamide and sodium citrate, in vitro dissolution profiling from solid dosage forms incorporating these hydrotropic systems, and pharmacokinetic studies to confirm in vivo bioavailability improvement

References

[1] Lipinski, C. A. (2004). Lead- and drug-like compounds: The rule-of-five revolution. Drug Discovery Today: Technologies, 1(4), 337–341. [2] Amidon, G. L., Lennernäs, H., Shah, V. P., & Crison, J. R. (1995). A theoretical basis for a biopharmaceutic drug classification. Pharmaceutical Research, 12(3), 413–420. [3] Lobenberg, R., & Amidon, G. L. (2000). Modern bioavailability, bioequivalence and biopharmaceutics classification system. European Journal of Pharmaceutics and Biopharmaceutics, 50(1), 3–12. [4] Yalkowsky, S. H., & Roseman, T. J. (1981). Solubilization of drugs by cosolvents. In Techniques of Solubilization of Drugs (pp. 91–134). Marcel Dekker. [5] Jadhav, S. P., Singh, S. K., & Chawra, H. S. (2023). Review on nanosuspension as a novel method for solubility and bioavailability enhancement of poorly soluble drugs. Advances in Pharmacology and Pharmacy, 11(2), 117–130. [6] Loftsson, T. and Brewster, M.E. (2011) Pharmaceutical Applications of Cyclodextrins: Effects on Drug Permeation through Biological Membranes. Journal of Pharmacy and Pharmacology, 63, 1119-1135. [7] Patel, A. D., & Desai, M. A. (2023). Progress in the field of hydrotropy: Mechanism, applications and green concepts. Reviews in Chemical Engineering, 39(4), 601–630. [8] Subramanian, D., Anisimov, M. A., & Soper, A. K. (2019). Hydrotrope-induced clustering of amphiphilic molecules. Journal of Physical Chemistry B, 123(10), 2305–2316. [9] Sharma, U., & Saroha, K. (2024). A review of hydrotropic solubilization techniques for enhancing the bioavailability of poorly soluble drugs. International Journal of Toxicology, 43(1), 63–71. [10] U.S. Food and Drug Administration. (2023). Substances Generally Recognized as Safe (GRAS). https://www.fda.gov/food/generally-recognized-safe-gras [11] Maheshwari, R. K., & Jagwani, Y. (2011). Mixed hydrotropy: Novel science of solubility enhancement. Indian Journal of Pharmaceutical Sciences, 73(2), 179–183. [12] Savjani, K. T., Gajjar, A. K., & Savjani, J. K. (2012). Drug solubility: Importance and enhancement techniques. ISRN Pharmaceutics, 2012, 195727. [13] Avdeef, A. (2012). Absorption and drug development: Solubility, permeability, and charge state (2nd ed.). Wiley. [14] Dressman, J., & Reppas, C. (2013). In vitro–in vivo correlations for lipophilic, poorly water-soluble drugs. European Journal of Pharmaceutical Sciences, 11(2), S73–S80. [15] Serajuddin, A. T. M. (2007). Salt formation to improve drug solubility. Advanced Drug Delivery Reviews, 59(7), 603–616. [16] Allu, S., An, J.-H., Park, B. J., & Kim, W.-S. (2023). Solubility enhancement of the nonsteroidal anti-inflammatory drug of pelubiprofen salts. Crystal Growth & Design, 23(10), 7231–7242. [17] Manallack, D. T. (2007). The pKa distribution of drugs: Application to drug discovery. Perspectives in Medicinal Chemistry, 1, 25–38. [18] Lomba, L., Sánchez-Romero, N., et al. (2022). Phase behaviour and pH-solubility profile prediction of aqueous buffered solutions of ibuprofen and ketoprofen. Fluid Phase Equilibria, 560, 113504. [19] Tripathi, D., Sharma, D. K., & Sahoo, J. (2025). Enhancing ketoprofen solubility using solid dispersion and response surface methodology. Current Radiopharmaceuticals, 18(2), 100–119.

Copyright

Copyright © 2026 Naincy Jain , Anjali Dhakad, Dr. Manoj Goyal. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.