Hydrotropic Solubilization: An Emerging Approach
Drug development plays an important role in patient safety and effectiveness. The therapeutic suitability of a new drug depends on the solubility. The solubility of the sparingly soluble drug remains a problem in identifying new active compounds. Solubility plays an important role in achieving optimal drug concentration. Low solubility is not only a concern for the production of formulations, but also an obstacle from the outset when identifying active chemicals for therapeutic purposes. Due to its simplicity in terms of ease of administration and economy, the oral route is the preferred route of drug administration over other routes. Effective aqueous solubility is the first prerequisite for oral medication, since low solubility has poor absorption and bioavailability and unpredictable toxicity of the gastrointestinal mucosa. To avoid these crises, different methodologies are used to improve the solubility and bioavailability of poorly soluble drugs, and hydrotropic solubilization is one of them. Hydrotropic agents have the potential to improve the solubility of water-insoluble drugs. In this review, we try to address hydrotropic solubilization methodologies.
Keywords: Hydrotropy, Micelles, Solubility, Formulation.
2. Martin, S. and Karl, B., Chasing equilibrium: measuring the intrinsic solubility of weak acids and bases. Anal. Chem. 2005; 77(4):983–990.
3. Horter, D., Dressman, J. B. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv Drug Deliv Rev. 2001; 46(1-3):75-87.
4. Devane, J., Oral drug delivery technology: Addressing the solubility/permeability paradigm. Pharm. Technol. 1998; (11):68-74.
5. Asmat, M., Syed, N. R. and Nisar, A. K. Hydrotrophy: Novel solubility enhancement technique: a review. IJPSR, 2019; 10(3):1025-1036.
6. Thipsay, M.P., Ross, S., Zhang, F., Bandari, S., Repka, M.A. Preparation of a crystalline salt of indomethacin and tromethamine by hot melt extrusion technology. Eur J Pharm Biopharm. 2018; 131(10):109–119.
7. Khadka, P. Et al. Pharmaceutical particle technologies: an approach to improve drug solubility, dissolution and bioavailability. Asian J. Pharm. Sci. (2014; 9:304–316.
8. Brahmankar, D., Jaiswal, S., Biopharmaceutics and Pharmacokinetics: A Treatise. Third ed., Vallabh Prakashan, India, 2011.
9. Vemula, V., Lagishetty, V., Lingala, S. Solubility enhancement techniques. Int. J. Pharm. Sci. Rev. Res. 2010; (5):41–51.
10. Serajuddin, T. M., Mufson, D., pH-Solubility profiles of organic bases and their hydrochloride salts. Pharm Res. 1985; ( 5): =65–68.
11. Kevin W. G., Richard A. P. Aqueous solubility properties of a dibasic peptide-like compound. International Journal of Pharmaceutics. 1990; 63(2): =15:167-172.
12. Serajuddin, T. M., Jarowski, C. I. Effect of diffusion layer pH and solubility on the dissolution rate of pharmaceutical bases and their hydrochloride salts I: Phenazopyridine. J. Pharm. Sci. 1985; (74):142.
13. Hodgdon, T., Kaler, E., Hydrotropic solutions. Curr. Opin. Colloid. In. 2007; 12:121–128.
14. Saleh, L., Khordagui, E. Hydrotropic agents: A new definition. Int. J. Pharm. 1985; 24:231–238.
15. Tooru, O., Sang, C. L., Kang, M. H., Kinam, P., Mozafari, M. hydrotropic nanocarriers for poorly soluble drugs. Nanocarrier Technologies: Frontiers of Nanotherapy. 2006; 51–73.
16. Girija, R., Vilas, G. G. Extraction of piperine from piper nigrum (black pepper) by hydrotropic solubilization. Ind. Eng. Chem. Res. 2002; (41):2966-2976.
17. Jain, N., Patel, V., Taneja, L., Hydrotropic solubilization of nifedipine. Pharmazie. 1988; (43):194–196.
18. Kumar, V., Raja, C., Jayakumar, C. A review on solubility enhancement using hydrotropic phenomena. Int. J. Pharm. Pharm. Sci. 2014; (6):1–7.
19. Dhapte V, Mehta, P. Advances in hydrotropic solutions: An updated review, St. Petersburg Polytechnical University Journal: Physics and Mathematics. 2015; (1): 424–435.
20. Maheshwari, R.K. et al. Novel application of hydrotropic solubilizing additives in the estimation of aspirin in tablets. Indian. J. Pharm. Sci. 2010; (72): 649–651.
21. Maheshwari, R. K. Mixed hydrotropy in spectrophotometric analysis of Aceclofenac. The Indian Pharmacist. 2007; 64(6):67-69.
22. Maheshwari, R.K., Indurkhya, A. Formulation and evaluation of aceclofenac injection made by mixed hydrotropic solubilization technique. Iran. J. Pharm. Res. 2010; 9:233–242.
23. Maheshwari, R. K., Chaturvedi S. C., Jain, N.K. Novel application of hydrotropic solubilization in the quantitative analysis of some NSAIDs and their solid dosage forms. Ind. J. Pharm. Sci.2007; 69(1):101-105.
24. Ravi, S. S., Asha, P., Soni, M. L., Modi, V., Jaliwala. Y. A. Quantitative spectrophotometric estimation of Cefadroxil using hydrotropic solubilization technique. Asian J Pharm. 2008; 7:146- 147.
25. Jain, K. Solubilization of indomethacin using hydrotropes for aqueous injection. Eur. J Pharm. Biopharm. 2007; (68):701–714.
26. Nahar, M., Jain, N. K. Formulation and evaluation of Sanquir injection. Ind. J Pharm. Sci. 2006; 10:608- 614.
27. Agrawal, S., Pancholi, S.S., Jain, N.K., Agrawal, G.P. Hydrotropic solubilization of nimesulide for parenteral administration. Int. J Pharm. 2004; (274): 149–155.
28. Neuberg, C. Hydrotropic phenomena. Biochem. Z. 1916; 76:107-108.
29. Neuberg, C. Hydrotrophy. Biochem. J. Pharm., 1989; 75(7):577.
30. Poochikian, G.D., Gradock, J.C., Enhanced chartreusin solubility by hydroxybenzoate hydrotropy. J.Pharm. Sci. 1979; (68):728-732.
31. Badwan, A.A., Khordagui E., Saleh, A.M. and Khalil, S.A., The solubility of benzodiazepines in sodium salicylate solution and a proposed mechanism of hydrotropic solubilization. Int. J. Pharm. 1983; 13:67-74.
32. Saleh, A.M. and Khordagui E., Hydrotropic agents: a new definition. Int. J. Pharm. 1985; 24:231.
33. Winsor, P.A., Hydrotropy, Solubilization and related emulsification process. Trans Faraday Soc., 1950; 54:762-772.
34. Higuchi, T., Drubulis, A., Complexation of organic substance in aqueous solution by hydroxy aromatic acids and their salts relative contribution of several factors to the overall effects. J. Pharm. Sci. 1961; 50:905.
35. Ueda S. The mechanisms of solubilization of water insoluble substances with sodium benzoate derivatives-I. Chem Pharm Bull. 1966; (14):22.
36. Saleh, A. M., Daabis, N. A. Study of the Interaction of Menadione with Hydrotropic Salts Pharmazie. 1974; 29(8):525-7
37. Hamza, Y.E., Paruta, A.N., Enhanced solubility of paracetamol by various hydrotropic agents. Drug Dev. Ind. Pharm. 1985; (11):1577.
38. Feldman, S., Gibaldi, M. Effect of urea on solubility, role of water structure. M., J. Pharm. Sci. 1967; (56):370.
39. Suzuki, H., Sunada, H. mechanistic studies on hydrotropic solubilization of nifedipine in nicotinamide solution. Chem Pharm Bull. 1998; 46(1):125-30.
40. Jain, N.K., Agrawal, R.K., Singhai, A.K. Formulation of aqueous injection of carbamazepine. Pharmazie. 1990; (45):221-222.
41. Agarwal, M., Gaikar,V. G. Extractive separations using hydrotropes, Sep. Technol. 1992; (2):79–84.
42. Rathore, K. S., Tanwar, Y. S., Nema, R. K., Gupta, G. D. A review on hydrotropes; compounds for solubility enhancement of poorly water-soluble compounds. The Pharma Review. 2007; (12).
43. Maheshwari, R. K., Indurkhya, A. Novel application of mixed hydrotropic solubilization technique in the formulation and evaluation of hydrotropic solid dispersion of aceclofenac, Asian J. Pharm 2010; 4:235–238
44. Madan, J., Pawar, K., Dua, K. Solubility enhancement studies on lurasidone hydrochloride using mixed hydrotropy. Int. J. Pharm. Investig. 2015; 5:114–120.
45. Ruchi, J. et al. Novel UV spectrophotometer methods for quantitative estimation of metronidazole and furazolidone using mixed hydrotropy solubilization. Arabian Journal of Chemistry. 2017; 10:151–156.
46. Lai K, Liquid Detergents, second ed., CRC Press, Boca Raton, FL, 2006
47. Ansari K, Gaikar V, Green hydrotropic extraction technology for delignification of sugarcane bagasse by using alky benzene sulfonates as hydrotropes. Chem. Eng. Sci. 2014; 115:1157– 1166.
48. Gaikar, V., Sharma, M. Separations with hydrotropes, Sep. Technol. 1993; 3:2–11.
49. Kumar, V., Raja, C., Jayakumar, C., A review on solubility enhancement using hydrotropic phenomena. Int. J. Pharm. Pharm. Sci. 2014; 6:1–7.
50. Rub, M., Azum, N., Kumar, D., Khan, F., Asiri, A. Clouding phenomenon of amphiphilic drug promazine hydrochloride solutions: Influence of pharmaceutical excipients., J. Ind. Eng. Chem. 2015; 21:1119–1126.
51. Kamble, S., Kumbhar, A., Jadhav, S., Salunkhe, R., Micheal, A. Reaction in glycerol as a sustainable hydrotropic medium. Mater. Today: Proc. 2015; 5:1792–1798.
52. Jyoti, J., Nidhi, N. S., Vikas, A. S., A review on hydrotropy: a potential approach for the solubility enhancement of poorly soluble drug. Asian J Pharm Clin Res, 2019; 12(10):19-26.
53. Ammar, H.O., Nahhas, Effect of aromatic hydrotropes on the solubility of allopurinol Part 3: Sodium Salts of Toluic acids, Pharmazie. 1993; 48(H10):751-754
54. Khalafallah, N., Hammouda, Y. The solubility and Complexing properties of acetohexamide in the presence of hydrotropic agents. Pharmazie. 1973; 28(H7):452-454.
55. Coffman, R.E., Kildsig D.O. Self Association of Nicotinamide in aqueous solution: Light scattering and Vapour pressure Osmometry studies. J. Pharm. Sci. 1996; 85(8):848-853.
56. Ammar, H.O., Ibrahim, S.A., El-Faham, T. H. Interaction of chlorothiazide and hydrochlorothiazide with certain amide, Imides and xanthaines. Pharm. Ind. 1981; 43(Nr 3):292-295.
57. Jain, N. K., Singhai, A. K., Jain, S. Hydrotropic solubilization of ketoprofen. Pharmazie, 1996; 51(4):236-239.
58. Ammar, H.O., Nahhas, Effect of aromatic hydrotropes on the solubility of allopurinol Part 2: Effect of nicotinamide and sodium salts of benzoic, napthoic and nicotinic acid Pharmazie. 1993; 48(H7):534-536.
59. Pedersen, M., Effect of hydrotropic substances on the complexation of clotrimazole with β-cyclodextrin. Drug dev. Ind. Pharm. 1993; 19(4):439-448.
60. Elsamaligy, M.S., Hamza, Y.E., Abd-Elgawad, N. A. Hydrotropic and complexing solubilization of acetazolamide. Pharm. Ind. 1992; 54(Nr5):474-477.
61. Gaikar, V. G., Latha, V. Hydrotropic properties of sodium salts of ibuprofen. Drug Del. Ind. Pharm. 1997; 23(3):309-312.
62. Zughul, M. B., Omari, M., Badwan, A. A. Enhancement of thioacetone solubility by Isoniazide in aqueous solutions. Drug Dev. Ind. Pharm. 1996; 22(9 and 10):1013-1019.
63. Kavita, S., Ashu, S., Singha, S. K., Kakkar, S. Self-Emulsifying Drug Delivery System: A Tool in Solubility Enhancement of Poorly Soluble Drugs. Indo Global Journal of Pharmaceutical Sciences, 2012; 2(3):313-332.
64. Kumari, R., Chandel, P. A Kapoor. Paramount Role of Solid Dispersion in Enhancement of Solubility. Indo Global Journal of Pharmaceutical Sciences, 2013; 3(1):78-89.
65. Gawade, A. R., Boldhane, S. P. Solid Dosage Form Development of Dabigatran Etexilate Mesylate With Increased Solubility and Dissolution Using Cocrystallization. IJPSR, 2020; 11(5):2899-2905.
66. Kuchekar, A. B., & Pawar, A. P. Capecitabine loaded polymeric micelles: Formulation, characterization and cytotoxicity study. International Conference on Advanced Nanomaterials & Emerging Engineering Technologies. 2013, pp. 412-415.
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