Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter June 18, 2020

Aggregation Behavior and Thermodynamic Studies of Hydrotropes: A Review

Aggregationsverhalten und thermodynamische Studien von Hydrotropen: Ein Übersichtsbeitrag
  • Akash D. Patel and Meghal A. Desai


Under the aspect of strict environmental regulations, hydrotropy is accepted as an environmentally friendly (“green”) approach to solubilise hydrophobic compounds. Above the minimum hydrotrope concentration (MHC), hydrotropes are capable of self-aggregation; the MHC is considered the minimum requirement for solubilisation. In this article a comprehensive overview of the aggregation behaviour of different hydrotropes is presented. Details about the methods used for aggregation are given. The role of additives is discussed with respect to their influence on the MHC. Thermodynamic studies are used to evaluate the stability of a hydrotrope at different temperatures. A modern approach to the solubilization mechanism using hydrotropes is also presented in this review article. The aim of this article is to provide guidance for conducting such studies on a number of hydrotropes.


Unter dem Aspekt der strengen Umweltauflagen wird die Hydrotropie als ein umweltfreundlicher Ansatz zur Solubilisierung hydrophober Verbindungen angenommen. Hydrotrope sind oberhalb der minimalen Hydrotrop-Konzentration (MHC) fähig zur Selbstaggregation; die MHC gilt als Mindestanforderung für eine Solubilisierung. In diesem Artikel wird eine umfassende Übersicht über das Aggregationsverhalten verschiedener Hydrotrope vorgestellt. Es werden Details über die für die Aggregation verwendeten Methoden angegeben. Die Rolle der Additive wird hinsichtlich ihres Einflusses auf die MHC diskutiert. Zur Bewertung der Stabilität eines Hydrotrops bei verschiedenen Temperaturen werden thermodynamische Studien herangezogen. Ein moderner Ansatz zum Solubilisierungsmechanismus mit Hilfe von Hydrotropen wird in diesem Übersichtsartikel ebenfalls vorgestellt. Ziel dieses Artikels ist, Hilfestellung für die Durchführung solcher Studien an einer Anzahl von Hydrotropen zu geben.

Correspondence address, Dr. Meghal A Desai, Department of Chemical Engineering, Sardar Vallabhbhai National Institute of Technology, Surat-395007, Gujarat, India, E-Mail:

Akash Patel is the research scholar at Chemical Engineering Department, Sardar Vallabhbhai National Institute of Technology, Surat, Gujarat, India (E-Mail: ).

Dr. Meghal Desai (corresponding author) is serving as an Associate Professor at Chemical Engineering Department, Sardar Vallabhbhai National Institute of Technology, Surat, Gujarat, India (E-Mmail: , ). He is working in the area of amphiphillic compounds, he is involved in the extraction of phytochemicals from the plant materials using various extraction techniques and optimization of process parameters using statistical techniques.


1 C. J. Clarke , W. C.Tu, O.Levers, A.Brohl and J. P.Hallett: Green and sustainable solvents in chemical processes, Chem. Rev.118(2018) 747800. 29300087 10.1021/acs.chemrev.7b00571Search in Google Scholar PubMed

2 G. Raman and V. G.Gaikar: Extraction of piperine from piper nigrum (black pepper) by hydrotropic solubilization, Ind. Eng. Chem. Res. 41 (2002) 29662976. 10.1021/ie0107845Search in Google Scholar

3 C. Neuberg : Hydrotropy, Biochem Z. 76 (1916) 107.Search in Google Scholar

4 D. Balasubramanian , V.Srinivas, V. G.Gaikar and M. M.Sharma: Aggregation behavior of hydrotropic compounds in aqueous solution, J. Phys. Chem. 93 (1989) 38653870. 10.1021/j100346a098Search in Google Scholar

5 V. Srinivas and D.Balasubramanian: When does the switch from hydrotropy to micellar behavior occur?Langmuir. 14 (1998) 66586661. 10.1021/la980598cSearch in Google Scholar

6 S. Kumar , P.Nahid and Kabir-ud-din: Additive induced association in unconventional systems: A case of the hydrotrope, J. Surfactants Deterg. 8 (2005) 109114. 10.1007/s11743-005-0338-2Search in Google Scholar

7 V. S. Chirravuri , P. K. C.Ichapurapu, A. V. S. L. S.Bharadwaj and M. M. K. P.Kommuri: Functions of hydrotropes in solution, Chem. Eng. Technol. 35 (2012) 225237. 10.1002/ceat.201100484Search in Google Scholar

8 V. Dhapte and P.Mehta: Advances in hydrotropic solutions: An updated review, St. Petersburg Polytechnical University Journal: Physics and Mathematics, 1 (2015) 424435. 10.1016/j.spjpm.2015.12.006Search in Google Scholar

9 R. H. McKee : Use of hydrotropic solution in industry, Ind. Eng. Chem. 38 (1946) 382384. 10.1021/ie50436a012Search in Google Scholar

10 P. A. Winsor : Hydrotropy, solubilization and related emulsification process, Trans. Faraday Soc.54 (1948) 376. 10.1039/TF9484400376Search in Google Scholar

11 A. A. Badwan , L. K.El-Khordagui, A. M.Saleh and S. A.Khalil: The solubilities of benzodiazepines in sodium salicylate solution and a proposed mechanism for hydrotropic solubilization, J. Pharm. Pharmacol.32 (1980) 74P. 10.1111/j.2042-7158.1980.tb10877.xSearch in Google Scholar

12 A. M. Saleh , A. A.Badwan and L. K.El-Khordagui: A study of hydrotropic salts, cyclohexanol and water system, Int. J. Pharm. 17 (1983) 115119. 10.1016/0378-5173(83)90024-8Search in Google Scholar

13 A. M. Saleh and L. K.El-Khordagui: Hydrotropic agents: A new definition, J. Pharm. Sci.24 (1985) 231238. 10.1016/0378-5173(85)90023-7Search in Google Scholar

14 V. Gaikar and M.Sharma: Extractive separation with hydrotrope. Solvent Extr. Ion Exch. 4 (1986) 839846. 10.1080/07366298608917896Search in Google Scholar

15 A. Mahapatra , V. G.Gaikar and M. M.Sharma: New strategies in extractive distillation: use of aqueous solutions of hydrotrope and organic base as solvent for organic acids. Sep. Sci. Technol. 23 (1988) 429436. 10.1080/01496398808060714Search in Google Scholar

16 P. O. Raynaud-Lacroze and N. S.Tavare: Separation of 2-napthols: hydrotropy and precipitation, Ind. Eng. Chem. Res. (32) 1993685691. 10.1021/ie00016a015Search in Google Scholar

17 E. J. Colonia , A. B.Dixit and N. S.Tavare: Separation of o and p chlorobenzoic acid: Hydrotropy and precipitation, J. Cryst. Growth. 166 (1996) 976980. 10.1016/0022-0248(96)00058-9Search in Google Scholar

18 Y. P. Koparkar and V. G.Gaikar: Hydrotropic separation of mixtures of o-/p-hydroxyacetophenones, Sep. Sci. Technol. 39 (2004) 38793895. 10.1081/SS-200041547Search in Google Scholar

19 R. Natarajan , J.Chinnakannu and N.Gandhi: Effective separation of petro products through hydrotropy, Chem. Eng. Technol. 32 (2009) 129133. 10.1002/ceat.200800328Search in Google Scholar

20 V. G. Sadvilkar , S. D.Samant and V. G.Gaikar: Claisen-Schmidt reaction in hydrotropic medium, J. Chem. Technol. Biotechnol. 62 (1995) 405410. 10.1002/jctb.280620415Search in Google Scholar

21 S. J. Chandratre and Z. A.Filmwala: Syntheses of quinolines by Friedlander's heteroannulation method in aqueous hydrotropic medium, J. Dispersion Sci. Technol. 28 (2007) 279283. 10.1080/01932690601061954Search in Google Scholar

22 M. Barge , S.Kamble, A.Kumbhar, G.Rashinkar and R.Salunkhe: Hydrotrope: Green and rapid approach for the catalyst-free synthesis of pyrazole derivatives, Monatshefte fur Chemie. 144 (2013) 12131218. 10.1007/s00706-013-0944-4Search in Google Scholar

23 S. Kamble , A.Kumbharb, S.Jadhav and R.Salunkhec: Aza-Micheal reaction in glycerol as a sustainable hydrotropic medium. Mater. Today. 2 (2015) 17921798. 10.1016/j.matpr.2015.07.022Search in Google Scholar

24 A. Patil , M.Barge, G.Rashinkar and R.Salunkhe: Aqueous hydrotrope: an efficient and reusable medium for a green one-pot, diversity-oriented synthesis of quinazolinone derivatives, Mol. Divers. 19 (2015) 435445. 25790788 10.1007/s11030-015-9580-8Search in Google Scholar PubMed

25 M. Desai and J.Parikh: Hydrotropic extraction of citral from Cymbopogon flexuosus (Steud.) Wats, Ind. Eng. Chem. Res. 51 (2012) 37503757. 10.1021/ie202025bSearch in Google Scholar

26 M. Dhinakaran , A.Bertie and N.Gandhi: Extraction of vanillin through hydrotropy, Asian J. Chem. 25 (2013) 231236. 10.14233/ajchem.2013.12915Search in Google Scholar

27 D. Prakash , P.Panneerselvam, S.Madhusudanan and V.Aditya: Hydrotropic extraction of xanthones from mangosteen pericarp, Adv. Mater. Res. 984–985 (1014)372376. 10.4028/ in Google Scholar

28 R. Lebeuf , E.Illous, C.Dussenne, V.Molinier, E.Da Silva, M.Lemaire and J.Aubry: Solvo-surfactant properties of dialkyl glycerol ethers: Application as eco-friendly extractants of plant material through a novel hydrotropic cloud point extraction (HCPE) process, ACS Sustainable Chem. Eng.4 (2016) 48154823. 10.1021/acssuschemeng.6b01101Search in Google Scholar

29 M. Thakker , J.Parikh and M.Desai: Ultrasound assisted hydrotropic extraction: A greener approach for the isolation of geraniol from the leaves of Cymbopogon martini, ACS Sustainable Chem. Eng. 6 (2018) 32153224. 10.1021/acssuschemeng.7b03374Search in Google Scholar

30 R. Maheshwari and A.Indurkhya: Novel application of mixed hydrotropic solubilization technique in the formulation and evaluation of hydrotropic solid dispersion of aceclofenac, Asian J. Pharm.4 (2010) 235239. 10.22377/ajp.v4i3.224Search in Google Scholar

31 K. Girishpai , S.Divya, M.Reddy, L.Kumar and K.Vamshi: Solubility enhancement of norfloxacin by hydrotropy technique, Int J Pharm Pharm Sci.6 (2014) 395397. ISSN: 0975-1491.Search in Google Scholar

32 A. Beig , D.Lindley, J.Miller, R.Agbaria and A.Dahan: Hydrotropic solubilization of lipophilic drugs for oral delivery: The effects of urea and nicotinamide on carbamazepine solubility-permeability interplay, Front. Pharmacol. 7 (2016) 18. 27826241 10.3389/fphar.2016.00379Search in Google Scholar PubMed PubMed Central

33 R. Kamble , S.Sharma and P.Mehta: Norfloxacin mixed solvency based solid dispersions: An in-vitro and in-vivo investigation, J Taibah Univ Sci.11 (2017) 512522. 10.1016/j.jtusci.2016.11.003Search in Google Scholar

34 K. Takahashi , M.Komai, N.Kinoshita, E.Nakamura, X.Hou, T.Nakase and M.Kawase: Application of hydrotropy to transdermal formulations: hydrotropic solubilization of polyol fatty acid monoesters in water and enhancement effect on skin permeation of 5-FU, J. Pharm. Pharmacol. 63 (2011) 10081014. 21718283 10.1111/j.2042-7158.2011.01308.xSearch in Google Scholar

35 S. Agrawal , S.Pancholi, N.Jain and G.Agrawal: Hydrotropic solubilization of nimesulide for parenteral administration, Int. J. Pharm. 274 (2004) 149155. 15072791 10.1016/j.ijpharm.2004.01.012Search in Google Scholar

36 R. Maheshwari and A.Indurkhya: Formulation and evaluation of aceclofenac injection made by mixed hydrotropic solubilization technique, Iran J Pharm Res. 9 (2010) 233242. PMCID: PMC3863437.Search in Google Scholar

37 S E. Friberg : Hydrotropes, Curr Opin Colloid Interface Sci.2 (1997) 490494. 10.1016/S1359-0294(97)80096-9Search in Google Scholar

38 S. E. Friberg and M.Chio: Hydrotropes, J Dispersion Sci Technol.9 (1988–89) 443457. 10.1080/01932698808944004Search in Google Scholar

39 J. Eastoe , M.Hopkins Hatzopoulos and P.Dowding: Action of hydrotropes and alkyl hydrotropes. Soft Matter. 7 (2011) 59175925. 10.1039/C1SM05138ESearch in Google Scholar

40 T. K. Hodgdon and E. W.Kaler: Hydrotropic solutions, Curr Opin Colloid Interface Sci12 (2007) 121128. 10.1016/j.cocis.2007.06.004Search in Google Scholar

41 W. Kunz , K.Holmberg and T.Zemb: Hydrotropes, Curr Opin Colloid Interface Sci, 22 (2016) 99107. 10.1016/j.cocis.2016.03.005Search in Google Scholar

42 V. G. Gaikar , V. B.Wagle and P. S.Kothari: Effect of temperature on aggregation behavior of aqueous solution of sodium cumene sulfonate, J Mol Liq. 133 (2007) 6876. 10.1016/j.molliq.2006.07.006Search in Google Scholar

43 J. Parikh and M.Desai: Thermodynamic study for aggregation behavior of hydrotropic solution. World Acad. Sci. Eng. Technol. 3 (2009) 485487.Search in Google Scholar

44 J. Chinnakannu and N.Gandhi: Thermodynamic study on hydrotropic aggregation behavior of benzamide, J. Chem. Eng. Data. 55 (2010) 43624368. 10.1021/je100533uSearch in Google Scholar

45 A. Bertie , C.Jayakumar and N.Gandhi: Hydrotropic effect and thermodynamic analysis on the solubility and mass transfer coefficient enhancement of ethylbenzene, Korean J Chem Eng. 30 (2013) 16. 10.1007/s11814-012-0213-ySearch in Google Scholar

46 V. Sampath , C.Jayakumar, C.Raja and N.Gandhi: Hydrotropic aggregation behavior of butyl stearate, Chem. Mat. Eng. 1 (2013) 17. 10.13189/cme.2013.010101Search in Google Scholar

47 Kabir-ud-din , P.Nahid and Z. N.Andleeb: Hydrotropic behavior of sodium salicylate in presence of additive, J. Dispersion Sci. Technol. 30 (2009), 15001505. 10.1080/01932690903123437Search in Google Scholar

48 K. Pawar , M.Desai and J.Parikh: Minimum hydrotrope concentration behavior of aqueous solution of sodium salicylate in presence of additive, J. Dispersion Sci. Technol. 33 (2012) 17461751. 10.1080/01932691.2011.629532Search in Google Scholar

49 K. Pawar , M.Desai and J.Parikh: Parametric optimization and thermodynamic studies on the influence of electrolytes on sodium salicylate in aqueous solution, Tenside Surf. Det. 50 (2013) 289296. 10.3139/113.110262Search in Google Scholar

50 M. Alibrahim : Cloud point extraction of polycyclic aromatic hydrocarbons in aqueous solution with nonionic surfactants. Tenside Surf. Det. 51 (2014) 333338. 10.3139/113.110315Search in Google Scholar

51 M. A. Rub ; A. M.Asiri; N.Azum; A.Khan; A. A. P.Khan; and Kabir-ud-Din: Clouding behavior of amphiphilic drug clomipramine hydrochloride with pharmaceutical excipients. Tenside Surf. Det. 50 (2013) 376384. 10.3139/113.110270Search in Google Scholar

52 R. Sharma , R.Murali and C. N.Murthy: Clouding and Aggregation Behavior of PPO-PEO-PPO Triblock Copolymer (Pluronic® 25R4) in Surfactant Additives Environment. Tenside Surf. Det. 49 (2012) 136144. 10.3139/113.110175Search in Google Scholar

53 R. K. Sharma and U.Shah: Aggregation Behavior of PEO-PPO-PEO Tri-Block Copolymer (Pluronic® L64) in Nonionic Surfactant Additives Environment. Tenside Surf. Det. 51 (2014) 274281. 10.3139/113.110308Search in Google Scholar

54 J. Booth , S.Abbott and S.Shimizu: Mechanism of hydrophobic drug solubilization by small molecule hydrotropes, J. Phys. Chem. B. 116 (2012) 1491514921. 23236952 10.1021/jp309819rSearch in Google Scholar PubMed

55 S. Shimizu , J.Booth and S.Abbott: Hydrotropy: binding models vs statistical thermodynamics, Phys. Chem. Chem. Phys. 15 (2013) 2062520632. 24189644 10.1039/C3CP53791ASearch in Google Scholar PubMed

56 S. Shimizu and N.Matubayasi: Hydrotropy: monomer-micelle equilibrium and minimum hydrotrope concentration, J. Phys. Chem. B. 118 (2014) 1051510524. 25144510 10.1021/jp505869 mSearch in Google Scholar

57 J. Booth , M.Omar, S.Abbott and S.Shimizu: Hydrotrope accumulation around the drug: the driving force for solubilization and minimum hydrotrope concentration for nicotinamide and urea, Phys. Chem. Chem. Phys. 17 (2015) 80288037. 25723588 10.1039/C4CP05414HSearch in Google Scholar

58 S. Shimizu and N.Matubayasi: The origin of cooperative solubilization by hydrotropy, Phys. Chem. Chem. Phys., 18 (2016) 2562125628. 27711657 10.1039/C6CP04823DSearch in Google Scholar

59 S. Abbott , J.Booth and S.Shimizu: Practical molecular thermodynamics for greener solution chemistry, Green Chem. 19 (2017) 6875. 10.1039/C6GC03002ESearch in Google Scholar

60 S. Shimizu and N.Matubayasi: Unifying hydrotropy under Gibbs phase rule, Phys. Chem. Chem. Phys. 19 (2017) 2359723605. 28492648 10.1039/C7CP02132ASearch in Google Scholar PubMed

61 S. Das and S.Paul: Exploring molecular insights into aggregation of hydrotrope sodium cumene sulfonate in aqueous solution: a molecular dynamics simulation study, J. Phys. Chem. B. 119 (2015) 31423154. 25602712 10.1021/jp512282xSearch in Google Scholar PubMed

62 S. Das and S.Paul: Mechanism of hydrotropic action of hydrotrope sodium cumene sulfonate on the solubility of di-t-butyl-methane: A molecular dynamics simulation study, J. Phys. Chem. B. 120 (2016) 173183. 26684411 10.1021/acs.jpcb.5b09668Search in Google Scholar PubMed

63 S. Das and S.Paul: Computer simulation studies of the mechanism of hydrotrope-assisted solubilization of a sparingly soluble drug molecule, J. Phys. Chem. B. 120 (2016) 35403550. 26982198 10.1021/acs.jpcb.5b11902Search in Google Scholar PubMed

64 S. Das and S.Paul: Hydrotropic action of cationic hydrotrope p-toluidinium chloride on the solubility of sparingly soluble gliclazide drug molecule: A computational study, J. Chem. Inf. Model. 57 (2017) 14611473. 28530396 10.1021/acs.jcim.7b00182Search in Google Scholar PubMed

65 S. Das and S.Paul: Hydrotropic solubilization of sparingly soluble riboflavin drug molecule in aqueous nicotinamide solution, J. Phys. Chem. B. 121 (2017) 87748785. 28825492 10.1021/acs.jpcb.7b05774Search in Google Scholar PubMed

Received: 2019-11-28
Accepted: 2020-01-16
Published Online: 2020-06-18
Published in Print: 2020-05-15

© 2020, Carl Hanser Publisher, Munich

Downloaded on 6.12.2023 from
Scroll to top button