{{Short description|Chemical substance}} A '''hydrotrope''' is a compound that solubilizes hydrophobic compounds in aqueous solutions by means other than micellar solubilization. Typically, hydrotropes consist of a hydrophilic part and a hydrophobic part (similar to surfactants), but the hydrophobic part is generally too small to cause spontaneous self-aggregation. Hydrotropes do not have a critical concentration above which self-aggregation spontaneously starts to occur (as found for micelle- and vesicle-forming surfactants, which have a critical micelle concentration (CMC) and a critical vesicle concentration (CVC)). Instead, some hydrotropes aggregate in a step-wise self-aggregation process, gradually increasing aggregation size. However, many hydrotropes do not seem to self-aggregate at all, unless a solubilizate has been added. Examples of hydrotropes include urea, tosylate, cumenesulfonate and xylenesulfonate.

The term ''hydrotropy'' was originally put forward by Carl Neuberg<ref name="neuberg">{{cite journal|last1=Neuberg|first1=C|year=1916|title=Hydrotropic phenomena. I|journal=Biochem. Z.|volume=76|pages=107–76}}</ref><ref>{{Cite journal|last1=Mehringer|first1=Johannes|last2=Kunz|first2=Werner|date=August 2021|title=Carl Neuberg's hydrotropic appearances (1916)|url=https://linkinghub.elsevier.com/retrieve/pii/S0001868621001172|journal=Advances in Colloid and Interface Science|language=en|volume=294|article-number=102476|doi=10.1016/j.cis.2021.102476|pmid=34229180 |s2cid=235757195 |url-access=subscription}}</ref> to describe the increase in the solubility of a solute by the addition of fairly high concentrations of alkali metal salts of various organic acids. However, the term has been used in the literature to designate non-micelle-forming substances, either liquids or solids, capable of solubilizing insoluble compounds.

The chemical structure of the conventional Neuberg's hydrotropic salts (proto-type, sodium benzoate) consists generally of two essential parts, an anionic group and a hydrophobic aromatic ring or ring system. The anionic group is involved in bringing about high aqueous solubility, which is a prerequisite for a hydrotropic substance. The type of anion or metal ion appeared to have a minor effect on the phenomenon.<ref name=neuberg/> On the other hand, planarity of the hydrophobic part has been emphasized as an important factor in the mechanism of hydrotropic solubilization<ref>{{cite journal | last1 = Evstigneev | first1 = M.P. | last2 = Evstigneev | first2 = V.P. | last3 = Hernandez Santiago | first3 = A.A. | last4 = Davies | first4 = David B. | year = 2006 | title = Effect of a mixture of caffeine and nicotinamide on the solubility of vitamin (B<sub>2</sub>) in aqueous solution | url = https://eprints.bbk.ac.uk/382/1/Binder1.pdf| journal = European Journal of Pharmaceutical Sciences | volume = 28 | issue = 1–2| pages = 59–66 | doi = 10.1016/j.ejps.2005.12.010 | pmid = 16483751 | s2cid = 24920111 }}</ref><ref>{{cite journal | last1 = Suzuki | first1 = H. | last2 = Sunada | first2 = H. | year = 1998 | title = Mechanistic studies on hydrotropic solubilization of nifedipine in nicotinamide solution | journal = Chemical & Pharmaceutical Bulletin| volume = 46 | issue = 1| pages = 125–130 | doi = 10.1248/cpb.46.125 | pmid = 9468644 | doi-access = free }}</ref>

To form a hydrotrope, an aromatic hydrocarbon solvent is sulfonated, creating an aromatic sulfonic acid. It is then neutralized with a base.<ref name=Stanton2010>{{cite journal|last=Stanton|first=Kathleen|author2=Caritas Tibazarwa |author3=Hans Certa |author4=William Greggs |author5=Donna Hillebold |author6=Lela Jovanovich |author7=Daniel Woltering |author8=Richard Sedlak |title=Environmental Risk Assessment of Hydrotropes in the United States, Europe, and Australia.|journal=Integrated Environmental Assessment and Management|year=2010|volume=6|issue=1|pages=155–163|doi=10.1897/IEAM_2009-019.1|pmid=19558203|s2cid=11467860 }}</ref>

Additives may either increase or decrease the solubility of a solute in a given solvent. These salts that increase solubility are said to "salt in" the solute and those salts that decrease the solubility "salt out" the solute. The effect of an additive depends very much on the influence it has on the structure of water or its ability to compete with the solvent water molecules.<ref>{{cite journal | last1 = Da Silva | first1 = R.C. | last2 = Spitzer | first2 = M. | last3 = Da Silva | first3 = L.H.M. | last4 = Loh | first4 = W. | year = 1999 | title = Investigations on the mechanism of aqueous solubility increase caused by some hydrotropes | journal = Thermochimica Acta | volume = 328 | issue = 1–2| pages = 161–167 | doi = 10.1016/s0040-6031(98)00637-6 }}</ref> A convenient quantitation of the effect of a solute additive on the solubility of another solute may be obtained by the Setschetow equation:<ref>Singhai, A., 1992. Studies on solubilization, formulation and evaluation of some drugs, Dept. of Pharm. Sci. Dr. H. S. Gaur vishwavidhyalaya., Sagar, 10.</ref>

: <math>\log{\frac {S_0}{S}} = K \cdot C_a</math>, where

: ''S''<sub>0</sub> is the solubility in the absence of the additive

: ''S'' is the solubility in the presence of the additive

: ''C<sub>a</sub>'' is the concentration of the additive

: ''K'' is the salting coefficient, which is a measure of the sensitivity of the activity coefficient of the solute towards the salt.

== Applications == Hydrotropes are in use industrially and commercially in cleaning and personal care product formulations to allow more concentrated formulations of surfactants. About 29,000 metric tons are produced (i.e., manufactured and imported) annually in the US.<ref name=Stanton2010 /> Annual production (plus importation) in Europe and Australia is approximately 17,000 and 1,100 metric tons, respectively.<ref name="HERA2005">{{cite web|url=http://www.heraproject.com/files/24-F-HERA%20Hydrotropes%20Sept%202005.pdf|title=Hydrotropes|last=Human & Environmental Risk Assessment on ingredients of household cleaning products (HERA)|year=2005|work=Risk Assessment}}</ref><ref name=SIDS>{{cite web|last=Hydrotropes Consortium |title=SIDS Initial Assessment Report for SIAM 21 Hydrotropes. |url=http://www.chem.unep.ch/irptc/sids/OECDSIDS/Hydrotropes.pdf |year=2005 |archive-url=https://web.archive.org/web/20130402032100/http://www.chem.unep.ch/irptc/sids/OECDSIDS/Hydrotropes.pdf |archive-date=2013-04-02 }}</ref> Common products containing hydrotropes include laundry detergents, surface cleaners, dishwashing detergents, liquid soaps, shampoos and conditioners.<ref name=Stanton2010/> They are coupling agents, used at concentrations from 0.1 to 15% to stabilize the formula, modify viscosity and cloud-point, reduce phase separation in low temperatures, and limit foaming.<ref name=SIDS/>thumb|Sodium xylene sulfonate, a commercial hydrotrope [[File:Adenosintriphosphat protoniert.svg|thumb|Adenosine triphosphate, a proposed hydrotrope.<ref name="PatelMalinovska2017">{{cite journal|last1=Patel|first1=Avinash|last2=Malinovska|first2=Liliana|last3=Saha|first3=Shambaditya|last4=Wang|first4=Jie|last5=Alberti|first5=Simon|last6=Krishnan|first6=Yamuna|last7=Hyman|first7=Anthony A.|title=ATP as a biological hydrotrope|journal=Science|volume=356|issue=6339|year=2017|pages=753–756|issn=0036-8075|doi=10.1126/science.aaf6846|bibcode=2017Sci...356..753P|pmid=28522535|s2cid=24622983 }}</ref>]] {| class="wikitable" |+Examples of hydrotropes used for industrial and commercial purposes<ref name="Stanton2010" /><ref name="HERA2005" /> |- ! Chemical !! CAS# |- | Toluene sulfonic acid, Na salt || 12068-03-0 |- | Toluene sulfonic acid, K salt|| 16106-44-8 30526-22-8

|- | Xylene sulfonic acid, Na salt|| 1300-72-7 827-21-4

|- | Xylene sulfonic acid, ammonium salt|| 26447-10-9 |- | Xylene sulfonic acid, K salt|| 30346-73-7 |- | Xylene sulfonic acid, Ca salt|| 28088-63-3 |- | Cumene sulfonic acid, Na salt|| 28348-53-0 32073-22-6

|- | Cumene sulfonic acid, ammonium salt|| 37475-88-0 |}

Adenosine triphosphate (ATP) has been shown to prevent aggregation of proteins at normal physiologic concentrations and to be approximately an order of magnitude more effective than sodium xylene sulfonate in a classic hydrotrope assay.<ref name="PatelMalinovska2017"/> The hydrotrope activity of ATP was shown to be independent of its activity as an "energy currency" in cells.<ref name="PatelMalinovska2017"/> Additionally, ATP function as biological hydrotope has been shown proteome-wide under near native conditions.<ref>{{Cite journal|last1=Savitski|first1=Mikhail M.|last2=Bantscheff|first2=Marcus|last3=Huber|first3=Wolfgang|last4=Dominic Helm|last5=Günthner|first5=Ina|last6=Werner|first6=Thilo|last7=Kurzawa|first7=Nils|last8=Sridharan|first8=Sindhuja|date=2019-03-11|title=Proteome-wide solubility and thermal stability profiling reveals distinct regulatory roles for ATP|journal=Nature Communications|language=en|volume=10|issue=1|page=1155|doi=10.1038/s41467-019-09107-y|pmid=30858367|issn=2041-1723|pmc=6411743|bibcode=2019NatCo..10.1155S}}</ref> In a recent study, however, the hydrotropic capabilities of ATP have been questioned as it has severe salting-out characteristics due to its triphosphate moiety.<ref>{{Cite journal|last1=Mehringer|first1=Johannes|last2=Do|first2=Tuan-Minh|last3=Touraud|first3=Didier|last4=Hohenschutz|first4=Max|last5=Khoshsima|first5=Ali|last6=Horinek|first6=Dominik|last7=Kunz|first7=Werner|date=February 2021|title=Hofmeister versus Neuberg: is ATP really a biological hydrotrope?|journal=Cell Reports Physical Science|language=en|volume=2|issue=2|article-number=100343|doi=10.1016/j.xcrp.2021.100343| issn=2666-3864 |doi-access=free}}</ref>

== Environmental considerations == Hydrotropes have a low bioaccumulation potential, as the octanol-water partition coefficient is <1.0.<ref name=Stanton2010/> Studies have found hydrotopes to be very slightly volatile, with vapor pressures <2.0x10-5 Pa.<ref name=Stanton2010/> They are aerobically biodegradable. Removal via the secondary wastewater treatment process of activated sludge is >94%.<ref name=SIDS/> Acute toxicity studies on fish show an LC50 >400&nbsp;mg active ingredient (a.i.)/L. For Daphnia, the EC50 is >318&nbsp;mg a.i./L. The most sensitive species is green algae with EC50 values in the range of 230–236&nbsp;mg a.i./ L and No Observed Effect Concentrations (NOEC) in the range of 31–75&nbsp;mg a.i./L.<ref name=SIDS/> The aquatic Predicted No Effect Concentration (PNEC) was found to be 0.23&nbsp;mg a.i./L.<ref name=HERA2005/> The Predicted Environmental Concentration (PEC)/PNEC ratio has been determined to be < 1 and, therefore, hydrotropes in household laundry and cleaning products have been determined to not be an environmental concern.<ref name=Stanton2010/><ref name=HERA2005/>

== Human health == Aggregate exposures to consumers (direct and indirect dermal contact, ingestion, and inhalation) have been estimated to be 1.42&nbsp;ug/Kg bw/day.<ref name=HERA2005/> Calcium xylene sulfonate and sodium cumene sulfonate have been shown to cause temporary, slight eye irritation in animals.<ref name=SIDS/> Studies have not found hydrotropes to be mutagenic, carcinogenic or have reproductive toxicity.<ref name=SIDS/>

==References== {{reflist}}

Category:Cleaning product components Category:Surfactants