Mechanism of Hydrotropic Action of Hydrotrope Sodium Cumene Sulfonate on the Solubility of Di-t-Butyl-Methane: A Molecular Dynamics Simulation Study Shubhadip Das and Sandip Paul* Department of Chemistry, Indian Institute of Technology, Guwahati, Assam 781039, India * S Supporting Information ABSTRACT: Hydrotropes are special class of amphiphilic molecules that have an ability to solubilize the insoluble or sparingly soluble molecules in water. To find out the mechanism of hydrotropic action of hydrotropes on hydrophobic molecules, we have carried out classical molecular dynamics simulation of hydrophobic solute di-t-butyl- methane (DTBM) and hydrotrope sodium cumene sulfonate (SCS) in water with a regime of SCS concentrations. Our study demonstrates that, above the minimum hydrotrope concentration (MHC), the self-aggregation of SCS starts, and it creates a micellar-like environment in which the hydrophobic tail part of SCS points inward while its hydrophilic sulfonate group points outward to make favorable contact with water molecules. The formation of the hydrophobic core of SCS cluster creates a hydrophobic environment where the hydrophobic DTBM molecules are encapsulated. Interestingly, the determination of average water−SCS hydrogen bonds further suggests that the aggregate formation of SCS molecules has a negligible influence on it. Moreover, the calculations of Flory−Huggins interaction parameters also reveal favorable interactions between hydrotrope SCS and solute DTBM molecules. The implications of these findings on the mechanism of hydrotrope assisted enhanced solubility of hydrophobic molecules are discussed. I. INTRODUCTION One of the most important parameters to check for newly designed drugs is its solubility in water. Since tablets and aqueous solutions are the most common and usual methods for drug delivery, it is extremely important to make the drugs water-soluble. Furthermore, since the solubility of many newly designed drugs in water is very poor, it poses a serious problem in drug design. However, there are several methods to overcome this problem, within which one method is formulating the water insoluble or sparingly soluble drugs with nontoxic, water-soluble molecules that are commonly termed as hydrotropes. 1−4 Neuberg 1 first reported that the solubility of hydrophobic molecules can be enhanced substantially by addition of some organic salts. This phenomenon is commonly known as hydrotropy, and the solubilizing agent of a hydrophobic molecule is called a hydrotrope. Although hydrotropes have been classified on the basis of their molecular structures, it is very difficult to differentiate them. Alkyl benzenesulfonates, polyhydroxyben- zene, and sodium salts of some lower alkanols and derivatives of aromatic acids are studied the most, and they act as potential hydrotropes. 5 Hydrotropes with anionic hydrophilic groups were studied the most because of their higher number of isomers and the presence of interactive π-orbitals that is considered to be crucial reason behind their hydrotropic action. Hydrotropes composed of cationic headgroups, such as salts of aromatic amines and so on, are barely studied. 6 Hydrotropes have a wide range of industrial applications. Since the hydrotrope additives have effectiveness in both aqueous and oil phases, they have used in detergent industries. Moreover, they are extensively used as solubilizing agents to solubilize drugs, biochemicals, and organic compounds. 7−10 Furthermore, hydrotropes are used for extractive separations of mixtures, 11−13 for cleaning, washing, and cosmetics purposes. 14 They have been used in the paper and pulp industry too. 15 As hydrotropes possess some catalytic properties, they can be used to execute organic synthetic reactions. 16,17 Besides these, micelle and microemulsion formation can also be influenced by hydrotropes. 18−20 Even though hydrotropes are considered to be primitive amphiphiles, they have similarities and dissimilarities with regard to the molecular structures and self-association propensities. Analogous to surfactants, hydrotropes also show mild surface activity. Note that, depending on chemical structure and type, like surfactants, hydrotropes also reduce the surface tension of water about 20 mN/m. 21 Moreover, some hydrotropes can increase the solubility of organic solutes more in comparison to normal surfactants. Like a classical surfactant, which forms a micelle above its critical micelle concentration (cmc), a hydrotrope also exhibits aggregation behavior above the minimum hydrotrope concentration (MHC). 22,23 The main structural difference between a typical surfactant and a hydrotrope is that the latter has a much higher hydrophile/lipophile balance (HLB). This is because a Received: October 3, 2015 Revised: December 18, 2015 Article pubs.acs.org/JPCB © XXXX American Chemical Society A DOI: 10.1021/acs.jpcb.5b09668 J. Phys. Chem. B XXXX, XXX, XXX−XXX