Hydrotropy: binding models vs. statistical thermodynamics

Abstract

Hydrophobic drugs can often be solubilized by the addition of hydrotropes. We have previously shown that preferential drug-hydrotrope association is one of the major factors of increased solubility (but not "hydrotrope clustering" or changes in "water structure"). How, then, can we understand this drug-hydrotrope interaction at a molecular level? Thermodynamic models based upon stoichiometric solute-water and solute-hydrotrope binding have long been used to understand solubilization microscopically. Such binding models have shown that the solvation numbers or coordination numbers of the water and hydrotrope molecules around the drug solute is the key quantity for solute-water and solute-hydrotrope interaction. However, we show that a rigorous statistical thermodynamic theory (the fluctuation solution theory originated by Kirkwood and Buff) requires the total reconsideration of such a paradigm. Here we show that (i) the excess solvation number (the net increase or decrease, relative to the bulk, of the solvent molecules around the solute), not the coordination number, is the key quantity for describing the solute-hydrotrope interaction; (ii) solute-hydrotrope binding is beyond the reach of the stoichiometric models because long-range solvation structure plays an important role.

Hydrotropy: Monomer–Micelle Equilibrium and Minimum Hydrotrope Concentration

“…Upon the basis of the above three different representations (eqs 8−10), we can now show that μ 1 -, μ 2 -, and P-dependences of μ u * correspond to the following well-known experiments: 6,7,23,27,40,41 Preferential Hydration Parameter.…”

“…6,7,23,27,40,41 By equating the species u in eq 7 with the species 2 and 3 at dT = 0, respectively, we obtain the following:…”

Practical molecular thermodynamics for greener solution chemistry

“…23 As we shall see, the analogy is positively wrong. [14][15][16][17] Another temptation has been to invoke the phrase "water structure" to suggest that the hydrotrope breaks up the structure, allowing the solute to dissolve. 24,25 However, invoking the phrase seldom brings helpful formulation understanding and we shall show that water structure is thermodynamically irrelevant for hydrotrope solubilization.…”

“…[6][7][8][9][10][11] Although such systems offer much promise, it is hard to formulate rationally because of the confusing terminology and the obscurity of the mechanisms by which solubility is increased. [14][15][16][17] The confusion leads directly to a waste of intellectual and developmental resources, as well as sub-optimal formulations. The aim of this paper is to provide a set of practical tools to counter this wastefulness.…”

A simple and effective method to improve bioavailability of glimepiride by utilizing hydrotropy technique

“…It is also an important strategy being considered to prepare hydrophobic substances aqueous solution (Eastoe et al, 2011). Fluctuation Theory of Solutions (FTS) is employed to explain the mechanisms of hydrotropic drug solubilization (Shimizu et al, 2013). FTS has identified two major factors of hydrotrope-induced solubilization, one is preferential hydrotrope-solute interaction (Durand et al, 2009;Suzuki and Sunada, 1998) and the other is water activity depression (Badwan et al, 1982;Balasubramanian et al, 1989;Coffman and Kildsig, 1996;Cui, 2010;Cui et al, 2010;da Silva et al, 1999;Friberg et al, 1986).…”