The Hydrophobic Effect. 2. Relative Importance of the Hydrophobic Effect on the Solubility of Hydrophobes and Pharmaceuticals in H-Bonded Solvents

Abstract

The quantitative development of the nonergodic mobile order thermodynamics involving the new interpretation of the hydrophobic effect leads to a general solubility equation. This equation is applied to predict the aqueous and alcohol solubility of chemicals ranging from nonpolar or slightly polar with no H-bonding capacity to polyfunctional polar compounds including pharmaceuticals. The analysis of the relative importance of the contributions involved in the solubility model [i.e., the fluidization of the solute (for solids), the correction for the mixing entropy, the change of the nonspecific cohesion forces, and the formation of solvent-solvent (hydrophobic effect), solute-solute, and solute-solvent H-bonds] unambiguously demonstrates that the hydrophobic effect is essential for predicting the aqueous or alcohol solubility of any substance in general, and of nonpolar compounds in particular. The difference between the origin of the solubility of hydrocarbons in water and of water in hydrocarbons is furthermore presented. In both cases, the quasilinear solubility dependence on the molar volume of the hydrocarbon is of an entropic nature.

In Silico Approaches to Prediction of Aqueous and DMSO Solubility of Drug-Like Compounds: Trends, Problems and Solutions

“…The molar refraction, R 2 , refers to the tendency of a solute to interact with surrounding σ and π electrons while the volume of the solute, V x , corresponds to the size of the solute and is proportional to energy to create a cavity in water. Other authors Ruelle and Kesserling used mobile order theory [53] to predict the water solubility. Unfortunately, both these approaches require experimental constants and their application is limited.…”

Study of equilibrium solubility measurement by saturation shake-flask method using hydrochlorothiazide as model compound

“…The most likely explanation for this discrepancy can be the effect of particle size, crystallinity and other molecular features of the sample [10,20] or the great differences in the applied experimental conditions. 30] 0.025-2600 Dexamethasone [11,29] 89.1-121.0 Diclofenac [8,12b,13] 0.6-2.4 Digoxin [11,29] 28.0-97.9 Estradiol [11,29] 0.16-5.00 Hydrocortisone [11,29] 280-359 Ibuprofen [8,[13][14][15] 20-80 Indomethacin [11,19] 4.00-14.0 Lidocaine [16][17][18][19] 2.30-4.60 Progesterone [11,29] 7.90-200 Riboflavine [11,29] 66.0-99.9…”

The correlation and prediction of the solubility of compounds in water using an amended solvation energy relationship

“…Mobile Order Theory [23][24][25] has recently been applied to the estimation of aqueous solubility with impressive results. 24 However, the method requires not only the entropy of fusion of solid solutes (or a mp correction term), but also a modified nonspecific solute cohesion parameter.…”

“…24 However, the method requires not only the entropy of fusion of solid solutes (or a mp correction term), but also a modified nonspecific solute cohesion parameter. The latter is obtained either from experimental solubilities in hydrocarbon solvents or is "...deduced by analogy to similar compounds."…”