Thermodynamic aqueous solubility

Aqueous solubility, potency and permeability are three factors under medicinal chemistry control that must be optimized to achieve a compound with acceptable oral absorption. Typically, a lead (chemistry starting point) is deficient in all three parameters. The inter-relationships of these three parameters has been described in a series of publications from Pfizer researchers [7, 8]. Figure 9.1 depicts graphically the minimum acceptable solubility as a function of projected clinical potency and intestinal permeability. A minimum thermodynamic aqueous solubility of 52... 

From the standpoint of thermodynamics, the dissolving process is the estabHsh-ment of an equilibrium between the phase of the solute and its saturated aqueous solution. Aqueous solubility is almost exclusively dependent on the intermolecular forces that exist between the solute molecules and the water molecules. The solute-solute, solute-water, and water-water adhesive interactions determine the amount of compound dissolving in water. Additional solute-solute interactions are associated with the lattice energy in the crystalline state. 

This chapter is not simply a treatise on the highest capacity methods for measuring aqueous solubility in a discovery setting that most closely approximate a lower capacity thermodynamic solubility measurement. Rather it is the author s viewpoint that dealing with the problem of poor drug solubility in an early discovery setting requires an appreciation of recent changes in three related but distinct areas. The areas to be considered are ... 

The thermodynamic solubility of a drug is the concentration of the compound that is dissolved in aqueous solution in equilibrium with the undissolved amount, when measured at 25°C after an appropriate time period. Aqueous solubility has long been recognized as a key molecular property in pharmaceutical science. Drug delivery, transport and distribution phenomena depend on solubility thus, it is of considerable value to possess information of the solubility value of a drug candidate, to be able to predict the solubility for unknown compounds and, finally, to be able to modify the structure of a compound in order to modulate its solubility value in an appropriate manner. 

Dohanyosova, P., Sarraute, S., Dohnal, V., Majer, V., Costa Gomes M. (2004) Aqueous solubility and related thermodynamic functions of nonaromatic hydrocarbons as a function of molecular structure. Ind. Eng. Chem. Res. 43, 2805-2815. 

Ruelle, P., Kesselring, U.W. (1997) Aqueous solubility prediction of environmentally important chemicals from the mobile order thermodynamics. Chemosphere 34, 273-298. 

The most important area in the pharmaceutical and related industries for the application of thermodynamic models is in solid-liquid equilibria. Once developed these same models are applicable to a range of unit operations. Aqueous solubility and concerns about pharmaceuticals in the environment is an obvious extension. Liquid-Liquid extraction and distillation are frequently used operations, and techniques that predict the partitioning and impact of... 

A number of empirical relationships have been published which could be used to predict partition coefficients from solubility data [19-29, 65, 72, 78-97]. Comparisons among these relationships may be confusing since different sets of compounds and different solubility terms are used. A theoretical analysis of partition coefficient with reference to aqueous solubility is important because it illustrates the thermodynamic principles underlying the partitioning process. The objective of that relationship is its utility for both predicting and validating reported values for partition coefficients. 

When a NAPL reaches the subsurface, it may by subject to mechanical forces that lead to the formation of a mixed NAPL-water micro-/nanoemulsion characterized by the presence of micro- and nanodroplets of organic compounds. These micro- and nanoemulsions are transparent or translucent systems, kinetically (nano-) or thermodynamically (micro-) stable, and display an apparent increase in aqueous solubility as compared to the intrinsic solubility of the NAPL itself (Tadros 2004). The very small droplet size (50-200 nm in the case of a nanoemulsion) causes a large reduction in the force of gravity, enabling the system to remain dispersed and... 

Explain qualitatively how the aqueous solubility of a (a) liquid, (b) solid, and (c) gaseous compound changes with temperature. Which thermodynamic quantity(ies) do you need to know for quantifying this temperature dependence ... 

The solvatochromic approach has been criticized by Yalkowsky et al. [24]. In particular, they claim n to be an insignificant parameter for the estimation of aqueous solubilities and they contend that models in which the solubility is correlated with Kov/ and Tm (models 11.4.3 to 11.4.5, 11.4.10 and 11.4.11) are more versatile and have a firmer thermodynamic basis. 

Many additional consistency tests can be derived from phase equilibrium constraints. From thermodynamics, the activity coefficient is known to be the fundamental basis of many properties and parameters of engineering interest. Therefore, data for such quantities as Henry s constant, octanol—water partition coefficient, aqueous solubility, and solubility of water in chemicals are related to solution activity coefficients and other properties through fundamental equilibrium relationships (10,23,24). Accurate, consistent data should be expected to satisfy these and other thermodynamic requirements. Furthermore, equilibrium models may permit a missing property value to be calculated from those values that are known (2). 

The solvophobic model of liquid-phase nonideality takes into account solute—solvent interactions on the molecular level. In this view, all dissolved molecules expose microsurface area to the surrounding solvent and are acted on by the so-called solvophobic forces (41). These forces, which involve both enthalpy and entropy effects, are described generally by a branch of solution thermodynamics known as solvophobic theory. This general solution interaction approach takes into account the effect of the solvent on partitioning by considering two hypothetical steps. First, cavities in the solvent must be created to contain the partitioned species. Second, the partitioned species is placed in the cavities, where interactions can occur with the surrounding solvent. The idea of solvophobic forces has been used to estimate such diverse physical properties as absorbability, Henry s constant, and aqueous solubility (41—44). A principal drawback is calculational complexity and difficulty of finding values for the model input parameters. 

Aqueous Solubility. Solubility of a chemical in water can be calculated rigorously from equilibrium thermodynamic equations. Because activity coefficient data are often not available from the literature or direct experiments, models such as UNIFAC can be used for structure—activity estimations (24). Phase-equilibrium relationships can then be applied to predict miscibility. Simplified calculations are possible for low miscibility, however, when there is a high degree of miscibility, the phase-equilibrium relationships must be solved rigorously. 

Puri, S., J. S. Chickos, and W. J. Welsh. 2003. Three-dimensional quantitative structure-property relationship (3D-QSPR) models for prediction of thermodynamic properties of polychlorinated biphenyls (PCBs) Enthalpies of fusion and their application to estimates of enthalpies of sublimation and aqueous solubilities.J. Chem. Inf. Comput. Sd3 55-62. 

The second important characteristic of the micellar solution that relates to solubilization is the micelle size. Poor aqueous soluble compounds are solubilized either within the hydrocarbon core of the micelle or, very commonly, within the head group layer at the surface of the micelle or in the palisade portion of the micelle. Predictions of the micelle size have relied on the use of empirical relationships employed within a thermodynamic model, for instance the law of mass action where micellization is in equilibrium with the associated and unassociated (monomer) surfactant molecules (Attwood and Florence, 1983). 

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