Chemical properties of mixed solvents

Solvating abihty of mixed solvent differs from solvating ability of individual components. In addition to the permittivity change and the correspondent electrostatic interaction energy change, this is also caused by a number of reasons, the most important of which are discussed in the chapter. 

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In theory, if composition of the mixture is known, then calculation of any characteristic property of the multi-component mixture can be performed by the classical physical and chemical analysis methods. For binary liquid system, it is possible only if all chemical forms (including all possible associates), their stoichiometry, stability constants, and their individual physical and chemical properties are well determined. A large volume of correct quantitative thermodynamic data required for these calculations is not available. Due to these obstacles, data on permittivity, viscosity and other macro-properties of mixed solvents with interacting components are obtained by empirical means. Data on empirical physical properties of liquid systems can be found in published handbooks.Principles of characteristic changes due to the compositional change of liquid mixtures with interacting components are discussed here. Assessment of nature of such interactions can only be made after evaluation of the equilibrium constant (energy) of such interactions between solvents. 

The physical and chemical properties of (binary) solvent mixtures, necessary for understanding the solvation of ions in the mixtures, are dealt with in Sections 3.4.1 and 3.4.2, respectively. The preferences of ions for certain solvents over others are described in terms of their standard molar Gibbs energies of transfer from a source solvent (water has generally been arbitrarily selected as this source) to neat target solvents in Section 4.3.2.I. These sections should be consulted to complement the present discussions regarding ions in mixed solvents. 

Any impurity removal or isomeric separation will be successful only if the solubility of the impurity in the solvent or fluid is significantly higher than that in the parent molecule. As pure solvents might not exhibit a sufficiently large solubility difference, mixed solvents or, in the case of SCFs, modifiers can be used (51) that will alter the chemical properties of the solvent. As a result this can enhance the solubility of the unwanted product and therefore facilitate its removal. Solubility in liquid solvents can be expressed as (52) ... 

Unless otherwise indicated, chemical and physical properties are for the pure or production quality material. Properties of mixed, binary, thickened, or dusty agents, even those in solutions, will have physical and chemical properties that vary from the listed values. These variations will depend on the proportion of agent to other materials (e.g., solvents, thickener, etc.) and the properties of these other materials. If available, data on mixtures or modified agents (e.g., salts) are included. For any given parameters, a dash (i.e., —) means that the value is unavailable because it has not been determined or has not been published. 

Water-miscible solvents alone can be used when the drug is chemically unstable in the presence of any water. The number of solvents available for this purpose is extremely limited. The classic review of this subject was made in 1963 (Spiegel and Noseworthy), and some 30 years later, no additional solvents are available. This is unlikely to change in the near future due to the extensive effort necessary to determine the safety of a solvent used as a vehicle. When a nonaqueous vehicle is used, one can invariably expect some degree of pain upon injection, and subsequent tissue destruction is possible. This damage may be due to the heat of solution as vehicle mixes with body fluids it may be associated with tissues rejecting the solvent or, it may be an inherent property of the solvent. 

Mixed nonaqueous solvent systems are also of great interest and potential versatility as protein solvents, as they are for simple electrolytes (Evers and Kay, 1960). Their systematic use should enormously extend the range of nonaqueous solvent systems and properties. This is already suggested by several studies (cf. Doty et al, 1956 Yang and Doty, 1957). Many solvents not capable of dissolving a given protein may do so in mixtures with a small amount of a nonaqueous good solvent for the particular solute. In another connection, the addition of less than 1 % of one nonaqueous solvent to a solution of a macromolecule in another nonaqueous solvent can profoundly alter the physical chemical properties of the solution (Eirich et al., 1951 Doty et al., 1956). 

A solution made by dissolving a solute in a liquid, such as adding sulfuric acid to water, has particular chemical properties that the solvent alone did not have. The physical properties of water, such as how well the water mixes with other compounds, are also changed when substances dissolve in it. 

The problem of preferential solvation (PS) arises naturally in many studies of the physical-chemical properties of a solute in mixed solvents. Suppose we are interested in a property 8 which could be chemical reactivity, spectroscopy, diffusion coefficient, etc., of a solute s in mixed solvents of A and B. The question is how to relate the value of the measured property 8AB of the solute s, in the mixture of composition xA, to the values SA and SB in the pure solvents A and B, respectively. We shall first discuss the simplest case of one solute s which is very diluted in a solvent composed of two components A and B. 

Such studies, however, rely upon changing the chemical identity of the solvent in order to vary tl, and D, with the attendant risk that specific solvation phenomena or (in the case of mixed solvents) differential solvation may be responsible in part for the observed effects. This particular conundrum may avoided by the use of high pressures to tune the solvent properties, because the viscosity of normal liquids rises sharply and exponentially with increasing pressure (Fig. 5.4). 

A process which takes advantage of both the solubility characteristics and chemical properties of the amines is One which employs selective absorption in weakly acidic compounds such as cresols. Solubility is in- uenced not only by the solvent, but by the different basicities of the amines, as indicated under dissociation constants in Table 8-19. According to this process, mono- and dimethylamine are separated from trimethylamine by countercurrent extraction of the mixture with cresol saturated with water. The undissolved trimethylamine overhead is the least soluble In various solvents and is more weakly basic than dimethylamine. Prior to extraction, NHj can be removed, under specific conditions, from the three amines by countercurrent extraction with 17 per cent NaOH solution. This operation gives a mixed amine gas overhead and an NaOH solution of NHj. Under another set of conditions employing 10 per cent NaOH lolution in lower volumes, 100 per cent trimethylamine is the overhead gas. 

If examinations are to be carried out in a solvent mixture, the latter is always prepared by mixing in an exact ratio the carefully purified and controlled components. Hence, the characterization of such mixtures might in effect be traced back to the characterization of the components. However, in the mixture these components are involved in interactions of various strengths with one another. Futher, the interactions existing between the molecules in the pure solvents are changed by the act of mixing. Accordingly, the chemical and physical properties of a solvent mixture may differ appreciably from those of the components. 

The chemical characterization of a solvent mixture is much more difficult because it is not the mixture, but its components, that take part in the solvation reactions. However, the solvating powers of the components are affected by their interactions with one another. Depending on the chemical properties of the system, the solvating powers of the individual components may differ widely. Hence, the effects of the components in forming a solvate sheath will not be proportional to their ratio in the mixture. An understanding of the system is made even more complicated by the fact that, besides solvates that contain only one or the other solvent, the solute can also form mixed solvates in the solvate spheres of which both solvents are present together, possibly in various ratios. This topic is treated in greater detail in Chapter 8. 

Many thermodynamic properties of interest can be directly related to the change that the chemical potential of the solvent undergoes on mixing. 

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