(w + w -2w )

Figure 5.1 Diagrammatic representation of the three processes involved in the dissolution of a crystalline solute: the expression for the work involved is w22 + wn - 2w12 (solute-solvent interaction in the last stage is -2w12 as bonds are made with one solute and two solvent molecules).

considered in three stages:

1 A solute (drug) molecule is 'removed' from its crystal.

2 A cavity for the molecule is created in the solvent.

3 The solute molecule is inserted into this cavity.

Placing the solute molecule in the solvent cavity requires a number of solute-solvent contacts; the larger the solute molecule, the more contacts are created. If the surface area of the solute molecule is A, the solute-solvent interface increases by a12A, where a12 is the interfacial tension between the solvent (subscript 1) and the solute (subscript 2). a is a parameter not readily obtained for solid interfaces on the molecular scale, but reasonable estimates can be made from knowledge of the interfacial tensions of molecules at normal interfaces.1-5

The number of solvent molecules which can pack around the solute molecule is considered in calculations of the thermodynamic properties of the solution. The molecular surface area of the solute is therefore the key parameter and good correlations can be obtained between aqueous solubility and this parameter. 45

Of course, most drugs are not simple nonpolar hydrocarbons and we have to consider polar molecules and weak organic electrolytes. The term w12 in Fig. 5.1, a measure of solute-solvent interactions, has to be further divided to take into account the interactions involving the nonpolar part and the polar portion of the solute. The molecular surface area of each portion can be considered separately: the greater the area of the hydrophilic portion relative to the hydrophobic portion, the greater is the aqueous solubility. For a hydrophobic molecule of area A, the free energy change in placing the solute in the solvent cavity is -a 12A. Indeed, it can be shown that the reversible work of solution is (w 11 + w22 - 2w12)A.

Implicit in this derivation is the assumption that the solution formed is dilute, so that solute-solute interactions are unimportant. The success of the molecular area approach is evidenced by the fact that equations can be written to relate solubility to surface area. For example, equation (5.1) has been shown to hold for a range of 55 compounds (some of which are listed in Table 5.1):

where S is the molal (not molar) solubility, and A is the total surface area in nm2.

The compounds in Table 5.1 are liquids, so the process of dissolution is simpler than that outlined in Fig. 5.1.

5.2.1 Structural features and aqueous solubility Shape

Interactions between nonpolar groups and water were discussed above, where the importance of both size and shape was indicated. Chain branching of hydrophobic groups influences aqueous solubility, as shown by the solubilities of a series of straight and branched-chain alcohols in Table 5.2.

What other predictors of solubility might there be? The boiling point of liquids and the melting point of solids are useful in that both reflect the strengths of interactions between the molecules in the pure liquid or the solid state. Boiling point correlates with total surface area, and in a large enough range of compounds we can detect the trend of decreasing aqueous solubility with increasing boiling point (see data in Table 5.2).

As boiling points of liquids and melting points of solids are indicators of molecular cohesion, these can be useful indicators of trends in a series of similar compounds. There are other empirical correlations that are useful. Melting points, even of compounds which form nonideal solutions, can be used as a guide to the order of solubility in a closely related series of compounds, as can be seen in the properties of sulfonamide derivatives listed in Table 5.3. Such correlations depend on the relatively greater importance of w22 in the solution process in these compounds.


The influence of substituents on the solubility of molecules in water can be due to their effect on the properties of the solid or liquid (for example, on its molecular cohesion) or to the effect of the substituent on its interaction with water molecules. It is not easy to predict what effect a particular substituent will have on crystal properties, but as a guide to the solvent interactions, substituents can be classified as either hydrophobic or hydrophilic, depending on their polarity (see Table 5.4). The position of the substituent on the molecule can influence its effect, however. This can be seen in the aqueous solubilities of o-, m- and p-dihydroxy-benzenes; as expected, all are much greater than that of benzene, but they are not the same, being 4, 9 and 0.6 mol dm 3, respectively. The relatively low solubility of the para compound is due to the greater stability of its crystalline state. The melting points of the derivatives indicate that is so, as they are 105°C, 111°C, and 170°C, respectively. In the case of the ortho

Table 5.1 Experimental aqueous solubilities, boiling points, surface areas and predicted aqueous solubilities0



Surface area

Boiling point

Predicted solubilities

0 0

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