Bile acids — solubility behavior

The thermodynamic functions associated with water solubility of the bile acids were unifomJy associated with a positive enthalpy term ( + A//25) negative 

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The aggregation behavior of C21-DA salt in dilute electrolyte medium appears to resemble that of certain polyhydroxy bile salts (25,16). That C21-DA, with a structure quite different from bile acids, should possess solution properties similar to, e.g., cholic acid is not entirely surprising in light of recent conductivity and surface tension measurements on purified (i.e., essentially monocarboxylate free) disodium salt aqueous solutions, and of film balance studies on acidic substrates (IX) The data in Figure 3 suggest that C21-DA salt micelles Incorporate detergents - up to an approximate weight fraction of 0.5 -much like cholate Incorporates lecithin or soluble... 

A detailed consideration of the behavior and solubility of lipolytic products in aqueous systems not containing bile acids has two justifications. First, digestion is an aqueous process and significant intestinal absorption of certain lipolytic products may occur in the absence of bile acids, despite their low solubility. It is a reasonable assumption that such absorption occurs from a molecular solution, or at lest a nonmicellar solution, and we therefore seek information on molecular solubility or types of aggregation or both in aque-our systems. Second, behavior of lipolytic products in the absence of bile acids provides a framework from which to predict the behavior of these compounds when bile acids are added. 

Fig. 9. Phase equilibria for the bile salt (bile acid)-fatty acid-water system at constant water concentration in relation to temperature (see Fig. 5). Six mixtures varying in molar ratios of bile salt (bile acid) and palmitic acid with total concentration of micellar bile acid plus palmitic acid equal to 40 mM were examined. Fatty acid has a finite solubility in the micellar bile acid solution, the excess being crystalline at body temperature. At 50-60 C, there is a marked increase in micellar solubility, and the fatty acid melts. At higher fatty acid/bile acid ratios, the micellar solubility is exceeded, and an immiscible oil phase occurs. The melting point of fatty acid in the presence of water is nearly identical to that in the anhydrous state (38), in contrast to the behavior of monoglyceride (Table I). As shown in Fig. 3, the size of the micellar area decreases with increasing chain length. Unsaturated fatty acids (not shown) behave similarly to saturated fatty acids, but their micellar solubility is greater, and at most experimental temperatures a crystalline phase will not occur.

Since saturated fatty acids are insoluble in bile acid solutions, and since saturated fatty acid soaps are only soluble in terms of the mole fraction of a soap-bile acid mixture having a critical micellar temperature of 37° C, one would anticipate saturated fatty acid-soap mixtures to have negligible solubility in bile acid solutions. Some years ago, we compared the behavior of sodium, palmitate, and stearate at pH 5.8, 6.2, 6.6, and 7.0 in buffer or buffer containing bile acid. In the absence of bile acid, the saturated fatty acids remained as unwetted crystals. When bile acid was added, the solubility increased measurably but only very slightly. 

In this case, the solubility is extremely poor, even at pH 7, which is considerably above the pKa of troglitazone and corresponds to pH values commonly found in the mid section of the small intestine. Other well-known compounds with analogous behavior are mefenamic acid, glyburide, and phe-nytoin. For troglitazone, the presence of bile salts improves the solubility quite dramatically and lipophilic constituents in the dissolution medium (e.g., in full-fat milk) lead to better dissolution, and in turn better absorption when troglitazone is administered in the fed than the fasted state, as reported by Nicolaides (13). Use of biorelevant dissolution testing permitted these authors not only to qualitatively predict the food effect, but also to predict relative bioavailability of three test formulations. 

Effect of Bulk pH on Behavior and Solubility of Oleic Acid in Bile Salt Solution. Figure 2 shows the effect of bulk pH on the behavior and solubility of oleic acid in 0.15M buffer (above) and in 4 mM sodium glycodeoxycholate (below). In buffer, oleic acid has an extremely low solubility, and the excess, below pH 6.8, is present as an emulsion. In micellar bile salt solution, the oleic acid is solubilized to some extent. Above pH 6.5, its solubility rises markedly, and the excess now forms a dispersed phase which probably consists of droplets of fatty acid emul-... 

Fig. 12. Solubility and behavior at 37°C of mixtures of oleic acid (HA), sodium oleate (A ), and mono-olein (MG) the experimental design is as indicated in Fig. 11. Solid black line separates dispersions of large aggregates from dispersions of micellar size—turbid dispersions from clear dispersions. In 150 misi NaCl, fatty acid is present as oil droplets (black with white stippling) and mono-olein as a nondispersed liquid crystalline phase (horizontal hatching) or a viscous water-in-oil emulsion (cross-hatching). Increased ratios of sodium oleate result in a dispersed phase (white with black stippling), and at 10 and 15 mM sodium oleate alone is present in micellar form. In bile salt, fatty acid is also present as oil droplets (black with white stippling), and at higher concentrations mono-olein and fatty acid form a dispersed liquid crystalline phase (white with dots). In 20 mM bile salt, most of the lipid mixtures are now present in micellar solution (clear). From Hofmann (60), with the publisher s permission.

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