Behavior in bile acid solution

Feld KM, Higuchi WI, Su C-C. Influence of benzalkonium chloride on the dissolution behavior of several solid-phase preparations of cholesterol in bile acid solutions. ] Pharm Sci 1982 71 182-188. 

B. Behavior of Individual Lipolytic Products in Bile Acid Solutions... 

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. 

We have now considered the behavior of each of the individual lipid classes in water and in bile acid solutions. We now wish to compare the behavior of appropriate mixtures of lipid classes in water with that in bile acid solution. We are interested in two major types of mixture (a) the mixture of lipolytic products, fatty acid, 2-monoglyceride, and soaps and (b) the mixture of lipolytic products plus their precursors—di- and triglycerides. We are also interested in the behavior of long-chain unsaturated compounds versus that of long-chain saturated compounds versus that of medium-chain compounds. 

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-... 

The number and position of hydroxy groups on the bile acid nucleus strongly influence the behavior of bile acids in solution. Bile acids appear to differ from typical anionic detergents in having a critical micellar tem-... 

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.

Fig. 11. Experimental design to assess the behavior of mixtures of lipolytic products in 150 mM NaCl (left) for 20 mM bile acid solution (right). In these experiments, the water concentration was constant at 99%.

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... 

This paper considers the interaction of monoolein, oleic acid, and sodium oleate with bile salt solution in model systems whose compositions have been chosen to simulate those which may occur in small intestinal content. In addition, the behavior of several monoglyceride analogs has been examined to determine the influence of the type of polar head of the lipid on its dispersion by bile salts. Finally, titration experiments were performed to measure the extent of ionization of oleic acid in such systems. 

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. 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.

Numerous applications of chemical engineering—for example, the dissolution of drugs into aqueous solution and their transport through the body, the preparation of agricultural chemical solutions, and the recovery of oil—depend on solubilization by suitable surfactants. In addition, studies of the physical chemistry of bile acids and bile salts, on one hand, and of their physiological function as solubilizers, on the other hand, make it clear that the behavior of bile salts in vitro and their functions in vivo are closely related. Solubilization will be increasingly important in the future. 

In 1997 Esumi and Ueno [1] edited a book on the structure-performance relationships in surfactants, in which the authors stress the need to understand the properties and performance of surfactants at various interfaces such as air-liquid, liquid-liquid and solid-liquid. The book has a few chapters on adsorption theories and some information on the microstructure of nonionic surfactants in solution, some modeling aspects of the association and adsorption of surfactants, and several chapters on the particular behavior of specific surfactants (polymeric, gemini, bile acids, and others) in solution. No significant clear guidelines... 

---