Griseofulvin solubilization

The same process was applied with the griseofulvin solubilized in the organic phase for the formulation of emulsions loaded with griseofulvin. Different loadings of griseofulvin could be easily checked. 

Table 12.4 shows the effect of temperature on the solubilization of griseofulvin by bile salts. The data indicate that there is an approximate 50% increase in griseofulvin solubility oVSEa 17 temperature range. 

Another important factor that may inLuence solubility, dissolution rate, and therefore absorption of water-insoluble compounds is the contents ofthe Gl Luids. The Gl Luids contain various materials, such as bile salts, enzymes, and mucin. Bile salts are surface active and as such could potentially enhance the rate or extent of absorption of water-insoluble drugs. Thus, the increased absorption of a water-insoluble compound, griseofulvin (GF), after a fatty meal may be facilitated by bile salt secretion into the gut resulting in solubilization [1,2],... 

An alternative is the solubilization with the help of cyclodextrins because these are soluble in water and can incorporate organic molecules inside their hydrophobic cavity [11-13]. P-cyclodextrin is the most useful regarding the typical size of molecules to be solubilized. Griseofulvin forms inclusion complexes of 1 1 stoichiometry with P-cyclodextrin [14, 15]. One possible problem is the moderate solubility of P-cyclodextrin in water (18.5 g/L) and the even lower solubility of most inclusion complexes. A more dramatic problem is the preparation of inclusion complexes of water-soluble cyclodextrins and organic molecules that are not soluble in water. The complexation takes place by means of hydrophobic interactions inside the cavity, which require the presence of water as a solvent. 

Griseofulvin and PMHS-CD(40) were solubilized together in acetone and subsequently emulsified in water. The emulsions were observed by optical microscopy. No crystal could be observed when the griseofulvin amount in acetone was less than the 1 1 stoichiometric ratio with respect to cyclodextrin. On the contrary, coexistence of needle-shaped crystals and emulsion droplets was observed for larger amounts of griseofulvin, in excess with respect to the cyclodextrin content of PMHS-CD(40). 

Ketones can be solubilized as carboxymethoximes (Figure 38.14). Menadoxime is freely water soluble, can be sterilized by autoclaving and, like menadione itself, shows high antihemorrhagic activity. The carboxymethoxime of griseofulvin, on the other hand, is devoid of activity in vitro as well as in vivo. This may be due either to an absence of conversion to the parent molecule, or to rapid renal elimination. Unsubstituted oximes can be converted enzymatically to their corresponding ketones. For carboxymethoximes... 

Bates, Gibaldi and Kanig have studied the relative solubilizing tendencies of four bile salts with respect to hexesterol, griseofulvin and glutethimide. The effect, which is ascribed entirely to micellar solubilization, was determined at several temperatures and at salt concentrations up to 0.6m. The most marked effect was noted with hexestrol and least for glutethimide. Connors and Mollica have compared the theoretical relationships of stability constants obtainable by solubility and other methods. 

One must ask the question—why don t the rest of the bile salts form large micelles with one cholesterol molecule per micelle Unless this is a thermodynamically unstable situation the existence of two markedly different kinds of bile salt micelles in the same solution at cholesterol saturation seems unlikely since one must postulate that some bile salt micelles have a specific affinity for cholesterol while other chemically identical molecules do not. These observations may also apply to other compounds solubilized only slightly by bile salts [e.g., large fat-soluble dyes, methyl cholanthracine, griseofulvin, and glutethemide (12, 44b, 143, 147-148, 176)]. 

The contrary effect is also observed. It is known in pharmaceutical science that the bioavailability of scarcely soluble compounds can be increased by adsorption [21]. Adsorption of a drug from a non-polar solution at the solid interface can produce an arrangement different from that of the pure, crystalline drug and with increased solubility. Another mechanism is solubilization by colloidally dispersed solids. The solubility of griseofulvin in water is remarkably increased in the presence of sodium montmorillonite [22]. The drug is adsorbed at the external surface of the smectite from acetone solution (Fig. 4). When this complex is dispersed in water, the smectite delaminates and the silicate layers with the drug attached act as carriers. The maximum solubilization is obtained for loadings <0.2 mmol/g montmorillonite. Solubilization at a somewhat reduced level is also observed for... 

Table 5.14 from KolthofF and Strides [137] shows the effect of temperature on the solubilizing powers of a number of surfactants. It is interesting to note that the relative increase in amounts solubilized at the higher temperature is inversely proportional to the amount solubilized at the lower temperature. A similar pattern of results has been shown by Bates et al. [22] for the solubilization of hexoestrol, glutethamine, and griseofulvin in bile salt solutions (Table 5.15). 

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