Steroids solubilization

Table 4.24(a) Weight of steroid solubilized per weight of lecithin. All sols were prepared from 4% (w/w) lecithin. 

In contrast, Barry and El Eini [145] have reported a decrease in the amount of steroid solubilized in aqueous solutions of long-chain polyoxyethylene non-ionic surfactants with increase in temperature. The essential difference between these... 

Very little work has been published on the effect of additives on steroid solubilization. Lundberg et al [166] have, however, measured the uptake of three... 

The effect of alphadalone acetate on the solubility of alphaxolone is a phenomenon that remains to be explained. Simultaneous solubilization of steroid hormones has only been studied by Lbvgren and co-workers [168,169]. Oestradiol was solubilized independently of the C21 steroids and testosterone studied, i.e. the capacity for oestradiol was unaffected by the solubilization of the latter. However, the solubilization of ethinyl oestradiol with progesterone and with testosterone was dependent on the presence of the other. The solubility of 11 a-hydroxyprogesterone was enhanced by ethinyl oestradiol-an effect akin to that of alphaxolone and alphadalone acetate. In several other pairs of steroids solubilization was reduced. When a progesterone-saturated solution of poly-sorbate 40 was equilibrated with an excess of ethinyl oestradiol, 96% of the solubilized progesterone precipitated while the oestrogen component was... 

Probably more work has been carried out on steroid solubilization than on most other classes of drug. In spite of the mass of data the behaviour of some steroid-surfactant systems, especially those containing two steroids, is by no means understood. The use of oil-water partition coefficients allows us to predict with a reasonable degree of precision the rank order solubility of a given steroid of a series in a surfactant, but not yet to relate surfactant properties to micellar capacity. 

Relative rates of reduction of the carbonyl group of several steroids solubilized by hexadecyltrimethylammonium borohydride micelles have been related to the structure of the steroids [50] shown in Fig. 11.8. Relative rates are shown underneath the structures in the diagram and show that micelles cause an increase... 

Aromatic steroids are virtually insoluble in liquid ammonia and a cosolvent must be added to solubilize them or reduction will not occur. Ether, ethylene glycol dimethyl ether, dioxane and tetrahydrofuran have been used and, of these, tetrahydrofuran is the preferred solvent. Although dioxane is often a better solvent for steroids at room temperature, it freezes at 12° and its solvent effectiveness in ammonia is diminished. Tetrahydrofuran is infinitely miscible with liquid ammonia, but the addition of lithium to a 1 1 mixture causes the separation of two liquid phases, one blue and one colorless, together with the separation of a lithium-ammonia bronze phase. Thus tetrahydrofuran and lithium depress the solubilities of each other in ammonia. A tetrahydrofuran-ammonia mixture containing much over 50 % of tetrahydrofuran does not become blue when lithium is added. In general, a 1 1 ratio of ammonia to organic solvents represents a reasonable compromise between maximum solubility of steroid and dissolution of the metal with ionization. 

A surfactant is a surface-active agent that is used to disperse a water-insoluble drug as a colloidal dispersion. Surfactants are used for wetting and to prevent crystal growth in a suspension. Surfactants are used quite extensively in parenteral suspensions for wetting powders and to provide acceptable syringability. They are also used in emulsions and for solubilizing steroids and fat-soluble vitamins. 

Certain compounds are known to achieve higher absorption rates from the GI tract if they are taken with food, and this observation has been linked to their solubilization by bile salts [74], Bile salts, especially those of cholic and deoxycholic acids, have been used to solubilize steroid hormones [75], antibiotics [76], and nonsteroidal antiinflammatory drugs [77]. For example, amphotericin B (an antifungal agent) has been solubilized for parenteral use in micelles composed of sodium desoxycholate [78], As illustrated in Fig. 11, the degree of solubilization of carbamazepine by sodium desoxycholate is minimal below the critical micelle concentration but increases rapidly above this value [79]. At sufficiently high concentrations, when the micelles become saturated in carb-amezepine, the apparent solubility reaches a limiting value approximately seven times the true aqueous solubility in the absence of desoxycholate. 

The structure proof for cholesterol paralleled that for two other important steroids, the so-called bile acids, cholic and desoxycholic acid, which function to help solubilize fats in the intestinal tract. Proof that cholesterol and the bile acids have the same general ring system was achieved by dehydration and reduction of cholesterol to two different hydrocarbons, 5a-cholestane and 5/3-cholestane (coprostane), which differ only in the stereochemistry of the junction between rings A and B ... 

Testosterone and its esters progesterontyalcolmson and Lawrence (1993) medroxyprogesterone acetate Solubilization of steroids in emulsions high drug loading achievable depending on l[Pg.209]

This interconversion is catalaysed by 17)3-hydroxysteroid dehydrogenase (17/3-HSD), an enzyme generally found in the ER of numerous tissues such as adrenal, liver, testis, ovary and kidney. Like many of the enzymes described above, there appear to be different forms [52,87]. For example, rat adrenal cytosol and ER contain separate 17/3-HSDs, with NADH as the preferred cofactor. The rat testicular enzyme, however, prefers NADPH. Guinea-pig liver also contains two 17j3-HSDs, one solubilized from cytosol, the other associated with the ER [88], These enzymes exhibit different activities towards C19 steroids, the cytosolic one preferring 5/3-reduced 17-oxosteroids and the microsomal counterpart being involved with 5a-reduced steroids, such as 5a-DHT. In this case, the product of the reaction would be 5a-an-drostane-3,17-dione. 

The major benefit of the solubilization principle is the increased water solubility of water-insoluble drugs such as phenolic compounds, iodine, steroids, and vitamins. The solubilization of water-insoluble materials in micelles may have some effects on drug activity and absorption. In addition, drugs in the micelles may prefer to stay... 

If as above we simply represent alicyclic rings sharing two Gs by a vertical line, then we can represent the basic tetracyclic structure of lanosterol as G61G61 G6 C5 (noting that there are two double bonds and various alkyl substituents and also a 3-hydroxyl on the first of the alicyclic rings). Many subsequent reactions yield cholesterol, a major triterpene membrane component that modifies the fluidity of animal cell membranes and is a precursor for synthesis of animal bile acids (fat solubilizing amphipathic detergents) plant triterpenes and steroid hormones such as the corticosteroids cortisol and cortisone, the mineralocorticoid aldosterone and the sex hormones testosterone and 17-(3-oestradiol. The structure and bioactivity of the plant terpenes is sketched below. 

Figure 9.82 (/4) HPLC chromatogram obtained with 10 fiL of a mixture of authentic steroid standards (1.0 /xg of each) on a Varian 0.22 mm X 25 cm MicroPak silica column with 16% tetrahydrofuran in water. The flow rate was 60 mL/h at 300 atm. (B) Typical chromatographic profile obtained with extracts of rat adrenal mitochondria incubated with 60 nM 11-deoxycorticosterone. An aliquot (0.8 mL) was removed at 5 minutes of incubation and extracted with 10 mL of methylene chloride containing 10 fig of internal standard (11-deoxycortisol). The extract was evaporated to dryness and solubilized with 50 /xL of ethanol. Then 10 /xL was injected onto the column. (From Gallant et al., 1978.)...

The solubilizing capacity of micelles and microemulsions prepared using the surfactant N,N-dimethyl-dodecylamine-N-oxide (C12AO), and containing either one of two semipolar ethyl ester oils (i.e., EH or EO) for the poorly water soluble, lipophilic steroidal drug, testosterone enanthate, has been determined recently (Barlow, D.J. Lawrence, M.J. Zuberi, T. Zuberi, S. Heenan, R.K. Personal communication, 2005). 

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