Solubilities alkaloidal free bases

Solubilities of the Alkaloidal Free Bases and Salts in Supercritical CO2 421... 

Opium alkaloids such as codeine, thebaine, papaverine, and noscapine exhibit high solubility (0.09-0.9 mg/g) in supercritical fluids including CO N,0, CHF, [37]. However, in spite of their high solubilities, they were not extracted from plant material by pure CO, to the degree expected [29], possibly because these alkaloids exist as their salt forms in plant tissue. In this chapter, the examples that show the difference of the solubilities between alkaloidal free bases and salts are presented. For this comparison, the solubilities of the free bases of hyoscyamine (1), scopolamine (2), pseudoephedrine (6) were measured and compared with those of their hydrochloride salts (Figures 3 and 4). 

Laudanosine, C21H27O4N. This alkaloid occurs in the liquor from which thebaine is precipitated, and can be isolated by Hesse s method. The crude alkaloid is purified by extraction with small quantities of ether, in which laudanosine is soluble, and finally by precipitation with potassium iodide. The free base crystallises from hot benzene in needles, m.p. 89°, [ ] f 103-23° (EtOH), is soluble in alcohol, chloroform, hot benzene or... 

Now we must basify our solution. By doing this we will "unhook" the salt and transform the alkaloid into its "free base" form. The alkaloids will no longer be a salt, nor will they be soluble in water. This allows us to extract them with the organic solvent added in STEP 7. Ammonium hydroxide is normally used, but for our experiment we will be using NaOH found in household lye crystals (Red Devil drain cleaner) and purchased at hardware stores. Lye is very caustic and can react violently. Take the proper precautions when using lye. 

You have now formed the free base alkaloids that are soluble in non-polar solvents. 

DETAILS - Nicotine is well Imown as the alkaloid extracted f rom tobacco, where it exists in a proportion of 2% to 8%, by weight. It is soluble in water and alcohol. Nicotine is very useful as a projectile poison due to its sticky nature. It works well by itself or as a binder for powdered poisons. It is available commercially in some parts of the country, notably the South, where it is used as an insecticide. The most common form is the sulfate (Black Leaf 40), but the free base is also available. It sometimes requires some search-... 

Most alkaloids exist in nature not in their free-base form but rather as the salt of naturally occurring acids known as tannins, a group of phenol-based organic acids that have complex structures. The alkaloid salts of these acids are usually much more soluble in hot water than in cold water. The caffeine in coffee and tea exists in the form of the tannin salt, which is why coffee and tea are more effectively brewed in hot water. As Figure 12.19 relates, tannins are also responsible for the stains caused by these beverages. 

Alkaloid salts are not very soluble in the organic solvent diethyl ether. What might happen to the free-base form of caffeine dissolved in diethyl ether if gaseous hydrogen chloride, HC1, were bubbled into the solution ... 

Certain free bases of alkaloids were found to be quite soluble in pure supercritical C02 even under mild supercritical conditions. However, the alkaloids were not extracted as much as expected from their solubilities [37]. This discrepancy was assumed to be due to the fact that most alkaloids exist in the form of salts in the plant. Alkaloids have been extracted from plant materials traditionally by extraction processes with the addition of ammonia or calcium hydroxide. Accordingly, the use of basified modifiers in SFE, rather than simple polar modifiers was investigated, in the hope that the extraction efficiencies of alkaloids from their plant of origin would be enhanced. 

This chapter documents enhancements of the efficiency of SFE extraction of alkaloids from plant matrices using basified modifiers. Hence (1) The pure compound solubility of some free bases in pure supercritical C02 has been measured by investigating the effects of temperature, pressure or density of C02 (2) The solubilities of the alkaloidal salts were compared with those of their free bases in order to evaluate the difference of their solubilities influenced by a changing from free bases to salts (3) Polar solvents such as methanol and water, as initial modifiers, were used for the enhancement of the solubilities (4) The solubilities of the salts by non-basified modifiers such as neat methanol or water were compared with those of methanol or water basified with diethylamine (5) The effect of modifiers employed on the desorption of the compounds from a matrix were measured and compared with each other (5) On the basis of the results of pure compound extractability, SFE was performed on alkaloids from the plant... 

Although there were some differences on the effects of temperature and pressure according to each particular compound, the free bases of hyoscyamine (1), scopolamine (2), and pseudoephedrine (6) were all found to be highly soluble in supercritical CO,. However, the hydrochloride salts of these compounds were scarcely extracted by pure CO, under any conditions employed. These results were consistent with preliminary evidence indicating that these alkaloids are not extracted from plant materials by pure CO,. This means that the alkaloids in living cells in the plant are not in the form of their free bases but rather as water-soluble salts in the cell vacuole [40]. Therefore, it was necessary to develop a procedure to enhance the solubilities of alkaloidal salts in CO,. 

Generally, alkaloidal salts are insoluble in nonpolar solvents but their free bases are quite soluble in the solvents. Therefore, the basified modifier should be introduced into the SFE to solubilize alkaloids in CO,. For the evaluation of the effects of basified modifiers, diethylamine was added to methanol or water at a 10% (v/v) concentration level. Then, the basified modifiers were continuously incorporated into the extraction cell at concentrations of 1, 5, and 10 % (v/v). The effects of methanol basified with diethylamine as a modifier on the solubilities of hyoscyamine (1) and scopolamine (2) are shown in Figure 8. The addition of diethylamine (10% v/v) into methanol dramatically enhanced the solubilities of the alkaloidal hydrochloride salts compared with those of pure methanol alone. This may be due to the fact that methanol basified with diethylamine changed the salts to the free bases. 

The basification of the mixture results in the alkaloids being present in their free base forms and hence they are soluble in apolar organic solvents (in this case, kerosene) into which they extract. Addition of the aqueous acid results in the sulfate form of the drug being produced, which preferentially partitions into the aqueous phase. Addition of the base neutralizes the acid, returning the drugs to their apolar, free base forms, which are not soluble in water, and hence will precipitate. 

Cobeine is the methyl-phenyl ether with the hydroxyl hydrogen in position 3 replaced by methyl. Both morphine and codeine are crystalline compounds reacting as tertiary mono-acid bases. Morphine is slightly soluble in water, codeine being more so, the former being more bitter in taste than the latter. The salts are soluble and in this form the alkaloids are used in medicine though codeine is also used as the free base. 

The standard CCC separation is solely based on the difference in the partition coefficients of solutes between the two phases of a solvent system. Most alkaloids have basic properties with pK values ranging from 6 to 12, but usually 7 to 9. Although the free base is soluble only in organic solvents, protonation of the nitrogen in the free base usually results in a water-soluble compound. This behavior serves as the basis for the selective extraction or... 

The free bases are soluble in lipophilic organic solvents, like chloroform. The different solubility for bases and salts is used for isolation and purification. Alkaloids are generally colourless solid materials. Some alkaloids that do not contain oxygen, like coniine, nicotine and sparteine, are liquid, and berberine and chelidonine are intensely yellow. Several alkaloids, e.g. strychnine and quinine, have a very bitter taste. Alkaloids give precipitates with heavy metals like mercury and bismuth. DragendorfPs reagent is used to show the presence of alkaloids. 

That phenolic alkaloids are soluble in aqueous solutions of fixed alkalies need not be stressed but it is important to note that some free bases (notably corydine and ochotensine) are extracted from such solutions by ether while others (bulboeapnine and hunnemanine) are not. A convenient method for recovery of these phenolic bases is to saturate their aqueous alkaline solutions with carbon dioxide or ammonium chloride. The latter reagent, however, is not invariably satisfactory (e.g., hunnemanine). 

Tetanin—CisHjoN iOt—is an alkaloid obtained from cultures of a bacillus originating from a wound which had been the cause of death by tetanus. It forms a deliquescent chlorid, and a very soluble chloroplatinate. The free base or its chlorid, when injected into mice or guinea-pigs, causes clonic or tonic convulsions of the greatest intensity, which terminate in death. 

This alkaloid has been isolated by the writer from D. chrysantha (7), C. sibirica (4), C. ochotensis Turcz. (25), Fumaria officinalis L. (26), and C. ophiocarpa Hook. f. et Thoms. (27). It yields a sparingly soluble hydrobromide which salt is useful in its isolation and purification. The free base is sparingly soluble in most solvents. It is however moderately soluble in chloroform and crystallizes in colorless fine prisms, melting at 223°, when the chloroform solution is concentrated to a sirup and treated with hot methanol. 

The fraction of more soluble Chelidonium alkaloids from which most of the bases have been removed is treated in dilute acid solution with an excess of aqueous potassium cyanide. The precipitate is separated by filtration and washed thoroughly with dilute acetic acid. After drying it is repeatedly crystallized from acetone until most of the chelerythrine -cyanide is recovered in the least soluble fractions. The more soluble product is then decomposed by boiling in ethanol with hydrochloric acid, and the free base is recovered and converted to its hydrogen tartrate. The tartrate crystallizing from the more soluble fractions is that of pure sanguinarine, does not have methoxyl, and is identical with -chelerythrine (19). 

It may be conveniently prepared from V. viride. The benzene extract of the crude alkaloids when treated with dilute sulfuric acid yields a mixture of the sparingly soluble sulfates of veratramine and jervine. The sulfates are converted to hydrochlorides, conveniently via the free bases. The jervine hydrochloride is only sparingly soluble in ethanol and the veratramine remains in the mother liquor (38). 

---