Hyoscyamine solubility

The alkaloid may be separated from accompanying hyoscyamine by extracting most of it with ether and then crystallising the mixed oxalates from water, that of norhyoscyamine separating first. It crystallises in colourless prisms, m.p. 140°, [a]j, — 23-0° (50 per cent. EtOH), is soluble in alcohol or chloroform, less so in ether or acetone, and sparingly in water... 

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). 

Figure 3. Solubilities of hyoscyamine (I) and scopolamine (2) free bases in supercritical CO, [39]. Reprinted from J. Chromatogr. A, 863, Y. H. Choi et al., Strategies for supercritical fluid extraction of hyoscyamine and scopolamine salts using basified modifiers, 47-55 (1999), with permission from Elsevier Science.

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,. 

To improve supercritical C02 solubilities of target alkaloidal salts, an appropriate modifier to raise the polarity of C02 had to be used. As previously mentioned, the most common modifier used in SFE is methanol because of its high solvation parameters, which can greatly increase the resultant polarity of C02. Water has been chosen as another modifier because some alkaloidal salts are freely soluble in water as well as methanol. Moreover, the addition of water into C02 has been reported to improve the extraction yield of some alkaloids [29]. Methanol or water as a modifier was added into the extractor at the concentration levels of 1, 5 and 10% (v/v), respectively. The effect of methanol and water on the solubilities of hyoscyamine (1) and scopolamine (2) is shown in Figure 5. Analogous information on ephedrine derivatives such as methylephedrine (3), norephedrine (4), ephedrine (5), and pseudopehedrine is illustrated in Figure 6. 

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. 

When the extractabilities using diethylamine/methanol as a modifier were compared with diethylamine/water, the former was more effective on the extractabilities of hyoscyamine (1) and scopolamine (2) salts than the latter, as seen in the comparison of pure methanol and water. Although the water with added diethylamine was less effective than basifled methanol, it could largely increase the solubilities wben compared with pure water, similar to the comparison of basic methanol with pure methanol (Figure 9). 

For ephedrine derivatives, basified methanol or water showed solubilities greater than for neutral conditions (Figure 10), similar to the results for hyoscyamine (1) and scopolamine (2). 

In both results of solubility and desorption from filter papers, diethylamine in methanol as a modifier was found to offer greater efficiency for SFE of the alkaloids than any other modifiers employed. The yields of hyoscyamine (1) and scopolamine (2) from the roots and aerial parts by SFE and conventional organic solvent extraction are listed in Tables 2 and 3. The SFE yields from both plant parts were greatly enhanced by the addition of methanol basified with diethylamine. From the results of solubility and desorption from filter paper, methanol and diethylamine/methanol (10% v/v) were much more efficient for both compounds than water and diethylamine/water (10% v/v) because of their low miscibility with C02. The extraction profile of hyoscyamine (1) when present in plant material was in good agreement with that when extracted as a pure compound. However, in the case of scopolamine (2), there... 

Atropin was obtained from belladonna roots and by racemisation of L-hyoscyamine with dilute alkali or by heating in chloroform solution. The alkaloid was crystallised from alcohol on addition of water, or from chloroform on addition of light petroleum, or from acetone in long prisms, m.p. 118°C, sublimed unchanged when heated rapidly. It is soluble in alcohol or chloroform, less soluble in ether or hot water, sparingly so in cold water (in 450 L at 25°C) and almost insoluble in light petroleum. Atropine is optically inactive. 

Hyoscyamine is found in Atropa belladonna (night-shade) and in several species of Hyoscyamus from which its name is derived. It is a crystalline compound, m.p. 108.5°, somewhat soluble in water but more readily in chloroform, alcohol or benzene. It is levo rotatory and yields crystalline salts more soluble in water than the base itself. With acids or alkalies hyoscyamine hydrolyzes as previously stated yielding tropine and tropic acid. 

Atropine does not occur as such in the solanaceae plants but is formed from the hyoscyamine present by treatment with dilute alkalies, when isomerization takes place and the inactive form of the alkaloid is obtained. It is crystalline, m.p. 115.5°, and only slightly soluble in water but soluble in alcohol and chloroform. The salts are crystalline and soluble in water. 

Tropine is a simpler base than the other alkaloids and is not found as such in the plants but is obtained by hydrolyzing not only atropine and hyoscyamine but other solanacese alkaloids as well. It is crystalline, m.p. 63°, and is soluble in water, alcohol, ether or benzene. As shown in its formula it is an alcohol yielding esters with tropic acid. 

Hyoscyamine Sulfate. USP. Hyo.scyaminc sulfate (laavsin sulfate) is a white, odorless, crystalline compound of a deliquescent nature that also is affected by light. It is soluble in water 1 0.5) and alcohol (1 5) but almost insoluble in ether. Solutions of hyo.scyamine sulfate are acidic to litmus. 

One gram of hyoscyamine sulfate dihydrate dissolves in 0.5 ml water in about 5 ml alcohol, very slightly soluble in chloroform and ether (1). 

Hyoscyamine and atropine so obtained are converted to their oxalate salts and separated from each other by fractional crys-tallization from acetone and ether (hyoscyamine oxalate is the more soluble one). 

The separation of atropine, Z-hyoscyamine and Z-scopolamine has been effected by the fractional crystallization of their aurichlorides. It has been pointed out, however, that the solubility relations of these derivatives are dependent upon impurities and the relative amoimts of each present in the mixture (50). The bases may be recovered by decomposing an aqueous solution of the aurichloride with hydrogen sulfide and filtering to remove the gold sulfide. The base is liberated by addition of potassium carbonate to the filtrate and extraction with chloroform. An alternate method for the separation of atropine and Z-hyoscyamine (25) is by fractional crystallization of their oxalates from acetone and ether in which the Z-hyoscyamine derivative has the greater solubility. Z-Scopolamine and dioscorine on the other hand are purified through their insoluble hydrobromides. 

Although the two common solvents, chloroform and carbon tetrachloride, are very closely related in composition, the table of dielectric constants suggests considerable variation in the solvent powers of these two compounds. which prediction is in agreement with actual experience. In many instances, chloroform exhibits an unusual solvent power. This is e.spc(dally noticeable in the solubilities of some of the well-known alkaloids, such a.s atropine, quinine, cinchonine, quinidinc, and hyoscyamine. 

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