Hyoscyamine and Atropine

Chapter 6 Datura Alkaloids Hyoscyamine and Atropine C17H2303N M.W. 289 

Atropine is the optically inactive mixture of dextro- and laevo-hyoscyamine. Laevo-hyoscyamine alone occurs in nature. The hest source of hyoscyamine is a variety of henbane indigenous in Egypt, Soudan and India, known as Hyoscyamus muticus, in the various parts of which it has been shown to be present in the following proportions leaves 1.4% stems 0.6 % seeds 0.87-1.34%. Atropine is also manufactured from the root of Scopolia carniolica, in which hyoscyamine is present to the extent of 0.43-0.51% and from A ropa belladonna, the leaves of which contain, on the average, 0.4%, and the roots 0.5%, of hyoscyamine. Many other solanaceous plants of the Datura species contain these alkaloids, in varying, and smaller, amounts, often associated with hyoscine or scopolamine. 

The drug should be dried immediately after collection and should be extracted as soon as possible, as the alkaloid content gradually diminishes on keeping. 

For the manufacture of atropine and hyoscyamine the drug is powdered and extracted, in a copper extractor, by percolation with hot alcohol (S.V.M.), until free from alkaloid. The alcohol is removed from the extract by distillation, preferably under somewhat diminished pressure, and the syrupy extract is allowed to flow, in a thin stream, and with good stirring, into very dilute (0.5-1.0%) acid, hydrochloric or sulphuric. The aqueous portion is separated from undissolved resinous matter, etc., and is further freed from impurity by being shaken out with petrol. It is then made neutral, or faintly alkaline, by addition of ammonia solution, and set aside for a time, when a quantity of resinous material is precipitated and removed. An excess of ammonia is then added, whereby the alkaloids are precipitated. They are extracted by 

The alkaloid is converted by neutralisation with the required quantity of oxalic acid into the oxalate (B)2H2C204 (see Trans. Chem. Soc. (1912), 101, 946). 

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Atropa Belladonna Linn. Leaves, 0-4 roots, 0-5 seeds, 0-8 whole plant, 0-2 to 1-0 h5mscyamine with some hyoscine atropine has been found but may have resulted from racemisation during extraction apoatropine and possibly belladonnine (Kreitmair Atropa bcetica. Leaves, 0-82-1-06 roots, 0-94 fruit, 1-09 hyoscyamine and atropine. 

Spectra for the diastereoisomeric pairs quinine-quinidine, cinchonine-cinchonidine alkaloids are mirror images of each other and mixtures have been determined using CD detection [57]. Spectra for the pilocarpine-isopilocarpine pair were such low quality that they could be used only for qualitative distinction. CD detection combined with UV detection was used to measure enantiomeric excesses in mixtures of L-hyoscyamine and atropine, i.e. racemic hyoscyamine. This subject is returned to in greater depth later. 

Hyoscyamine and atropine are therefore tropic acid esters of the base tropine. The constitution of tropine according to Willstater is as follows ... 

The ethyl ether solution of bases is dehydrated with anhydrous sodium sulfate, filtered and the ether concentrated and cooled to crystallize a mixture of hyoscyamine and atropine. The mixture is mixed with one quarter its weight in chloroform and refluxed at 116° to 120° for 2 hours. The racemization of hyoscyamine produces atropine. 

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). 

Hyoscyamine and atropine as solutions in 0.1 N HC1 can be determined by UV spectroscopy (98). The absorbance of such solution is measured in 3-cm cells... 

CD spectra in aqueous buffer solution can be used to distinguish between stereoisomers including hyoscyamine and atropine (102). Hyoscyamine can be determined from its CD spectrum at 222 nm in the presence of atropine, and the sum of the two alkaloids can be determined from their absorbance at 257 nm. 

Datura, Dried leaves and dried seeds of Datura fastuosa L., var. alba Nees (also leaves from D metel L ), Soianaceae. Habit. India. Gmsru. About 0.5% hyoscine, with traces of hyoscyamine and atropine the seeds contain also resin and fixed oil- Comprehensive monograph A. F. Blakeslee, The Genus Datura (Ronald Press, New York, 1959) 289 pp. 

The relation of the various transformation products of Z-hyoscyamine and atropine is summarized schematically in Chart II. 

Tropane alkaloids, including hyoscyamine, its race mic form atropine and scopolamine are anticholinergic agents that have been extensively used as pharmaceuticals [11-13], These alkaloids were historically and widely used and they are among the oldest drugs applied in medicine [14]. Scopolamine is the more valuable alkaloid, having a 10 times higher commercial demand than that of hyoscyamine and atropine [13, 15-17]. 

PoETHKE et al. [125, 173] have worked with belladonna herbs and tinctures. They used silica gel G and chloroform-acetone-diethylamine (50 + 40 + 10) as solvent. Oswald and Flhck [151—153] have chromatographed hyoscyamine and other alkaloids from this material, notably belladonnine, apoatropine, aposcopolamine, scopine and scopoline. Six solvents were used, of which the best was found to be butanone-methanol-7.5% ammonium hydroxide (60 + 30 + 10) the Dragendorff reagent was employed for detection. The method was worked out also for quantitative determination (planimetric evaluation) (limit of error 5.8%). A linear relation was found between spot area and amount of alkaloid, provided that the amount of substance did not fluctuate by more than 20%. In this way it was possible to determine the mixture of hyoscyamine and atropine in the presence of scopolamine (hyoscine) in some of the plant organs of Atropa belladonna. Datura stramonium, Hyoscyamus niger and H. muticus [153]. 

The separate determination of hyoscine, hyoscyamine and atropine in a mixture is of considerable interest. Rowson has investigated this problem and has proposed the following method based on the observation that at pH 8-5 hyoscine is quickly and completely extracted by chloroform whereas atropine is extracted with difficulty the hyoscyamine extracted is calculated from the optical rotation of the mixed alkaloids after correction for the hyoscine content. The specific rotation of /-hyoscyamine was taken as —22° and /-hyoscine as —18°,... 

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