Comparison of ephedrine and pseudo-ephedrine from ma-huang (Ephedra vulgaris, Var Helvetica.)

T.-Q. CHOU & B. E. READ PROC. SOC. EXP. BIOL. MED. 618-620 (1926)

The alkaloids ephedrine and pseudo-ephedrine were isolated by Nagai (1) and Merck (2), respectively, from Ephedra vulgaris. The Chinese drug Ma-huang, variously identified as Ephedra vulgaris, Rich. var. helvetica, Hk. et Thoms.(3), Ephedra equisetina, Bge.(4), has been recently studied by K. K. Chen and Carl F. Schmidt (5,6). From this they isolated the alkaloid ephedrine and conducted various physiological experiments. They gave the following physical constants for ephedrine and its salts:

Ephedrine - mp 210°C.
Ephedrine HCl - mp 214°C, [α]D25 -35°.
Ephedrine H2SO4 - mp 242°C.

It has been found that the basic substance isolated from Ma-huang, contains about 20% of pseudo-ephedrine as well as ephedrine, the former being identical in all respects with that obtained by the action of HCl upon ephedrine. The ephedrine, having a melting point of 43°C, and being considered to be laevo-rotatory up to now, is found to be dextro-rotatory in water and laevo-rotatory in alcohol. Its specific rotation suffers no change towards the action of dilute HCl, Na2CO3 and pepsin in acid solution. Some difference in optical activity has, however, been observed by the introduction of trypsin into its alkaline solution.

Salts of both ephedrine and pseudo-ephedrine were prepared and studied. Generally speaking the salts of ephedrine are better crystallized and less soluble in water and alcohol than those of pseudo-ephedrine. The remarkable difference in solubility of their oxalates in cold water affords a good means of separating ephedrine from pseudo-ephedrine, whenever a mixture of these two isomers has to be dealt with.

SALTS OF EPHEDRINE

Hydrochloride. C10H15NO·HCl. Prismatic needles, mp 216°C. [α]D22 -32.5°. Easily soluble in alcohol and water. Its aqueous solution is stable at boiling temperature.

Sulfate. C10H15NO·½H2SO4 (Analysis: S=7.48%) Hexagonal plates, mp 257°C [α]D22 -30° difficulty soluble in alcohol, easily soluble in water, neutral to litmus.

Oxalate. 2 C10H15NO·C2H2O4. Prismatic needles from water mp 245°C (dec.), neutral to litmus, only very slightly soluble in cold water.

Phosphate. C10H15NO·H3PO4 (Analysis: P=11.7%). Crystallized from alcohol in long silky needles, mp 178°C, acid to litmus.

SALTS OF PSEUDO-EPHEDRINE


Hydrochloride
. C10H15NO·HCl. Crystallized from alcohol in stout needles. mp 179-181°C. [α]D22 +58.75°, very soluble in water and in alcohol.

Sulfate. C10H15NO·½H2SO4, Prismatic needles, no sharp mp [α]D22 +52.5°, easily soluble in water and in alcohol.

Oxalate, 2 C10H15NO·C2H2O4. Needles. mp 218°C with decomposition difficulty soluble in alcohol. Very soluble in cold water, neutral to litmus.

As far as is known pseudo-ephedrine is very similar to ephedrine in its physiological action. Previous workers have laid particular emphasis on its mydriatic effect (see Ladenburg & Oelschlägel (7), Lewin & Guillery (8), and Günsberg (9)). The latter states that, "Pseudoephedrine is a powerful mydriatic. A 10% solution excites the sympathetic nerve and dilates the pupil after fifteen minutes".

Reference books make the general statement that like ephedrine, "pseudoephedrine is also poisonous". This statement appears to be based on scant information. A set of preliminary experiments conducted in these laboratories show that pseudoephedrine is less toxic than ephedrine for rabbits. When introduced subcutaneously and intravenously the mean lethal dose is about 500 mg and 100 mg respectively, which makes its toxicity relative to ephedrine about 0.645. If pseudoephedrine exhibits the same excellent clinical results obtained with ephedrine, it would be preferable for use on account of its lower toxicity.

REFERENCES

1. Nagai, Pharm. Ztg., XXXII, 700 (1887)
2. Merck's Berichte, 13 (1893)
3. Botanical Nomenclature, Commercial Press, Shanghai, 1004 (1917)
4. Cowdry, N. H., J. N. China Royal As. Soc., LIII, 158 (1922)
5. Chen, K. K., and Schmidt, Carl F., J. Pharm. Exp. Therap., XXIV, 339 (1924)
6. Chen, K. K., Am. Perm. Assn., XIV, 189 (1925)
7. Ladenburg und Oelschägel, Bericht. Chem. Gesell., XXII, 1823 (1889)
8. Lewin et Guillery, Wirkungen von Arzneimitteln und Giften auf das Augen, 1913, Berlin.
9. Günsberg, Virchow's Arch., CXXIV, 75 (1891)
10. Henry, T. A., Plant Alkaloids, 2nd edition, Philadelphia, 1924.
11. Chen, K. K., Proc. Soc. Exp. Biol. and Med., XXII, 404 (1925)




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