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Ephedrine And Its Salts
Isolation And Properties

By T. Q. Chou, J. Biol. Chem. 70, 109-115 (1926)

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With the development in scientific medicine of the clinical use of the alkaloid ephedrine, there has been an increasing interest in the preparation of this alkaloid, and an immediate need for accurate data in the standardization of its salts.

In these laboratories large amounts of ephedrine have been prepared and it has been found that the basic substance isolated from the Chinese shrub Ma Huang, variously identified as Ephedra vulgaris Rich. var. helvetica Hk. et Thorns1 and Ephedra equisetina, Bge.,2 consists chiefly of ephedrine together with about 20 percent of its isomer pseudoephedrine. These two alkaloids were first prepared by Nagai3 and Merck4 respectively. They were found to be mutually convertible by boiling with hydrochloric acid and in other ways5, and have the empirical formula C10H15ON.

The chemical structure of ephedrine, and its isomer OH-CH-C6H5-CH-CH3NH-CH3, has been studied by many workers6-8 and synthetically proven for both alkaloids9-12. It shows a close relationship in chemical structure to epinephrine, to which it has been found to have similar, and in some respects superior physiological effects13-16.

The separation of the two alkaloids by some clear cut method has been the object of this investigation. While the salts of ephedrine are better crystallized and less soluble in water and alcohol than those of pseudoephedrine it has been found that the best means of separation depends upon the striking difference in the solubility of their oxalates in cold water.

Pure preparations of the alkaloids and their salts were made and studied. While some of the physical constants of the salts obtained do not agree with those published by Chen17, they do confirm such as are published by several other workers18. The pure base heretofore considered to be levorotatory was found to be dextrorotatory in water, and levorotatory in alcohol.



1 kilo of powdered Ma Huang was extracted with cold benzene in the presence of dilute Na2CO3 solution, and the benzene extract was shaken up with a sufficient quantity of dilute HCl to remove the basic substances. The acid solution was made alkaline with solid K2CO3 and the liberated base was then extracted with chloroform. The chloroform solution, when dried over anhydrous Na2SO4 and distilled, gave 2.6 g of crude base.

Preparation of Ephedrine HCl by Fractional Crystallization

The crude base obtained as above was taken up with about twice its weight of alcohol and neutralized with concentrated HCl diluted with twice its volume of alcohol. Nearly pure ephedrine hydrochloride crystallized out on standing. After filtering it was washed with a mixture of alcohol and ether, and then with pure ether, and dried. A further quantity of ephedrine hydrochloride may be got by concentrating the mother liquors and washings. The final mother liquor was kept for the isolation of pseudoephedrine (see below).

Ephedrine hydrochloride crystallized out from alcohol in prismatic needles, mp 216°C, [α]D22 -32.5° (see Fig. 1).

The salts prepared by fractional crystallization show no change in the melting point when recrystallized seven times. In many of our experiments the salts were recrystallized twelve times.

Separation of the Oxalates by Difference of Solubility

The crude base as obtained when treated with oxalic acid give a clear-cut separation of the two alkaloidal salts. Ephedrine oxalate being only very slightly soluble in cold water and pseudoephedrine oxalate being exceedingly soluble, the soluble and insoluble products represented a separation of the two alkaloids.

Preparation of Pure ephedrine Base

5g of pure ephedrine hydrochloride, dissolved in a sufficient quantity of water, were made alkaline with solid K2CO3 until two layers were formed and extracted twice with chloroform. The chloroform solution was well dried over anhydrous Na2SO4 and distilled. On cooling the residue crystallised out in rhombic crystals. It was recrystallized by dissolving in a small quantity of alcohol and then adding a sufficient quantity of petroleum ether, mp 43°C. (see Fig. 2).

Properties of Pure Ephedrine

Ephedrine was found to be very soluble in water, alcohol, and chloroform and nearly insoluble in petroleum ether upon cooling. Being a strong base, ephedrine displaces ammonia from its salts. Solutions of the salts in water varying from 1 to 10 percent were found to be exceedingly stable. No change in strength occurred after 6 months storage at room temperature. The solutions are quite sable at boiling temperature. Its specific rotation varied with the different solvents used.

  1. [α]D22 +13.75° in water.
  2. [α]D22 - 5.5° in absolute alcohol

A part of the pure ephedrine so obtained was transformed into its corresponding salts. They gave the following physical constants.

Ephedrine Hydrochloride. C10H15ON·HCl
Prismatic needles, mp 216°C., [α]D22 -32.5°. Easily soluble in alcohol and water. Its aqueous solation is stable at boiling temperature.

Ephedrine Sulfate. C10H15ON·H2SO4
Hexagonal plates; mp 257°C, [α]D22 -30°. Difficultly soluble in alcohol, easily soluble in water, neutral to litmus.

Ephedrine oxalate. 2 C10H15ON·C2H2O4.
Prismatic needles from. water; mp 245°C. with decomposition; neutral to litmus; only very slightly soluble in cold water (see Fig. 3).

Ephedrine Phosphate. C10H15ON·H3PO4.
Crystallized from alcohol in long silky needles; mp 178°C; acid to litmus.


The alcoholic mother liquor obtained after the removal of ephedrine hydrochloride as indicated above was first concentrated and then evaporated to dryness an a water bath. The residue was taken up with a little water, made alkaline with K2CO3, extracted with chloroform, and distilled. The basic residue was transformed into its corresponding sulfate by neutralizing with concentrated sulfuric acid diluted previously with alcohol. The crude sulfate so obtained consisted chiefly of pseudoephedrine sulfate. Its free base was obtained by dissolving in water, making alkaline with K2CO3, and extracting with chloroform. Pure pseudoephedrine crystallized out from alcohol in rhombic prisms, mp 118°C, [α]D22 +50° (see Fig. 4). Unlike ephedrine it was only slightly soluble in water. Its salts were prepared and gave the following physical constants.

Pseudoephedrine Hydrochloride. C10H15ON·HCl.
Crystallized from alcohol in stout needles; mp 179-181°C, [α]D22 +58.75°; very soluble in water and in alcohol (see Fig. 5).

Pseudoephedrine Sulfate. C10H15ON·H2SO4 .
Prismatic needles; no sharp mp; [α]D22 +52.5°; easily soluble in water and in alcohol.

Pseudoephedrine Oxalate. 2 C10H15ON·C2H2O4
Needles; mp 218°C with decomposition; difficultly soluble in alcohol; very soluble in cold H2O; neutral to litmus (see Fig. 6).

Action of HCl upon ephedrine. Preparation of Pseudoephedrine.

Boiled gently with reflux condenser for 12 hours. The acid solution was evaporated low over a water bath and allowed to crystallize; the crystallized HCl salt consisted of nearly pure unchanged ephedrine hydrochloride. If the acid solution had been, sufficiently concentrated practically all the unchanged ephedrine hydrochloride would have crystallized out, Filtered, washed with a little dilute HCl, and used the filtrate for the preparation of pseudoephedrine. The acid filtrate eves then evaporated to dryness over a water bath. The residue was taken up with a little water, made alkaline with K2CO3, and extracted with chloroform. The chloroform solution, then well dried over anhydrous Na2SO4, and concentrated, deposited pseudoephedrine in rhombic crystals. The base obtained melted at 118°C and was identical in all respects with pseudoephedrine obtained from the crude drug.



  1. Botanical nomenclature, Shanghai, 1917, 1004.
  2. Chou, T. Q., and Read, B. E., Proc. Soc. Exp. Biol. and Med., 1926, xxiii, 618.
  3. Nagai, N., Pharm. Z., 1887, xxxii, 700.
  4. Merck's Ber, 1893, 13.
  5. Schmidt, E., Arch. Pharm., 1908, cxlvi, 210; 1912, cl, 154; 1913, cli, 320; Apoth.-Ztg., 1913, xxviii, 667.
  6. Ladenburg, A,, and Oelschlägel, C., Ber, Chem. Ges., 1889, xxii, 1823.
  7. Rabe, P., Ber, chem. Ges., 1911, xliv, 824.
  8. Schmidt, E., Arch. Pharm., 1915, ccliii, 52.
  9. Eberhardt, A., Arch, Pharm., 1920, cclviii, 97.
  10. Fourneau, E, An. soc. espan. fis. y quim., 1922, xx, 394.
  11. Späth, E., and Gökring, R., Monatsh, f. Chem., 1920, xli, 319.
  12. Späth, E., and Koller, G., Ber. chem. Ges., 1925, lviii, 1268.
  13. Chen, K, K., and Schmidt, C. F., J. Pharmacol. and Exp. Therap., 1924, xxiv, 339.
  14. Amatsu, H., end Kubata, S., Kyoto Igaku Zasshi, 1917, xiv, 77.
  15. Fetteralf, G., and Sponsler, M. B., Arch. Otolaryng., 1925, ii, 132.
  16. Miller, T. G., Am J. Med. Sc., 3925, clxx, 157.
  17. Chen, K. K., Am. Pharm. Assn., 1925, xiv, 189.
  18. Henry, T. A., Plant alkaloids, London, 2nd edition, 1924.