Dec.

1933

AMERICAN PHARMACEUTICAL ASSOCIATION

1241

QUALITATIVE TESTS FOR EPHEDRINE AND ITS DERIVATIVES*,'
BY C . T. FENG AND B. E. READ.

In the course of our research upon the best quantitative method of assay for
ephedra and its alkaloids we undertook a large number of qualitative tests with a
view of possibly finding one which would prove of worth in quantitative work.
While this has not been definitely attained much useful information has been
brought together concerning the reaction of ephedrine and its derivatives toward
various laboratory reagents which we herewith report.
Chen in 1925 (1) in one of his first reports from these laboratories gave a list of
reactions of ephedrine with several of the commoner laboratory reagents, and later
Chen and Kao (1926) (2) summarized the various tests known q. v., which it is
unnecessary for us to go over again now.
Tsiang and Brown (1927) (7) gave a more complete report upon the gold and
platinum salts made with solutions of ephedrine varying in strength from 1in 10,000
to 1 in 1000. With Krant's reagent they obtained a characteristic crystalline
precipitate.
On account of the fact that Chinese ephedra has been shown to contain (a)
ephedrine, (b) pseudoephedrine (6), and (c) methyl-ephedrine (5), we have carefully extended our tests to all three of these compounds; also to the (d) butyl,
(e) benzyl and (f) quaternary halide compounds which have been synthesized in
these laboratories (4).
Unless indicated otherwise, solutions of the above compounds were found to
give their best reactions in the following concentrations: (a) and (b) five to ten per
cent, (c) two and a half to five per cent, (d) and (e) one to two and a half per cent,
and (f) one-tenth to one per cent.
1.

BIURET TEST (MODIFIED)

(3).

(a) Ephedrine Hydrochloride.-A violet pigment very soluble in ether giving a brilliant
solution, which when evaporated to dryness yields a gelatinous residue (3).
( b ) Pseudoephedrine Hydrochloride.-The pigment is more slowly soluble in ether yielding
a solution of dull appearance, which when air dried produces beautiful violet crystals (3).
(c) Methyl-Ephedrine Hydrochloride.-Vigorous shaking of the reaction mixture showed
that the pigment was not extractable by ether, but before shaking the ether dissolved some of
the pigment.
(d) Butyl-Ephedrine Hydrochloride.-Identical with ( c ) .
(e) Benzyl-Ephedrine Hydrochloride.-The pigment was absolutely insoluble and was not
extractable by ether.
(f) Quaternary Halide.-No biuret coloration produced.
2.

POTASSIUM IODIDE TEST.

A SATURATED SOLUTION ADDED TO A FIVE PE R CENT

SOLUTION OF EACH COMPOUND.

(a)

Prisms or rhombic bars.

(Fig. 1.)
(Fig. 2.)
(c) Slowly producing thin flaky crystals. (Fig. 3.)
(d) Producing oily drops immediately, from which rosettes separate later.

(b) Hexagonal rhomboid plates.

(Fig. 4.)

* The cost of these experiments was defrayed partly by a grant from the Council on
Pharmacy and Chemistry of the American Medical Association.
From the Department of Pharmacology, Peiping Union Medical College, Peiping, China.

-Potassium iodide and methyl-ephedrine hydrochloride. Fig. 5. Fig.-Potassium iodide and ephedrine hydrochloride. 12 Fig. 6.-Potassium iodide and pseudoephedrine hydrochloride. . 11.JOURNAL OF THE 1242 Fig. 12. 10. Fig.-Cadmium potassium iodide and ephedrine.-Ammonium thiocyanate and ephedrine. Fig. 1. No. 9. Fig. Fig. Vol. 8. Fig. 4.-Cadmium potassium iodide and methyl ephedrine. 10.-Picric acid and ephedrine.-Potassium iodide and butyl-ephedrine hydrochloride. Fig.-Picric acid and pseudoephedrine. Fig.--Ammonium thiocyanate and pseudoephedrine. Fig. Fig. 12. 3.-Ammonium thiocyanate and methyl ephedrine. 2.Picric acid and methyl ephedrine. X X I I . 11. 7. Fig. Fig.

separate out. ephedrine in strong solution certainly yields a crystalline precipitate with picric acid one per cent. 6. MICROCHEMICAL TEST. soluble in water and alcohol.) (c) Yellow feathery leaflets. (Fig. soluble in water. Slightly soIuble in water. (d) Yellow oily drops. 12. (f) Readily producing clusters of characteristic rhombic crystals (4). (e) Similar to (d). CADMIUM POTASSIUM IODIDE. 5 . 7.) (d) Oily. ONE PER CENT. 1933 1243 ( e ) Oily droplets which do not crystallize in one or two hours. earlier workers using weaker solutions reported negative results (I).) (c) (Five to ten per cent. The butyl-ephedrine mixture (d) evaporated to dryness yields a gelatinous mass which in scveral days crystallizes out. 3. (Fig. ( b ) Similar to (a). soluble in water and alcohol. which later crystallize out in irregular forms. (d) Pale yellow rhombic-hemihedral crystals. (1) Characteristic fine needles (already published. (Fig. droplets first appear. ( e ) Pale yellow drops. All of the above crystalline precipitates are soluble in alcohol or acetic acid. ( b ) Pale yellow bunches of long needles. (Fig. TWENTY PER CENT.) ( d ) (Two and a half to five per cent. (6) Golden-yellow feathery needles. Less fine than (a). 5. 9. ) Readily soluble in water. slightly soluble in water. slightly soluble in water. (f) Characteristic crystals. ( a ) Golden-yellow sharp needles. (c) On standing clusters of characteristic needles are formed.) (b) (Saturated solution of pseudoephedrine hydrochloride.) It sets to a glassy paste not showing discrete crystals.) Leaflets crystallize out on standing from the oily droplets which first separate out. 7. Slightly soluble in water. benzyl-ephedrine yields no crystals. MICROCHEMICAL TEST. 10. SATURATED SOLUTION.) Oily droplets. soluble in water and alcohol. MICRO-TEST (7). 8. (e) (Two and a half to five per cent. readily soluble in water. 4. (Fig.AMERICAN PHARMACEUTICAL ASSOCIATION Dec. soluble in water. very soluble in water or alcohol. Slightly soluble in water and very soluble in alcohol. Shaped like pine needles. readily in alcohol. 11. (a) Oily droplets separate which on standing crystallize out.) ( d ) Yellowish flakes. (c) Characteristic yellow needles. (a) . slightly soluble in water. (Fig. cf) Fine flakes readily separate out which are almost insoluble in water. (e) Yellow needle-shaped crystals. very soluble in water. (Ephedrine in ten per cent solution. Soluble in water. Feng 1932 (4)). very soluble in alcohol. THREE PER CENT. PLATINIC CHLORIDE. These results are sufficiently characteristic to be used to distinguish these six compounds one from the other. soluble in water or alcohol. It is important to use the strengths of solutions given a t the beginning of this report. (c) Yellow prisms. (Fig.) Elongated prisms. (e) Similar to (d). cf) Characteristic yellowish needles. AURIC CHLORIDE.) ( 6 ) Yellow needle-shaped crystals. TWO PER CENT. A quicker reaction than that with auric chloride. ( a ) Pale yellow silky needles. PICRIC ACID. which do not crystallize. ( e ) Yellowish globules. 6. very soluble in water or alcohol. AMMONIUM THIOCYANATE.) Rhombic hemihedral plates. MICRO-TEST (7).shaped like thorns. (Fig.

All of the compounds with this reagent yielded a pale yellow precipitate. POTASSIUM BISMUTH IODIDE. the solubility in water or dilute acids varying with the compound used. TEN PER CENT. WAGNER’S REAGENT. They all yield white precipitates soluble in excess of nitric acid. especially with the quaternary halides cf). ( b ) and (c) were readily soluble. MERCURIC CHLORIDE. SLIGHTLY ACIDIFIED WITH NITRIC ACID. One of these quaternary compounds might be used to estimate bismuth. ( e ) and (f) yielded white precipitates soluble in excess of the reagent. gave no permanent precipitate with ephedrine in one per cent solution and only a cloudy effect with pseudoephedrine one per cent. The reagent diluted 0. which became blue on standing for a definite length of time varying. 1 to 2 days 2 to 3 days 3 to 4days 4 to 6 days 6 to 20 days 0 to 20 days. (c) Soluble. POTASSIO-MERCURIC IODIDE. Butyl and benzyl-ephedrine in dilute solution of 0.1 per cent gave heavy precipitates. soluble in excess of water. . KRANT’S OR THRESH’S REAGENT. (a) and ( b ) Readily soluble. F I V E PER CENT.2 per cent. ( d ) and ( e ) Not very soluble.JOURNAL O F THE 1244 cf) (One to two and a half per cent. No. Vol. 15. A strong solution of iodine five per cent and potassium iodide five per cent gave brown precipitates with all the compounds. or on the addition of water and weak acids. (Tsiang and Brown (7) used this test with ephedrine 1 in 1000 solution. 12 Prismatic hemihedral plates.) 12. SODIUM NITROPRUSSIDE. AMMONIUM MOLYBDATE. (d). The compounds all yielded a whitish precipitate. (f) Almost insoluble. All of the above TEN PER CENT. XXII. FIVE PER CENT. (d) and ( e ) were difficultly soluble and (f) was almost insoluble. FIVE PER CENT. This test is more sensitive than some. 16. BISMUTH NITRATE. FIVE PER CENT. MAYER’S REAGENT.) were readily soluble on the addition of water. All the compounds form white precipitates soluble in excess of the reagent or on the addition of water. White curdy precipitates of nonspecific character were produced by all the compounds. No precipitate was obtained from ( a ) . the solubilities decreasing in the order cited. each of which give a characteristic result described in another report (4). Only butyl-ephedrine and benzyl-ephedrine in five per cent solution formed flesh-white precipitates. 13. as was the case in other tests. 11. POTASSIUM TRI-IODIDE. PHOSPHOTUNGSTIC ACID. PHOSPHOMOLYBDIC ACID. 10. 14. A reddish precipitate insoluble in water is produced by all the compounds but on the addition of acetic acid (a). with the compound tested: In In In In In In (f) Methyl-ephedrine-methyl-iqdide (d) Butyl-ephedrine hydrochloride (e) Benzyl-ephedrine hydrochloride (a) Ephedrine hydrochloride (2) ( b ) Pseudoephedrine hydrochloride (c) Methylephedrine hydrochloride 9. 8. ( b ) or (c) in five per cent solutions.

4 14.3 20. No. A. 18. PH. 21 (1932). 87-96. KRANTZ. C. Ibid...A. Many of the above tests confirm earlier reports upon the various reactions of ephedrine. K. Feng. TABLE I.. K. Read and C . T. Kao. Feng and B. glycerine. PH. Chinese J. JOUR.8 3.3 19. Feng. T. D.5 No.5 per cent * Scientific Section. A. NOTE. JOUR. ZINC--OR-IODIDE. Physiol. glucose. SCHMIDT AND JOHN C. 1933 1245 17. Madison meeting.9 7. 297-304. JR. A. Per Cent Water.4 6.0 20.AMERICAN PHARMACEUTICAL ASSOCIATION Dec. E. JOUR. INTRODUCTION. In many instances the water content of the light variety exceeded the Pharmacopoeia1 limit.A. cobalt chloride. The rubric requires 96 per cent purity after ignition and permits 10 per cent water to be present in the compounds in general use. Chen. T. A. but soluble in dilute acetic acid. 625-639. 16 (1927).. A. Light. REAGENTS WITH NO VISIBLE REACTION. PH.5 Mean 18. A. Chinese J. 8 11.0 10 21. K. K. 1933. K.*. H. phthalic acid. The reactions with potassium permanganate and chromic acid were so unstable that they seem worthless as test reagents for this class of compound. 22. PH. The Pharmacopoeia recognizes dual standards for magnesium oxide and heavy magnesium oxide. E. C . the authors investigated the problem and recorded their observations in this communication. but this is the only comprehensive statement dealing with solutions of known strengths.2 19. Per Cent Water.-PERCENTAGE OF WATERIN COMMERCIAL SAMPLES OF MAGNESIUM OXIDE. barium nitrate. the authors had occasion to examine several commercial samples of each variety of magnesium oxide. nickel chloride. B. Brown.3 12 22. manganese chloride.9 11 19.. 1 (1927). potassium ferri and ferrocyanides. 15 (1926). On account of these findings. Read.5 13 14. Ibid. Per Cent Water. The percentage of water found in the specimens showed great variation. 294-296.' BY JACOB E. A NOTE ON THE WATER CONTENT OF MAGNESIUM OXIDE. In the preparation of the monographs for these compounds for the forthcoming edition of the Pharmacopoeia. 8-15. 189-194.0 17. There was obtained in all cases a brownish white precipitate insoluble on the addition of water. Tannic acid.. T..5 9 18. 1 2 3 4 5 6 7 Light. 397-406. Chen and C. 2 (1928). 14 (1925). Heavy. STEPHENSON'S REAGENT.8 7. The highest quantity of water found was 22 per cent. C.8 7. sodium benzoate or nitrite.Physiol. The expense of this investigation was defrayed in part by a grant from the Research Fund of the AMERICAN PHARMACEUTICAL ASSOCIATION. Feng. .. (1) (2) (3) (4) (5) (6) (7) LITERATURE CITED. 1 (1927). Tsiang and E.