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of each dye was placed in separate test tubes and various quantities of the solvent were added. The tubes were stoppered and allowed to stand at room temperature. The smallest amount of solvent dissolving the 0.5-gram portion of dye was observed. The solutions were agitated from time to time. I n this work the authors tried not only the dyes they thought were new but also a variety of other dyes made in the course of the work. Reduction of Oil-Soluble Dyes The usual SnClz-HCl reduction of water-soluble azo dyes was found impossible. After trying benzaldehyde and phenylhydrazine as reducing agents in alcoholic and benzene solutions of the dyes, with unsatisfactory results, a reduction of the alcoholic solution of the dye by means of sodium amalgam gave good results. A solution of 1 gram Sudan I in 250 cc. 95 per cent alcohol was heated on a water bath with 75 grams 4 per cent amalgam for 2 hours. The pale brown solution was steam-distilled to remove the aniline and alcohol, and acidified with HC1 until the 1-amino-2-naphthol separated. This was filtered, washed, and recrystallized from alcohol and found to be the desired product. A solution of 2 grams Xylidine Brown M in 95 per cent alcohol, with 75 grams 4 per cent amalgam, was heated under a water condenser a t the boiling point for 4 hours. After the color was successfully bleached, the solution was filtered to remove the mercury and the distillate was evaporated t o a volume of 30 cc. The solution became highly colored on dilution with 200 cc. HzO and the addition of enough HCl to neutralize the NaOH formed. A dark red precipitate, readily soluble in alcohol, was obtained. 0.1070 gram substance gave 0.08719 gram N (Dumas) 0.0680 gram substance gave 0.1731 gram COZand 0.0250 gram
H20 0.200 gram substance gave 0.5091 gram COZand 0.0735 gram Hz0
Vol. 20, No. 4
Found: K = 8.15%; C = 69.42 and 69.41%; H = 4.11 and 4.10%
Theory CloHloNzO: C = 68.96%; H = 5.74%; N = 16.09% Theory ClOH7N02: C = 69.36%; H = 4.04%; N = 8.09%
The writer concluded that the reduction took place as expected but that the reduction product, a diamino naphthol, was too sensitive to oxidizing conditions to get it out in the unoxidized form. They were unable to obtain the colorless reduction product but got a quite pure oxidation product that their analytical data led them to believe was 4-amino1, 2-naphthoquinone (m. p. 136" C.). The substance was insoluble in water, strong caustic, and strong acid solutions, and gave the isocyanide test. An attempt was made to diazotize the new product and couple the diazo product with 2-naphthol. The diazotization was carried out in an alcoholic solution. From the mixture resulting on pouring the diazo product into an alkaline 2-naphthol solution, a bright red precipitate resulted. 0.0460 gram substance gave 0.00383 gram N (Dumas) 0.1100 gram substance gave 0.00956 gram N (Dumas) Found: N = 8.33% and 8.69%. Theory for Cz0H~zN208= 8.53%
Conclusion
The authors have prepared thirty new dyes that represented a monotony of color since they were all red or redbrown. Toluene and carbon tetrachloride were found to be very good solvents. Other solvents, such as gasoline and linseed oil, were useful but the degree of solubility was not determined. A method was found for the reduction of the dyes and this proved of interest on account of the products obtainable. Each dye made had some more or less antiseptic action on account of the phenolic hydroxyls present but the physiological action was not investigated.
Standardization of Ephedrine and Its Salts' Joel B. Peterson CHEMICAL LABORATORY O F AMBRICAN MEDICAL ASSOCIATION, 635 NORTRDEARBORN S T . , CHICAGO, ILL.
PHEDRIKE, the alkaloid discovered by Nagai forty years ago, was for many years an almost unknown and an almost unused drug. Owing to important discoveries of valuable therapeutic effects obtained through its use made within the last three years, ephedrine suddenly became a much talked-of and a widely sought article. When the pharmaceutical manufacturers were first asked to produce ephedrine preparations, some of them did not know, nor could they easily find out, just what would constitute a good ephedrine preparation, much less prepare it in large quantities. It is no wonder that isolated cases have been recorded in which ephedrine preparations have been prescribed, but in which ephedrine reactions have not been obtained. I n view of this situation the A. M. A. Chemical Laboratory thought it advisable to make a chemical investigation of the drug and to devise standards for it. I n devising standards this laboratory aims to secure for the medical profession the best possible product without placing undue hardship on the manufacturer. Many manufacturers are using the standards suggested by the A. M. A. Chemical Laboratory as guides for manufacture.
E
1 Received
December 3, 1927.
Relationship between Ephedrine and Epinephrine
I n examining the literature on ephedrine, the chemical similarities that exist between this drug and epinephrine become apparent, and it is not surprising to learn that, therapeutically, the two drugs have in part similar actions. These similarities can be strikingly seen by a comparative study of the structural formulas and, conversely,' the differences in action can be better appreciated by noting the chief points of difference in the molecular arrangement. H
H
It will be noted from these formulas that the side chain of ephedrine contains three consecutive carbon atoms; accordingly, the compound is named "a-hydroxy-P-methylaminopropylbenzene." The side chain in epinephrine contains Ohly two consecutive carbon atoms, and its name, therefore,
I S D USTRIAL AND ENGINEERING CHEMISTRY
April, 1928
389
ih "~-liydrox~-~-metliylaiiiino-3,4-dihydroxyethylbenzene."I n isolating the free base, a method was followed that has Epinephrine has two hydroxyl groups attached to the ben- often been used for isolating alkaloids and that has been dezene nucleus; these are lacking in ephedrine. The two hy- scribed as being applicable for the isolation of ephedrine. droxyl groups in the epinephrine molecule make it suscep- It consisted in extracting (shake-out method) an ammoniacal tible to oxidation-so susceptible, in fact, that the drug is solution of the ephedrine salt with chloroform. It was surnot stable in the air. On the other hand, the ephedrine prising that needle-shaped crystals began to form before molecule is stable in the air to the extent that no change two-thirds of the chloroform had evaporated. It was more was found in a 5 per cent solution of ephedrine hydro- surprising to find that these needles were identified as quite chloride after it had stood for six months. This great resist- pure ephedrine hydrochloride, in spite of the fact that the ance of ephedrine to oxidation offers one explanation why it shake-out had been started with ephedrine sulfate. This may exert therapeutic action when administered by mouth, in work was done before there had been any mention in the which respect it differs greatly from epinephrine. Ephe- literature of such a reaction. The reagents were tested for drine alkaloid does not show the same degree of stability as chloride ions, and when found negative the experiment was its salts. Attention should be drawn to the two asymmetric tried again. The same results were obtained. It was evicarbon atoms in ephedrine, and to the one in epinephrine. dent that the workers who had reported the melting point as 210" C. had neglected T h e c o n f i g u r a t i o n of to identify their pFoduct, e p h e d r i n e allows of four and had probably taken the p o s s i b l e isomers (d-epheSix specimens of ephedrine hydrochloride, six specimelting point of a mixture drine, I-ephedrine, d-pseudomens of ephedrine sulfate, and two specimens of epheof ephedrine hydrochloride e p h e d r in e , l-pseudo-ephedrine alkaloid have been examined and standards have a n d e p h e d r i n e . It was drine), all of which have been elaborated. Crystallographic studies of epheproposed to study this rebeen synthesized and isodrine hydrochloride and ephedrine sulfate are also reaction of ephedrine in the lated.2 It will be recalled ported. presence of chloroform with that, in the case of epinephWhen a water solution of ephedrine hydrochloride or a view of utilizing it as a rine, it was found that a sulfate is shaken with chloroform i n the presence of ready means of assaya3 It mixture of the two optically ammonia and the chloroform extract evaporated, quite has been found that the reactive isomers was not so pure ephedrine hydrochloride is obtained. If a solua c t i o n gives only grossly efficient as the product extion is made of ephedrine base in chloroform, epheq u a n t i t a t i v e amounts of tracted from the suprarenal drine hydrochloride may or may not be produced when ephedrine hydrochloride, as glands. This led to the disthe chloroform evaporates. The mechanics of the b e n z a l d e h y d e is formed covery that the dextro form reaction have not been worked out. s i m u l t a n e o u s l y . It has of epinephrine was almost inbeen found that ephedrine active, while the l-epinephhydrochloride m a y or may rine, t h e form present in the suprarenal extract, was very active. A similar con- not be formed when chloroform is added to ephedrine alkadition might have been expected to arise with ephedrine. loid and then evaporated therefrom. This is contrary to the that ephedrine hydroOf the four possible isomers, only one is of current therapeu- results already reported-namely, tic interest, and of the three unwanted isomers, d-ephedrine chloride is obtained when ephedrine is shaken into chloroand 1-pseudo-ephedrine are not found in Ephedra equisetina, form and the chloroform evaporated. The mechanism of according to reports, nor are they easily formed from the this reaction has not been worked out and is not underother two isomers. A fact of importance in a study of stood. It is suggested that it may be an induced reaction. The specimens examined in this investigation were obthis kind is that I-ephedrine and d-pseudo-ephedrine are easily interconvertible. It develops that material called tained from various sources as indicated in the tables of analyI-ephedrine, or that called d-pseudo-ephedrine, may be con- ses. Except where otherwise noted, the details of the analysidered as a n equilibrium mixture of both substances. The ses are given under standards. question then arises-what are the proportions of these two Ephedrine Hydrochloride (See Table I) isomers in our best preparations? An important step in this study is to learn the physical structure of this prodCRYSTALLOGRAPHIC REPORT-A sample of the material uct-whether it contains one type of crystals or whether represented in column I1 was submitted to Albert J. Walcott, a mixture is indicated. For this purpose the collaboration who gave the following report : of Albert J. Walcott, professor of mineralogy and crystallogEphedrine hydrochloride occurs as well-developed, decidedly raphy a t Northwestern University, was obtained. His elongated crystals, terminated at both ends. The crystals are crystallographic studies with samples obtained from this quite free from inclusions of crystalline impurities. laboratory indicated good purity. The crystals may be distinguished by the following optical Experimental Procedure
In the chemical investigation of ephedrine products the ordinary routine for examining new compounds was carried out. The qualitative tests and the physical properties of the salts agreed fairly well with the reports of the older workers. It then became necessary to isolate and study the free base. This had been done on several previous occasions, and the methods were found in the literature. Among other things the melting point of the free base had been described as melting as high as 210" C. The authors have since corrected this melting point. This was quite unusual, as the hydrochloride had frequently been described as melting at 217" C.
* Spath and Gohring, Monatsh
, 41, 319 (1920)
properties:
B i ax i a1 Optically negative 2 E is large Negative elongation Parallel extinction Dispersion of violet is greater than of red The optic axial plane is at right angles to the elongation. Indices of refraction: a = 1.530 * 0.002, B = 1.803 * 0 002; y 1638 * 0.002.
-
This report gives strong indication that these samples of ephedrine hydrochloride are quite pure compounds. S T a i v ~ a ~ ~ s - T hfollowing e ephedrine hydrochloride standards were prepared for New and Nonofficial Remedies4 J . A m Med. Assocn., 88, 482 (1927). Generally abbreviated as N. N. R. A volume published annually by the Council on Pharmacy and Chemistry of the American Medical Association. It describes new remedies of merit that have not been accepted as official by the Pharmacopeia1 Convention I 6
390
INDUSTRIAL AND ENGINEERING CHEMISTRY
Vol. 20, No 4
Table I-Analyses DETERMINATION Loss in weight at 100" C.,per cent
Melting point, C. Specific rotation, [a]?
of S a m p l e s of Ephedrine Hydrochloride BURROUGHSPARKE, B. E. READ, REPORTED OR. ABBOTT ABBOTT WELLCOME DAVIS PEKIN SWAN-MYERS THEORY I I1 I11 IV V VI VI1 0.4, 0.27 0.22 0.34 0.36 0.55 217 219.5 217a 219 219 218 216 -33.48 -34.57 -33.78 34.20 -33.99 -34.lb 1:::;6 17.53 17.49 17.51 17.56 17.27 17.47 17.58 80.06 80.73 80.73 81.00 81.19 81.40 81.91 -7.3 -6.53 -6.8 -6.7) -4.65 -6.95b -6.3 None None None None None Less than 0.01
{
Chloride, per cent Ephedrine, per cent Specific rotation of ephedrine base in absolute alcohol, [a]': Ash, per cent a Uncorrected. b Temperature 24' C.instead o f 20" C.
Table 11-Analyses
of S a m p l e s of Ephedrine Sulfate
PARKS, COMPLIMENTARY REPORTtD DAVIS P~EKIN SPECIMEN OR TEEORY (A) (B) (C) (D) (E) (F) (GI Loss in weight at 100' C . , per cent 0.24 0.32 0.10 None 1.8 0.12 Melting point, C. 233b 243 248 242 230b 242 235-238 Specific rotation, [a12,0 -26.12 -29.27 -31.16 -31.69 -5.97 -30.90 30 Sulfate, per cent 23.08 22.77 22.90 22.77 21.88 22.79 22.88 Ephedrine, per cent 75.16 76.19 75.90 75.19 71.64 75.64 77.12 Specific rotation of ephedrine base in absolute alcohol, [a]': -4.5 -6.06 -6.5 -7.09 -7.5 -6.8 -6.3 Ash None None None None None Trace a A comparison of the results in columns (A) and (B) indicates the advance that has been made in the manufacture of ephedrine salts. (A) was a n early specimen that was not accepted for inclusion in N. N. R.; (B)was a later and accepted specimen, and is representative of the present market specrmens of acceptable brands of ephedrine sulfate. b Uncorrected. DETERMINATION
LILLY"
LnLv
ABBOTT
-
~~
They were based on the results recorded in columns I, 111, curately weighed, in 200 cc. of water, heat to boiling, and add 4 cc. and VII. It should be noted that with one exception the of diluted nitric acid and silver nitrate solution in slight excess. Allow to stand for 6 hours, transfer to a Gooch crucible, wash other samples come up to the proposed standards. The well with hot water and then with cold; dry a t 100" C., cool in a specific rotation of the free base in absolute alcohol of the desiccator, and weigh. The chloride (Cl-) calculated from the silver chloride weighed is not less than 17.30 nor more than 17.7 Pekin sample is slightly too positive.
EPHEDRINE HYDROCHLORIDE-Ephedrine
hydrochloridum. 1Methylaminopropanolbenzene hydrochloride; a-hydroxy-pmethylaminopropylbenzene hydrochloride; 1-phenyl-2-methylamino- 1-propanol hydrochloride. CsH6.CHOH. CH (NHCHs).CHs.HC1. The hydrochloride of an alkaloid obtained from Ephedra equisetina. Ephedrine hydrochloride occurs as white, odorless crystals that are soluble in water and alcohol and insoluble in ether. The water solution is neutral to litmus. I t melts between 216' and 220' C. The specific rotation, [a]':, should fall between -33.0 and -35.50. Dissolve 0.005 gram of ephedrine hydrochloride in 1 cc. of water and add 0.1 cc. of copper sulfate solution (10 per cent) followed by 1 cc. of sodium hydroxide solution (20 per cent). A reddish purple color develops. To this solution add 1 cc. of ether, shake the mixture, and compare with a tube made up similarly but without using ether. The reddish purple color is partially extracted (apparently decolorized) by the ether. Dissolve 0.05 gram of ephedrine hydrochloride in 10 cc. of water, add 1 cc. of ammonia water, and shake out with two 15-cc. portions of chloroform. Filter the chloroform through a chloroform-soaked cotton pledget and allow to stand 12 hours; evaporate. White crystals of ephedrine hydrochloride appear. Was! with a little chloroform; dry The crystals melt between 214 and 220" C. To 1 cc. of a solution containing 0.005 gram of ephedrine hydrochloride add two drops of diluted nitric acid and two drops of silver nitrate solution. A white precipitate forms, soluble on addition of ammonia water in excess. Dissolve 0.05 gram of ephedrine hydrochloride in from 30 to 40 cc. of distilled water, add 1 cc. of diluted hydrochloric acid and 1 cc. of barium chloride solution. X o turbidity develops in 10 minutes (limit of sulfate). Dissolve about 0.2 gram of ephedrine hydrochloride, accurately weighed, in 10 cc. of water in a separatory funnel and add 5 cc. of ammonia water. Shake the mixture vigorously with six portions of ether, using 25, 20, 15, 15, 15, and 15 cc., respectively. Combine the ether extractions and distil to a small volume. Transfer to a tared beaker and evaporate spontaneously; dry in a desiccator for 12 hours; weigh. The weight of the residue is not less than 80 nor more than 82.5 per cent. The specific rotation, [a]':, of a residue obtained as described in the foregoing assay, weighing about 0.3 gram, dissolved in absolute alcohol to make 10 cc. of solution is between -6.0 and -7.5 (limit of isomers). Dissolve about 0.07 gram of ephedrine hydrochloride, ac8 This test is a modification of the biuret reaction. I t was proposed as a qualitative test for ephedrine by Chen and Kao, J . A m . Pharm. Assocn., 16, 625 (1926).
per cent. The ash from 0.1 gram weighs less than 0.0001 gram.
Three comments should be made, which apply as much to ephedrine sulfate and ephedrine alkaloid, to be discussed later, as they do to ephedrine hydrochloride. (1) The melting point of an ephedrine salt should be taken under carefully controlled and reproducible conditions, because with these compounds the experimental error is a function of the rate of heating. The apparent melting point of a single sample of an ephedrine salt has been varied through 20 degrees solely by changing the rate of heating. The U. S. P. X method for taking melting points has been chosen as being reproducible and accurate. In many cases the melting points submitted by manufacturers did not agree with those obtained in the A. M. A. Laboratory, a further indication that melting points should be taken under standardized conditions. (2) In some instances manufacturers have had trouble in meeting the requirement with regard to the specific rotation of the free base in absolute alcohol. In almost every case the problem was solved by suggesting to the manufacturers the necessity of testing the purity of the absolute alcohol by means of copper sulfate. (3) It is the policy of the A. M. A. Chemical Laboratory to use larger quantities of materials than have been used in the assays reported in this paper. When the original work was done, ephedrine and its salts were so difficult to obtain it was necessary t o use the small quantities indicated. Ephedrine Sulfate
(See Table 11)
CRYSTALLOGRAPHIC R E P O R T - I n addition to the chemical analyses, specimens of the material represented in columns (A) and (B) were submitted to Doctor Walcott for crystaIlographic examination. His report follows: Ephedrine sulfate possesses the following optical properties: Biaxial Optically positive Positive elongation 2 E is large Parallel extinction The optic axial plane is perpendicular to the large faces, and is at right angles to the elongation. Indices of refraction: a = 1.540 * 0.001; B = 1.565 * 0.002; Y = is very difficult to determine because the crystal habit does not permit the required orientation to obtain thisindex; it is unloubtedly higher than 1.590.
Samples (A) and (B) of ephedrine sulfate show crystals of identically the same crystal habit and the same optical properties.
April, 1928
ILVDU S T R I A L Ah'D ENGINEERING C H E M I S T R Y
The crystals of (A) contain very fine, needle-like inclusions of some impurity. The crystals of the impurity are also present among the crystals of ephedrine sulfate as separate crystals. The occurrence of the impurity as inclusions is an indication that the crystals of the impurity are formed before the crystals of the ephedrine sulfate. The crystals of (B) are generally quite free from crystalline inclusions of an impurity. hTow and then, however, a crystal will show inclusions of a few small, needle-like crystals. The difference in the relative amount of impurity present is very pronounced between (A) and (B). The crystals of (B) are generally quite perceptibly larger than those of (A).
391
Ephedrine, Ephedrina. a-Hydroxy-8-methylaminopropylbenzene CeH&H(OH)C.H.NHCHsCH3. An alkaloid derived from Ephedra epuisetina.
Ephedrine occurs as an unctuous, almost colorless solid that tends to crystallize as needles. The needles p e l t at 34-40' C., and the liquefied alkaloid boils above 200 C. The specific rotation, [a]:, falls between -6 and -7.5. It is soluble in alcohol, chloroform, ether, and water, the solutions being strongly alkaline to litmus paper moistened with water. Dissolve 0.005 gram of ephedrine in 1 cc. of water and add 0.1 cc. of copper sulfate solution (10 per cent) followed by 1 cc. of sodium hydroxide solution (20 per cent). ,4 reddish purple color develops. To this solution add 1 cc. of ether, shake the This report gives further indication of the almost complete mixture, and compare with a tube made up similarly, but without using ether. The reddish purple is partially extracted (appurity of the acceptable brands of ephedrine sulfate. decolorized by the ether). Dissolve 0.05 gram of STAiiDARDS-The following ephedrine sulfate standards parently ephedrine in 10 cc. of chloroform and allow to stand 12 hours; were prepared for K.N. R. They were based on the figures evaporate spontaneously. White crystals of ephedrine hydrorecorded in columns (A), (E), and (G). It will be noted that chloride appear. Wash with a little chloroform; dry. The the material represented in (A) and (E) does not comply crystals melt between 214" and 220" C. Dissolve 0.05 gram of ephedrine in 30 to 40 cc. of distilled with the standards, but that all of the others do comply. water; add 1 cc. of diluted nitric acid and 1 cc. of silver nitrate EPHEDRINE SumATE-Ephedrina? sulphas. 1-Methylamino- solution. Less turbidity results than in a control tube using 0.1 propanolbenzene sulfate; ru-hydroxy-p-methylaminopropylben- cc. of 0.02 N hydrochloric acid (limit of chloride). Dissolve zene sulfate; 1-phenyl-2-methylamino-1-propanol sulfate. 0.05 gram of ephedrine in from 30 to 40 cc. of distilled water; (GH6CHOH.CH (NXCHJ).CH&.H~SO~. The sulfate of an add 1 cc. of diluted hydrochloric acid and 1 cc. of barium chloride solution. No turbidity develops in 10 minutes (limit of sulfate). alkaloid obtained from Ephedra eguzsetzna. Dissolve about 0.2 gram of ephedrine accurately weighed in 10 Ephedrine sulfate occurs in fine, odorless, white crystals. It is easily soluble in water and hot alcohol, but more difficultly cc. of ether in a previously tared beaker, add an excess of hydrogen chloride in ether, evaporate to dryness, dry to constant weight soluble in cold alcohol. The water solution is neutral to litmus. The specific rotation, [a]:, ranges from -29 to -30. It over calcium chloride, and weigh. Dissolve the residue in distilled water and dilute with distilled water to 10 cc. Observe melts between 240" and 243" C. (cor.). (The rate of heating the angular rotation a t 20" C. The specific rotation, [a]2,0, must be strictly according to the method of U. S. P. X.) Dissolve 0.005 gram of ephedrine sulfate in 1 cc. of water and falls between -33 and -35.5. Dissolve about 0.2 gram, accurately weighed, in 10 cc. of neuadd 0.1 cc. of copper sulfate solution (10 per cent), followed by tralized alcohol; add 5 drops of bromocresol green solution 1 cc. of sodium hydroxide solution (20 per cent). A reddish purple color develops. To this solution add 1 cc. of ether, shake and an excess of 0.1 N hydrochloric acid; titrate the excess, the mixture, and compare with a tube made up similarly but using 0.02 N sodium hydroxide solution. The acid used in without using ether. The reddish purple color is partially ex- neutralizing the ephedrine is equivalent to not less than 97 nor more than 100 per cent of the ephedrine used. tracted (apparently decolorized) by the ether. Place about 0.3 gram of ephedrine, accurately weighed, in a Dissolve 0.05 gram of ephedrine sulfate in 10 cc. of water, add 1 cc. of ammonia water, and shake out with two 15-cc. por- previously tared, wide-mouthed weighing bottle in a desiccator and allow to stand over calcium chloride a t room temperature tions of chloroform; filter the chloroform through a chloroform for 18 hours (the temperature should not go above 22" C,). It soaked cotton pledget and allow t o stand 12 hours; evaporate. loses not more than 1.8per cent of its weight. White crystals of ephedrine hydrochloride appear. Wash with Heat about 0.1 gram of ephedrine, accurately weighed, in a a little chloroform; dry. The crystals melt between 214" and platinum dish until constant weight is obtained. The ash is 220" c. To 1cc. of a solution containing 0.005 gram of ephedrine sulfate, less than 0.1 per cent. add four drops of diluted hydrochloric acid, followed by one drop Table 111-Analysis of Ephedrine Alkaloid of barium chloride solution. A white precipitate forms. REPORTED DBTSRMINATION LILLY ABBOTT OR THEORY Dissolve 0.05 gram of ephedrine sulfate in 30 to 40 cc. of dis34 39 39-40 tilled water; add 1 cc. of diluted nitric acid and 1 cc. of silver Melting point, C. in weight, per cent 1,79 0.29 .. nitrate solution. Less turbidity results than in a control tube Loss Ash Negligible None .. using 1 cc. of 0.02 N hydrochloric acid (limit of chloride). Specific rotation in absolute alcohol, [a]'~ -6.6 - 6.2 - 6.3 Transfer about 0.2 gram of ephedrine sulfate, accurately Specific rotation of ephedrine hydrochloride, weighed, to a separatory funnel, and add 10 cc. of water and 5 cc. -34.9 34.55 -32.5 of ammonia water. Shake the mixture vigorously with six -36.6 portions of ether, using 25, 20, 15, 15, 15, and 15 cc., respectively. Yield of crude ephedrine hydrochloride from ephedrine by adding ether or alcohol hydroTransfer the combined ether fractions to a distillation apparatus, gen chloride solution, per centa 99.84 100.00 distil to a small bulk, transfer to a tared beaker, rinse the dis- Assay 97.36 99.18 100.00 by titration, per centb tillation flask with a small amount of ether, then evaporate A sample of the original weighing about 0.2 gram was dissolved in 10 spontaneously; dry in a desiccator for 12 hours; weigh. The cc. of alcohol. An excess of hydrogen chloride in ether was added: the weight of ephedrine should not be less than 74.5 nor more than solvent evaporated spontaneously and the residue dried over calcium chloride and weighed. A sample weighing 0.2281 gram yielded a residue weighing 77.25 per cent. 0.2762 gram, a weight equivalent to 99.81 per cent of the theoretical weight The specific rotation, [aI2D,of a residue obtained as described of ephedrine hydrochloride obtainable from the weight of ephedrine base in the determination of ephedrine, weighing about 0.3 gram, dis- taken. A sample of the original was treated in precisely the same manner. solved in absolute alcohol to make 10 cc. of solution, is between except t h a t i t was dissolved in ether. A sample weighing 0.1239 gram yielded a residue weighing 0.1501 gram, a weight equivalent to 99.86 per cent -6.0 and -7.5 (limit of isomers). of the weight of ephedrine hydrochloride obtainable from the weight of Dissolve about 0.05 gram of ephedrine sulfate, accurately ephedrine base taken. Average 99.84 per cent. weighed, in 200 cc. of water, add 1 cc. of diluted hydrochloric b An accurately weighed sample of the original weighing from 0.2 t o acid, followed by sufficient barium chloride solution to pre- 0.5 gram was dissolved in 10 cc. of neutralized alcohol. An excess of 0.1 N hydrochloric acid and 5 drops of bromocresol green were added, and the cipitate all the sulfate; allow to stand for 1 hour; transfer excess titrated with 0.1 N sodium hydroxide solution. The following rethe precipitate to a previously prepared Gooch crucible; wash sults were obtained: well with hot water, and then with cold water, dry a t 120" C., WT. OF SAMPLE 0.02 N HC1 EPHEDRINE EQVIVALENT cool in a desiccator; weigh. The sulfate (SO4--), calculated Gram CC. Per cent from the barium sulfate weighed, is not less than 21.80 nor more 0.2378 69.91 97.09 than 23.10 per cent. 70.01 97.40 0.2374 0.5184 152.61 97.18 The ash from 0.1 gram weighs less than 0,0001 gram. 0.5046
Ephedrine Alkaloid
STAXDARDS-The following ephedrine alkaloid standards were prepared for N.N. R. based on the results given in Table 111:
149.50
97.88 Av. 97.36
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