Mar., 1921
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T H E J O U R N A L OF I N D U S T R I A L A N D E N G I N E E R I N G C H E M I S T R Y
moments. T h e cork must be held tightly in t h e test tube while shaking. Remove t h e cork and immerse t h e tube nearly its full length in a bath of water a t 50' t o 60' C. Allow the t u b e t o remain in t h e hot water until the emulsion is pretty well broken u p or until no f a t drops can be seen dropping from the bottom of t h e soap frotb when the tube is given a slight shake. If there is a large amount of annatto present i t will not all be in the soap froth, though there will be plenty for a test. Remove t h e soap froth from the tube t o a small beaker with a spatula or small spoon, add I O cc. of water and 2 cc. of the sodium hydroxide solution. Then add enough of the paper pulp t o make a thin felt in a Gooch crucible. Let stand on the steam bath for about one-half hour with frequent stirring and the annatto will be absorbed by t h e paper pulp. If t h e quantity of annatto is small, i t is well t o leave the beaker on t h e steam bath until the liquid has concentrated t o about one-third its original volume. I n this way a more positive test is obtained with a small quantity of annatto. Filter with light suction on a Gooch crucible containing a small disk of filter paper. When the liquid has passed through, if annatto is present, t h e paper pulp will have a n orange color. At once drop a few drops of stannous chloride solution on t h e paper and again suck dry. If annatto is present t h e paper pulp will be colored pink. Reverse the crucible and blow the felt out in t h e palm of t h e hand. The mat may then be dried if i t is t o be preserved. I n case t h e available sample is small the quantities used in t h e test may be reduced. One author recommends 5 per cent citric acid in place of stannous chloride and this was found t o work well.' Boric, tartaric, acetic, sulfuric, hydrochloric, and nitric acids of from 3 t o 5 per cent also give satisfactory results. Even so dilute a n acid as t h a t obtained by blowing one's breath through water for a few minutes may be used, but its action is slower t h a n with stronger acids. The stannous chloride solution, however, gives better results t h a n anything else tried. There is a n aqueous solution of annatto on t h e market t h a t is used b y ice cream manufacturers. A few drops of this may be added t o 1 5 cc. of colorless oleomargarine freed from moisture, salt, and curd, and the test run as described. We have used the test in this way on some food materials after extracting t h e annatto from the bulk of the material. An easier way t o handle an aqueous solution of a n n a t t o is t o dilute the solution and make slightly acid with hydrochloric acid. The annatto will precipitate in a form resembling ferric hydroxide. Filter this on a soft Munktell paper about the size of a silver dollar. Wash once with water and place paper and precipitate in a small beaker with I O cc. of water and 2 CC. of t h e sodium hydroxide solution, and proceed as usual. The small filter paper can be disintegrated 1
Bolton and Revis, "Fatty Foods, Their Practical Examination," p 113.
217
with the help of a glass rod and will furnish the necessary paper pulp. After the soap froth has been removed from a butter or oleomargarine determination i t will sometimes be noticed t h a t the sodium hydroxide layer over the chloroform-fat mixture still has a deep color. This is t h e case when the annatto is present in large amounts. If desired, this sodium hydroxide layer may be pipetted off and annatto tested for as in a n aqueous solution. The acidification of t h e solution should be carefully done and the solution placed on the water bath so t h a t the fine precipitate may collect. It will then filter quite easily. BENZYL SUCCINATE: PRELIMINARY REPORT ON ITS COMPOSITION, MANUFACTURE, PROPERTIES, AND PROBABLE THERAPEUTIC USES' By Mortimer Bye SCIENTIFIC LABORATORIES, FREDERICK STEARNS & Co., DETROIT, MICHIGAN
The extremely important pharmacological studies of Macht have recently led t o t h e clinical application of benzyl esters-especially benzyl benzoate-in the treatment of cases of excessive peristalsis, or excessive spasm of smooth muscle, with surprisingly gratifying results. However, certain objections t o the use of benzyl benzoate have arisen which make desirable the finding of less objectionable substitutes. The benzoate is a fluid of disagreeable taste and odor, practically insoluble in water. It is highly objectionable t o most patients, and cannot be tolerated b y some. By the mouth, i t must be administered in a flavored solution of alcohol, or as a flavored emulsion. It may cause vomiting, or may develop severe gastric disturbances if used in large amounts or over a considerable period of time. Gelatin capsules containing the benzoate dissolved in oil are also given, but are open t o one or more of the preceding objections. With these facts in mind, and being especially interested in the production of various compounds of succinic acid, t h e writer was prompted t o take up the study of benzyl succinate. This substance was prepared, with certain modifications, according t o the method of Bischoff and von Hedenstrom, b y heating succinic acid with benzyl alcohol. The succinate was obtained in t h e form of beautiful snow-white crystals, with a very slight aromatic "benzyl" taste, a n d with practically no odor. The percentage of benzyl group in benzyl succinate is 61.08, or considerably greater t h a n t h a t present in benzyl benzoate (42.89 per cent). Investigations so far show t h a t benzyl succinate may be administered by the mouth in powdered, tablet, or capsule form, without fear of nausea or other intestinal disturbances, even when given in large doses or over considerable periods of time. Exhaustive preliminary experiments have demonstrated t h a t this product is practically nontoxic. Guinea pigs inoculated subcutaneously with as much as 4 cc. of a 1 2 . 5 per cent alcoholic solution of benzyl succinate became perfectly normal after several 1 Presented before the Division of Medicinal Products Chemistry at the 60th Meeting of the American Chemical Society, Chicago, Ill., September 6 to 10, 1920.
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T H E JOURNAL OF IlVDUSTRIAL A N D ENGINEERING CHEMISTRY
hours of lassitude. A rabbit weighing about 2 kg. was fed 2 g. of the pure product in a bread paste and 2 4 hrs. later received a subcutaneous injection of 6 cc. of 1 2 . 5 per cent alcoholic solution of the drug. Beyond a sedative action, this high dosage of the benzyl succinate had no apparent effect. The animal was kept under observation for 2 wks. and developed no untoward symptoms. Feeding tests upon guinea pigs and rabbits have demonstrated the surprising fact t h a t a guinea pig may eat at least I O g. of berhzyl succinate per kilogram of b o d y weight without harm and t h a t rabbits may eat a t least 6 g. per kilogram of body weight and show no bad results. Comparative subcutaneous injections of the benzyl succinate and the benzyl benzoate show the former t o be less toxic t h a n t h e latter, and inasmuch as the benzyl group-which is recognized as the significant group-makes up a far greater portion of the molecule, the succinate should prove t o be a valuable therapeutic agent. By analogy, for any condition where benzyl benzoate is indicated, benzyl succinate should prove applicable, with the added advantages of ease of administration, safety of retention, freedom from nausea a n d after-intestinal disturbances, and greater benzyl strength. Many clinical cases are proving the t r u t h of the above statement daily. The writer has compiled a number of such cases which it is hoped will prove t h e basis of a future paper on the subject. ATROPINE SULFATE FROM DATURA STRAMONIUM1 By H. W. Rhodehamel and E. H. Stuart RESEARCH DEPARTMENT ELI LILLYS: Co., INDIANAPOLIS, INDIANA
Datura stramo?zium, commonly known as Jimson weed, grows in almost all parts of the United States and Europe. Atropine was first isolated from this plant in 1833 b y Geiger and Hesse,2 but hyoscyamine is t h e chief alkaloidal constituent. The latter is isomeric with atropine, and is converted into i t during the process of extraction and purification. The percentage of total alkaloids varies froin 0.15 t o 0.6 per cent in the dried plant, the variation depending mainly on the age and vigor of growth of the plant. The moisture content of the whole plant is from 75 t o 85 per cent. Assays made of the plant in flower showed the distribution of alkaloid t o be as follows: Stems below the first f o r k . , ....................... Stems above the first f o r k . . ....................... Seed pods without seeds.. ......................... Seeds Leaves
........................................... ..........................................
Per cent 0.054 0.069 0.054 0.45 0.414
The comparatively small amount of alkaloids occurring in Datura s t r a m o n i u m made their commercial extraction impracticable until the discovery in 1913 by J. U. Lloyd t h a t under certain conditions fuller’s earth would adsorb alkaloids from dilute solutions of 1 Presented before the Division of Medicinal Products Chemistry a t the 60th Meeting of the American Chemical Society, Chicago, Ill., September 6 to 10, 1920. 2 A n n . , 6 . 43; 6 , 44; 7 , 269
1701.
13,
NO.3
their salts. The entire green plant was ground, percolated with acidulated water, and t o the percolate Lloyd’s reagent was added. After drying, the Lloyd’s reagent contained b y assay from 2 t o 2 . 5 per cent alkaloidal material. I n this manner a considerable concentration of the alkaloids was effected. COMMERCIAL E X T R A C T I O N O F T H E ALKALOID
The stramonium plant was harvested frpm about the middle of July t o the first hard frost, which usually occurred during October. The entire plant, except the roots, was ground in the green state, packed in large wooden tanks, and percolated with water containing 0.2 per cent sulfuric acid and 0.5 per cent formaldehyde. Maceration was allowed t o continue 3 days, and the rate of percolation controlled so t h a t about 300 gal. each day were obtained from a 4000-gal. tank. Fifteen hundred gallons of the dilute atropine sulfate solution were treated a t one time with Lloyd’s reagent. The minimum amount of the latter necessary for maximum adsorption was controlled by assay of the percolate prior t o its addition. To insure adequate agitation, air was blown into the mixture for about 20 min. T t required about 12 t o 14 hrs. for the Lloyd’s reagent t o settle, after which the exhausted percolate was decanted, and the precipitate drained and thoroughly dried a t a temperature of about 50’ C. Percentage Alkaloidal Alkaloidal of Total Lloyd’s Percolate Material Material Alkaloidal Reagent Collected per 100 Cc. in Percolate Material Added Portion Gallons Grams Pounds Removed Pounds Taizk 1’ l . . . . . 1266 0.0123 1.30 10.75 60 1.34 0.0107 2 . .... 1500 11.08 60 1500 0.0075 0.94 7.77 45 3..... 0.0042 0.53 4.38 20 4 . . . . . 1500
TOTAL .....................
-
- -
4.11 33.98 Assay of extracted drug gave 0.07 per cent alkaloid.
185
Tank 22 l..... 2... .. 3..... 4.....
1600 900 1500 950
0.03676 0.0319 0,0028 . 0,0006
TOTAL ....................
4.91 2.40 0.35 0.05
-.
59.28 28.98 4.23 0.57
I
7.71 93.06 Assay of extracted drug gave 0.024 per cent alkaloid. T a n k 33 3.14 0.0251 25,99 l . . . . . 1500 1.79 1500 0.0143 2..... 14.81 0.0071 0.89 3 . . . . . 1500 7.35 0.23 1500 0.0018 1.36 4.....
-.
230 110, 16 3
-
359
150 90 45 12
-
TOTAL ..................... 6.05 50.01 297 Assay of extracted drug gave 0.054 per cent alkaloid. Average Percentage of S o . of Tanks Packed in Alkaloid Present 10 JLtb 40.69 11 August 69.03 September 58.89 8 7 October 39.02 Average for the year 51.9 per cent 1 Packed July 15 with 26 000 lbs. of green stramonium. Moisture 85 per cent. Assay o f dried sample gave 0.31 per cent alkaloidal material. From the assay the tank contained 12.09 Ibs. alkaloidal material, Moisture 2 Packed August 23 with 15,500 lbs. o f green stramonium. 85 per cent. Assay of dried sample gave 0.356 per cent alkaloidal material. From the assay the tank contained 8.28 lbs. alkaloidal material. a Packed October 4 with 26,000 Ibs. o f green stramonium. Moisture 85 per cent. Assay of dried sample gave 0.31 per cent alkaloidal material. From the assay the tank contained 12.09 lbs. alkaloidal material.
Results obtained on a great number of tanks would be of no especial interest. The percolation records of three tanks have therefore been selected t o show, first. the poor adsorption obtained when using young drug harvested in July; second, the best adsorption from August drug; and third, the decrease in adsorption in October drug.
