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attended with some loss in iodine, which is reflected in the above analytical findings obtained on different samples. I n order t o determine experimentally the conditions best’ suited t o the iodometric estimation of theobromine in commercial samples, it was necessary to carry through several hundred analyses on controls involving this substance, both a l m e and in various combinations. As typical of thess experiments, t h e following tabulated results show the percentage recovery from precipitates prepared with varying amounts of hydrochloric acid, as also with and without t h e addition of brine. No. l... 2... 3.. 4 5 6... 7... 8.. . . . . 9.. . . . . 10.. . . . . 11.. , , , . 12.. . . . . 13.. 14.. ....
...
... ..... ...... ...... ... ... ....
Tbeo- Glacial bromine AcOH G. cc. 0.1000 2 2 0.1000 2 0.1000 0.1000 2 2 0.1000 2 0.1000 2 0.1000 2 0.1000 0.1000 2 2 0.1000 0.1000 2 2 0.1000 2 0.1000 2 0.1000
0.1 N Iodine cc. 50
50 50 50 50 50 50 50 50 50 50 50 50
Concd. Satd. NaCl HCl Soh. cc. cc.
Theobromine Found Per G. cent
1
1 3 3 5 5 2
2 2 2
50
2 2
2
2
The influence of other factors like sodium acetate, sodium salicylate, sodium benzoate, and sodium formate on the estimation of theobromine is shown in the following series, this substance and the component salt being applied in molecular proportions : Satd. Theo- Glacial 0.1 N Concd. NaCl bromine AcOH Iodine HCl Soh. No. G. Cc. Cc. Cc. Cc. 20 2 2 50 l..... 20 2 50 2 2.. 20 2 2 50 3. 20 2 50 2 4.. 20 2 2 50 5.. 20 2 2 50 6.. 20 50 2 2 7..... 20 50 2 2 8.. ... 2 20 2 50 g..... 4 2 2 50 10. 8 2 2 50 11 2 15 2 50 12.. 20 2 50 2 13.. 20 2 2 50 14.. 20 2 2 50 15.. * 20 2 2 50 16.. 2 5 2 50 17.. 5 50 2 2 18.. 20 2 50 2 19 2 20 50 2 20.. 20 50 2 2 21..
. ._. .... ... ... ...
*. .. .... .... .. ... ..
... ... ... ....; ... ...
Org. Salt
NaAc NaAc N a Sal. N a Sal. N a Sal. N a Sal. N a Sal. Na Sal. N a Sal. N a Sal. N a Sal. N a Form. N a Form. N a Form. N a Form, N a Benz. N a Benz. N a Benz.
Theobromine Found Per ‘G. cent 0.0981 98.1 0.0990 99.0 0.0993 99.3 0.0995 99.5 0.0994 99.4 0.1002 100.2 0.1004 100.4 0.0997 99.7 0,0998 99.8 0. .. .0.9. .7 4 97.4 99.0 0.0990 99.8 0.0998 99.4 0.0994 99.6 0.0996 0.1078 107.8 0.1064 106.4 0.1054 105.4 0.1064 106.4 99.7 0.0997 99.5 0.1105 0,0554 99.9
From these experiments i t is evident t h a t t h e periodide method may be safely applied in the quantitative estimation of theobromine, both alone and, in admixture with sodium acetate, sodium salicylate, and sodium benzoate. The abnormal results obtained in the presence of sodium formate, however, for which no satisfactory explanation based upon experimental data is as yet available, clearly indicate t h a t some special treatment would be necessary in combinations of t h a t character. METHOD
In a small (50 cc.) lipped Erlenmeyer flask dissolve 0 . I g. of the sample (with about the molecular equivalent of sodium acetate, in the case of theobromine alone) in z cc. glacial acetic acid by gentle heat on a wire gauze. Dilute with 3 to 5 cc. hot water. Transfer the perfectly clear solution to a 100 cc. graduated glass-stoppered flask containing 50 cc. standard 0 . I N
iodine, using warm water for rinsing. Next add 20 cc. saturated sodium chloride solution, and finally z cc. concentrated hydrochloric acid while rotating the flask. Stopper the latter and
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allow t o stand at room temperature over night. Make up to the’ mark with water and mix thoroughly. Pass the liquid through a small (5.5 cm.) filter previously fitted to funnel by wetting and drying, reject the first I j cc. and collect 50 cc. in a graduated 5 0 cc. flask. Transfer this aliquot by pouring and rinsing t o an Erlenmeyer flask of about 250 cc. capacity, and titrate the excess of iodine with staridard 0 . 1 N sodium thiosulfate. The quantity of theobromine involved in the sample under examination is thereupon readily calculated from the expression : Theobromine = I (0 0045026 X normality of thiosulfate used), in which I represents the number of cubic centimeters of thiosulfate equivalent to the iodine expended in periodide formation. The foregoing method has been successfully applied to several commercial mixtures or combinations of theobromine, or its sodium salt, with sodium acet a t e and sodium salicylate. Thus, in the case of a well-known brand alleged t o consist of theobromine and sodium acetate, with a calculated theobromine content of 63.9 per cent, t h e following values were obtained: 57.4, 5 8 . 6 , 5 8 . 7 and 59.0 per cent. Another brand of a similar mixture gave 3 2 . 1 9 and 31.87 per cent. A sample alleged t o be the double salt of sodium salicylate and sodium theobromine was found t o contain 49.78 and 49. 73 per cent (calculated 49.73 per cent theobromine). SUMMARY
A method has been developed for estimating the0 bromine, both alone and in combination with sodium acetate and sodium salicylate, based on the formation of its periodide, C , H B N ~ O ~ . H I . I ~ . SYNTHETIC PRODUCTS LABORATORY BUREAUO F CHEMISTRY WASHINGTON. D. C.
STUDIES IN SYNTHETIC DRUG ANALYSIS. VI-EVALUATION OF HEXAMETHYLENETETRAMINE TABLETS By W. 0. EMERY AND C. D. WRIGHT Received May 15, 1918 INTRODUCTION
The present study had its inception in certain preliminary experiments connected with codperative work on synthetic drugs, and instituted with a view t o adapt a known or devise a new procedure for the estimation of hexamethylenetetramine as i t ordinarily occurs in tablet preparations. A series of tests looking t o its quantitative isolation by t h e use of immiscible solvents early demonstrated the f u d i t y of attempting a solution of the problem in this way. I n operations with like volumes of water and chloroform, for example, only about 3 t o 4 per cent of the substance are taken up by the latter solvent in one extraction. Attempts t o utilize the condensation product of hexamethylenetetramine with antipyrine as a basis for the quantitative determination met with scarcely better success. After several other equally fruitless trials, recourse was finally had t o a procedure substantially identical with a method proposed by ‘Stuewe,l primarily for formaldehyde and formalin, but quite as applicable t o hexamethylenetetramine. 1
Arch. Pherm., 969 (1914), 430; Pherm. Z l g . , 159 (1914), 215
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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
Stuewe's method, however, while essentially a reversal of the procedure first employed by Ruppl in the evaluation of mercuric chloride tablets, was unfortunately so formulated as t o \cave the operator very much in the dark respecting the influence of certain, presumably determining, factors like time, temperature, and concentration on t h e quantitative outcome. I n the original, as also in t h e amplified and amended procedure presently t o be described, advantage is taken of the fact t h a t , when a n aqueous solution of formaldehyde is treated with alkalized potassium mercuric iodide, the former is converted into a formate with a corresponding separation of slaty gray colloidal mercury, in accordance with the equation: CHzO KzHgIi 3KOH = Hg HCOzK 4KI zHz0 If now the acidified mixture is treated with standar iodine, solution of the precipitated mercury resul s, and by subsequent titration with thiosulfate the quantity of iodine thus entering into combination with the mercury is easily ascertained. The procedure, therefore, resolves itself into five principal opeyations, namely : I--Hydrolysis of hexamethylenetetramine to formaldehyde and ammonia. 2--Interaction of formaldehyde with potassium mercuric iodide. 3-Aaidification with acetic acid. 4--Solution of the precipitated mercury in standard iodine. titration of the unexpended iodine with sodiuni thiosulfate. From the data thus gained, the quantity of hexamethylenetetramine is readily calculated.
+
+
+
+
+
G"
EXPERIMENTAL
I
I n the preliminary survey, the findings obtained with apparently pure samples were in part so contradictory as t o indicate t h a t a more detailed study of the method was indispensable t o its successful operation. Accordingly, numerous experiments were carried out on controls with a view t o ascertain, if possible, the more predominating factors, and t o eliminate any such calculated t o unfavorably affect the quantitative results. Thus, i t was found t h a t , while precipitation of the mercury is practically instantaneous and hence complete after the lapse of one minute from the time the mixture has attained homogeneity, there can be no objection t o allowing the product t o stand for a longer period, if desired, before the addition of acetic acid. I n order t o determine t o what extent, if any, the final result may be influenced by varying the time during which the precipitated mercury is in actual contact with acetic acid, and as a consequence subjected to its solvent action, the following tests were made. The data show conclusively, first, t h a t protracted contact of the separated mercury with the acid is detrimental, invariably leading t o a corresponding diminution in the quantity of substance sought, and, second, t h a t any considerable excess of acetic acid above t h a t required t o produce distinct acidity in the 1
Arch. Pharm., 243 (1905), 300; 444 (1906), 540.
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reacting menstruum is likewise calculated t o impair the efficiency of the method. I added after Min.
Glacial AcOH
cc.
No.
1.............. 4 2. . . . . . . . . . . . . . 4 3. . . . . . . . . . . . . . 4 4............... 4 5. . . . . . . . . . . . . . 4 6. . . . . . . . . . . . . . 4 7. . . . . . . . . . . . . . . 4 8. . . . . . . . . . . . . . 4 9. . . . . . . . . . . . . . 4 10 . . . . . . . . . . . . . . 3 11.............. 12 . . . . . . . . . . . . . . 13 . . . . . . . . . . . . . . 14 . . . . . . . . . . . . . .
'/4
1 2 3 4
5 10 20 30
'
4 3
5
4 5 15 . . . . . . . . . . . . . . 10
5
'/4 '/4
5 5
found Per cent 100.1 99.5 98.9 98.5 97.9 97.7 97.3 96.7 96.3 99.8 99.9 98.5 97.9 97.4 96.1
C s H n N 4
T h a t the presence of vehicles or diluents like starch, lactose, and acacia has no appreciable effect on the quantitative findings is clearly shown in experiments on controls involving the materials in question, whereby recoveries of 99.8,99.9,and 1 0 0 . 2 per cent, respectively, of hexamethylenetetramine were effected. I n the following series will be found the results obtained with the perfected method pn three samples: Nos. I t o 6, a well-known commercial brand of pure granulated hexamethylenetetramine; Nos. 7 t o 1 2 , a C O ~ mercial brand of hexamethylenetetramine tablets containifig about I O per cent of a vehicle or diluent; and Nos. 13 t o 18, a laboratory product consisting of a triturated mixture of equal parts of pure hexamethylenetetramine and air-dried talc. No. 1
40 Per cent AcOH cc.
............. 10 2 ............. 10 3 ............. 10 4 ............. 10 * 5 ............. 10 6 . . . . ......... 10 7 ............. 10 8 ............. 10 9 ............. 10 10 ............. 10 ll... .......... 10 12 .............10 13 ............. 10 14 ............. 10 15 ............. 10 16 ............. 10 17 ............. 10 18 ............. 10
I added after Min. '/4 '/4 '/4 '/4 '/4 :/4
./a /4 '/4
1/4 '/4 '/4 '/4 '/4
'/4 '/4
'/4
'/
1
C6HnNn found Per cent 99.9 99.7 99.8 99.8 99.7 99.8 90.7 90.6 90.8 90.7 90.6 90.7 50.8 50.8 50.9 50.7 50.9 50.7
The entire procedure as developed on numerous controls contemplates the following: REAGENTS
A-Modified Nessler's reagent, involving: ( a ) Solution of I O g. HgC12, 30 g. K I , and 5 g. acacia dissolved in 2 0 0 cc. H20 and filtered through a pledget of cotton wool. ( b ) Solution of 1 5 g. NaOH in I O O cc. HzO. B-Tenth normal iodine. C-Twentieth normal thiosulfate. PRELIMINARY TREATMENT
Ascertain the weight of 2 0 or more tablets, triturate in a mortar t o a fine powder, and keep in a small capsule tightly closed with a cork or glass stopper. Weigh out 0 . 5 g. of the powdered sample on a metal scoop or watch glass, transfer with sufficient water t o a round bottom flask, add additional water t o a total volume of I O O cc., and finally 2 5 cc. of I O per cent hydrochloric acid. Connect with a reflux condenser (preferably of the worm -type) and boil gently 1 5 min.; then, after cooling, wash out the condenser tube with a little water,
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and transfer the contents of flask quantitatively t o a graduated 2 5 0 cc. flask, finally diluting t o the mark with water. METHOD
.
With a pipette withdraw I O cc. (containing in the case of a pure product the elements of 0 . 0 2 g. of hexamethylenetetramine) of the solution so prepared t o a zoo cc. Erlenmeyer flask containing a mixture (previously chilled in ice water if available) of 20 cc. of reagent A ( a ) and I O cc. of A ( b ) , wash down neck of container with a fine jet of water, and allow the mixture t o stand a t least one minute after gentle rotation of the flask. Now add I O cc. of 40 per cent acetic acid in such manner t h a t t h e inside ,of neck is completely washed by the reagent, mix quickly and thoroughly by gently rotating and tilting the flask, and immediately run in from a burette 20 cc. of reagent B, then titrate with reagent C (adding 5 t o I O drops of starch solution toward the end of the operation) t o the disappearance of the blue coloration. The final color of the solution is a pale straw-green. If preferred, t h e end-point may be determined by the reformation of a faint blue coloration, induced b y the addition of a drop of iodine solution. Since the standard iodine (reagent B) employed has twice the titrimetric strength of the thiosulfate (reagent C), and I cc. of N / I O iodine is equivalent t o 0.001167 g. of hexamethylenetetramine (0 = 1 6 ) , the quantity of this product, as represented b y its elements formaldehyde and ammonia, in the aliquot under examination may be readily calculated from t h e expression H-I N X 0.001167 2
in which H = the number of cubic centimeters of reagent C equivalent t o 20 cc. of reagent B, I = the number of cubic centimeters of reagent C required t o offset the unexpended iodine, and N = the normality of reagent C. SUMMARY
A procedure is described for the estimation of hexamethylenetetramine, whereby advantage is taken of t h e fact t h a t , when a n aqueous solution of formaldehyde is allowed t o react with alkalized potassium mercuric iodide, the former b y virtue of oxidation t o a formate effects a corresponding separation of mercury, which latter on treatment with an excess of standard iodized potassium iodide and subsequent titration with thiosulfate affords all necessary data for calculating t h e hexamethylenetetramine originally involved. SYNTHETIC PRODUCTS LABORATORY BUREAUO F CHEMISTRY WASHINGTON, D . c .
AN IMPROVED METHOD FOR DETERMINING CITRAL A MODIFICATION OF THE HILTNER METHOD By C. E. PARKER AND R. S. HILTNER Received November 27, 1917
I n the determination of citral by the Hiltner colorimetric methodl with metaphenylenediamine hydrochloride, it not infrequently’ occurs t h a t lemon and orange oils and extracts produce blue or green colors I U. S. Dept. Agr., Bureau of Chemistry, Bull. 122, 34; 132, 102; 137. 70.
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instead of yellow. This abnormal behavior has somewhat restricted the applicability of the method. An investigation having for its object the study a n d . removal of this difficulty proceeded upon the theory t h a t a n oxidation phenomenon is involved therein. I n cases where the blue color develops slowly i t appears t o spread downward from the surface of the mixture. The metaphenylenediamine hydrochloride reagent acquires a blue color by the action of hydrogen dioxide solution, and the formation of peroxide compounds by the action of air and moisture upon terpenes is noted in the 1iterature.l Nevertheless, observations of Mory,ZHilts3 and the writers t h a t i t is not a matter of indifference whether fullers’ earth, or animal charcoal, or nothing whatever be used for decolorizing the reagent, suggested t h a t oxidation of the citrus oil might not be the sole cause of the phenomenon. It has even been stated t h a t by omitting the use of fullers’ earth the difficulty may be avoided. This is not always the case. I N F L U E N C E OF DECOLORIZING AGENTS
Experiments, unnecessary t o detail here, with fullers’ earth, animal charcoal, talcum, pumice, zinc powder, platinized asbestos, eponite and kaolin, led t o the conclusion t h a t besides their obvious decolorizing action upon the reagent, such substances affect i t in a more obscure way, rendering it more responsive t o the action of a citrus oil which has the property of producing the blue color. I t was possible, by’washing the powdered metaphenylenediamine hydrochloride with small amounts of 94 per cent alcohol, t o prepare a reagent which had less tendency t o produce the blue color t h a n a reagent made with the unpurified metaphenylenediamine hydrochloride. The purified reagent had a lighter color, but it is not supposed t h a t the substance producing dark reagent solutions is identical with t h a t causing the blue color. T H E CONSTITUENTS OF CITRUS OILS GIVING RISE TO T H E B L U E COLOR
A decided blue coloration was obtained with a sample of d-limonene (carven) from Kahlbaum, with one marked “Limonene, pure, Schimmel and CO.” which was quite yellow and sirupy, and with several samples of commercial oil of turpentine “for technical use.” No blue color was obtained with available samples of citral. Orange oil which failed t o give the blue coloration was exposed t o the air b y standing over night in a shallow receptacle, and also by bubbling air through i t for one-half t o four hours, after which it gave a blue color with the reagent in a short time. These experiments are considered t o favor the presumption t h a t oxidation of the terpene is in part responsible for production of the blue color. EFFECT OF REDUCING AGEKTS
Stannous chloride was found t o prevent the formation of the blue color, whether added in the solid form 1 Engler and Weissberg, Be?., 31 (1898), 3046; Roscoe and Schorlemmer, C h e m i s t r y , 1 (1905), 257; Kingzett, J. SOC.C h e m . I n d . , 1898, 691: Thorpe, Dict. A p g l . Chem., 3 (1912), 68. 2 U . S. Dept. Agr., Bdreau of Chemistry, Bull. 132, 1 0 7 a Ibzd., 123, 32.
