Chapter XXX: Foreword: The Chemical Laboratory of the American Medical Association (2)

[190] Rep. Mass. Bd. Health, 1909, 41, 477.

In 1912 Pullen[191] reported that he had prepared two specimens of iodine ointment according to the British Pharmacopeia, one being from new lard and the other from a specimen of lard at least 2 years old. Assays for free iodine were carried out immediately after the preparations were made, and at intervals afterward up to four months. The following values were found:

[191] Pharm. Jour., 1912, 89, 610.

Sample I Sample II

Ointment from Ointment from
new lard, old lard,
per cent. per cent.
Iodine introduced 4.0 4.0
Iodine found immediately after making 3.95 3.38
Iodine found after twenty-four hours 3.30 3.15
Iodine found on the third day 3.18 2.62
Iodine found on the seventh day 3.15 2.46
Iodine found on the fourteenth day 3.00 2.45
Iodine found after one month 3.00 2.39
Iodine found after two months 2.90 2.31
Iodine found after four months 2.92 2.26

Pullen found that the loss in free iodine could be accounted for by the iodine which had gone into combination with the fats of the ointment base.

Pullen also found that if the potassium iodide and glycerin were omitted in the preparation of the ointment, the loss in free iodine was very rapid, the preparation containing practically no free iodine (only 1/20) after a few hours. He concludes that the use of potassium iodide and glycerin is necessary for the preservation of the ointment. He obtained specimens of iodine ointment in drug stores, and assayed them for free iodine. It is to be presumed that the ages of the several specimens were not known. The results are found in the following table:

Specimen No. 1 2.74 per cent.
Specimen No. 2 2.85 per cent.
Specimen No. 3 2.62 per cent.
Specimen No. 4 2.48 per cent.
Specimen No. 5 2.53 per cent.
Specimen No. 6 2.79 per cent.

Fried[192] prepared iodine ointment according to the U. S. P. VIII formula, and assayed it at intervals. His results are tabulated herewith:

[192] Pharm. Jour., 1912, 89, 610.

Per cent.
Iodine introduced 4.00
Iodine found immediately after making 3.89
Iodine found one hour after making 3.51
Iodine found one day after making 3.48
Iodine found five days after making 3.06
Iodine found ten days after making 2.84
Iodine found thirty days after making 2.81
Iodine found ninety days after making 2.81
Iodine found eight months after making 2.81

Iodine ointment has been official in the U. S. Pharmacopeia since 1870. Briefly, the method now used for making the preparation is as follows:

Four gm. of iodine, 4 gm. of potassium iodide and 12 gm. of
glycerin are weighed into a tared mortar and the mixture triturated
until the iodine and potassium iodide are dissolved and a dark,
reddish-brown, syrupy liquid is produced. Eighty gm. of benzoinated
lard are then added in small portions and with trituration after
each addition. The mass is then triturated until of uniform
consistence.[193]

[193] The time required to complete the process after the initial portion of lard has been added should be about twenty minutes.

PARAFFINS AND PARAFFIN PREPARATIONS--TABLE A

KEY: A: Formula B: Substance C: Melting Point, U. S. P. D: Ductility Limit E: Plasticity Limit F: (a) Adhesiveness and Detachability (b) Strength of Film at 38 C.

=======================================================================
A B C D E F
1 “Parowax,” 50.8 32.5 29.0 (a) Adheres and
Stand. Oil Co. of Ind. detaches well;
rather hard
(b) Pliable and
strong
3 “Paraffin 118-120 F.,” 46.8 28.5 24.5 (a) Does not adhere
Stand. Oil Co. of Ind. well; detaches
easily
(b) Pliable but not
strong
4 “Paraffin 120-122 F.,” 47.2 29.0 24.5 (a) Adheres well;
Stand. Oil Co. of Ind. detaches well
(b) Pliable and
fairly strong
5 “Paraffin 123-125 F.,” 48.8 31.5 28.5 Same as 4
Stand. Oil Co. of Ind.
6 “Paraffin 128-130 F.,” 52.0 33.0 30.0 (a) Adheres well;
Stand. Oil Co. of Ind. detaches not so
easily
(b) Pliable and
strong
7 “Texwax,” Texas Co., 51.2 32.5 29.8 Same as 6
Port Arthur, Texas
8 “Paraffin Wax 122-124 F.,” 50.6 36.0 34-35 (a) Unsatisfactory;
Warren Refining Co., does not adhere
Warren, Pa. (b) Only slightly
pliable;
too tough
9 “Paraffin No. 910,” 47.0 30.5 26-27 (a) Adheres well;
Waverly Oil Works, detaches well
Pittsburgh (b) Pliable and
strong
10 “Paraffin No. 920,” 44.4 27.5 25.0 (a) Adheres well;
Waverly Oil Works, detaches well
Pittsburgh (b) Pliable and
fairly strong
11 “Hard Paraffin,” 48.0 28.5 24.5-25.5 (a) Adheres well;
Rob’t Stevenson & Co., detaches well
Chicago (b) Pliable and
strong
12 “Paraffin,” 47.2 33.0 32.5 Not quite as good
Island Petroleum Co., as 11
Chicago
13 “Paraffin 122 F.,” 46.8 30.5 27.5-28 (a) Does not adhere
Gulf Refining Co., so well;
Pittsburgh detaches well
(b) Very pliable
14 “Paraffin 125 F.,” 50.0 32.0 31.0 About as 13
Gulf Refining Co.,
Pittsburgh
15 “Paraffin 132 F.,” 54.8 35.5 34.0 (a) Does not adhere
Gulf Refining Co., well
Pittsburgh (b) Not very pliable,
but strong
16 “Paraffin No. 301,” 50.2 33.0 32-32.5 (a) Does not adhere
National Refining Co., well
Cleveland (b) Not very pliable
18 Paraffin recovered 48.6 30.5 28-28.5 (a) Adheres well;
from “Ambrine” detaches well
(b) Pliable but not
strong
19 “Hyperthermine” 49.4 33.5 30.5-31 (a) Does not adhere
well;
detaches well
(b) Very pliable and
strong
20 “Ambrine” 48.4 30.5 27.0 (a) Adheres well;
detaches well
(b) Very pliable and
strong
21 Paraffin 120-122 F. 45.4 29.0 28.5 (a) Adheres
(see 3), 97.5; excellently;
olive oil, 1.5; detaches well
asphalt, 4 drops (b) Very pliable and
strong
22 “Parowax” (see 1), 97.5; 49.2 32.0 30.5 (a) Adheres well;
olive oil, 1.5; detaches well
asphalt, 4 drops (b) Pliable and
strong
23 “Mulene” 51.0 36.0 28.0 (a) Adheres but
detaches with
difficulty
(b) Pliable but not
strong
24 “Parresine,” 46.0 29.5 26.0 (a) Adheres well;
Abbott Laboratories, detaches easily
(b) Pliable and
fairly strong
25 “Paraffin 118-121 F.,” 45.8 26.4 23.2 (a) Adheres well;
The Atlantic Refining detaches easily
Co., Philadelphia (b) Pliable and
Chicago fairly strong

TABLE B

26 “Cerelene,” 50.0 30.5 26.5 (a) Adheres well;
Holliday Lab.,* detaches with
Pittsburgh pulling
(b) Not strong at
38 C.
27 “Stanolind” Surgical 47.0 28.8 25.0 (a) Adheres well;
Wax,† Standard detaches easily
Oil Co. of Ind. (b) Fairly strong at
38 C.

* On being heated, it readily loses eucalyptol, and a small amount
of resinous substance forms in the bottom of the beaker. If
“Cerelene” is heated to 145 C. and cooled, the resulting product no
longer has the properties of the original “Cerelene.”

† Accepted by the Council on Pharmacy and Chemistry for inclusion
in New and Nonofficial Remedies.

Iodine ointment is officialized also in several foreign pharmacopeias, although the iodine strength of the several preparations is not uniform. The formula in the British Pharmacopeia is exactly like that in the U. S. Pharmacopeia except that pure lard is directed to be used instead of benzoinated lard. Some of the foreign pharmacopeias also specify that the preparation must be freshly prepared when wanted. In the earlier editions the U. S. Pharmacopeia directed the ointment to be prepared by using water as the solvent for the potassium iodide. In the U. S. Pharmacopeia VIII the formula was changed so as to employ glycerin, and that solvent is now official. Water is still prescribed as the potassium iodide solvent by the Pharmacopeias of the Netherlands and of France.

From the examination of the literature it seems probable that iodine ointments which contain petrolatum products only as the ointment bases are apt to be relatively stable, so far as the content of free iodine is concerned. On the other hand, ointments the bases of which contain fats of the unsaturated fatty acid series, such as oleic acid, do not satisfactorily preserve the iodine in the free state. In the latter class it seems likely that the iodine enters into combination with the unsaturated fatty acids. Accordingly, on theoretical grounds, an ointment base composed of pure stearin (if such substance were available) but softened by an admixture of liquid petrolatum would preserve the iodine satisfactorily. Cocoanut oil (iodine No. 8) ought to be suitable also if mixed with hard paraffin.

Since the literature was not sufficiently concordant to warrant positive conclusions concerning the stability of ointments containing free iodine, it seemed worth while to conduct experiments with preparations of known origin. Accordingly, a number of preparations containing free iodine were made under varying conditions and each was assayed for its free iodine content immediately after its manufacture and from time to time later.

Leaf lard of the best quality obtainable was purchased from a butcher. This was rendered in an open dish on the steam bath. The preparation was of a fine color, and uniform consistence and had a faint but not unpleasant odor. Two specimens of lard were furnished by the research department of Armour and Company. An effort was made to procure specimens of lard having iodine absorption numbers as far apart as possible, _i. e._, one with a low and the other with a high iodine value. This was done in order to determine whether the keeping qualities of the ointments prepared from the two would be alike.

One of the specimens (_a_) was described as

“Natural lard; iodine value, 57.1. Leaf lard used exclusively for
butterine and benzoinated lard.”

The other specimen was described as

“Prime steam lard. Good, commercial grade of lard for general use;
iodine value, 69.0.”

The iodine absorption numbers of the three specimens were determined by the U. S. P. process to be as follows:

Laboratory rendered specimen 57.1
Armour specimen (_a_) 57.65
Armour specimen (_b_) 67.55

Each specimen was benzoinated according to the process described in the U. S. P. IX and 100 gm. of iodine ointment were prepared from each according to the U. S. P. process. Another specimen was made from benzoinated lard and iodine only[194] without the addition of either glycerin or potassium iodide. This was made to contain 4 per cent. of iodine.

[194] In order to facilitate the incorporation of the iodine with the fatty base the iodine was first powdered by trituration with alcohol and drying the powder in the air.

Immediately after preparation each of these iodine ointments was assayed for free iodine, and each was reassayed at intervals later. The method for the determination of iodine in the ointment was that employed in this laboratory for the determination of iodine in Iocamfen Ointment.[195] It is essentially the same as was employed by Pullen for the determination of uncombined iodine in iodine ointment.[196] As carried out in this laboratory for iodine ointment it is as follows:

[195] Rep. Chem. Lab., A. M. A., 1916, 9, 118.

[196] Pharm. Jour., 1912, 89, 610.

From 5 to 8 gm. of the ointment were weighed in a small porcelain
capsule, the capsule and contents placed in a 16 oz. salt mouth
bottle together with 20 c.c. of chloroform, 10 c.c. of potassium
iodide solution and 40 c.c. of water. Tenth-normal sodium
thiosulphate was slowly added with agitation until the pink color
of the chloroform layer had nearly disappeared. A little soluble
starch was then added and the titration continued until a blue
color in the aqueous layer could no longer be obtained by repeated
shaking.

The findings for the several assays are tabulated herewith:

U. S. P. U. S. P. U. S. P. Ointment
Ointment Ointment Ointment from
Age at from from from lard and
time laboratory commercial commercial iodine only
of rendered lard lard (laboratory
assay lard Grade I Grade II rendered lard)

(% I) (% I) (% I) (% I)
Freshly made 3.32 3.26 3.30 0.32
After 3 days 3.25 .... .... 0.23
After 7 days 2.99 3.17 3.15 ....
After 3 weeks 3.01 3.19 3.07 ....
After 7 weeks 3.12* 3.10 3.02 ....
After 3 months 2.98 2.88 2.88 ....

* This slight rise in iodine content followed by a fall could not
be accounted for. The specimen was believed to have been very
thoroughly mixed at the time of manufacture.

That the fatty constituents of the ointment contained iodine after the preparation had been made for some time was demonstrated. Some of the material was examined as follows:

A portion of the ointment which had been made for nearly three
months was shaken in a separator with chloroform and a dilute
mixture of potassium iodide and sodium thiosulphate solutions.
After all of the free iodine had been removed the chloroformic
solution of the fats was washed several times with a very dilute
solution of sodium thiosulphate. The chloroformic solution was
filtered, evaporated and the residue dried over sulphuric acid.[197]

[197] The resultant fatty residue was of a brownish-green color. It no longer had either the taste, color or odor of lard. It was noted that the fats, after removal by this method from the freshly prepared ointment, were nearly white. As the ointment aged the fat became successively darker in color.

The separated fat was then tested for iodine by Kendall’s method.[198] It was found to contain iodine in considerable amounts, but quantitative determinations were not made.

[198] The method depends upon the conversion of all of the iodine compounds into iodate by fusion with sodium hydroxide and oxidation with potassium nitrate. The melt is dissolved in water, a little sodium bisulphite added, the solution cooled and neutralized with phosphoric acid, using methyl orange as indicator. An excess of bromine water is added, and the mixture boiled to expel carbon dioxid and bromine. A little sodium salicylate is added, the solution cooled, an excess of potassium iodid added, and the liberated iodine titrated with tenth-normal sodium thiosulphate in the usual way. One sixth of the iodine found is obtained from the material assayed, the balance being furnished by the potassium iodide added.--_Jour. Biochem._, 1914, 19, 251.

The Pharmacopeia of the Netherlands directs that iodine ointment shall contain 3 per cent. of potassium iodide and 2 per cent. of iodine instead of equal proportions (4 per cent. of each) as prescribed by the U. S. Pharmacopeia. Likewise the French Pharmacopeia directs that 10 per cent. of potassium iodide and only 2 per cent. of iodine shall be used. Both of these pharmacopeias use water instead of glycerin as the solvent. Loose combinations of iodine and potassium iodide, such as are represented by the compound having the formula KI₃, have been described. The quantity of potassium iodide prescribed by the U. S. Pharmacopeia for the preparation of iodine ointment is not sufficient to form such a compound as KI₃ with all of the iodine directed to be used. Since some of the pharmacopeias use larger proportions of potassium iodide (more than sufficient to form the compound, KI₃), it seemed worth while to determine whether an ointment containing a greater proportion of potassium iodide than that required by the U. S. Pharmacopeia would be more stable than the official article. Accordingly a specimen was prepared to contain 4 per cent. of iodine, 8 per cent. of potassium iodide (twice the U. S. P. requirement), 12 per cent. of glycerin and 76 per cent. of lard. This was assayed for its free iodine content immediately after preparation, and found to contain 3.68 per cent. Nine days later it contained 3.70 per cent. Another specimen of the same iodine strength prepared from grade No. 2 of commercial lard assayed 3.69 per cent. at the initial assay, and seven days later 3.40 per cent. From these experiments it seems likely that the free iodine content of the U. S. Pharmacopeia iodine ointment could be raised somewhat by increasing the proportion of potassium iodide.

The results of these studies confirm the findings of Pullen and of Fried in all essential particulars. It appears that during the process of manufacture of iodine ointment about 20 per cent. of the free iodine goes into combination with the fatty constituents of the ointment. On standing for a month approximately an additional 5 per cent. goes into combination, after which there is practically no loss in free iodine content. In other words iodine ointment which is a month old is a relatively stable preparation. It appears to make no noticeable difference upon the rate and amount of iodine absorption whether the lard from which the ointment is made has a high or a low iodine absorption value. The composition of iodine ointment, which has been made sufficiently long to have reached equilibrium, is approximately as follows:

Free iodine 3 per cent.
Iodine combined with fat 1 per cent.
Potassium iodide 4 per cent.
Benzoinated lard (containing iodine) 80 per cent.

The U. S. Pharmacopeia requirement that iodine ointment shall be freshly prepared when wanted appears to be unnecessary. Probably most pharmaceutical manufacturers are aware of this, for many of them include the preparation in their trade lists. The presence of an iodide appears to be necessary, to prevent practically all of the iodine from entering into combination with the fat.[199]--(_From the American Journal of Pharmacy, August, 1917._)

[199] In order to determine whether the iodine which is in combination with fat is absorbed through the skin, a few experiments were carried out. The dark-colored iodine-containing fat (obtained from the ointment and washed free from potassium iodide by the method described above) was rubbed thoroughly into the skin of the forearm. It was allowed to remain for four hours, after which the limb was scoured with soap suds. Beginning at the time of the application the urine was collected for forty-eight hours. This was evaporated to small bulk and the residue tested for iodine by Kendall’s method. Small amounts of iodine were found. These findings were taken to indicate that the iodine-containing fat is absorbed to some extent by the skin. It is generally believed that potassium iodide is not absorbed by the unbroken skin. Therefore it seems reasonable to suppose that the principal iodine effects obtainable from iodine ointment are those due to the free iodine contained in the preparation, supplemented to a slight extent by the iodine which is contained in the fatty ointment base.--_Jour. Biochem._, 1914, 19, 251.

IODOLENE AND THE SOLUBILITY OF IODIN IN LIQUID PETROLATUM

The Council on Pharmacy and Chemistry was asked to examine a preparation submitted with the statement that it was “iodin crystals incorporated in a petroleum product.” The name “Iodolene” was proposed by the promoters, providing the product was found eligible for New and Nonofficial Remedies.

Iodolene was stated to have been prepared by treating a liquid petrolatum, obtained from Gulf Coast petroleum, with an excess of iodin; the mixture was subsequently “placed in an oven for three hours.” The claim was made that this method of procedure produced a preparation containing more iodin than market specimens which had been examined, namely: “over 1.50 per cent. free iodine.”

Two specimens of the product were submitted, one stated to have been unfiltered, and the other filtered. Both of the specimens emitted a strong odor of hydrogen sulphide upon removing the stopper from the respective containers.

_Iodin Content of Iodolene._--The iodin content of the filtered specimen was determined thus: A weighed amount--3 to 5 gm.--was transferred to a separator by means of 20 c.c. of ligroin, used in portions. Twenty c.c. of 10 per cent. potassium iodid solution was added and the free iodin titrated with tenth-normal sodium thiosulphate solution (with agitation), the end point being the absence of a yellow color in the _aqueous_ layer. The amount of free iodin was found to be 1.32 per cent.

_The Solubility of Iodin in Liquid Petrolatum._--To determine the solubility of iodin in Liquid Petrolatum, 200 c.c. of Liquid Petrolatum-Squibb (said to be composed of hydrocarbons of the naphthene series) and 200 c.c. of Stanolind Liquid Paraffin (said to be composed chiefly of marsh gas hydrocarbons) were each treated with 5 gm. of iodin crystals. The two mixtures were maintained for a week at a temperature somewhat above that of the room and agitated occasionally. Each was then cooled to room temperature (about 22 C.), agitated for a day and then filtered. The amount of iodin in the preparation made with Liquid Petrolatum-Squibb was found to be 1.42 per cent. The iodin content of the preparation made with Stanolind Liquid Paraffin was 1.30 per cent.

In view of these findings the prospective manufacturer was advised that the Council cannot countenance a proprietary name for an unofficial, simple solution of iodin in liquid petrolatum.--(_From Reports A. M. A. Chemical Laboratory, 1917, p. 87._)

AMERICAN-MADE SYNTHETIC DRUGS--I

Examination of American-Made Acetylsalicylic Acid

Paul Nicholas Leech, Ph.D.

At the request of the Council on Pharmacy and Chemistry, the A. M. A. Chemical Laboratory has undertaken examinations of American-made synthetic drugs. The most extensively used synthetic is acetylsalicylic acid and hence an investigation of this product was deemed expedient.

For seventeen years acetylsalicylic acid was protected by a United States Patent (the proprietors were not given a patent in other countries) and sold under the name “Aspirin.” In February, 1917, the patent expired, and since then a number of firms have engaged in the manufacture of acetylsalicylic acid, selling it either as such or as aspirin, modified, of course, by a distinctive firm designation. During this period the former manufacturers (The Bayer Co., New York, in past years called Farbenfabriken of Elberfeld Co., New York) have been extensively advertising, both to physicians and the public, the alleged superior qualities of their product. The chemical examination, therefore, was concerned chiefly with tests of purity, and the comparison of the American brands with the formerly patented product.

In European countries, acetylsalicylic acid[200] is described in the various pharmacopeias as a condensation product of acetic anhydride or acetyl chloride with salicylic acid (_o_-hydroxybenzoic acid). Generally the test of identification is hydrolysis of acetylsalicylic acid and qualitative tests for acetic acid and salicylic acid. For purposes of purity the requirements are essentially that the specimen should have a certain melting point, should show absence of salicylic acid by means of ferric chloride (the manipulations for the tests are variously described) and leave no appreciable ash. The two tests of purity most generally employed, however, are the melting point and the reaction with ferric chloride.

[200] Unfortunately, the nondescriptive name “aspirin” has been used extensively in European literature and has even got into European pharmacopeias, instead of the scientific name “acetylsalicylic acid.”

MELTING POINT

The melting point of acetylsalicylic acid has been given at various temperatures from 118 to 137 C.[201]; the British Pharmacopeia describes the melting point at 133 to 135 C.; the German Pharmacopeia “about 135 C.;” the French Pharmacopeia at 135 C.; New and Nonofficial Remedies, 1917, 134 to 136 C. The Bayer Company, in the patent trial at Chicago a number of years ago, gave among the “four infallible tests” a melting point of “about 135 C.” Several men have carefully determined the melting point in recent years. Emery and Wright[202] in 1912 found that “Aspirin, Bayer” melted at 130.5 to 131 C. In France, François[203] has determined the melting point of pure acetylsalicylic acid, which, according to his method, is 132 C. When various samples of acetylsalicylic acid were examined in this laboratory, it was found that the melting point of none was as high as that described in New and Nonofficial Remedies or the British, French, or German pharmacopeias when taken according to the general method of the U. S. Pharmacopeia, Vol. 9, p. 596. On critical observation, it may be seen that the melting point of acetylsalicylic acid is preceded and accompanied by decomposition. If the sample in the melting tube is heated from the original room temperature of the bath to 120 C., the temperature of melting will be lower than if the bath is first heated to 120 C. and the melting-point tube then placed in the bath.[204] Thus the melting point of acetylsalicylic acid, like so many organic compounds which decompose and do not melt sharply, is unsatisfactory and cannot be taken as an “infallible test” of purity, especially when determined by different operators who do not give their method in detail. After making a large number of melting-point determinations of acetylsalicylic acid, alone and in parallel with other operators, it was decided to use the method described in the U. S. Pharmacopeia modified by first heating the bath to 120 C. before attaching the melting-point tube to the thermometer.

[201] For reference to older literature see Beilstein, II, 1496 (889).

[202] “The Melting Temperature of Aspirin and Salicylic Acid Mixtures,” _Proc. Assoc. Off. Agr. Chem._, 1912; Bureau of Chemistry, Department of Agriculture, _Bull._ 162.

[203] “Assay of Aspirin,” _J. Pharm. Chem._, 15 (117), No. 7, 213.

[204] Similar observations were made by Emery and Wright, who state: “An accurate determination of the melting temperature in this way (the rate of heating was such as to give a rise in temperature of about 1° per minute) is rendered difficult by the fact that ‘aspirin’ decomposes on heating, as evidenced in the depression of the melting temperature of the pure substance of about 1° for every five minutes’ heating just below its melting temperature.”

The melting point of purified acetylsalicylic acid was found to be 131.5 to 132.5 C. (corr.).[205] With the exception of one specimen, which was obviously impure, the various specimens examined melted between 128 and 133 C. as may be seen in the accompanying table. It would appear that this range of melting points would be more acceptable and reliable than the melting points described in various standards.

[205] Isolated crystals attached to the walls of the melting-point tube, apart from the bulk acetylsalicylic acid, melted at a lower temperature.

PRESENCE OR ABSENCE OF FREE SALICYLIC ACID

It is generally conceded that the presence of salicylic acid in amounts more than traces is deleterious. Furthermore, the amount of salicylic acid is a good index of the purity of the acetylsalicylic acid, because the test is so delicate that, under favorable conditions, mere traces may be determined and, as a rule, the better the product, the less the amount of free salicylic acid.

The tests appearing in various pharmacopeias for salicylic acid as an impurity in acetylsalicylic acid do not give concordant results, different workers interpreting the results differently, nor are they detailed in such a manner as to yield maximum delicacy.

After experimentation, it was decided to establish a “limit” test of approximately 0.1 per cent. free salicylic acid, when carried out according to the following method:

0.1 gm. of the substance was placed in a dry colorimeter tube and
1 c.c. of alcohol,[206] previously distilled over NaOH, was added.
After the acetylsalicylic acid had dissolved, 48 c.c. of water and
1 c.c. of fresh 0.1 per cent. ferric chloride (FeCl₃.6H₂O) solution
were added. At the same time a control was run by treating 1 c.c. of
a “standard” salicylate solution the same as above.[207] If within
two minutes the color given by acetylsalicylic acid is not more
intense than the color given by the “standard,” the presence of not
more than 0.1 per cent. free salicylic acid is proved.[208]

[206] An excess of alcohol destroys or lessens the color when only a
very minute amount of salicylic acid is present.

[207] The control should be made each time as standing in the air
changes its tinctorial power.

[208] The presence of pure acetylsalicylic acid does not seem
to affect the iron (Fe+++) salicylic acid coloration. The small
amount of acetic acid was added to the sodium salicylate control
solution (1) to stimulate an acidity approximating the acidity of
the acetylsalicylic acid, and (2) since acetylsalicylic acid gives
by hydrolysis both acetic acid and salicylic acid, it was thought
advisable to add acetic acid to the standard. If there is any free
acetic acid in a sample of acetylsalicylic acid containing salicylic
acid (which I believe is generally the case when salicylic acid is
present) then it would modify the color given by the same amount
of salicylic acid alone. For this reason it was thought to be more
comparable to have the standard contain a slight amount of acetic
acid.

The solutions used were prepared as follows:

Redistilled alcohol was treated with a small amount of sodium
hydroxide for twenty-four hours, then again distilled.

The color standard was made by dissolving 0.116 gm. of dried sodium
salicylate in water, adding 1 minim of glacial acetic acid, and
making up to 1,000 c.c. Each c.c. represents 0.1 mg. of salicylic
acid.[209]

[209] This standard is somewhat similar to the one proposed by T. W.
Thoburn and Paul J. Hanzlik, _J. Biol. Chem._, 23, 175.

The ferric chloride solution was made by diluting 1 c.c. ferric
chloride (FeCl₃.6H₂O) test solution U. S. P. with 99 c.c. of water.
The diluted solution must be freshly prepared each day.

With one exception, all of the commercial specimens examined responded satisfactorily to the above test showing less than 1 part salicylic acid in 1,000 parts acetylsalicylic acid. The individual results are given in the accompanying table.

MELTING POINT AND SALICYLIC ACID DETERMINATIONS

Melting Point Free Salicylic Acid
BRAND Corrected Colorimetrically

Acetylsalicylic acid, 130.0-131.0° Colored, but showing
P. W. R.[1] less than 0.1 per cent.

Acetylsalicylic acid, 130.0-131.0° No color
Millikin[2]

Acetylsalicylic acid, 129.0-130.0° No color
Millikin[2]
5-grain capsules

Acetylsalicylic acid, 128.0-129.0° (_a_) Colored, but showing less
Millikin,[1] than 0.1 per cent. (_a_)
5-grain capsules[3] 125.5-126.5° (_b_) Considerably more than
0.1 per cent. (_b_)

Acetylsalicylic acid, 131.0-132.0° No color
Squibb[2]

Acetylsalicylic acid 131.0-132.0° No color
(Aspirin),[1]
Monsanto

Acetylsalicylic acid, 130.5-131.5° Colored, but showing less
M. C. W.[1] than 0.1 per cent.

Acetylsalicylic acid, 131.5-132.5° Colored, but showing less
M. C. W.[1] than 0.1 per cent.

Acetylsalicylic acid, 131.0-132.0° Colored, but showing less
M. C. W.[1] than 0.1 per cent.

Aspirin, Bayer[1]
(before patent 131.5-132.5° No color
expired)
Aspirin, Bayer[1] [4]
(after patent 128.5-129.5° Colored, but showing less
expired) than 0.1 per cent.

Aspirin, Bayer[1] [4]
(after patent 129.5-130.5° Colored, but showing less
expired) than 0.1 per cent.

Aspirin, Lehn 130.5-131.5° 0.1 per cent.
and Fink[2]

Aspirin, Lehn 130.5-131.5° Colored, but showing less
and Fink[2] than 0.1 per cent.

Aspirin, Lehn 131.0-132.0° Colored, but showing less
and Fink[1] than 0.1 per cent.

[1] Obtained on the open market.

[2] Obtained from manufacturer.

[3] One-third of the capsules (_a_) contained a white powder;
two-thirds of the capsules (_b_) contained a pink powder having
strong odor of acetic acid and not complying with the tests.

[4] Not described in “New and Nonofficial Remedies, 1917”; the
other products are.

OTHER TESTS

New and Nonofficial Remedies, 1917, requires that acetylsalicylic acid shall form a clear solution with warm sodium carbonate solution; that sulfates, chlorides and heavy metals shall be absent; that 0.5 gm. shall leave no weighable ash. All the brands reported in this paper complied with these requirements.

So far there has been no satisfactory quantitative estimation of acetylsalicylic acid. True, various methods have been proposed, but they are objectionable. It was thought that hydrolysis of acetylsalicylic acid and then titrating the solution by comparing the color formed by ferric chloride with that of a standard control might yield interesting results, providing that the conditions were alike. For this purpose 1 gm. of acetylsalicylic acid was dissolved in 10 c.c. of alcohol and diluted to 1,000 c.c. The solution was then heated at 98 to 100 C. for two hours, allowing the alcohol to evaporate, then allowed to stand at room temperature (22 C.) for twenty-two hours. After adding water sufficient to make 1,000 c.c., it was compared colorimetrically for salicylic acid strength. The amount of hydrolysis varied so with different samples under the same conditions, that it was realized that an approximate assay by this method was unreliable. If the assay were made under more exact conditions, quantitative comparisons might be possible. In one experiment, after sixty days the hydrolysis of the acetylsalicylic acid was 61 per cent., which is in rough agreement with the work of Tsaklatos and Horsh.[210]

[210] _Apoth. Ztg._, 1915, p. 247; _Bull. soc. chem._, 17 (1915), 401. “Studies of the decomposition of aspirin determined by titrametric methods and by conductivity measurements indicate that the reaction is exceedingly complex,” T. and H. _Chem. Abs._, 10, 591.

DISCUSSION

Apart from the proposed revision of the standards for the melting point and limit of salicylic acid in acetylsalicylic acid, the examination shows that there is no appreciable difference between the various brands of acetylsalicylic acid examined, all of them with one exception (acetylsalicylic acid, Millikin, 5-grain capsules, purchased on the open market) complying with the tests described in this paper. The Journal of the American Medical Association, in past years, has protested repeatedly against the monopoly given to the Bayer Company for their “Aspirin,” contending that acetylsalicylic acid (aspirin) was not new, and that “Aspirin, Bayer” was simply a good brand of acetylsalicylic acid which could be bought in foreign countries at much lower prices than here. Although the patent in the United States has expired, “Aspirin, Bayer” is still being retailed at higher prices than other products which are now enjoying the privilege of American manufacture.

Mr. Paul Bakewell,[211] in an opinion answering the warning circular of the Bayer Co. in reference to the use of the word “aspirin” by firms other than Bayer, argues very ably that acetylsalicylic acid, before the patent was granted, meant the impure substance which was not used therapeutically, while “aspirin” was designated as the improved product (a new article of manufacture, the particular acetylsalicylic acid made under the Hoffman patent) and “is the substance now known in pharmacy as aspirin” (statement made by an officer of the Farbenfabriken of Elberfeld Co. in U. S. Circuit Court, 1909). The products reported in this paper are (with the one exception) the same as described in the Hoffman patent, and, in the sense of Mr. Bakewell’s argument, are “aspirin.” However, it would seem better if the name acetylsalicylic acid, instead of aspirin, were used, especially by physicians in their prescriptions because (1) it is a generic, scientific name; (2) “Aspirin, Bayer” is sold at higher prices than other products, whereas chemically equivalent products sold under the descriptive name may be purchased at a lower price. Finally, the manufacture of acetylsalicylic acid in this country is another example of the fact that American chemists can produce the drug synthetics, and at the same time make products as good as, if not better than, those of German origin.

[211] “In the Matter of Aspirin. Answer to the warning circular of the Bayer Co. of June 1, 1917,” by Mr. Paul Bakewell, Monsanto Chemical Works.

I express my appreciation to Dr. W. A. Puckner for his kind interest.--(_From the Journal of Industrial and Engineering Chemistry, April, 1918._)

THE STANDARDIZATION OF COMMERCIAL BISMUTH TRIBROMPHENATE

William Rabak, Ph.G., Sc.B.

This work was begun in view of a request received by the Council on Pharmacy and Chemistry from the Medical Section of the Council of National Defense for a report on the quality of bismuth tribromphenate, offered to the government by a certain firm.

In submitting a specimen of its product, “Bismuth Tribromphenolate,” the firm claimed that “it is of high character, matching exactly the German product formerly imported into this country,” and expressed the belief that it would be found to conform to the standards for this preparation in New and Nonofficial Remedies. Later a second specimen was received from the same company, with the request that this be substituted for that first received. It was explained that the first had been taken from an experimental lot, and that the second, taken from the regular factory output, was identical with the first except that it was free from odor because of the more thorough washing to which it had been subjected. Accordingly, the examination which is reported below refers to the second specimen only.

New and Nonofficial Remedies, 1918, defines bismuth tribromphenate as basis bismuth tribromphenate having the formula Bi(C₆H₂Br₃O)₂OH.Bi₂O₃, and it is required to yield not less than 49.5 per cent. of bismuth oxid (the chemical formula requires 46.2 per cent. bismuth, or 51.6 per cent. bismuth oxid, Bi₂O₃, and 49.2 per cent. tribromphenate, C₆H₂Br₃.OH). It describes it as a “fine, yellow, nearly odorless and tasteless powder, neutral in reaction,” and “only slightly soluble in water, alcohol, chloroform, liquid petrolatum and vegetable oils.” It is required to yield tribromphenol (to which a melting point of 95 C. is assigned) when decomposed by alkali and the alkali tribromphenate decomposed by acid, the separated tribromphenol purified and dried.

As the New and Nonofficial Remedies description appeared loosely drawn--it had been based on information furnished for the product Xeroform when this, because of patent protection, was the only bismuth tribromphenate on the market--it was decided to include in the examination also specimens of the two brands of Bismuth Tribromphenate included in New and Nonofficial Remedies, namely, Bismuth Tribromphenate-Merck (Merck and Company) and Xeroform-Heyden (The Heyden Chemical Works). The Merck specimen had been received by the Council from Merck and Company in 1915, while the Heyden preparation was obtained direct from the firm’s Chicago branch in April, 1918. At this time Bismuth Tribromphenate-Merck could not be obtained from the Chicago wholesale houses.

All three specimens were nearly odorless. Two of the specimens (the Research Council Specimen and Merck products) were of a lemon-yellow color, while the Heyden preparation was of a grayish color.

BISMUTH DETERMINATION

Four methods for the determination of the bismuth content of the specimens were tried:

(_A_). _Direct Ignition to Bismuth Oxid._--This method was abandoned because of the tendency to ignite suddenly during the incineration and the consequent loss of material.

(_B_). _The Method of the Japanese Pharmacopeia, Third Revised Edition, Translated by the Pharmaceutical Society of Japan._--The method consists in treatment of the product with nitric acid, evaporation and subsequent heating to bismuth oxid. This method also was abandoned because of tendency toward sudden ignition with loss of material.

(_C_). _The Method of Kollo (Apotheker Zeitung, 1910, p. 99)._--The method consists in decomposition of the product by heating on water bath with normal sodium hydroxid solution, with formation of soluble sodium tribromphenate and insoluble bismuth hydroxid. The bismuth hydroxid is collected on a filter, washed with hot water until a few drops of the filtrate no longer turn litmus paper blue, dried and heated to constant weight and weighed as bismuth oxid.

(_D_). _A. M. A. Method (Reports A. M. A. Chem. Lab., 1911, p. 18)._--This method consists in dissolving the product in hot, strong hydrochloric acid, diluting, filtering and precipitating by saturation with hydrogen sulphid. The bismuth sulphid obtained is dissolved in nitric acid and from the solution obtained the bismuth is precipitated by addition of an excess of ammonium hydroxid and ammonium carbonate. The precipitate is collected and converted to bismuth oxid by heat.

The following tabulation shows the results obtained by Methods “C” and “D”:

TABLE 1.--BISMUTH CONTENT OF BISMUTH TRIBROMPHENATE

Gm. of Gm. of Per Cent.
Method Salt Bi₂O₃ of Bi₂O₃
No. 1 Research Council Spec C 2.1312 1.1754 55.1
No. 1 Research Council Spec D 0.5151 0.2772 50.03
No. 2 (Merck & Company) C 2.0287 1.2543 61.8
No. 2 (Merck & Company) D 0.5064 0.2634 52.01
No. 3 (Heyden Chem. Works) C 2.0472 1.6020 78.2
No. 3 (Heyden Chem. Works) D 0.5227 0.3546 67.8

It is seen from the tabulation that the results obtained by the Kollo method (Method C) are higher than those by the sulphid method (Method D) and that duplicate determinations show a rather wide variation. The results by the sulphid method are somewhat lower than those by the Kollo method, but duplicates agree fairly well. In view of the fact that the Kollo method will give excessive results if impurities such as talcum, etc., are present and in consideration of the satisfactory results obtained in previous work with the sulphid method, the figures obtained by this method are taken as indicative of the bismuth content of the specimens examined. Calculating the per cent. of bismuth oxid obtained to bismuth (Bi), the following values are obtained:

Bismuth Tribromphenolate, Research Council Specimen: Bismuth, 44.8
per cent.

Bismuth Tribromphenate-Merck, Merck & Co.: Bismuth, 46.6 per cent.

Xeroform, Heyden Chemical Works: Bismuth, 60.7 per cent.

TOTAL TRIBROMPHENOL

The content of tribromphenate radical, C₆H₂Br₃O-, was determined by the method of Kollo (Apotheker Zeitung, 1910, p. 99). It consists in titrating the filtrate of the bismuth oxid determination of Kollo, described under “C” (bismuth determinations), with normal hydrochloric acid, using phenolphthalein as an indicator. The cubic centimeters of normal alkali consumed multiplied by the theoretical factor 0.331 gives the weight of tribromphenol (combined and free) contained in the specimen.

The following results were obtained:

TABLE 2.--DETERMINATION OF TOTAL TRIBROMPHENOL IN BISMUTH TRIBROMPHENATE

Gm. Tribromphenol
Gm. of Calculated from Per Cent.
Salt Theoretical of Total
Taken Factor Tribromphenol
No. 1 (Research Council Spec.) 1.7817 1.0592 59.44
No. 2 (Merck & Co.) 0.9743 0.5627 57.75
No. 3 (Heyden Chem. Works) 2.0440 0.4303 21.04

UNCOMBINED TRIBROMPHENOL

The definite chemical formula given in New and Nonofficial Remedies for bismuth tribromphenate and the statement that it is “only slightly soluble in ... alcohol ...” requires the absence of uncombined tribromphenol, but no method for its detection or determination is provided.

In the U. S. Patent 516,358 (expired March 13, 1911), issued to Bruno Richard Seifert, assignor to Dr. F. Von Heyden, for “Phenol Bismuth Compound” the freedom from uncombined tribromphenol was provided for by the direction to wash with alcohol the product obtained.

In the Swiss Pharmacopeia the permissible content of uncombined tribromphenol is limited thus:

“If 0.5 gm. be shaken with 5 c.c. of alcohol and 1 c.c. of the
filtrate be diluted with 15 c.c. of water, neither a turbidity nor
a flocculent precipitate should appear....”

When this test was applied to the three specimens under examination, the Merck and Heyden specimens complied, while the Research Council specimen did not comply, with this requirement.

_Method 1._--About 1 gm. of bismuth tribromphenate was placed in a flask, 20 c.c. of 95 per cent. alcohol added and shaken for fifteen minutes, after which it was filtered by suction through a Gooch filter into an Erlenmeyer flask. The flask was rinsed with 10 c.c. of alcohol and finally the filter was washed with 10 c.c. of alcohol, 25 c.c. of tenth-normal sodium hydroxid solution were added to the alcoholic filtrate (which was nearly but not perfectly clear) containing the tribromphenol, and the residual alkali titrated with tenth-normal hydrochloric acid.

The number of cubic centimeters of tenth-normal alkali consumed multiplied by 0.331 gave the weight of tribromphenol (Table 3).

TABLE 3.--DETERMINATION OF FREE TRIBROMPHENOL

Gm. Tribromphenol
Calculated from Per Cent.
Gm. of Theoretical Free
Salt Taken Factor Tribromphenol
Research Council Spec. 2.3351 0.3806 16.31
Merck & Co. 0.7980 0.0364 4.56
Heyden Chemical Works 1.9460 0.0132 0.68

_Method 2._--About 2 gm. of bismuth tribromphenate were placed in a glass stoppered Erlenmeyer flask, 100 c.c. of alcohol were measured in and shaken during one-half hour and allowed to stand over night. Fifty c.c. of the supernatant liquid were then removed by means of a pipet, a slight excess of tenth-normal sodium hydroxid added and the residual alkali titrated with tenth-normal HCl.

Table 4 gives results obtained.

TABLE 4.--PER CENT. OF TRIBROMPHENOL BY METHOD 2

Gm. Tribromphenol
Calculated from Per Cent.
Gm. of Theoretical Free
Salt Taken Factor Tribromphenol
Research Council Spec. 2.0712 0.3905 18.85
Merck & Co. 1.9417 0.0760 3.92
Heyden Chemical Works 2.0440 0.0198 0.97

Table 5 gives a comparison of the results obtained by the two methods.

TABLE 5.--COMPARISON OF RESULTS BY METHODS 1 AND 2

Method 1 Method 2
Research Council Spec. 16.31 18.85
Merck & Co. 4.56 3.92
Heyden Chemical Works 0.68 0.97

The results obtained in Method 1 (the percolation method) apparently are reliable and, as the method is the more simple, may be given preference.

COMBINED TRIBROMPHENOL (TRIBROMPHENATE)

The amount of tribromphenol existing in the specimen in combination was calculated by subtracting from the per cent. of total tribromphenol determined, the per cent. of free tribromphenol found by Method 1.

The figures obtained are given in Table 6.

TABLE 6.--THE TRIBROMPHENATE CONTENT OF BISMUTH TRIBROMPHENATE

Per Cent. of
Combined
Tribromphenol
Research Council Specimen 43.13
Merck & Co. 53.19
Heyden Chemical Works 20.36

SUMMARY

From the foregoing the specimens examined contain the percentages shown in Table 7 of bismuth (Bi), combined tribromphenate and free tribromphenol.

TABLE 7.--PERCENTAGES OF BISMUTH AND OF COMBINED TRIBROMPHENATE AND FREE TRIBROMPHENOL

Per Cent. Per Cent.
Per Cent. Combined Free
Bismuth Tribromphenate Tribromphenol
Research Council Specimen 44.8 43.13 16.31
Merck & Co. 46.6 53.19 4.56
Heyden Chemical Works 60.7 20.36 0.68

This examination shows:

1. The Bismuth Tribromphenolate submitted to the Council of National Defense, does not correspond to the description of bismuth tribromphenate in New and Nonofficial Remedies.

2. As now supplied, Xeroform-Heyden does not meet the requirements for bismuth tribromphenate, nor does its composition correspond to that of the product formerly supplied.

3. The description in New and Nonofficial Remedies of bismuth tribromphenate should provide an upper, as well as a lower, limit for the bismuth content; it should provide tests for the absence of adulterants, and also set a limit of permissible uncombined tribromphenol.

Report to Council of National Defense

The results of this examination with reference to the Research Council specimen having been submitted to the Council on Pharmacy and Chemistry, this body advised the Medical Section of the Council of National Defense as follows:

1. The specimen of “Bismuth Tribromphenolate” sent to the Council of National Defense complies with the New and Nonofficial Remedies description for bismuth tribromphenate, except that it contains considerable amounts (approximately 16 per cent.) of alcohol-soluble, uncombined tribromphenol.

Revision of N. N. R. Standards

The results of the examination of the three specimens were sent to the Heyden Chemical Works and to Merck and Co. (in each case disclosing the identity of the particular firm’s product), asking aid in the standardization of the product. After Merck and Co. had submitted valuable advice for a revision of the somewhat loosely drawn standards for bismuth tribromphenate in N. N. R., 1918, the inquiry whether the following proposed revision of the description of bismuth tribromphenate in New and Nonofficial Remedies was acceptable, was submitted to both firms:

=BISMUTH TRIBROMPHENATE.--Bismuthi Tribromphenas.--Bismuth Tribromphenol.--Xeroform.=--A basic bismuth tribromphenate of variable composition.

An amorphous, yellow, nearly odorless and tasteless powder, neutral
to moistened litmus paper.

It is only slightly soluble in water, alcohol, chloroform, liquid
petrolatum and vegetable oils. Alkalies and strong acids decompose
it. It is stable at temperatures below 120 C.

When about 1 gm. of the salt is boiled with 10 c.c. of sodium
hydroxide test solution, the liquid filtered, and the filtrate
acidulated with sulphuric acid, the white curdy precipitate produced,
when washed and dried, melts at 90 to 95 C. (_tribromphenol_). The
contents of the filter dissolve completely in dilute hydrochloric
acid (insoluble _inert material_).

Boil 1 gm. of bismuth tribromphenate with 20 c.c. of a mixture of
equal parts of acetic acid and distilled water, cool the solution and
filter. Free the filtrate from bismuth by the addition of hydrogen
sulphide, boil the mixture and again filter. The latter filtrate
leaves not more than 0.005 gm. of residue on evaporation and gentle
ignition (_alkalies and alkali earths_).

Shake for one minute in a separatory funnel, 2 gm. of bismuth
tribromphenate, 20 c.c. of ether, and 20 c.c. of a mixture of
equal volumes of hydrochloric acid and distilled water. Draw off
the aqueous portion and concentrate to about 4 c.c.; pour it into
100 c.c. distilled water, filter, evaporate the filtrate on the water
bath to 30 c.c., again filter and divide this filtrate into portions
of 5 c.c. each. Mix one portion with an equal volume of dilute
sulphuric acid; it does not become cloudy (_lead_). Treat another
portion with a slight excess of ammonia water; the supernatant liquid
does not exhibit a bluish tint (_copper_). Another portion is not
immediately affected by barium nitrate test solution (_sulphate_).

Heat gently a mixture of about 0.2 gm. of bismuth tribromphenate
with 5 c.c. of potassium hydroxide test solution and about 0.2 gm.
of aluminum wire; the vapors evolved do not turn red litmus blue
(_nitrates_).

Shake 1 gm. of bismuth tribromphenate frequently during fifteen
minutes with 30 c.c. of alcohol (95 per cent.), filter and rinse
flask with two separate 10 c.c. portions of alcohol, allowing the
washings to run through filter. To the combined filtrate and washings
add 20 c.c. of tenth-normal sodium hydroxide and a few drops of
phenolphthalein solution and determine the excess of alkali with
tenth-normal hydrochloric acid. Not more than 1 c.c. of tenth-normal
sodium hydroxide should have been consumed by the alcoholic liquid
(_free tribromphenol_).

Add 2 c.c. of nitric acid to 2 gm. of bismuth tribromphenate in a
porcelain crucible, carefully evaporate to dryness on a sand bath
and incinerate. Dissolve the residue in 5 c.c. of concentrated
hydrochloric acid and add to the solution 10 c.c. of a saturated
solution of stannous chloride in concentrated hydrochloric acid. The
mixture should not darken on standing thirty minutes (_arsenic_).

Mix 0.5 gm. of the salt with 10 c.c. of a mixture of equal parts of
hydrochloric acid, U. S. P., and distilled water. No effervescence
should occur (_carbonate_).

To about 0.5 gm. of bismuth tribromphenate, accurately weighed, add
20 c.c. of hydrochloric acid and digest on water bath. Add 150 c.c.
of distilled water and filter. Rinse the beaker with 30 c.c. of
distilled water and allow the washings to run through the filter.
Saturate the combined filtrate and washings with hydrogen sulphide,
filter off the bismuth sulphide, wash and dissolve in hot dilute
nitric acid. Add a slight excess of ammonia water followed by 2 c.c.
of ammonium carbonate test solution. Allow to stand thirty minutes,
filter off the precipitated bismuth hydroxide and heat to constant
weight at dull red heat. The residue of bismuth oxide (Bi₂O₃) should
not be less than 45 per cent. nor more than 55 per cent. of the
original weight of bismuth tribromphenate taken, corresponding to not
less than 40 per cent. nor more than 49 per cent. of bismuth.

The Heyden Chemical Works accepted the proposed monograph. Regarding the Laboratory’s findings, the firm stated that “the product had to be made in this country after importations from Europe became impossible and the first lots were not fully up to the standard.” Later the firm stated that it could furnish a product which it considered equal to that which was previously imported and offered to submit “samples of the new material.”

Merck and Co. acknowledged the receipt of the monograph but made no statement as to its acceptance or suggestions for its revision. As the new monograph was accepted by the Heyden Chemical Works and as Merck and Co. offered no objections, it was adopted for N. N. R., 1919, by the Council on Pharmacy and Chemistry.

In November, 1918, Merck and Co. sent a specimen labeled “Bismuth Tribromphenate-Merck,” “Merck and Co., New York, Distributors and Guarantors” and wrote: “You will notice this sample conforms in nearly all details to the tests submitted with our letter of June 4. We have been able to produce better goods, but just at present unsatisfactory starting material confronts us.”

Examination of the specimen demonstrated that it was soluble to a considerable extent in alcohol (the N. N. R., 1918, description provides that it should be only slightly soluble in alcohol) and, according to the standards adopted for New and Nonofficial Remedies, 1919, contained 18 per cent. of uncombined tribromphenol (more than five times the permitted amount).

In December, 1918, Merck and Co. submitted another specimen and said: “We believe this is a better grade than we have been able to make in the recent past. It seems to meet all the tests for N. N. R., 1919, with two exceptions: these are (a) solubility in alcohol, and (b) the test for uncombined tribromphenol.{”}

When the two recent samples of bismuth tribromphenate-Merck and two samples of Xeroform-Heyden were examined according to the new monograph the results given in Table 8 were obtained.

TABLE 8.--EXAMINATION OF TRIBROMPHENATE AND XEROFORM

1. BISMUTH.
Weight of Per Cent.
Weight Bi₂O₃ of
Brand and Date Received Taken, Obtained, Bismuth,
Gm. Gm. Gm.
Xeroform-Heyden (from mfr.) July, 1918 0.6754 0.3565 47.2
Xeroform-Heyden (open market) July, 1918 0.8259 0.6156 66.7
Bismuth tribromphenate-Merck Nov., 1918 0.4882 0.2512 46.1
Bismuth tribromphenate-Merck Dec., 1918 0.8869 0.4495 45.5

2. UNCOMBINED TRIBROMPHENOL.
No. C.c. Per Cent.
Weight of Tenth- of Free
Brand and Date Received Taken, Normal NaOH Tribrom-
Gm. Consumed, phenol
C.c.
Xeroform-Heyden (from mfr.) July, 1918 1 7.4 24.5
Xeroform-Heyden (open market) July, 1918 1 0.7 2.3
Bismuth Tribromphenate-Merck Nov., 1918 1 5.7 18.8
Bismuth Tribromphenate-Merck Dec., 1918 1 5 16.5

In view of the laboratory’s report the referee of the Council on Pharmacy and Chemistry in charge of bismuth tribromphenate recommended that the acceptance of Xeroform-Heyden and bismuth tribromphenate-Merck be withdrawn, but that this should be without prejudice to their reinstatement when satisfactory products are again offered for sale. The Council adopted the recommendation of the referee and accordingly Xeroform-Heyden and bismuth tribromphenate-Merck are omitted from New and Nonofficial Remedies, 1919.