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
| Method | Gm. of Salt | Gm. of Bi2O3 | Per Cent. 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. of Salt Taken | Gm. Tribromphenol Calculated from Theoretical Factor | Per Cent. of Total 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. of Salt Taken | Gm. Tribromphenol Calculated from Theoretical Factor | Per Cent. Free 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. of Salt Taken | Gm. Tribromphenol Calculated from Theoretical Factor | Per Cent. Free 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. Bismuth | Per Cent. Combined Tribromphenate | Per Cent. Free 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. | |||
| Brand and Date Received | Weight Taken, Gm. | Weight of Bi2O3 Obtained, Gm. | Per Cent. of Bismuth, 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. | |||
| Brand and Date Received | Weight Taken, Gm. | No. C.c. of Tenth-Normal NaOH Con- sumed, C.c. | Per Cent. of Free Tribromphenol |
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.
When the laboratory’s findings with regard to Xeroform-Heyden and the action of the Council deleting the article from New and Nonofficial Remedies was reported to the Heyden Chemical Works, the firm expressed regret that efforts to produce a product equal to that formerly obtained from Germany had so far not been successful and announced that it had decided to withdraw Xeroform-Heyden from the market for the present. When Merck and Co. was advised in regard to the report of the laboratory and Council’s action, this firm questioned the feasibility of producing a product meeting the Council’s standards and suggested that the test for free tribromphenol be revised to permit as much as 15 per cent. of this constituent. When Merck and Co. was reminded that its product submitted in 1915 essentially complied with the adopted standards (an old sample of Xeroform-Heyden was also found to comply) and that the estimate of the therapeutic value of bismuth tribromphenate is based on a product essentially devoid of free tribromphenol, the firm replied:
“As stated in our letter of the 12th inst., we do not wish to market the chemical unless it meets all legitimate requirements of the physicians that use it. If, therefore, your standard proves to be good and it is commercially possible to make supplies conforming to it, we shall do so. We shall discontinue the article unless it is of suitable quality.”—(From Reports A. M. A. Chemical Laboratory, 1918, p. 93.)