THEOBROMIN SODIUM SALICYLATE VERSUS “DIURETIN”: THE ECONOMICAL ASPECT
W. A. Puckner and Paul N. Leech
The following inquiry is from Dr. Reid Hunt, recently appointed professor of pharmacology at Harvard Medical School:
“Have you ever made an examination of the theobromin sodium salicylates on the market to determine if they are identical with ‘Diuretin?’ The description of theobromin sodium salicylate in New and Nonofficial Remedies agrees with the statements as to the composition of Diuretin, but I wondered if, at times at least, the theobromin sodium salicylate on the market might be a simple mixture of theobromin and sodium salicylate just as the Caffeinae Sodio-Salicylas, N. F., seems to be a simple mixture. Diuretin is quoted in current price-lists at $1.75 an ounce, whereas the price of theobromin sodium salicylate is only 35 cents an ounce. Many hospitals use diuretin, and both physicians and students often have only hazy ideas as to what it is. If the preparations of theobromin sodium salicylate now on the market are identical with Diuretin they should certainly be used, not only because they are less expensive, but because the descriptive name will continually remind the physicians of what they are using.”
Theobromin for some time has been regarded as a valuable therapeutic agent. The obstacle to its use has been its insolubility and the consequent uncertainty of the degree of its absorption. For this reason a soluble salt of theobromin, theobromin sodium salicylate, first introduced and advertised under the proprietary name “Diuretin,” has come to be used to a considerable extent.
Theobromin sodium salicylate—also called theobromin and sodium salicylate—is prepared by interaction, in molecular proportions, of theobromin, sodium hydroxid and sodium salicylate, the theobromin first being treated with sodium hydroxid in the presence of a suitable solvent, then the sodium salicylate added and the whole brought to dryness. The soluble compound which is formed is generally considered to be a double salt of theobromin sodium and sodium salicylate.
Theobromin sodium salicylate is described in New and Nonofficial Remedies and in several foreign pharmacopeias. It is also to be described in the forthcoming United States Pharmacopeia.
Although the product is not controlled by patents of any kind, and although it is offered for sale under its chemical name by the leading chemical manufacturers at from 35 to 45 cents per ounce, the proprietary product, Diuretin, sells for $1.75 an ounce. This is probably because the manufacturers think that those who have been using it under its chemically non-descriptive but therapeutically suggestive title, Diuretin, will remain ignorant of the fact that the same product is on the market under its chemical name. In view of these conditions, emphasized by Dr. Hunt’s letter, it was deemed important to examine the market-supply of theobromin sodium salicylate and to compare the several specimens with the proprietary brand Diuretin.
The following specimens, purchased in 1-ounce original packages, were examined:
Diuretin, “Knoll,” Knoll & Co.
Theobromine and Sodium Salicylate, Mallinckrodt Chemical Works.
Theobromine and Sodium Salicylate, Merck & Co.
Theobromine and Sodium Salicylate Powder, Powers-Weightman-Rosengarten Co.
Theobromine and Sodium Salicylate, “Roche,” Hoffmann-La Roche Chemical Works.
Theobromine and Sodium Salicylate, Squibb, E. R. Squibb & Sons.
The theobromin content prescribed for theobromin sodium salicylate by the various standards ranges from 45 to 50 per cent., that of New and Nonofficial Remedies being the highest. A requirement of not less than 46.5 per cent. theobromin in the dried powder has been proposed for the new U. S. Pharmacopeia.
The methods of quantitative estimation laid down by the various authorities are all very similar and consist, in the main, of a determination of water, of the sodium hydroxid, free and in combination with theobromin, and of the theobromin itself. For the theobromin estimation the following method was employed:
A weighed sample (about 2 gm) which had previously been dried, under slightly reduced pressure, over sulphuric acid, to constant weight, was dissolved in five times its weight of warm water. Two drops of phenolphthalein were added, and the solution titrated with normal hydrochloric acid. To the neutral solution, 1 drop of 10 per cent. ammonium hydroxid solution was added, and the mixture allowed to stand, with occasional stirring, for three and one-half hours at the temperature of 15 C. The precipitate was filtered on a weighed Gooch crucible, washed with just ten times the weight (of the original sample taken) of water (temperature 15 C.) and the precipitate dried at from 100 to 104. To the weight obtained, a correction factor (proved satisfactory by quantitative extraction experiments on the filtrate) of 0.13 gm. was added, for every 2 grams of the original sample taken.
The full details of the examination will be published in the 1914 Reports of the A. M. A. Chemical Laboratory. The results of the examination have been abstracted and are compiled in the accompanying table:
SUMMARY OF ANALYSIS
Column Headings:
2 = Physical Appearance*
3 = Gm. in 1-Ounce Bottle
4 = Price per Ounce
5 = Moisture, Per Cent.
6 = Alkalin. as NaOH on Dry Powder† Per Cent.
7 = Theobromin in Dry Powder† Per Cent.
8 = Theobromin in Orig. Specimen† Per Cent.
| 2 | 3 | 4 | 5 | 6 | 7 | 8 | |||||||
| Diuretin | 3 Pure White | 28 | .5 | $1 | .75 | 0 | .01 | 10 | .44 | 48 | .61 | 48 | .61 |
| Theo. Sod. Sal. M. C. W | 3 Pure White | 27 | .5 | 0 | .35 | 1 | .89 | 9 | .95 | 46 | .11 | 45 | .24 |
| Theo. Sod. Sal. Merck | 1 Pure White | 29 | .0 | 0 | .35 | 0 | .48 | 10 | .38 | 47 | .87 | 47 | .58 |
| Theo. Sod. Sal. P. W. R. Co. | 2 Pure White | 29 | .1 | 0 | .35 | 2 | .46 | 10 | .30 | 47 | .57 | 46 | .39 |
| Theo. Sod. Sal. Roche | 3 Pink | 28 | .6 | 0 | .35 | 2 | .27 | 9 | .92 | 49 | .05 | 47 | .92 |
| Theo. Sod. Sal. Squibb | 1 Pure White | 26 | .8 | 0 | .45 | 0 | .39 | 9 | .97 | 46 | .82 | 46 | .63 |
* In this column, 1, 2 and 3 denote the following:
1. Quite crystalline, under microscope.
2. Fairly crystalline, under microscope.
3. Not crystalline, under microscope.
† Average of determinations.
While the results show some variation in the moisture content and also in the actual theobromin content of the dried specimens, the variation is unimportant. The products in their original state (undried), as compared in relation to the theobromin content (the highest percentage of theobromin being 48.61, the lowest 45.24), reveal a variation of only about 3 per cent.—a variation which is negligible in the case of drugs such as theobromin.
From the preceding investigation, it is concluded that (1) practically there is no difference between the non-proprietary brands of “theobromin sodium salicylate” and “Diuretin;” (2) the several specimens examined were not simple mixtures of “theobromin” and “sodium salicylate”; (3) essentially all the brands complied with the standards laid down and can be rated as satisfactory; (4) “Diuretin,” though sold at an exorbitant price, is not superior to the product supplied under the descriptive term “theobromin sodium salicylate,” and (5) “Diuretin” sells wholesale for $1.75 an ounce, against 35 cents for the “theobromin sodium salicylate,” and therefore its employment cannot be interpreted otherwise than as a useless and unnecessary expense.—(From The Journal A. M. A., April 4, 1914.)