THE STANDARDIZATION OF PROCAIN AND EXAMINATION OF THE MARKET SUPPLY
Procain, which chemically is the mono-hydrochlorid of para-amino-benzoyldiethyl-amino-ethanol, is the nonproprietary name selected by the Federal Trade Commission as the official designation for the drug previously known under the proprietary name “novocaine.” Before the war procain was obtainable in this country only through the Farbwerke Hoechst Co., the American representative of the German establishment, Farbwerke, vorm, Meister, Lucius and Bruening, under the name “novocaine.” This monopoly on “novocaine” was exercised by virtue of United States patent No. 812554, which was issued to Alfred Einhorn, Munich, Germany, assignor to Farbwerke, vorm, Meister, Lucius and Bruening, Hoechst a. M., in 1906. With the outbreak of hostilities, Congress passed the Trading with the Enemy Act, and under this, the Federal Trade Commission took charge of the novocain patent with a view of securing the production of this product in the United States. To ensure an adequate supply of the drug, the Federal Trade Commission on recommendation of the Committee on Synthetic Drugs of the National Research Council, in addition to issuing a license to the Farbwerke Hoechst Company (which license was later transferred to the H. A. Metz Laboratories) granted authority to the Abbott Laboratories and the Rector Chemical Company to manufacture it under the U. S. patent after specimens submitted by these firms had been found satisfactory in the Association’s laboratory and at the Cornell Pharmacologic Laboratory.
When the first specimen of American made procain was sent to the American Medical Association Chemical Laboratory it was necessary to work out adequate standards. The standards were formulated on the basis of the novocain monograph in the German Pharmacopeia, 1910, Ed. 5, p. 363, Remedia “Hoechst,” p. 242, and New and Nonofficial Remedies, 1918, p. 32, and the work carried out in this laboratory.
The following description has been adopted for New and Nonofficial Remedies, 1919, and all specimens of procain were subjected to these tests:
Procain occurs in small colorless and odorless crystals, or a crystalline powder which if placed on the tongue produces a transient sense of numbness.
It melts at 153–155 C.[212]
One gm. of procain is soluble in 0.7 c.c. of water and in 20 c.c. of alcohol U. S. P. (95 per cent.) at 20 C. From the aqueous solution, which is neutral, alkali hydroxids and carbonates precipitate the free base in the form of a colorless oil, which soon congeals to a crystalline mass, but solutions of sodium bicarbonate are miscible with solutions of procain without producing precipitations or turbidity.
Dissolve 1 gm. of procain in water. Separate portions of the solution yield a white precipitate with potassium mercuric iodid solution, a white precipitate with mercuric chlorid test solution, a brown precipitate with iodin test solution and a yellow precipitate with picric acid test solution. Acidify a portion with dilute nitric acid. A white curdy precipitate is thrown down on the addition of silver nitrate test solution.
Dissolve about 0.1 gm. of procain in 5 c.c. of water, add 2 drops of dilute hydrochloric acid and 2 drops of sodium nitrite solution (10 per cent.) and mix with a solution of 0.2 gm. of betanaphthol in 10 c.c. of sodium hydroxid solution (10 per cent.). A scarlet red precipitate is thrown down.
To a solution of about 0.1 gm. of procain in 5 c.c. of water add 3 drops of dilute sulphuric acid and mix with 5 drops of potassium permanganate test solution. The violet color of the latter disappears immediately (distinction from cocain).
Dissolve about 0.1 gm. procain in 1 c.c. sulphuric acid U. S. P. The solution is colorless (organic impurities).
Dissolve 0.1 gm. of the salt in 10 c.c. of water and saturate with hydrogen sulphid. No coloration or precipitation occurs (salts of the heavy metals).
Incinerate about 0.5 gm. of procain accurately weighed. Not more than 0.1 per cent. of residue remains.
To obtain specimens representing the market supply, orders for the three brands of procain were placed with pharmaceutical firms in New York, Baltimore and San Francisco. The Baltimore and San Francisco firms supplied specimens of procain-novocain brand and procain-Rector brand but reported that the Abbott brand was not procurable. The New York correspondent was able to supply procain-Rector only. As the entire output of the Abbott Laboratories was stated to go to the government, specimens of this product were obtained through the surgeon-general of the army from the general purchasing office, Medical Dept., U. S. Army. The following specimens were obtained and examined:
1. Procain-Abbott, 6 specimens: The first specimen bore no serial number but the five later specimens were designated respectively, No. 89999, No. 89998, No. 89997, No. 89996, and No. 810995, representing batches from which shipments are to be made on contracts placed by the general purchasing office, Medical Department, U. S. Army, with the Abbott Laboratories of Chicago.
2. Procain-novocain brand, 4 specimens: These were designated respectively, A56, A57, A63, and A67. The first two specimens were labeled “Manufactured by the Farbwerke-Hoechst Co. at the H. A. Metz Laboratories.” The third specimen (not in original container) was labeled “H. A. Metz Laboratories” and the fourth was marked “Manufactured by the H. A. Metz Laboratories.”
3. Procain-Rector, 3 specimens: Each bore the statement “Manufactured by the Rector Chemical Company” but had no “lot number.”
From this examination it appears that all the specimens of procain received complied satisfactorily with all tests of identity and purity with the following exceptions: (1) One specimen of procain-Abbott had a melting point slightly below the permitted range; however, the last five specimens had the required melting point. (2) Five specimens of procain-Abbott and the last three specimens of procain-Rector were not entirely colorless, but had a yellow or light brown tinge.
The toxicity experiments, which were carried out by Dr. R. A. Hatcher of the Cornell Pharmacologic Laboratory, were reported as being satisfactory.
When the Council on Pharmacy and Chemistry referred the matter of the discolored specimens of procain to the Rector Chemical Company for explanation, the firm wrote that for a short time for some unexplainable reason its procain had been slightly yellowish in color, but that every batch had been carefully tested and found to answer all chemical requirements. The firm stated that the product which it had sent out for some time past had been white and yielded a colorless solution.
To a like inquiry from the Council the Abbott Laboratories replied that the five samples which were found discolored were products manufactured by the Rector Chemical Company and represented goods which it had purchased to assist in filling delayed orders, because the firm had found itself unable to keep pace with the demand on account of delay in securing needed apparatus. The firm submitted protocols to show that the procain made by it, by Rector and by Metz were of equal toxicity.
In the accompanying table the results of the examination are given. For comparison the findings for the specimens examined previously are included.
| Brand | Date Received | Color | Melting Point, C. | Ash % |
| Procain (Abbott), from Committee on Synthetic Drugs | 12/21/17 | White | 154–155 | None |
| Procain (Abbott), submitted to Council P. and C | 1/29/18 | White | 153.5–154.5 | None |
| Procain (Abbott), Gen. Pur. Off. U. S. Army | 8/31/18 | White | 152.5–153.5 | None |
| Procain (Abbott), Gen. Pur. Off. U. S. Army, No. 89999 | 9/30/18 | Slight brownish tint | 153.5–154.5 | None |
| Procain (Abbott), Gen. Pur. Off. U. S. Army, No. 89998 | 9/30/18 | Slight brownish tint | 153–154.5 | 0.005 |
| Procain (Abbott), Gen. Pur. Off. U. S. Army, No. 89997 | 10/ 8/18 | Slight brownish tint | 153–154 | None |
| Procain (Abbott), Gen. Pur. Off. U. S. Army, No. 89996 | 11/ 4/18 | Slight brownish tint | 153.5–154.5 | None |
| Procain (Abbott), Gen. Pur. Off. U. S. Army, No. 810995 | 11/ 4/18 | Slight brownish tint | 153.5–154.5 | None |
| Procain (Farbwerke Hoechst Co.), submitted to Council | 10/24/17 | White | 153–154 | None |
| Procain (Farbwerke Hoechst Co.), submitted to Council | 12/10/17 | White | 153–154.5 | None |
| Procain (Farbwerke Hoechst Co.), submitted to Council, market spec. “A56” | 8/ 9/18 | White | 153.5–154.5 | None |
| Procain (Farbwerke Hoechst Co.), submitted to Council, market spec. “A57” | 9/ 9/18 | White | 153.5–154.5 | None |
| Procain (H. A. Metz Lab.), market spec. “A63” | 8/23/18 | White | 153–154 | None |
| Procain (H. A. Metz Lab.), market spec. “A67” | 9/23/18 | White | 153–154 | 0.018 |
| Procain (Rector), from Com. on Synthetic Drugs | 12/18/17 | White | 153–154.5 | None |
| Procain (Rector), market spec. | 8/20/18 | Slight brownish tint | 153–155 | None |
| Procain (Rector), market spec. | 8/23/18 | Slight brownish tint | 153–155 | None |
| Procain (Rector), market spec. | 8/23/18 | Slight brownish tint | 153–154.5 | None |
So far as the evidence goes, there was nothing to indicate that the yellowish or brownish colored specimens of procain were seriously impure. On the contrary, the compliance with the chemical and toxicologic tests indicated that the color was due to an insignificant trace of some colored substance produced in the manufacturing process. In view of this, the Council considered the use of the discolored product to be justified in the present emergency, although it urged that the future supply of procain should be free from color and also comply to the tests of purity. It made this request in the interest of the medical and dental professions, which use the drug, and also in a desire that in the manufacture of synthetic drugs, the United States should occupy a high place.—(From The Journal A. M. A., Jan. 11, 1919, with additions.)