Massengill's Elixir Sulfanilamide: Inspiration, Formula, and Distribution
[W]e are here concerned with a preparation not standardized by any reliable agency, semisecret in composition and apparently hastily rushed into the market to meet an overenthusiastic reception of a new remedy.
———Journal of the American Medical Association, October 23, 1937
In June 1937, drug salesmen for the S. E. Massengill Co. of Bristol, Tennessee, reported demand for a liquid preparation of the new, wildly popular antibiotic sulfanilamide [1], which was currently sold in capsule and tablet forms by several US pharmaceutical interests, including the Massengill company.
Only 5 years earlier, a corporate chemist for the German conglomerate I. G. Farben, Gerhard Domagk (left), had demonstrated the life-saving properties of a related compound, an azo dye trade-named Prontosil, in streptococcal-infected mice [2]. One year later, a German physician reported dramatic recovery of an infant with staphylcoccal septicemia after receiving Prontosil [3], and Domagk successfully used the agent on his own daughter, who was near death with streptococcal septicemia [4].
Then in 1935, French investigators showed that the active metabolite of the patented Prontosil was actually sulfanilamide—a compound that had been synthesized by an Austrian chemist more than 25 years earlier [5,6]. Consequently sulfanilamide was in the public domain and available for general production. Quick, follow-up studies of Prontosil and sulfanilamide by physicians in London and at Johns Hopkins established the equivalence of the 2 agents in human streptococcal infections [7,8].
But the real enthusiasm for sulfanilamide would be generated by a high-profile case study. Shortly before the Hopkins work was printed in the medical literature, news reports were buzzing with the recuperation of the American President's son, Franklin D. Roosevelt, Jr., from a serious throat and sinus infection. While hospitalized at the Massachusetts General Hospital in December 1936, the junior Roosevelt was treated with sulfanilamide tablets (branded as Prontylin by the Winthrop Chemical Co., NY) in a near last-ditch effort. The dramatic recovery of the President's son after treatment with the antibiotic was chronicled faithfully by Associated Press reports in the country's newspapers, including the New York Times [9].
Scientific endorsement and the glowing anecdoctal publicity for sulfaniladmide fueled widespread zeal for the drug among physicians and the American public. And zeal gave way to near fanaticism when medical studies described sulfanilamide's efficacy in cases of gonorrhea. News reports, overstating the medical findings, startled some readers by broadcasting that the drug was "the best thing ever for gonorrhea" and cured the veneral disease in 48 hours [10].
Soon the American market was flooded with several competitive brands of the antibiotic, including Prontosil (the original Farben drug), sulfanilamide, and several brand names for identical preparations. In May 1937, the AMA's Council on Pharmacy and Chemistry attempted to avert confusion by adopting "sulfanilamide" as the preferred nonproprietary term for the drug and stated, "It is regretted that certain firms in America are using proprietary names [for sulfanilamide]" [11].
Established in 1905, the Council's job was to determine standards for pharmaceutical manufacturing and advertising and to eradicate quackery [12]. In the absence of any federal legislation that required proof of safety, efficacy, or advertising claims for pharmaceutical products, the Council, in 1937, was the leading authority that reviewed and endorsed or dismissed commercial medicines that were submitted for inclusion in its widely read pharmacopoeia, New and Nonofficial Remedies. In July 1937, the Council published its "Examination of Certain American Brands of Sulfanilamide," which included assessments of products from the major American pharmaceutical firms Eli Lilly, Merck, Parke Davis, and E. R. Squibb & Sons [13]. The preparations were in powder, tablet, and injectable forms; no orally administered solution existed. The Council advised that the drug "has the apparent disadvantage of being relatively insoluble" and has a tendency to crystallize out of solution [11].
In the wake of continued enthusiasm for the drug, an editorial in the October 2nd issue of the AMA's journal—while acknowledging that the drug was "truly remarkable"—warned against its indiscriminate use [14]. Toxic reactions, including dermatitits, photosensitization of the skin, and hemoglobin abnormalities, had been reported. Specifically some cases of self-medication for venereal disease were associated with severe drug reactions, which necessitated hospitalization. (Although sulfanilamide was largely dispensed by means of prescription in the United States, no federal law in 1937 prevented pharmacists from providing the drug directly to the patient, on request.) The editorial warned, "Responsibility lies considerably with pharmacists who are willing to sell dangerous drugs to anybody over the counter."
In 1937, the S. E. Massengill Company introduced its own versions of sulfanilamide tablets and capsules for human consumption to the US market [15]. Originally a small family operation, the Bristol-based company began manufacturing nonproprietary pharmaceuticals for regional distribution at the end of the 19th century. Since 1916, the company had been led by one of its founding brothers, president Samuel E. Massengill, a proud and locally respected descendant of East Tennessee's original Massengill settlers and a 1899 medical graduate of the University of Nashville.
Steady growth of Massengill's company during the early 20th century, from a 1-room laboratory to a 4-building plant on "spacious grounds" in the piedmont city of Bristol, eventually led to the establishment of a manufacturing and distribution branch in Kansas City, Missouri, and warehouses in New York City and San Francisco. Sales offices were also established in Hawaii and Puerto Rico. Massengill himself boasted that his company was "the largest pharmaceutical manufacturer for the entire South." At the end of 1936, net annual sales were recorded at more than $1.6 million (more than $24 million in 2007 USD) [16].
The firm's 1936 catalog, which offered hundreds of tablets, capsules, elixirs, or ointments, reads like a drug compendium on the cusp of modern medicine. Products like antimony wine, mercurial ointment, and rhubarb elixir share index space with aspirin, novocaine, and phenobarbital. The catalog promised," Every step in the manufacture of our general line of pharmaceuticals is under the supervision of skilled workmen and strict chemical control, and the physician may rely upon our products for prompt and full therapeutic effect" [17].
In fact, the FDA had brought charges against the S. E. Massengill Company on 3 previous occasions, all during the 1930s. The cases, however, were not unusual in character or frequency given the nature of the pharmaceutical industry at the time. In 1 case, the company's Fluidextract of Colchicum, a gout treatment, was found to be overstrength; in another, the strenth of its Tincture of Aconite was determined to be below its stated concentration. Fines of $250 and $150, respectively, were paid by the company for these 2 infractions. In the third instance, the seizure of Massengill's Elixir Terpin Hydrate and Codeine, a steadfast cough suppressant, was based on charges of adulturation and misbranding. The case was successfully prosecuted in court [18].
Despite the fact that sulfonilamide was relatively insoluble in the typical pharmaceutical solvents, Massengill's head chemist, Harold Cole Watkins, was not deterred [1]. The son of a Maine newspaper publisher, Watkins had graduated from the University of Michigan in 1900 with a degree in pharmaceutical chemistry and thereafter had led an itinerant career in the drug industry. He performed laboratory work for Merck and was employed briefly in "various wholesale and pharmaceutical houses" [19]. US census records show that Watkins worked as a chemist in Spokane, Washington, in 1910, and in Brooklyn, New York, in 1920 (where he lived with his Norweigian wife, Marie, and their 4-year-old son, who was born in California). Census records from 1930 suggest that Watkins may have tried his luck at farming in the town of Benton in northeastern Pennsylvania (with Marie and their 2 sons). This brief career change may have had something to do with the fact that Watkins (as Watkins Laboratories) had been cited by the Solicitor of the Post Office Department on charges of fraud the previous year. Records indicate that, on October 30, 1929, the chemist agreed to discontinue the promotion of a weight-loss medicine, which he had claimed produced a "perfect slenderness" and a "trim, youthful, athletic look" [1].
In any event, 5 years later, Watkins moved his family to the relatively cloistered city of Bristol to join the Massengill company as head chemist. He was 55. In the summer of 1937, he set out to find a liquid vehicle for sulfonilamide at the company and turned his attention to the glycols. He based this decision on their chemical similarity to glycerine, a commonly used solvent in liquid pharmaceuticals [19]. He soon discovered that he could dissolve as many as 75 grains of sulfanilamide in 1 fluid ounce of clear, odorless diethylene glycol. However, the resultant solution tended to separate on chilling, so he reduced the antibiotic concentration to 40 grains per fluid ounce and quickly settled on the following mass-quantity recipe for a stable product [1]:
Sulfanilamide, 58½ pounds
Elixir flavor, 1 gallon
Raspberry extract, 1 pint
Saccharine, soluble, 1 pound
Amaranth solution, 1-16, 1½ pints [a synethic, bright red, azo dye, which was presumably added to resemble the color of the patented Prontosil]
Caramel, 2 fluid ounces
Diethylene glycol, 60 gallons
Water q. s., 80 gallons
No animal or clinical tests were conducted by Watkins or the company at large to determine the toxicity of the individual ingredients or that of the combination. Any possible effects of diethylene glycol on sulfanilamide were also left to chance. The company's sole process for quality control consisted of checking the elixir for its appearance, flavor, and fragrance. The Acting Chief of FDA's Drug Division, Theodore Klumpp, bluntly described the company's elixir development: "[T]he only criteria of its safety and value as a medicine were that the ingredients were mixed, did not immediately explode, and the color, taste and smell of the product were satisfactory to their so-called control department" [20].
Watkins was evidently unaware that, for several years, the FDA had advised against the use of glycol solvents in foods, on the basis of limited safety data [21]. He was also presumably ignorant of 2 published reports, one in 1931 and one in early 1937, which described the lethality of diethylene glycol in experimental animals [22,23].
In late August, Watkins's formula for Massengill's Elixir Sulfanilamide was sent to the company's Kansas City branch in Missouri (208-214 W. 19th St.), where 40 gallons of the product were mixed in a large "stone jar" on September 20 [24,25]. Supplied instructions were remarkably simple: "Dissolve sulfanilamide in the diethylene glycol, add the other ingredients and mix" [25]. Sulfanilamide was obtained by the company from Ganes Chemical Works in New York, and diethylene glycol was purchased (at 23 cents per gallon) from Carbide & Chemical Corporation in West Virginia. No assay was made of the finished product, despite the fact that tests for sulfonilamide in blood and urine had been described several months earlier by pharmacologists at Johns Hopkins in the Journal of the AMA [18]. Another batch of 40 gallons was produced by Watkins himself at the company's Bristol plant, which began shipping the product to its San Francisco and New York branches on September 4 [1,26,27]. Two more batches of 80 gallons each were manufactured at Bristol; most of these batches also went into distribution.
Commercial lots from 1 pint to 1 gallon were shipped from Massengill's Bristol and Kansas City plants, as well as from its New York and San Francisco sales branches. In all, 633 shipments were made. The product label (example below) failed to list the product's ingredients, other than sulfanilamide. In addition, a total of 671 physicians' or salesmen's samples were sent from Bristol or Kansas City.* In time with the mass distribution, a promotional brochure for physicians announced, "Our research department has just released an Elixir Sulfanilamide...It is ideal for your patients who can take liquids—but little else. Also, it is not unpleasant to take, so is suitable for children" [28].
Both commercial and sample lots were distributed nationwide through October 15, 1937—the same day that Tulsa physicians telegraphed the AMA to convey their autopsy findings from 5 children who had consumed the elixir.
* The company employed approximately 200 salesmen.
1. Wallace HA. Report of the Secretary of Agriculture on the deaths due to Elixir-Sulfanilamide-Massengill. November 16, 1937.
2. Domagk G. Ein beitrag sur chemotherapie der bakteriellen infektionen. Deutsche Medizinische Wochenschraft. 1935;xx:250-253. Domagk's company, I. G. Farben, received a German patent for Prontosil on December 25, 1932. However, the patent was not published until January 1935, for reasons unclear. One month later, Domagk's landmark article was printed. The author offered clear credit to his company above the article's title ("Aus den Forschungslaboratorien der I. G. Fabenindustrie...") and little explanation for Prontosil's mechanism of antibacterial action, only writing that the agent possibly bolstered the immune system. For this work, Domagk would receive the Nobel Prize for Physiology or Medicine in 1939; however, he was prevented from accepting the prize at the time by the Nazi government.
3. Foerster R. Sepsis im anschluß an ausgedehnte periporitis: heilung durch streptozon. Zentralbl Haut Geschlechtskr Grenzgeb. 1933;45:549-550.
4. Dictionary of Scientific Biography. 1972:4:153-156.
5. Trefouel J, Trefouel J, Mitti F, Bovet D. Activite due p-aminophenylsulfamide sur les infections streptococciques expeimentales de la souris et du lapin. C R Seances Soc Biol Fil. 1935:120:756-760. English bacteriologist Ronald Hare—mistrusting German pharmaceutical development—argued that Domagk, in fact, knew in 1932 that the no-longer-patented sulfanilamide was the active ingredient in Prontosil. Hare further claimed that the intervening time between Domagk's initial experiments and his 1935 publication was sucked up by the creation and testing of a patentable analog of sulfanilamide (ie, Prontosil) for the interests of his company, I. G. Farben. (See Dowling HF. Fighting Infection: Conquests of the Twentieth Century. Cambridge, Mass.: Harvard University Press; 1977:108-124.)
6. Gelmo P. Uber sulfamide der p-amidobenzolsulfonsaure. J Praktische Chemie. 1908;77:369-382.
7. Colebrook L, Kenny M. Treatment of human peurperal infections, and of experimental infections in mice, with Prontosil. Lancet. 1936;June 6:1279-1286.
8. Long PH, Bliss EA. Para-amino-benzene-sulfonamide and its derivatives. J Am Med Assoc. 1937;108:32-37. For a contemporaneous history of the development of sulfanilamide and its introduction into the United States, see Long PH, Bliss EA. The historical aspects of sulfanilamide therapy. In: The Clinical and Experimental Use of Sulfanilamide, Sulfapyradine and Allied Compounds. New York, NY: MacMillan Company; 1939:1-13.
9. F D Roosevelt Jr is in
10. Drug and Cosmetic Industry. July 1937.
11. Council on Pharmacy and Chemistry. Sulfonilamide and related compounds. J Am Med Assoc. 1937;108:1888-1890.
12. Smith A. The Council on Pharmcy and Chemistry and the Chemical Laboratory. In: Fishbein M, ed. A History of the American Medical Association, 1847 to 1947. Philadelphia, Pa.: W. B. Saunders Co. 1947:865-886. Note that the federal Food and Drugs Act of 1906, still in effect in 1937, merely required manufacturers to accurately label and brand medicinal products that were intended for interstate commerce.
13. The Chemical Laboratory. Examination of certain American brands of sulfanilamide. J Am Med Assoc. 1937;109:353-359.
14. Sulfonilamide--a warning [editorial]. J Am Med Assoc. 1937;109:1128.
15. Masengill Brothers Company and the S. E. Massengill Company, 1897-1971. Knoxville, Tenn.: Tennessee Valley Publishing; 1996.
16. Massengill, Samuel Evans. In: National Cyclopaedia of American Biography. Vol 34. New York City, NY: James T. White and Company; 1948; FDA records. Company assessment by Dun & Bradstreet, Inc. November 8, 1937.
17. Complete Catalog of the Products of the Laboratories of the S. E. Massengill Company. Bristol, Tenn.: King Printing Co.; 1936.
18. Citations of Notices of Judgment Under the Food and Drugs Act (23228 [1935], 27136 [1937], 24029 [1935]) and FDA correspondence (George Larrick to Central District Chief, November 21, 1934). In: Parascandola J, Whorton JC, eds. Chemistry and Modern Society: Historical Essays in Honor of Aaron J. Inde. Washington, DC: American Chemical Society; 1983:105-125.
19. Citations of FDA reports in Young JH. Sulfanilamide and diethylene glycol. In: Parascandola J, Whorton JC, eds. Chemistry and Modern Society: Historical Essays in Honor of Aaron J. Inde. Washington, DC: American Chemical Society; 1983:105-125. Young writes, "During the depression, Watkins had been idle some of the time, before joining Massengill."
20. FDA correspondence. Theodore O. Klumpp to Perrin H. Long. November 1, 1937. Klumpp also wrote, "It is also a sad but true fact that the chemist told me that they could not assay the sulfanilamid because there were no assay methods known. This might lead Doctor Marshall to wonder what he has been doing with his time all these months." Presumably Klumpp is referring to pharmacologist Eli Kennerly Marshall, PhD, of Johns Hopkins, who was lead author of "Para-aminobenzenesulfonamide: absorption and excretion--method of determination in urine and blood." The article, describing assays for sulfonamide, was printed several months earlier, in the March 20 issue of the Journal of the AMA (1937;108:953-956).
21. FDA correspondence. July 26, 1938.
22. von Oettingen WF, Jirouch EA. Pharmacology of ethylene glycol and some of its derivatives. J Pharmacol Exp Ther. 1931;42:355-372.
23. Haag HB, Ambrose AM. Studies on the physiological effect of diethylene glycol. J Pharmacol Exp Ther. 1937;59:93-100.
24. FDA correspondence: October 18, 1937, and Leo J. Cramer to Baltimore Station Chief. October 20, 1937. According to an FDA investigative report of the distribution of sulfanilamide (from FDA inspector Hugh F. Smyser, November 11, 1937, re interview with Otto B. May), the antibiotic was manufactured by heating acetanilid with chlorsulphonic acid, drowning in flake ice, and filtering in crocks. "The resulting paste is charged with ammonia, neutralized with sulfuric acid, filtered and charged with hydrochloric acid and neutralized with sodium hydroxide and filtered. Instead of recrystallizing twice as a matter of routine, the product is recrystallized from hot water repeatedly until two successive recrystallizations give a constant melting point. Three recrystallizations are the usual number."
25. FDA correspondence. Letter from Leo J. Cramer to Chief, Baltimore Station. October 21, 1937. The letter provides an inventory of samples sent from Massengill's Kansas City branch to the FDA's Baltimore laboratory for testing.
26. FDA correspondence. W. G. Campbell to Central District Chief. November 12, 1937.
27. FDA memorandum. Charles Hyak. October 21, 1937.
28. Citation of Massengill brochure in Young JH. Sulfanilamide and diethylene glycol. In: Parascandola J, Whorton JC, eds. Chemistry and Modern Society: Historical Essays in Honor of Aaron J. Inde. Washington, DC: American Chemical Society; 1983:105-125. For Massengill's salesmen's talking points, see FDA correspondence. J. F. Earnshaw to Baltimore Station Chief. October 19, 1937.
Photo of Gerhard Domagk from nobelprize.org.
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