1336
INDUSTRIAL A N D ENGINEERING CHEMISTRY
Vol. 18, No. 12
Medicinals and Dyes By Ernest H. Volwiler ABBOTTLABORATORI~S, NORTH CHICAGO, ILL.
YES would continue to be manufactured and consumed, no matter whether medicinal products were being made or not; and drugs would be demanded and produced, whether or not the dye industry could supply the needed raw materials. As every one knows, however, these two branches of the industry are so closely allied, and to a great extent mutually interdependent, that each can be successful to the greatest degree only with the cooperation of the other. This relation is twofold. In the synthesis of medicinal c h d c a l s the sources and intermediates of the dye industry are used extensively: nitrobenzene, aniline, toluidines, bensaldahyde, toluene, phenol, naphthalenesulfonic acids, and a great variety of others are just as important to the drug as to the dye industry. In the second place, dyes themselves, during the last decade, have assumed a position of great importance as antiseptics, diagnostic aids, and for other purposes. Picric acid, the methyl violets, methylene blue, etc., were among the first of these antiseptic dyes, and to them have since been added a number of other important ones, such as acriflavine, an acridine dye, and mercurochrome, a mercurated fluorescein, both of these being very widely used antiseptics. Phenolsulfonphthalein and tetraiodophenolphthalein have assumed great importance as diagnostic aids; and biological stains are indispensable to the bacteriologist. The production of drugs is not nearly so dependent upon coal-tar products as is the manufacture of dyes. The word “dyes” has become almost synonymous with “coal tar,” but many medicinals of non-coal-tar origin are of great importance. The important drugs of nonaromatic origin include the general anesthetics, ether and chloroform, and the newer ones such as ethylene and propylene; nearly all hypnotics in common use, such as barbital, neonal, amytal, ipral, dial, sulfonal, chloral hydrate, chloretone, etc.; many antiseptics, including iodine and its derivatives, bromine as dibromin (dibromobarbituric acid), and chlorine as the hypochlorites; mercuric chloride, boric acid, and many othors; inorganic chlorides, bromides, and iodides for internal administration; colloidal silver and silver halides; worm destroyers, such as carbon tetrachloride and tetrachloroethylene; hexamethylenetetramine; and many products of other types. Economic Status of Industry We are prone to think of the production and use of dyes in 100-pound or ton lots, and of drugs in 1-gram or pound lots. However, the tonnage and value of drugs is by no means infinitesimally small. The census report for 1925 shows that during last year 86 million pounds of finished dyes were produced in the United States, of which 79 million pounds were sold for 37 million dollars, equivalent to $0.466 per pound. During the same year, the 3l/3 million pounds of synthetic medicinals which were produced and sold had a value of 61/s million dollars, or an average of almost 2 dollars per pound. In other words, the amount of synthetic medicinals sold was over 4 per cent of the amount of dyes, while the value of the medicinals was 17 per cent of that of the dyes. This represents, of course, only the synthetic drugs of coal-tar origin, which constitute but a portion of the fiynthetic drugs; to these are to be added the nonsynthetic products, such as alkaloids and vegetable extracts, glandular products, etc.
D
A committee of the AMERICAN CHEM~CAL SOCIETY a halfdozen years ago estimated that the drug bill of the nation is in the neighborhood of 500 million dollars annually; of this amount about 300 million dollars are spent for so-called patent medicines, which in many cases contain no synthetic ingredients. The sum involved in the finished drugs that are sold annually is both stupendous and startling, and is far from insignificant even when compared with the value of textiles, in which dyes find their principal outlet. From about three thousand drug items which were on the market in this country thirty years ago, the number has grown to over fifty thousand items today, out of all proportion to the amount of research devoted to the subject. In volume, two of the leading synthetic medicinal products sold in 1925 were aspirin, 1,476,000pounds, worth $1,025,000, and acetanilide, 364,000 pounds worth $113,000. The figures for 1925 for most of the other individual items are not yet available, but the census for 1924 showed sodium salicylate to be second to aspirin, with sales of approximately 400,000 pounds, valued a t $140,000;phenolsulfonates, 200,000 pounds, and chloramine, whose amount was not given. In 1925, 60,000 pounds cinchophen were produced, worth almost $400,000. Other large selling items include salol, acetophenetidine, phenolphthalein, and medicinal dyes. It should be mentioned that the above values are based upon bulk prices; sold a t retail, in pharmaceutical preparations, the amounts given would be considerably greater. Although small in volume, the arsphenamines are among the leaders in money value. In 1925, the sales, which are ordinarily in small quantities, were approximately 350 pounds arsphenamine, worth $103,000; 3500 pounds neoarsphenamine, worth $1,125,000; and 800 pounds sulfarsphenamine, worth $330,000. The arsphenamines sold during 1925 represented a value of more than 1.5 million dollars, and were dispensed in about two million doses. These products are of very great economic as well as monetary importance. The dose is small, and the amount manufactured is very small, compared to such an item as aspirin; 5000 pounds would probably include all the arsphenamines manufactured and consumed annually in this country. Dyes as Therapeutic Agents Dyes as therapeutic agents have received a great deal of attention during the last twenty years, In addition to acriflavine and mercurochrome, already mentioned, and the methyl violets, including gentian violet, crystal violet, and methyl violet, there are quite a few others, such as methylene blue, malachite green, picric acid, trypan blue, trypan red, and afridol violet; as well as biological stains and the important diagnostic dyes and colors such as tetraiodophenolphthalein and phenolsulfonphthalein. Ehrlich’s proposal of his chemo-receptor theory, whether it is sound or not, has had much to do also with the interest in the therapeutic applications of dyes. The general dye structures seem to be of value in the selective affinities which medicinal substances, such as antiseptics, seem to have for the bacteria which it is aimed to kill. However, except in the cases of biological stains and certain diagnostic dyes whose applications depend upon color, there seems to be no reason why other products should not be found or developed which would have all the desirable therapeutic properties without the staining properties. That this ia
December, 1926
INDUSTRIAL A N D ENGINEERING CHEMISTRY
possible is indicated by the development of powerful organism-killing drugs, which resemble dyes in that they are complex chromophore-bearing molecules, but which lack the auxochrome groups. The outstanding representative of this class of substances is the much heralded and discussed remedy for sleeping sickness known as Bayer 205, which is presumably the same as Fourneau 309. Bayer 205 was developed primarily as the result of a desire to avoid the objectionable staining properties of dyes of the trypan series, which atherwise seemed promising. There is little doubt that this borderland of dye chemistry will in the future receive considerable attention. Developments of a Decade The drug industry ten years ago, so far as manufacturing was concerned, had to content itself mainly with the prepalration of alkaloidal products and other active principles of plants. The manufacture of synthetic medicinals was relatively unimportant. Compare the situation today, when the synthetic medicinals manufactured constitute a large proportion of the total drugs sold. There are very few important synthetic drugs known today which are not being manufactured in the United States, or whose analogs or equivalents are not being produced. But this is not the most important point. Ten or twenty years from now, the condition of the American industry will depend not so much upon how many competitive items of today our manufacturers are supplying, but upon how many
1337
valuable new contributions have been produced by our research in the medicinal chemical field, The outlook a t present is optimistic, for not only have the manufacturers themselves realized that the future of the industry lies in the strenuous development of the research side of the business, but, of equal significance, many of the best university workers have turned their attention and their abilities as chemists and biochemists to this field, with significant gain to the industry. No drug-manufacturing establishment of any consequence today is without a chemical research staff; and it is doubtful whether any other chemical industry is spending more money and effort upon the development of new and superior products in its field. A partial list of American contributions of new and valuable synthetic medicinals, all of which are developments of the last decade, is given below: General anesthetics: ethylene, propylene, butylene Local anesthetics: apothesine, butyn, butesin, butesin picrate Benzyl esters: benzoate, stearate, fumarate, succinate Chloramines: chloramine, dichloramine, halazone Antiseptics : dibromin, hexyl resorcinol Hypnotics: neonal, amytal, ipral Arsenic compounds: sulfarsphenamine, tryparsamide Mercury compounds: mercurochrome, mercurosal, metaphen Bismuth compounds: tartrate, salicylate, and others Dyes: tetraiodophenolphthalein, phenolsulfonphthalein
Probably no other country has made contributions of new products during this decade which are either more numerous or, in the aggregate, so valuable.
Aniline Dyes in the Treatment of Infection By John W. Churchman’ CORNELL ~JNIVERSXTY MEDICAL COLLEGE, NEWYORK,N. Y .
N IDLE question not infrequently put to those working in this field--l‘Will an ideal antiseptic ever be discovered?”--suggests two other questions not so idle since they strike a t the heart of the problems with which t h e investigation of the therapeutic possibilities of the aniline dyes is concerned. It leads us to ask ourselves, first, what are the defects of the antiseptics at present in use; and second, what would be the characteristics of an ideal antiseptic? Certainly there is no lack of chemical agents which are capable of killing bacteria. The fundamental objection to them is twofold. Either they are so highly toxic to all forms of protoplasm as to find only restricted application in therapeutics, or, because of their toxicity or for other reasons, they cannot be brought into contact with the bacteria which must be reached. An ideal antiseptic would therefore first of all be a substance which, though strongly antagonistic to bacteria, would be almost or quite non-toxic to animal cells in doses lethal for microorganisms. The use of such a substance would not be restricted to surface infections, but could be introduced into the tissues themselves or even into the cirqculation and thus really reach the bacteria which are causing the trouble. An ideal antiseptic would also have powers of penetration so that it could distribute itself beyond the point of application, or, if injected into the blood stream, percolate throughout the tissues. An ideal antiseptic would not cause any reaction of coagulation in the animal cells or humors which would impede its own progress, as bichloride of mercury, for example, does. Nor would its bactericidal activities be hindered by the
A
1
Professor of Experimental Therapeutics.
presence of serum or other animal substance in whose presence the agent must of necessity function. An ideal antiseptic would persist in the tissues long enough to accomplish its purpose and be quickly eliminated after its bactericidal work was over. It would be equally effective against all types of bacteria, against the heat-resistant spore as well as against the delicate gonococcus. It would, of course, be fatuous to hope and rash to predict that any one substance will ever be found combining all these desirable qualities. Yet the fact that investigation has actually succeeded in overcoming some of the apparently insuperable difficulties, and in providing substances which in some respects begin to approach our ideal, justifies a certain optimism as to the remaining obstacles. In this struggle to put the treatment of infection on a sound and scientific basis investigation of the bactericidal properties of the aniline dyes has played an important part, and it is within the last decade that they have aroused most widespread interest. The outbreak of the war stimulated-as wars always stimulate-an interest in the treatment of infected wounds, not particularly active in years of peace; and from 1914 on, the painstaking investigations of preceding years were precipitated by the acid of necessity as the salt of results. History of Aniline Dyes in Medicine
It is, of course, never possible in science-since the advance of one year issues always from the work of the preceding years-thus to segregate any one decade, and if we wish to date the birth of aniline dyes as therapeutic agents we must go back of 1914 many years. We must go back to Ehrlich’s observation on the selective activity of methylene blue made
