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alcoholic potassium hydroxide; stopper and weigh. Make up solution to volume with 95 per cent alcohol a t 20” C., pipet out a 5-cc. aliquot, and add to a mixture of 50 cc. water, 50 cc. 3 per cent hydrogen peroxide, and 10 cc. 10 per cent potassium hydroxide in a beaker. Heat on the steam bath for 1 hour, acidify with hydrochloric acid, filter, heat the filtrate to boiling, and add 10 cc. 10 per cent barium chloride drop by drop. After standing overnight filter the barium sulfate on an ashless filter paper, wash with hot water, and ignite in a platinum crucible. Add two drops of concentrated sulfuric acid to the cooled crucible, fume off the acid, heat the crucible to redness, then cool in a desiccator and weigh. Run a blank determination on the reagents alone. Bas04 X 0.16306 = CSt Results EMULSION No. 1
CSz present P e r cent 77.43
,
EMULSION No. 2
CSz found
CSa present
CSz found
Pev cent 74.81 75.13 74.90 76.19
P e r cent 74.97
P e r cent 71.30 71.30 70.99 71.34
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The average recovery of carbon disulfide by this method is about 96 per cent, assuming 100 per cent purity for the carbon disulfide used; however, analyses of the pure carbon disulfide alone showed about 98 per cent CSz. Almost faultless checks can be obtained in duplicate analyses on the same emulsion. This method estimates as carbon disulfide any sulfur present in an emulsion in any form which will be converted to sulfate by an alkaline peroxide solution. It is doubtful if any commercial carbon disulfide emulsion will contain more than a negligible amount of non-carbon disulfide sulfur. Of the two soap solutions used in making the emulsions employed in this work, the rosin-fish oil soap in emulsion No. 1 contained 0.10 per cent sulfur, corresponding to 0.02 per cent sulfur in the emulsion, while the rosin-oleic acid soap in emulsion No. 2 contained 0.00 per cent sulfur. For this reason it was not thought necessary to work out a method for determining non-carbon disulfide sulfur in these emulsions. Not all of the carbon disulfide is necessarily present in the free state in the finished emulsion; some of it may be combined, with the rosin or otherwise, and the method does not distinguish between that present in the combined and uncombined states,
AMERICAN CHEMICAL INDUSTRIES Parke, Davis & Company
T
HE production of medicinal substances on a large scale
is a relatively modern industry. Up t o the middle of the last century i t had been the almost universal custom for each pharmacist or apothecary or chemist, as he was variously known in different countries, t o prepare for himself such substances or compounds as he needed, but about this time the idea of centralized manufacture of medicinal preparations was beginning t o take root. In 1862 Samuel P. Duffield, a retail druggist in Detroit,.began t o make a number of preparations in larger amounts than required for his own use and sell them t o other pharmacists. Seeing the possibility of a larger business which could render useful service t o many and probably become financially profitable, Hervey C. Parke cast his lot with Dr. Duffield and there was founded, on October 26, 1866, the partnership of Duffield, Parke & Company. This is considered the birth of the present business. In January, 1869, A. F. Jennings bought the interest of Dr. Duffield and the firm became Parke, Jennings & Company, with Geo. S. Davis as one of the company. On November 16, 1871, Dr. Jennings retired from the firm and i t became Parke, Davis & Company, a co-partnership. Thus it continued for a few years, but with the business developing rapidly i t seemed desirable to perpetuate i t in some better form; so on January 14, 1875, i t was incorporated With a capital stock of $125,000, of which $81,950 was paid in. Today the business is represented by five million shares of no-par-value stock selling on the market a t about $30 per share. Besides the main laboratories in Detroit, there are also manufacturing laboratories in Walkerville, Canada; London, England; Syndey, Australia; Rio de Janeiro, Brazil; Santiago, Chile; and Havana, Cuba. There are fifteen branch offices in the United States, three in Canada, and ten in various foreign countries. In fact, there is practically no place in the world t o which the medicinal products of Parke, Davis & Company d o not reach.
The present directors of the business are 0. W. Smith, president; N. H. F. McLeod, secretary and treasurer; David Whitney, A. H. Buhl, and Jerome Remick, vice presidents; I,. B. Hayward, superintendent of manufacturing; and Henry Ledyard.
Guiding Principles In the development of great enterprises permanence and virility are determined not so much by personalities as by principles. Outstanding personalities may come and go, but the dominating principles whereby they express in business the best of their abilities may continually develop and give t o that business the ardor and strength of perpetual youthfulness. In the early days of Parke, Davis & Company the desire for immediate profit was made subservient to the hope of future growth, and the principle of being satisfied with nothing but the best that science could produce became the cornerstone of this commercial structure. The ideas which imbued the founders of the business, and which have been perpetuated through changing generations of control and ownership, may well be illustrated by a quotation from a little leaflet printed many years ago when the firm was very young, entitled “Our Creed and Code:” We believe that in combating disease only the best quality of drugs is permissible and that to their manipulation should be applied the highest scientific skill. We believe t h a t the issuing of inferior medicines of any kind is unjustifiable from any point of view. We believe in standing solely on the intrinsic merits of our preparations and in making no false pretenses; in doing the best that scientific knowledge and skill will accomplish and in doing it honestly and faithfully. We believe in working fully in harmony with our pharmacal and medical friends in gratefully accepting any suggestions t h a t may tend to our mutual profit. Our watchwords are Purity, Accuracy, Reliability. This same spirit permeates the whole organization at the present time, and when it is noted that the majority of shareholders,
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conceive that early t o a total of over steps taken in this one thousand men direction by Parke, and women, are also Davis & Company employees of the were criticized and company, the o p p o s e d . Being p o t e n c y of that convinced t h a t spirit will be better there was great variunderstood. Long ation in strength of years of service by drug extracts t h a t those in both high might be prevented, and humble posiendeavors were tions gives to Parke, made to accomplish Davis & Company this. I n September, an esprit de corps of 1879, t h e r e apimmeasurable value peared from their and assurance that laboratories the first replacements in the standardized medicr a n k s s h a l l fully inal drug product carry on, and inon the market-a deed improve, the p r e p a r a t i o n of t r a d i t i o n s of the e r g o t , k n o w n as past. Not long ago, at a dinner a t which Liquor Ergotae Pur& Original Laboratory ficatus, which was were present fortybrought to a unifour of the chief exform standard of strength by a chemical assay. At that time ecutives from various divisions of the organization in the United it was supposed t h t ergot owed its activity to sclerotic acid States and Canada, it was discovered that the average length and a crude estimation of this was made by precipitation with of service was twenty-two years, with two, one of whom was lead acetate. The standard was this: “Ten cubic centimeters the president, 0. W. Smith, having reached forty years of conof the normal liquid require for complete precipitation 100 cc. tinuous service. of a solution containing 1 per cent of lead acetate.” With the Beginnings of Research retrospect of nearly fifty years’ experience, this seems almost laughable, but it wiis the best the knowledge of the time afFrom the beginning the desire t o investigate new drugs, t o forded and was a step toward the dreams of the future that develop new methods of manufacture, to produce new medicinal were beginning t o take form. substances, and in every way to advance pharmaceutical knowlThus began a systematic study, with the result that in Febedge was a n effective spur t o progress. ruary, 1883, there was publicly announced a list of twenty About 1874 a systematic search was begun for unknown or “normal liquids” which were actually fluid extracts standardized little-used plants that might prove of medicinal value, and for a number of years much time and money were spent in spite by some form of chemical assay. The man responsible for establishing methods for their control was A. B. Lyons. The of the fact t h a t the influence of the panic of 1873 was still strongly process chiefly employed for determination of alkaloids was felt and the financial outlook was anything but pleasing. If the now obsolete method of titration of separated alkaloids by a new plant was heard of through correspondence or published Mayer’s reagent. The work was so well done that alkaloidal papers, i t was immediately investigated; and if it gave promise standards then adopted have in most cases been little changed of being really useful, preparations of i t were made and disin the later editions of the U. S. Pharmacopeia, even though tributed t o physicians with all available information. new and vastly better methods of assay are in vogue. The I n the course of these investigations representatives of the work of this sort has developed tremendously and is now unicompany explored the northwestern United States, British versally recognized as a necessity, but the standardization work Columbia, and Mexico. An intrepid explorer, Count Hansen, instituted by this firm, followed in later years by a host of helpers, was sent t o the Fiji Islands and brought back a supply of the has always kept far in advance of the official requirements of drug tonga. Another representative going to the West Indies the various pharmacopeias. returned with Jamaica dogwood and other drugs. A special I n 1894 the first fluid extract to be standardized by a physiorepresentative in 1881 made a trip from the mouth of the Amazon logical method appeared from these laboratories. It is an interRiver about two thousand five hundred miles into the interior, esting coincidence that this was the same fluid extract t h a t while another proceeded inland from Buenos Aires, across the had first been standardized by a chemical assay-viz., fluid Andes, t o the Pacific Coast. In 1885, H. H. Rusby made a n extensive trip in South America, bringing back much scierltific extract of ergot. Following this at intervals came physiologically standardized preparations of digitalis, strophanthus, cannainformation and, among many other plants, the drugs cocillana bis, and others, until now physiologic methods of a wide variety and pichi and large supplies of coca from Peru. have extensive application. Altogether in these early years this company was responsible for introducing t o American medicine forty-eight new drugs, Scientific a n d M a n u f a c t u r i n g Developments many of which are still widely used and recognized in the United States Pharmacopeia, while one, cascara sagrada bark, has A simple catalog of all the contributions of the technical and achieved a n extent of use equaled by but few drugs in the entire scientific staff of this company to progress in medicinal preparamateria medica. tions and development of pharmaceutical and biological manufacturing would alone far exceed the limits of this article, so Standardization only a few subjects, illustrative of numerous larger fields, may I n view of the present-day endeavors to establish and maintain here be touched on in brief outline. accurate standards for medicinal products, it is difficult to Methods for more thorough extraction of vegetable drugs
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INDUSTRIAL AND ENGINEERING CHEMISTRY
have repeatedly been devised. Years ago they developed new and unique apparatus for manufacture and perfect coating of pills, so that a single complex machine would produce more than a hundred expert individuals could originally do and that with greater accuracy. Likewise, many improvements were brought about in the manufacture of tablets of various kinds; as, for example, those relating t o unusual solubility of hypodermic tablets, rapid disintegration of compressed tablets, and the production of a special coating resistant t o the action of the stomach digestion but readily soluble in the small intestine, the resistance of which could be more accurately controlled than previously used coatings of this type. Gelatin capsules were produced elsewhere as early as 1833, but no material improvements had been made up to about 1875 and they were but little used. In that year Parke, Davis & Company began t o supply them as made by an associated factory of which they controlled the entire production. This was subsequently taken over as an integral part of the firm, new automatic apparatus was invented, both for the manufacture of empty capsules of extraordinary perfection and for fully automatic filling of such capsules with medicaments, until today this plant is the largest producer of capsules in the world. In more recent years, with a growing tendency toward hypodermic and intravenous medication, much research has been devoted t o the best means of preparing and stabilizing such solutions, involving the study of effects of minute impurities in materials used; the action of light, oxygen, and inert gases; the effect of pH concentration; the action of different qualities of glass upon solutions and numerous other special considerations. Digestive Enzymes The gradual development of this class of medicinal substances by the laboratories of Parke, Davis & Company well illustrates the commercial value of patient and continued research. PEPSIN-In 1874 they introduced a saccharated pepsin of such strength that “5 grains would digest 60 grains of coagulated albumin,” thus being of a 1:12 strength. Today that would be considered so weak as to be absolutely useless. In 1881 appeared a product dignified by the name “concentrated” of a 1 : l O O strength, but in 1883 this was displaced by a 1:500 pepsin. By 1888 a 1:2000 pepsin, relatively non-hygroscopic, was placed on the market, and by 1893 strengths of 1:3000 and
PANcREATIs-Less spectacular but important gradual improvements have been made in both the quality and strength of pancreatin, and a substance having three times the activity of the U. S. P. standard is regularly available. TAKADIASTASE-ASa result of the researches of Dr. Takamine, this company in 1895 for the first time marketed an enzyme for medicinal use, derived from certain species of fungi and having unusual potency in the conversion of starch into assimilable forms, one part being able t o convert three hundred times its weight of dry starch. This has come into wide use. Biologicals During the years 1887 to 1894 the thought that immunity against various diseases of bacterial origin could be produced in animals and human beings was the subject of much scientific work, culminating in that of von Behring and Roux, which definitely marks the beginning of the idea of producing on a manufacturing scale a substance that would produce immunity against diphtheria. This company, recognizing the great medicinal value of such a product and the possibilities in the field so opened up, established in 1894 a department for pharmacological work and the production of diphtheria antitoxin. It was their successful fight against the von Behring patents that made it possible later for all in the United States, who so desired, to make diphtheria antitoxin without the necessity of paying a royalty on foreign patents. In 1898 they brought out for the first time a package containing 3000 units of antitoxin. The first serum made contained about 50 to 60 antitoxic units per cubic centimeter. Since that time a great amount of research has been given by these laboratories to methods of producing more concentrated serum as free as possible from excess of inert albuminous substances, with the result that they are now supplying a serum with a potency of 3000 or more units per cubic centimeter, and researches still continue. I n 1897 antistreptococcic and antitetanic serums were added and then followed numerous other important preparations of bacterial origin. The first line of bacterial vaccines was put out commercially by this company in 1907. A very recent development of the research laboratories is a series of “immunogens,” improved products for development of active immunity against a number of pathogenic bacteria. Among other important biological medicinals introduced by
General View of Present Main Laboratories.
1:4000 were regularly supplied, while up to 1: 15,000 could be made. This 1:15,000 pepsin was probably considerably weaker than one that meets the tests of today a t t h a t figure. Now 1: 15,000 strength may be readily supplied and in the research laboratory as high as 1:42,000 strength has been obtained.
Vol. 19, No. 10
Research Building a t Extreme Right
this company may be mentioned rabies vaccine (Cumming) and hemostatic serum. More recently they have supplied scarlet fever antitoxin, and Ferry and Fisher, of the research laboratories, have announced the discovery of a specific measles antitoxin.
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In the line of purely chemical products there have appeared from time to time in recent years Formidine, an antiseptic powder; Dibromin, an organic bromine compound of powerful antiseptic properties; Neo-Silvol, an antiseptic colloidal compound of silver iodide and a protein; Proposote, a compound of creosote and phenylpropionic acid; Stearodine, an organic iodine Research Developments compound; Apothesine, a local anesthetic; Mercurosal, an orAs increasing research work and extending business mutually ganic compound of mercury for use as a spirocheticide; and reacted to the expansion of both, more adequate facilities for various other compounds. many types of scientific work and the prosecution of research The men responsible for scientific jurisdiction are E. hl. became increasingly necessary, so in the fall of 1902 there was Houghton, director of biological and medical research laboracompleted a new building for this purpose. This building and tories, associated from the beginning with the biological work; equipment were far in advance of any other laboratory devoted F. 0. Taylor, chief chemist, successor to J. M. Francis whose to research on medicinal preparations and fostered by commercial work contributed much to the high standards of the business; interests, and even today, with the rapid development of re- and Oliver Kamm, director of chemical research. search in all phases of industrial life, remains an outstanding The publications emanating from the medical and chemical example of research equipment in any industry. research staff mount into the hundreds. Books that have been One phase of work that deserves especial mention is that upon, written by members of the staff or t o which they have congland products. In 1893 “desiccated thyroid gland” was first tributed are numerous. In short Parke, Davis & Company supplied. In 1895 the first commercial preparation of supra- has counted i t a duty and a privilege to assist, through their renal glands appeared, “saccharated suprarenal glands,” and scientific representatives, in the development of the IJ.S. Pharin 1899 announcement was made that Dr. Takamine had isolated macopeia, the National Formulary, and the work of many the pure crystalline base, adrenalin, the exact chemical structure scientific societies whose aim is to promote scientific achievement, of which was determined by T. B. Aldrich the following year. foster education, and aid industry. These things have been In 1909, pituitrin, an extract containing the active principle done in the belief that financial rewards will be adequate if of the posterior lobe of the pituitary gland, was placed on the true motives, high standards, and sound policies are maintained, market. At the recent convention of the AMERICAN CHEMICAL to the end that human health and human welfare may be enSOCIETY in Detroit announcement was made by Kamm, Aldrich, hanced. Grote, Bugbee, and Rowe of the discovery and separation of two F. 0. TAYLOR distinct active principles.
Space limitation prevents all but this extremely brief indication of the extensive activities of a large staff of biological workers over a period of many years, whose contributions t o scientific progress in biological medication have been noteworthy and are reflected in the character of preparations marketed.
AMERICAN CONTEMPORARIES J. B. Francis Herreshoff
I
T WAS the late summer of 1888 that I first had the privilege
and joy of meeting Francis Herreshoff. He was then thirtyeight years of age, and I, less than twenty-two, seeking for a start in the chemical industry, had a definite appointment and clear-cut instructions from William H. Nichols to come to an understanding one way or another. Herreshoff impressed me tremendously, and I have never ceased to respect and admire his simple sincerity-a sort of guilelessness, with a complete absorption in his profession. We talked for two hours a t the old Pierrepont Hotel in Brooklyn, where he was living while his family were away for the summer; and now that I know him so much better, there is no doubt t h a t he would have talked for many more hours, for he was interested in the young Scot and wanted to get a new point of view if pos.;ible. That was characteristic of him. He has always been alert and ready to forget time, if he could rehearse with a n interested listener the ideas that were afloat in his mind but not yet safe to deliver. He would think and talk and get a little clearer in his own mind until conviction possessed him, and then the listener would begin to discern t h a t his genius was carrying him a little in advance of the world. The endless discussions that were beginning to look verbose and futile were not in vain-the Teutonic thoroughness and tenacity of purpose, though slow in process, mere absolutely sure in accomplishment. At this first meeting I rose to take leave, as a longer interview was likely t o expose my inexperience and betray my limitations. Herreshoff stood up, his back to the wall, his head thrown backa perfect Apollo in physique-handsome as a dragoon, and while he stood there he continued expressing views and asking ques-
tions. I left, exhilarated and satisfied that the combination of William H . Nchols and Francis Herreshoff had all the qualities of success in admirable proportions. And there the matter dropped and nothing developed until the following February. Time meant nothing to Herreshoff until he saw exactly how to attain the object. Then he became positively impatient to construct, complete quickly, and operate efficiently and economically without further rehearsal or discussion. All the preparation was past and apparently forgotten long ago, though the details were still in the drafting office unfinished, while bricklayers, carpenters, and mechanics were ready to proceed on orders. He was christened John Brown Francis Herreshoff, and invested with the honorary degrees of b1.A. and D S c . by his Alma Plater. He had been deterred from completing his course a t Brown University. He was the youngest of a large family and did not wish to put his parents to the expense of putting him through college. However, he found that he could accomplish his object without expense by becoming an instructor of analytical chemistry a t Brown for three years-1869 to 1872. He then went into the laboratory of the Habirshaw Company in Pearl Street, doing analytical work until 1876, when William H. Nichols heard of his unusual qualities and ability, and decided to take a chance and have him direct the Laurel Hill Chemical Works, hoping that the rule-of-thumb methods could be superseded by scientific standards. Very little was accomplished in the first year of his control a t Laurel Hill. He wanted t o learn from the foremen, mechanics, and process man how to produce sulfuric acid industrially. It was not the chemical reaction in itself that gave trouble in work:
