THE AMERICAN JOURNAL OF PHARMACY

A REcorD OF THE PROGRESS OF PHARMACY AND THE

ALLIED SCIENCES

Published Monthly by Authority of

THE PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE

COMMITTEE ON PUBLICATIONS

FOR 1935 H. LaWatt, Po. M., D.Sc. Ivor Grirrirn, P.D., Pa. M., D. Se.

Joun K. Tuum, Pu. M Jutrus W. Sturmer, Puar. D., Pu. M.

MircHey BernsteErn, P. D., M. D. Futrerton Coox, Px. M.

ARNO VIEHOEVER, Pu. D.

EDITOR IVOR GRIFFITH, P. D., Px. M., D. Sc.

VoLuME 108

PHILADELPHIA, PA.

1936

PRESS OF

INTERNATIONAL PRINTING Co. 236 Chestnut Street

PHILADELPHIA, Pa.

GATALOGED Jy.

THE AMERICAN

JOURNAL OF PHARMACY

VoL. 108 JANUARY, 1936 No. I

EDITORIAL

THE FORWARD MARCH OF SCIENCE—1935

T IS a bit disconcerting to learn* that the peak of the world’s in- ventive activity came about the year 1875, the rate for that year being twice as high as in any other year since 1900. Lewis Mum- ford’s Technics and Civilization records this intriguing List of In- ventions. It begins with a brief mention of the things that came before recorded history—fire, the wheel, hand tools, etc. Up to the tenth century the list is meager but with the release of the intellectual

shackles of the Dark Ages the scores begin to mount as follows:

14th Century 18 inventions 15th 16th

17th

18th

19th

20th (Ist quarter) .... 30

All of these are, of course, fairly basic inventions and with each one the chances for additional inventions grow less. States Furnas, though with doubtful accuracy—‘Almost everything has been discov- ered.”

Yet, in 1935, according to this record compiled by Science Serv- ice, discoveries in the several fields of science, seem to have been nu- merous and important, although none was really a “fundamental invention.”

*Furnas, “The Next Huydred: Years.”

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The Forward March of Science—1935 oe? a

Chemistry

The heavy isotope of neon, mass 22, was concentrated to 99 per cent. purity by Dr. Gustav Hertz of Berlin.

Work by Prof. F. W. Aston, Cambridge University, has indi- cated some 20 new isotopic varieties of chemical elements, bringing the total number of known isotopes to 247 stable varieties among 79 of the 92 elements.

First definite proof of the existence of a super-heavy element beyond No. 92 in the periodic table was obtained by Dr. Aristid V. Grosse, University of Chicago.

With an improved mass spectrograph Prof. A. J. Dempster, University of Chicago, obtained, for the first time, evidence of the existence of isotopes of gold and platinum.

Because atomic weights depend on the proportions of the vari- ous isotopes of the element present, further work in this once-impor- tant chemical field was held useless by Prof. Harold C. Urey, Colum- bia University.

By “boiling down” 75 tons of water over a period of a year, ten drops of precious liquid containing a high concentration of the rare hydrogen isotope of mass three was obtained at Princeton University.

Heavy water, made of ordinary hydrogen combined with the heavy isotope of oxygen, was announced by J. B..M. Herbert and M. Polanyi, Manchester University, England.

Using heavy water molecules as “tracers,” Prof. George von Hevesy and E. Hofer, Freiburg University, Germany, showed half the amount of any drink of water is still in the human body after nine days.

Evidence of “lost” chemical elements no longer present on the earth was found by Prof. George H. Henderson, Dalhousie Univer- sity, Halifax, Canada, from study of halos in mica formed by radio- activity.

New discoveries about the chemical structure of vitamin B, by Dr. R. R. Williams and his coworkers at Columbia University, led to hope that it may be synthesized.

Huge reserves of carbon dioxide gas, from which “dry ice” is made, were discovered near Imperial Valley in California.

A chemical method of plasticizing rubber in place of more expen- sive mechanical chopping and crushing was developed by Ira Wil- liams and C. C. Smith, E. I. du Pont de Nemours and Company.

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Jour ae Lhe Forward March of Science—1935 3

A new process of purifying potash developed by chemists of the U. S. Bureau of Mines holds the hope of freeing America from the necessity of potash imports in event of war.

A mixture of di-phenyl and di-phenyl oxide, chemical cousins of the synthetic geranium perfume, is being used to replace water in steam boilers for increased efficiency, C. G. Brown, G. A. Gaffert, P. H. Konz and D. S. Ullock, University of Michigan, reported.

Biology

Animal growth without either paternal or maternal nuclei was demonstrated by centrifuging sea-urchin eggs and then treating them with concentrated sea-water, by Dr. Ethel Browne Harvey working at the Marine Biological Laboratory at Woods Hole, Mass.

Units of cellulose, held together in a pectin matrix, were isolated and seen for the first time by Mrs. Wanda K. Farr, U. S. Depart- ment of Agriculture, and Dr. Sophia H. Eckerson, Boyce Thompson Institute for Plant Research.

Maturing fruits and vegetables produce ethylene gas in their own tissues, it was shown by researches at three laboratories: the Minne- sota Agricultural Experiment Station, the Low Temperature Re- search Station at Cambridge University, England, and at Boyce Thompson Institute for Plant Research, Yonkers, N. Y.

Eyes of the larva of the fruit-fly, or Wrosophila, were success- fully transplanted to the abdomens of other individuals, by Boris Ephrussi and G. W. Beadle, in Paris.

A monkey embryo in the blastocyst stage was found by Dr. George L. Streeter, director, Carnegie Institution of Washington’s department of embryology, in Baltimore.

An ornithological expedition made permanent records of the songs of rare birds in the South, working under the auspices of Cor- nell University and the Carnegie Institution of Washington.

Dyes of certain types render living cells more sensitive to the lethal effects. of light, Prof. D. H. Tennent of Bryn Mawr College discovered.

The air at 20,000 feet and over was found to be germ-free by Dr. George Walker of Baltimore.

Spores of fungi taken nearly 14 miles into the stratosphere on the flight of the National Geographic Society-Army Air Corps balloon Explorer II survived the cold, solar radiation and other extreme con- ditions of the journey.

4 The Forward March of Science—1935 {je

A lily that never sheds its pollen was produced by D. N. Moore in the laboratories of the General Electric Company, by X-raying bulbs for several successive generations.

The plant hormone auxin, chemical substance stimulating growth was produced synthetically by Drs. K. V. Thimann and J. B. Koepfli, California Institute of Technology.

Irritability in protoplasm was traced to a substance of unknown composition, called “R,” by Drs. W. J. V. Osterhout and S. E. Hill, Rockefeller Institute for Medical Research.

Pantothenic acid, believed to be a universal essential in growth and respiration of cells of living bodies, was isolated by Prof. Roger J. Williams, Oregon State College.

Southern pine forests produced an exceptionally large seed crop.

Properly controlled fires are beneficial to growing pine woods in the South, evidence preduced before the annual meeting of the Society of American Foresters indicated.

Forest fires increased in number but decreased in total area burned over.

A program of basic research in biology was planned by the De- partment of Agriculture.

Establishment of “wilderness areas” in all countries of the Amer- icas was advocated by Dr. John C. Merriam, president of the Car- negie Institution of Washington, in an address before the Pan-Amer- ican Institute of Geography.

Neon lamps were used instead of the conventional incandescents, in forcing plants and flowers in the greenhouses of the Agricultural College of Wageningen, The Netherlands.

A College of Agriculture was organized at Hebrew University in Jerusalem.

More than 3,300 ants, each part male, part female, were found in one colony in Trinidad, by Dr. N. A. Weber, Harvard.

The Sixth International Botanical Congress was held at Am- sterdam, during the first week in September.

Trees afflicted with Dutch elm disease were found in Virginia and Indiana.

A new food factor necessary for the growth of chickens was discovered by Dr. H. Dam of Copenhagen, and named vitamin K.

Plantings were begun in the great Western Shelterbelt project, largely utilizing species native to the region planted.

Ar i oi t SC ti a t d p a D t

The Forward March of Science—1935

Insect heads were successfully transplanted to bodies of other insects of the same species, by Dr. Atma Malabotti, Vienna Academy of Sciences.

A band of rays in the almost invisible red has a powerful re- tarding effect on plant growth, it was discovered by Dr. L. H. Flint, U. S. Department of Agriculture and Dr. E. D. McAlister, Smith- sonian Institution.

Methods were devoleped by U. S. Public Health Service inves- tigators to show graphically the bactericidal effect of the beta rays as compared with the non-bactericidal gamma rays of radium; and the irradiation of bacteria by radium emanations was shown to pro- duce profound cultural and morphological changes.

Air-conditioning methods were applied in the transportation of parasitic wasps used in combating insect pests.

A world-wide survey of breeding stocks of domestic plants and animals was inaugurated by the U. S. Department of Agriculture.

A “Farm Chemurgic Council,” to promote the use of agricultural products in industry, was formed, with Francis P. Garvan as its first president.

Chinch bugs, much feared at the beginning of the growing sea- son, did little damage in the Grain Belt.

On the occasion of the fifth anniversary of the plant patent law, a check-up disclosed that only 124 plants had been patented.

A comprehensive survey of the enemies of oysters was begun by the Bureau of Fisheries. :

Several large wilderness areas, comprising a total of nearly 8,000,000 acres, were set aside as game preserves by the Soviet Gov- ernment.

Medical Sciences

The virus that causes the plant disease, tobacco mosaic, was isolated by Dr. W. M. Stanley, Rockefeller Institute, Princeton, N. J., as a crystalline protein, thus, according to Dr. Stanley, character- izing a new class of disease-producers and indicating that viruses may not be living substances in the sense that bacteria, plants and animals are.

Identification of the virus of human influenza and its cultiva- tion outside the body were reported by Drs. Thomas Francis, Jr., and T. P. Magill of the Rockefeller Institute.

6 The Forward March of S cience—I9 13.5

First definite evidence of a vitamin participating directly in a physiological process was found by Dr. George Wald, Harvard Uni- versity, who found vitamin A in the eye’s retina and active in vision.

Relief and apparent cure of a fatal type of high blood pressure by surgical operation was reported by a number of surgeons, work- ing independently and using different surgical technics, among them Dr. Alfred W. Adson, Mayo Clinic; Dr. Max M. Peet, University of Michigan Medical School; Dr. Irvine H. Page, Hospital of Rocke- feller Institute for Medical Research; and Dr. George J. Heuer, New York Hospital.

Study, at many research centers, of electrical impulses secaanial by brain activity and known popularly as “brain-waves” shows that brain activity, like heart activity, is constant but unlike heart activity, proceeds at different rates during sleeping, waking, and mental proc- esses; that epilepsy is a sort of neurological storm set off by stimu- lation of a convulsion-causing brain center; that different kinds of brain activity occur under different anesthetic agents; and promises much future information about mental processes in health and dis- ease. Scientists engaged in this research were: Drs. F. A. Gibbs, E. L. Gibbs, H. Davis, E. L. Garceau, A. Forbes, A. J. Derbyshire, B. Rempel, E. Lambert, Harvard University; Drs. H. H. Jasper and L. Carmichael, Brown University; Dr. A. L. Loomis and Garret Hobart, Loomis Laboratories, Tuxedo Park, N. Y.; and Prof. E. Newton Harvey, Princeton University.

Electrical impulses generated in the brain during sleep and dreams are paralleled in the case of deaf-mutes by similar impulses in the hands and arms, which they use in speech, experiments by Dr. Louis W. Max, New York University, disclosed.

A substance that can be applied to the outside of teeth to relieve pain during drilling and other dental procedures was announced by Dr. L. L. Hartman, Columbia University.

Dr. William H. Howell, emeritus professor of physiology, Johns Hopkins University, discovered that the blood platelets are formed in the lungs by giant cells called megacaryocytes.

Heart muscle tone is the chief factor influencing the blood flow through the heart’s arteries and should be considered in prescribing drugs for heart disease due to occlusion of these arteries, Dr. Wil- liam B. Kountz, Washington University School of Medicine, re- ported.

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Lhe Forward March of Science—1935 7

Choline, produced by the pancreas, is a vitamin essential for liver function and probably an important factor in control of di- abetes, Dr. C. H. Best, co-discoverer of insulin, and Dr. M. Hershey and Miss M. E. Huntsman, all of the University of Toronto, found.

Relief of several cases of hitherto hopeless Pick’s disease by surgical removal of part of the pericardium was reported by Drs. Paul D. White and E. D. Churchill, Massachusetts General Hospital, Boston.

A new hormone, enterogastrone, produced by the upper intes- tinal walls, which may aid treatment of stomach ulcer because it in- hibits stomach activity, was announced by Prof. A. C. Ivy, North- western University Medical School.

Synthetic production of male sex hormones was reported by Dr. L. Ruzicka, Zurich, Switzerland.

Evidence presented by Dr. L. G. Rowntree and colleagues indi- cates that extract of pineal gland causes precocity of sexual develop- ment and premature cessation of body growth.

First scientifically controlled test of the Park-Brodie infantile paralysis, vaccine was made by U. S. Public Health Service on over’ 1,000 children during the North Carolina epidemic, but was incon- clusive as no cases developed in either control or vaccinated groups.

A slight drop in the cancer death rate appeared in life insurance statistics for the first nine months of 1935.

Length of life can be predicted by measuring change of the eye lens’ power of accommodation, early presbyopia indicating probabil- ity of a shorter than average life, Dr. Felix Bernstein, Columbia University, found from research on thousands of individuals in Ger-

many.

Progress in cancer research was marked by chemical studies of © cancer producing substances; one of these, methylchloranthrene, was made synthetically by Prof. Louis F. Fieser and M. Fieser, E. B. Hershberg, M. Newman and A. M. Seligman, Harvard University ; discovery of two new cancer-producing chemicals, tetraphenyl-meth- ane and triphenylbenzine, by Prof. Avery A. Morton and Dr. Daniel B. Clapp, Massachusetts Institute of Technology, and Dr. Charles F. Branch, Evans Memorial Hospital, Boston, show that the pro- duction of cancer by pure hydrocarbons is much more general than supposed.

8 The Forward March of Science—1935

Discovery that the female sex hormone produces tissue changes similar to beginning stages of cancer furnished evidence of a long- suspected but unproved relation between sex and cancer to Prof. J. B. Collip and Drs. H. Selye and D. L. Thomson of McGill Uni- versity.

Inoculating cancer cells into the skin instead of under it made mice immune to cancer, Prof. Alexandre Besredka and Dr. Ludwik Gross of the Pasteur Institute, Paris, reported.

Discovery, in connective tissue tumors, of sex hormones which definitely influenced growth of the tumor indicated to Drs. Charles F. Geschickter and Dean Lewis, Johns Hopkins Hospital and Uni- versity, that a connection may exist between sex and cancer.

Further support of the idea that heredity plays a part in cancer was seen by Dr. Raymond E. Militzer, Pondville Hospital, Massa- chusetts Department of Public Health, in the first known cases of simultaneous occurrence of stomach cancer in identical twins.

Isolation of the active principle of ergot, drug used in child- birth, was announced by several investigators, working independently.

A new amino acid, alpha-amino-beta-hydroxybutyric, essential for growth and life, was discovered, identified and prepared syn- thetically by Dr. William C. Rose and associates, Dr. H. E. Carter, Richard M. McCoy and Madelyn Womack, University of Illinois.

A substance which checks the action of the important digestive enzyme, trypsin, was discovered, isolated and prepared in pure crystal form by Drs. John H. Northrop and M. Kunitz, Rockefeller Institute for Medical Research, Princeton, N. J.

Ventricular fibrillation, fatal heart condition, and auricular fibrillation, another grave heart disorder, may be caused by the ex- ternal nerves of the heart, researches by Drs. Louis H. Nahum and H. E. Hoff, Yale School of Medicine, revealed.

Ultraviolet rays, heat and calcium salts are three interrelated factors in the production of cataract, Dr. Janet Howell Clark, Johns Hopkins School of Hygiene and Public Health, found.

Maternal instinct in young rats is due to the influence of pro- lactin, pituitary gland hormone, and can be aroused in young virgin rats by injections of this hormone, Drs. Oscar Riddle, Ernest L. Lahr and Robert W. Bates, Carnegie Institution of Washington found.

Effect on the body of thyroid gland hormone and thyroid: stimu- lating hormone of the pituitary gland is greatly influenced by tem-

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ee} The Forward March of Science—1935 9 perature, lowered metabolic rate being produced by either of these hormones when given at 59 degrees Fahrenheit, Drs. Oscar Riddle, Ernest L. Lahr and Robert W. Bates, Carnegie Institution of Wash- ington found.

Important aid for the treatment of liver disease and for pre- paring patients suffering from fatty livers for operation was the discovery by Drs. J. L. Bollman and F. C. Mann, Mayo Clinic, that the composition of the liver can be varied within wide limits by diet.

Breeding experiments with mice, reported by Dr. E. C. Mac- Dowell, Carnegie Institution of Washington, indicate that occurrence of leukemia, cancer-like condition of white blood cells, is increased through inheritance on the maternal side.

A method for keeping glands and possibly other organs alive outside the body by feeding a blood substitute by a mechanical “heart” was reported by Dr. Alexis Carrel, Rockefeller Institute, and Col. Charles A. Lindbergh.

Cause of the paralytic disease, multiple sclerosis, may be clotting of blood in the small veins of the brain, possibly as a result of in- fection, researches by Drs. Philip Solomon, Mary E. Dailey and Tracy J. Putnam, Harvard Medical School, indicated.

The world’s record smallest viable baby, weighing one pound at birth, was born in El Paso, Texas.

- Putting a specially prepared fat or olive oil mixture into the veins is a new method developed by Drs. L. Emmett Holt, Jr., Her- bert C. Tidwell and T. F. McNair Scott, Johns Hopkins Hospital, for treating babies suffering from severe nutritional disorders.

A new function of the pituitary gland, control of the reticulo- endothelial system, which is concerned with production of new blood cells and destruction of old ones, was indicated in experiments of Prof. E. C. Dodds, Courtauld Institute of Biochemistry, and Dr. R. L. Noble, London.

First part of the human brain to develop is the area controlling what scientists call the body sense, Dr. Frederick Tilney and asso- ciates at the Neurological Institute, New York City, found in a study of the correlation between brain development and human behavior.

New evidence for the resonance theory of hearing was found by Dr. Elmer Culler, University of Illinois, and Dr. S. S. Stevens, Harvard, who, working independently, mapped the basilar membrane,

10 Forward March of Science—1935 Jour. Pigg

locating experimentally the areas where each frequency range is picked up.

Very intense noise causes deafness for pitches other than that of the stimulus and injury in the ear’s organ of Corti at points not involved in picking up moderate tones of similar pitch, researches at Harvard, Clark, and Princeton Universities indicated, providing evi- dence that the resonance theory of hearing may need modification.

Evidence that the stimulus to the nerve of hearing is chemical and not electrical was obtained in researchs by Drs. A. J. Derbyshire and H. Davis, Harvard Medical School.

A loud high-pitched sound produces more ear strain and greater loss of hearing if it is interrupted every second instead of being con- tinuous, Dr. Elmer Culler and Glen Finch, University of Illinois, reported.

Chemical analysis of crystals of the fertility vitamin, E, show it to be a quite complex higher alcohol, Drs. H. M. Evans, O. H. Emerson and G. A. Emerson, University of California, reported.

An international clearing-house for serums used in treating, diagnosing or preventing disease was established at the Royal Danish Serum Institute, Copenhagen, by action of the Congress of Biologi- cal Standardization in’ connection with the League of Nations Hy- giene Congress.

First step toward a simpler, cheaper and safer method of making Rocky Mountain spotted fever vaccine was apparently taken by Dr. R. E. Dyer and Ida A. Bengston, U. S. National Institute of Health, when they succeeded in growing the virus of this fatal disease on chick embryos.

A new, physiological approach to methods for correction of stuttering was suggested by the finding of Hazle Geniesse, University of Michigan, that walking on all fours enabled stutterers to speak normally.

All in all, the record of 1935 is certainly not such as to lead us to believe with some “that the day of invention draws to its close.”

Ivor GRIFFITH.

Am. Jour. Pharm. ; Lucius Leedom Walton II January, 1936 \

LUCIUS LEEDOM WALTON AN APPRECIATION

N the passing of Lucius L. Walton after a busy and fruitful life | of seventy years, American Pharmacy loses one of its noblemen. Courteous and friendly colleague of two generations of pharmacists ; able examiner of thousands of candidates who have applied for reg- istration as pharmacists in the Keystone State in the past thirty years ; even-tempered and a diligent workman in the committees, conferences and organizations of his beloved profession and in-his church; pol- ished, fair, inspiring and extraordinarily capable presiding officer in the Pennsylvania Pharmaceutical Association, the National Associa- tion of Boards of Pharmacy and the American Pharmaceutical Asso- ciation; efficient secretary and later president of the Pennsylvania Board of Pharmacy; and leader in many activities within and outside of the profession which he graced—such is the memory, at least in part, which Dr. Walton leaves with those who knew him best.

To have known him intimately and to have come under the spell of his fine personality, his lofty idealism and his passion for service to pharmacy was in itself an education. His efforts to meet the prob- lems created by the dual aspect of the drug industry in a day when cynicism toward the professional ideals of pharmacy was on the in- crease were always inspiring.

In his Presidential Address to the American Pharmaceutical Association in 1926 he referred to the qualifications of members of Boards of Pharmacy in the following words:

“The persons who sit in judgment on the qualifications of those seking admission to the profession of pharmacy, and ad- minister the pharmacy laws, should be trustworthy and well qualified technically. They ought, also, to be free from all polit- ical, social or friendly interest. There is no duty which may fall to the lot of a pharmacist that requires such broad knowledge, careful discrimination, good judgment, keen appreciation of jus- tice, and conscientious preparation, as that of examiner on a’ board of pharmacy.”

All of these qualifications Lucius Walton possessed to an un- usual degree. He was in the minds of many, the ideal Pharmacy Board member. The Proceedings of the National Association of Boards of Pharmacy and of District No. 2 of that Association are replete with practical suggestions for conducting the work of Pharm-

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12 Lucius Leedom Walton

acy Boards and for elevating profession standards, emanating from the fertile mind and long experience of this Master of Pharmacy.

Dr. Walton’s life-span paralleled some of the most significant developments and changes in American Pharmacy. He was a keen student of these changes and sought to adapt himself and the pro- fessional activities for which he was responsible to the changing order, without ever sacrificing the fundamental principles of good pharma- ceutical practise to expediency.

Honors were bestowed upon Dr. Walton at various times dur- ing his career for services well rendered. Although richly deserved and without doubt greatly appreciated by the recipient, they were received in the spirit of humility which characterizes the truly great in every walk of life.

It was a treat to watch Lucius Walton preside over an assem- blage such as the House of Delegates of the American Pharmaceu- tical Association. He knew parliamentary procedure as well as he knew pharmacy—and that is saying a great deal. He was never at a loss for the proper procedure to handle a difficult situation and although very patient with those whose lack of knowledge of par- liamentary law caused many a snarl and tangle in the management of some of our pharmaceutical meetings he frequently deplored the fact that many of those who accept appointments as presiding offi- cers of our pharmaceutical associations do not take the trouble to acquaint themselves with the rules and by-laws under which they are expected to function. The tendency toward placing a premium on mediocrity sometimes resorted to in organizations in order to serve the ends of political expediency was always repugnant to Dr. Walton. He will be sorely missed in the councils of the National Association of Boards of Pharmacy, the American Pharmaceutical Association and the many other groups who leaned heavily upon his counsel and experience.

No better sentiment can be found to close this brief and totally inadequate appreciation of one of America’s most outstanding phar- macists, than the one which he himself uttered in commenting upon the departed in his Presidential Address of 1926:

“Death’s transfiguration into the dimly outlined image of

Eternal Love makes sacred our beloved. We are quickened to

new resolves and impulses to better living by the blessed lives

thus transmuted into our lives, and this birth in death tempers the sadness of the passing of our associates.”

Rosert P. FiscHe ts.

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Am. Jour. Pharm. I Jour Criticisms on Biological Products 3

ORIGINAL ARTICLES

CRITICISMS ON THE BIOLOGICAL PRODUCTS OF THE U.S. P. XI By Louis Gershenfeld, Ph. M., B. Sc., P. D. Professor of Bacteriology and Hygiene at the Philadelphia College of Pharmacy and Science HE U. S. P. XI has included several new biological preparations.

In the U. S. P. X, the following biological products were official :

1. Antitoxinum Diphthericum, (Diphtheria Antitoxin) ; 2. An- titoxinum Tetanicum, (Tetanus Antitoxin), and 2 (a). Antitoxinum Tetanicum Crudum, (Crude Tetanus Antitoxin); and 3. Vaccinum Variole (Smallpox Vaccine). The Crude Tetanus Antitoxin was deleted but the other three preparations were retained and are official in the new revision. In addition to these three the following ten (mak- ing thirteen in all) biological products are now official in U. S. P. XI: 4. Antitoxinum Scarlatinae Streptococcicum, (Scarlet Fever Antitoxin); 5. Serum Antimeningococcicum, (Antimeningococcic Serum); 6. Serum Antipneumococcicum—I, (Antipneumococcic Serum, Type I); 7. Toxinum Diphthericum Detoxicatum, (Diph- theria Toxoid); 8. Toxinum Diphthericum Diagnosticum, (Diph- theria Toxin for the Schick Test) ; 9. Toxinum Scarlatinae Strep- tococcicum, (Scarlet Fever Streptococcus Toxin) ; 10. Tuberculinum Pristinum, (Old Tuberculin) ; 11. Vaccinum Rabies, (Rabies Vac- cine) ; 12. Vaccinum Typhosum, (Bacterial Vaccine made from the Typhoid Bacillus) ; and 13. Vaccinum Typho-para-typhosum, (Bac- terial Vaccine made from the Typhoid Bacillus and Paratyphoid “A” and “B” Bacilli). j

Pharmacopeial requirements are employed at all times as the guides for standards of purity and potency by governmental agencies in the enforcement of the Pure Food and Drugs Act. However it is of sufficient import to note that all of the biological products official in U. S. P. XI must conform to the requirements and standards as set forth by the National Institute of Health and pharmacopeial com- mittees cannot overrule the latter. In fact the following situation

14 Criticisms.on Biological Products Jour. Pisum. is not at all impossible. If next month or anytime before the appear- ance of U. S. P. XII, a new method of designating potency is adopted by the National Institute of Health, for let us say the scarlet fever streptococcus toxin, manufacturers will have to abide by changes adopted by the latter institute. Of course with the new policy of the U. S. P. new titles and changes will be admitted by interim revision announcements in the form of supplements, so that it will be possible to adopt the new changes. We even find in the U. S. P. XI under “Nomenclature” the following statement: “The English titles of biological products are those established by the National Institute of Health of the U. S. Public Health Service.” However more uniformity should prevail in the English and Latin titles even though this may necessitate conferences with the National Institute of Health to agree upon uniformity. For instance the Latin title Antitoxinum Scarlatinae Streptococcicum is translated as Scar- let Fever Antitoxin, while the Latin title Toxinum Scarlatinae Strep- tococcicum is given the English title of Scarlet Fever Streptococcus Toxin, the latter of course being a more correct translation. One can even question the desirability of some of the existing titles, but again here the Committee on Nomenclature as far as English titles are concerned must employ those introduced by the National Insti- tute of Health. Inasmuch as the Director of the latter served as the Chairman of the Committee on Biological Products of the new U. S. P., it would appear that an agreement would have been pos- sible on uniformity in titles, translations, method of indicating dos- age, etc. The Antitoxins (pages 58 to 61 in U. S. P. XI)

Under “General Tests, Processes and Apparatus” are included numerous tests and assays. Units of Vitamins A and D are defined ; details are given for assays for vitamin content ; and biological stand- ards are discussed. The antigenic value of diphtheria toxoid is men- tioned. Would it, therefore, not be ‘desirable to mention what is meant by a unit of the various antitoxins, especially when, in this instance there exists a marked variancy in the standards of the three official antitoxins ?

The question may be raised by some that the Pharmacopceia is not a text book or a therapeutic guide and details are to be kept down to a minimum. However if this is to be accepted as a guide for noting the purity of recognized remedial agents, then for the

harm.} Criticisms on Biological Products 15 sake of uniformity there should be included a definition or assay and at least a brief statement concerning the meaning of units or other special terms for all important products, or these should be deleted in all instances. Why consider details of vitamin units and digitalis units and no mention is made about units of antitoxin? Further- more under Diphtheria Toxoid (on page 408) an explanation is given as to the requirements for the toxicity and the antigenic value of this product. Why? The statement that “the potency should be as prescribed by the National Institute of Health of the U. S. Public Health Service” would have been sufficient here as we are led to believe it is sufficient under the antitoxins. One might also observe a definition for the M. L. D. of Diphtheria Toxin (on page 409) and for the skin test dose of Scarlet Fever Streptococcus Toxin (on page

410).

Toxins and Toxoids Under Diphtheria Toxoid the average dose is given as I cc. Under Vaccinum Typhosum the average dose as given comprises three injections. It is a known fact that the average dose of Diphtheria

Toxoid is repeated until a negative Schick test is obtained. If the three injections are to be included under Typhoid Vaccine a more detailed statement of the average dose is to be included under Diph- theria Toxoid, and if for not other reason than for the sake of uni- formity the following or a similar statement is to be included, “to be repeated at proper intervals until the individual will give a negative Schick test.” Note a similar statement under Scarlet Fever Strep- tococcus Toxin that graduated doses are given until a negative Dick test is obtained.

Under Scarlet Fever Streptococcus Toxin we find the state-. ment under dosage: “for active immunization.” Under Diphtheria Toxoid, Typhoid Vaccine and other places where active immuniza- tion is employed the average dose is mentioned as “prophylactic.” Again for uniformity either one of the two phrases should be em- ployed throughout, rather than speak of prophylactic dose in one place and the active immunization dose in another. The answer may be given that under Scarlet Fever Antitoxin there is included a prophylactic dose and inasmuch as the latter preparation is used in passive immunity, the term “active immunization” is more desirable when considering dosage under “scarlet fever streptococcus toxin.” But the same conditions prevail in the case of diphtheria antitoxin

16 Criticisms on Biological Products { Av Jour. Pisum.

and diphtheria toxoid and in both instances, the phraseology em- ployed is the term “prophylactic.”

In the description on page 409, “Diphtheria Toxin for the Schick Test is a solution”, the word “sterile” should precede the word “solu- tion” as in definitions given for other soluble products of bacterial growth on pages 408, 410, and 415. It is of course true that in smaller type the statement is given “The product must be sterile”, but including the word “sterile” in the sentence where the larger type phrase describes the preparation is desirable.

Vaccines

The average dose under “Rabies Vaccine” should have the state- ment—‘‘Prophylactic, by hypodermic injection” preceding the pres- ent phraseology just as is mentioned under typhoid vaccine and under the other biological products. Under “Smallpox Vaccine” nothing is said about the dose. Why this is not given is not clear, as all of the other biological products have the average dose mentioned.

Conclusion

The criticisms offered here are not of a serious nature, serious in the sense that their omission may result in harm to anyone. The efficiency of these preparations sold in interstate sale within the juris- diction of the United States has been under the special protection of an act of Congress, approved July 1, 1902, antedating even the Pure Food and Drugs Act. Under this law, the National Institute of Health guards these products and makes the rules and regula- tions which concern their production and sale. Licensed manufac- turers must abide by their decisions and are not necessarily guided by U. S. P. requirements only insofar as the latter may be the same as that of the National Institute of Health. The suggestions offered are for the sake of uniformity and for the purpose in few instances of making the U. S. P. more useful.

> 2 @, e o?

Am. Jour. Pharm. r hens ‘ January, 1936 Preparation of -iodoxybenzow Acid 7

IMPROVED METHOD FOR THE PREPARATION OF CALCIUM OR AMMONIUM SALTS OF IODOXYBEN- ZOIC ACID

By Frederick R. Greenbaum, D. Sc. Philadelphia, Pa.

Introduction

OEVENHARD and coworkers, who did considerable pharma-

cologic work (1911-1913) on the salts of iodoxybenzoic acid, showed that on injection of the salts of iodoxybenzoic acid and iodoso- benzoic acid, the hemoglobin was immediately oxidized to oxyhemo- globin. Arkin, who reported its germicidal action against staphy- lococci, also found later that it stimulated the phagocytosis of strep- tococci and staphylococci by human leukocytes and that it stimulated production of hemolysin and agglutinin in rabbits. Hektoen found that intravenous injections of sodium iodoxybenzoate produced more antibodies than were present in the control animals. This led up to the clinical application of the salts of iodoxybenzoic acid in the treat- ment of arthritis by Young and Youman. They used the sodium salt or the ammonium salt intravenously; later they recommended the use of ammonium iodoxybenzoate. Patients presenting signs of an active infection of arthritis are reported to.respond best. This drug should preferably be given intravenously, however, for cases in which the drug cannot be given intravenously, oral administration and administration by high enema have been employed and found effective. Following intravenous injection, fever and chills have been noted, which Youman and Young regard as favorable rather than otherwise.

Chemistry

The chemistry of the iodoxybenzoates is exceedingly interesting. The ortho iodobenzoic acid is transformed by mild oxidation into the ortho iodosobenzoic acid and further oxidation will yield the ortho iodoxybenzoic acid. Ortho iodoxybenzoic acid resembles salicylic acid, chemically differing in that the hydroxyl group of the latter

has been replaced by an iodoxy group ei ,

It is interesting to note that these compounds were described as early as 1892 by Victor Meyer and his coworkers. The ortho-

18 Preparation of Iodoxybengoic Acid Jour. Pharm.

iodobenzoic acid is prepared according to the method of Griess and Richter (1) from anthranilic acid by diazotization and exchange of the diazo group for iodine according to equation I.

Equation I

=N—Cl COOH COOH + Nal > + NaCl + Ne

The ortho iodobenzoic acid is oxidized to the ortho iodosobenzoic acid.

Equation II

| \

and the ortho iodosobenzoic acid is oxidized to the ortho iodoxybenzoic acid.

Equation III

O

—COOH —COOH \Y

The iodosobenzoic acid is prepared by heating 1 gram of ortho iodobenzoic acid with 14 cc. of fuming nitric acid to not more than 50 degrees C. This is then precipitated from water. This method was developed by Victor Meyer and Askenasy (2).

Another method of preparing ortho iodosobenzoic acid consists in heating 2 grams of ortho iodobenzoic acid with 40 cc. of 2.3 per cent. of potassium permanganate solution and 30 cc. of a 12% per cent. sulphuric acid, boiled several times and then 280 cc. of hot

|

Preparation of Iodoxybenzoic Acid 19 water are added and filtered boiling hot. On cooling iodosobenzoic acid crystallizes out.

The third method consists in passing for one and a half hours, dry chlorine gas through 1 gram of ortho iodobenzoic acid dissolved in 20 cc. of chloroform. Then the chloroform is allowed to evap- orate in the open air and the residue is treated with water. This was done by Willgerodt in 1894 (3). The ortho iodosobenzoic acid crystallizes from the water in mother of pearl like leaflets. It has a melting point with decomposition of 244 degrees C. If added to acidified potassium iodide solution, iodine is liberated.

O The ortho iodoxybenzoic acid, Coa SO OOH

is formed by heating 10 grams of iodosobenzoic acid in 2 liters of water and 5 grams of sodium hydroxide and 4.1 grams of potassium permanganate. The filtered solution is evaporated to 550 cc. and from the still warm solution (about 30 degrees C.) ortho iodobenzoic acid is precipitated with dilute sulphuric acid, which is filtered off at once. On standing and cooling, iodoxybenzoic acid is precipitated which is, however, contaminated with unchanged ortho iodosoben- zoic acid. To free the ortho iodoxybenzoic acid from this impurity, it is dissolved in ammonia. The ammoniacal solution is evaporated to dryness ; the residue is treated with ammonia which does not dis- solve the ortho iodosobenzoic acid, but dissolves the iodoxybenzoic acid as its ammonium salt. This method was worked out by Victor Meyer and Hartmann (4).

Another method also described by Victor Meyer and Hartmann (5) consists in passing chlorine gas in the cold through a solution of 5-3 parts of ortho iodosobenzoic acid and 4 parts of sodium hydrox- ide. The iodoxybenzoic acid forms fine needles, which explode vigorously at 233 degrees C. They are almost entirely insoluble in water. Boiling with sodium hydroxide solution decomposes the com- pound into benzoic acid and sodium iodate. With methyl alcohol and dry hydrogen chloride gas the 2, iodoxybenzoic acid anhydride is formed ; with ethyl alcohol and dry hydrochloric acid gas, the 2,iodo- benzoic acid is formed.

The sodium, potassium, ammonium, barium, calcium, magnesium and silver salts are known. All salts are explosive.

Preparation of Iodoxybensoic Acid Jour. The method or preparation of ortho iodoxybenzoic acid com- prises therefore three steps: First, the preparation of ortho iodobenzoic acid. Second, the preparation of ortho iodosobenzoic acid. Third, the preparation of ortho iodoxybenzoic acid.

Improved Method

My improved method consists in only two steps:

First, the preparation of ortho iodobenzoic acid from anthranilic acid and

Second, the direct oxidation of ortho iodobenzoic acid into ortho iodoxybenzoic acid, without at first producing and isolating iodoso- benzoic acid. This is accomplished by the use of a new and original oxidinzing agent namely potassium bromate.

Potassium bromate in the presence of sulphuric acid and upon.

heating with ortho iodobenzoic acid will oxidize at once to ortho iodoxybenzoic acid and bromine vapors are given off. The following part contains a description of my improved method.

First Step: Preparation of Iodobenzoic acid.

4800 grams of anthronilic acid and 13,200 cc. of con. hydro- chloric acid to which 6000 grams of chopped ice has been added, are mixed, then 6000 grams of water is added and the entire mix- ture is stirred mechanically and cooled very thoroughly with ice and salt. When the temperature has gone to about 5 degrees C., a solu- tion of 2540 grams of sodium nitrite dissolved in 4200 cc. of HoO, is added slowly. Care should be taken that the temperature does not rise too much, so that no nitric oxide is formed. The solution is tested with potassium iodide starch paper, which indicates the pres- ence of free sodium nitrite by a blue iodine starch reaction. As long as this test