September, 1926
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INDUSTRIAL A N D ENGINEERING CHEAUISTRY
ago. This chemical knowledge generally possessed makes it possible to produce on a large scale ceramic wares of definite properties within exacting limits of variations. Freak effects due to combination of several factors in materials and processing are obtained today as in ancient times. These factors and their individual influence can be determined and evaluated, so that in place of museum freaks, the ceramists today, by machinery and shop men, fill repeat orders for large quantities of wares of surpassing quality, properties, design, and decoration. Chemistry has not only made easily available a production knowledge of ceramic wares of all sorts, but it has made possible a ready response for new wares called for by all sorts of human and industrial activities. The spark plug is typical of such new products. The increasing exactness in specifications of all things to meet the ever-increasing service severity has called for specific properties in ceramic wares. The promptness with which present-day manufacturers produce on a large scale and a t low cost the ceramic wares and parts
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required to meet severe service needs iq creditable to the wide spread knowledge of the chemistry of materials and products, translated and directed by the accumulated experience through centuries by ceramists who, prior to chemistry, were guided alone by intuition and empirical knowledge. Modern chemistry and its ally, physics, have given means of determining what transpires and transforms when silicates are fused. With the knowledge and tools thus proTided, ceramists are able to keep within hailing distance of the industrial demands. No study in silicate fusions has been so profoundly abstract or scientific but that almost instantly it has made it possible more quickly and surely to meet the more severe service requirements of ceramic wares. Ceramic science and technology have not been trailing the developments in chemistry. Chemical and ceramic science have developed together, first one then the other impelling or leading. The science of chemistry as we know i t today owes a great deal to ceramics-but that is the other side of the story, not to be told here.
Standardization and Evaluation of Medicinals’ By Paul Nicholas Leech CHEMICAL LABORATORY, AMERICANMEDICALASSOCIATION, CHICAGO, ILL.
E
VEN fifty years ago the Pharmacopeia of the United
States was a highly regarded book of standards. Today it is still highly regarded, but possesses the added prestige of being an integral part of the Pure Food and Drugs Act; furthermore, it enjoys the distinction of reflecting progressive medical opinion better than any foreign pharmacopeia. Standardization
To the chemist, the outstanding developments of standardization during this period as reflected by the Pharmacopeia are: (1) I n 1876 assay by any other means than chemical was considered as rank heresy. Now biologic standardization is so important that it is used not only to control the toxicity of certain substances, but as a method of estimating the active ingredients. It is, in the last analysis, a n ever-present reminder to the chemist that his methods for determining certain substances are still crude. It may be conjectured, however, that fifty years from now the biologic method of standardization will hare been superseded in a large measure by refined chemical and physico-chemical procedures. By that time also it is hoped that indefinite vaccines or biologic products will have given way to definite chemical compounds chemically assayed, as has happened notably in the case of epinephrine. The recent work of Abel on crystalline insulin is a step in this direction. (2) The old Pharmacopeia contained drugs of vegetable origin which today have gone into the therapeutic scrap heap. Assays of these were lacking-many of them possessed no definite active principle. The Pharmacopeia of 1880 contained mainly acid and alkali volumetric determinations and certain alkaloidal assays. There was a good sprinkling of qualitative tests, but relatively few tests for limits of impurities. The advent of synthetic organic chemistry within the past two or three decades has led to the formulation of methods of control which find their best expression in the new tenth edition of the Pharmacopeia. Consequently, the purveyors of pharmaceutics, large and small, are realizing more and more the necessity of adequate scientific staffs to insure the reliability of their products. I Received June 21, 1926.
Besides contributions for standardizing the newer materia medica, which have had their genesis in the laboratories of manufacturers, other scientific agencies have elaborated methods which make the U. S. P. X the peer of any in the world in this regard. Notable have been the contributions of the Bureau of Chemistry, particularly the methods worked out by W. E. 0. Emery and associates. The chapters on General Tests, Processes, and Apparatus, in the tenth revision, are excellent guides for high-grade analytic work. Even tests for absence of chlorides or sulfates are worked out to precision values. There is no doubt that American chemists have had a profound influence in making the U. S.Pharmacopeia the authority of the world on chemical standardization of drugs. The outstanding criticism of the assay methods in the new Pharmacopeia is the use of methyl orange as an indicator, when the more modern indicators are much more satisfactory. I n fact, methyl orange is practically a discarded indicator in progressive institutions. (3) The Pharmacopeia, official this year, also has the advantage that most of the additions are products which had previously been standardized and included in New and Non-Official RemediesS2 As the latter book is revised annually, there is opportunity to “try out” standards before inclusion in the Pharmacopeia. This aids in making the U. S. Pharmacopeia extraordinarily stable and is of service both to pharmaceutical manufacturers and to chemists engaged in drug control and research. Chemists have been slow to appreciate the value of the Pharmacopeia as a book of standardized reagents. Except in those few instances where the purity limits have been set by the Committee on Standardization of the AMERICAN CHEMICAL SOCIETY,the term C. P. means little. On the other hand, the designation U. 8. P. insures a product of definite strength and purity; in a number of laboratories the U. S. P. products are ordered whenever possible, thus avoiding haphazard standards.
* Published b y the Council on Pharmacy and Chemistry of the American Medical Association. In the last revision of the Pharmacopeia forty new drugs and preparations were added; of these thirty-one had been previously described in N e w and Non-Official Remedies, the standards for which had either been elaborated or verified Ln the A. AI A. Chemical Laboratory
I S D CSTRIBL A&D EitTGINEERI.VG CHEMISTRY
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Evaluation
Closely associated with the topic of drug standardization is that of drug evaluation. Possibly in no other phase of practical synthetic chemistry is there more confusion or misunderstanding of proper procedure. Often chemists smile a t physicians for lack of certain chemical knowledge, and physicians smile a t chemists for the lack of appreciation of bedside therapeutics. What, then, in general seems proper technic for introducing a new chemical as a drug? Experience causes one to venture the following: (1) The chemistry should be well worked out, including evidence of a definite compound (together with its molecular structure). The possible impurities should be eliminated altogether or limited by proper tests. The method of assay for its control is important in order that the pharmacologic and experimental clinical work may be comparable. I n case of extracts of organs, etc., or those few potent compounds which cannot be prepared in the pure state or are relatively unstable, biologic methods of control should also be determined-for instance, “insulin units.” (2) The action on experimental animals should be studied by a competent pharmacologist. This is important, not only for information regarding the various actions of the drug, but also to determine if trials on humans are warranted. (3) The crucial test of a drug is clinical experimentation under definite conditions. But first it is scientifically imperative that the preceding steps shall have been taken. A physician is not warranted in trying a drug until careful chemical and pharmacologic evidence is provided. Clinical therapeutics is recognized as most involved; the testing of a new drug, therefore, must be under rigorously controlled conditions-not simply the uncritical procedure of “trial” on this and that patient. For example, in case of a new drug for arthritis, it would be advisable to have under observation about fifty patients suffering from “rheumatism.” They would be divided fairly into two groups. To one group the usual treatment should be given; to the other exactly the same treatment-same food, etc.-except that the new drug should be used in place of the old drug, and in a manner to rule out psychic effects as far as possible. If carefully
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kept records are in favor of the second group over that of the controls, then there is evidence of superiority of the new drug. Such tests, it can be seen, can most readily be carried on a t hospitals. An added refinement, if possible, would be to label the two drugs for comparison with key numbers, known to the drug dispenser but not to the physicianthat is, the blind test, the only method that makes the results purely objective. Introduction of Drug
Often after a drug has shown promise of considerable merit, it has been introduced through the wrong channels. Many a substance has suffered because the promoters have announced the discovery and discussed the therapeutic use through the daily press rather than by presenting the claims supported by scientific data through proper scientific mediums which have a clientele capable of judging therapeutic evidence. The unfortunate premature newspaper introduction of the new synthetic fat for diabetes-a product resulting from excellent chemical reasoning-is in sharp contrast with the dignified presentation of insulin or tryparsamide which followed a period of well-matured experimentation. The selection of a proper name is important. The name should be indicative of its chemical composition. The medical profession justly looks with suspicion on a product which has a therapeutically indicative name. When the generic chemical name is too involved for practical usage, a coined contraction is quite in order-as an example, barbital for diethylbarbituric acid. Finally, purveyors of new products to the medical profession find it to their advantage to make conservative claims for a new drug; most of them present their new additions to materia medica to the official body appointed by organized medicine to inspect the competency of the evidence and to pass on the status of new or nonofficial medicaments. By these procedures the respect and confidence of progressive physicians are won. J
For excellent discussion on this topic, see Sollmann, J. A m M e d .
A s s o c , 69, 198 (1917)
Fifty Years of Developments of Compressed Gases’ By G. 0. Carter LINDE AIR
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PRODUCTSC O , h - E W Y O R K
K 1876 most of the gases that are now so commonly
used were known to scientists and many of their properties were understood. I n some cases the development in application has been a mere refining process. Both of the very important compressed gases of today, carbon dioxide and oxygen, were then used for major purposes, for which they are still used. Carbon Dioxide and Oxygen
The well-known soda water had been developed before the centennial year, and in the inherent uses of carbon dioxide for soda water the changes do not seem to have modified the earlier principles utilized. I n the same way the use of oxygen with fuel gases to obtain a very intense and hot flame was well known, and the art of melting metals in small quantities and of lead burning was well understood. New uses have been developed for both of these gases. Carbon dioxide has been very largely utilized in refrigeration 1
Received June 26, 1926.
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work, and this development of mechanics has grown from practically nothing to its present importance during the fifty years. Within the past few years many interesting uses, considered by that industry to be on a small scale, have resulted in the use of carbon dioxide in the manufacture of automobile tires, in fire-extinguishing, paint-spraying, etc. The volume of gas used in almost any one of these minor applications would far exceed the total use of compressed carbon dioxide fifty years ago. Oxygen has added a new use in metal cutting, which has been developed since 1907, and now assumes very large proportions. It is interesting to note, however, that the use of oxygen for rapid burning of iron was described by Fletcher, fifty years ago, but nothing was done until oxygen was readily available in reasonably large quantities with the development of the containers, which will be mentioned later. I n 1876 the gases which are being included under the heading of compressed gases, to distinguish them from illuminating gas, were really not available in compressed
