REPORT FOR ANALYTICAL
CHEMISTS
U S P : Guide for the Drug Analyst The 140-year old United States Pharmacopeial Convention is a unique, independent, almost purely voluntary o r g a n i z a t i o n . Its United States P h a r m a c o p e i a , carrying the mark of l e g a l authority, serves as an unobtrusive g u a r d i a n over the nation's health. ' T ' H E United States Pharmacopeial Convention, meeting once every ten years in Washington, D. C , usually draws relatively little attention from the nation's press. Yet few documents have greater potential personal influence on the health of the American people than the United States Pharmacopeia, primary product of the decennial meetings. This results from the quasi-legal standing that the book enjoys. It is not a legally binding code in itself. But the Pharmacopeia, or USP, together with the American Pharmaceutical Association's National Formulary and the American Institute of Homeopathy's United States Homeopathic Pharmacopoeia, forms the substantial basis upon which Food and Drug Administration purity standards for médicinale are set. That status—as a foundation for regulatory codes —does have legal recognition, not only within the Federal Government, but in the various state governments as well. Thus, if USP bears the character of a legal document—if the individual monographs sometimes seem almost cookbook-like in their procedural instructions—then this is because the book's provisions must lend themselves to unrestricted use by federal and state regulatory agencies. Herein it serves what has evolved as probably the most compelling purpose of its continued existence. For it is this selfsame character which enables the physician and the pharmacist to prescribe and supply in all confidence the drugs deemed necessary for a patient's well-being. Service to Physicians In main content, all recent editions of the USP have been divided
into two sections. The larger of these, consisting of the monographs, treats of the individual drugs and chemicals "admitted" to the book. As a rule, this section specifies the minimum purity of each compound and provides an assay to establish the degree of purity. It also offers a short description and specifies the limits of pertinent properties that each must meet in order to be classified as USP. The new edition, USP XVI, includes 908 monographs. The smaller section describes general test procedures that are specified repeatedly throughout the monographs, as well as the apparatus to be used and reagent and indicator qualities. This covers a wide range of topics. For example, in USP XVI the design and analysis of biological assays are carefully discussed in a 12-page treatment that includes formulas for experimental error, tables of factorial coefficients, and other details. Yet the book is not above taking the realistic approach about such mundane concepts as the ordinary teaspoon as a volumetric measure. After noting that the American Standards Association has designated the standard teaspoon as 4.93 ± 0.24 ml., USP XVI points out the universal practice of using the common household teaspoon for dispensing medicines. Then it settles on a rounded 5 ml. as representing what the patient generally gets in a one-teaspoon dose. Remembering that USP's primary purpose is to serve the medical profession, there might seem to be an anomaly in the fact that comparatively few physicians keep copies of the book at hand. Indeed, the neighborhood doctor in day-to-day practice rarely has occasion to use it. Likewise, practicing pharmacists, although they almost invariably have their own copies at hand,
consult it less as a reference on standards than for the information it gives on dosage. This has not always been true—there was a time when USP was on every physician's and pharmacist's shelf and was probably the most dog-eared book they owned. But regardless of its place on the shelf, the book probably never has been as indispcns-
Development of a USP Monograph A frequent question asked about USPC operations concerns the way a drug gains USP recognition and how USP standards of strength and purity are set. The choice is made by the Committee of Revision's Subcommittee on Scope from the hundreds of drugs in current use. This subcommittee, consisting mostly of physicians together with a few pharmacists as advisors, is responsible for picking drugs deemed to represent the best practice and teaching of medicine. Once a drug and its dosage forms are listed for recognition, chemists on the Revision Committee take over preparation of the monographs. This process starts with invitations to a number of producers (if there are more than one) to submit their house standards on the particular drug. The Committee weighs the information received against what is generally expected of similar drugs, taking account of the method of synthesis or purification and the significance of possible contaminants. From this a tentative monograph evolves. An effort is made to select standardized procedures for tests and assays, suitable limits are set, and proposed limits are put to actual laboratory trial on samples taken from current production. Criticisms are invited and received from a number of sources as the monograph proceeds through successive stages of printing toward the page proof phase of the book. At this stage, an open conference is held to give all interested parties a final opportunity to protest any decision of the Revision Committee or suggest possible improvements in standards. What finally appears in the next revision of USP reflects the final judgment of the Revision Committee.
VOL. 32, NO. 10, SEPTEMBER 1960
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REPORT FOR ANALYTICAL CHEMISTS
able to the intelligent practice of these professions as it is today. These points might seem contradictory. But medical practice today is not medical practice as it existed years ago. When the first edition of USP was published, the doctor not only diagnosed and decided on therapy—often he also gathered his own drugs and concocted his own medicines. There is vast contrast between the complex mechanism involved in maintaining the nation's health today and the self-sufficient local medical units centering on the neighborhood physician of decades gone by. In those years USP was a physician's deskside companion, a ready reference
on medical preparations to guide him in the proper selection and blending of ingredients. In the light of present medical knowledge and practice those early concoctions were not so likely to be pure, nor did their use constitute precision therapy. Moreover, today's physician could scarcely make our far more complex, far more uniform and pure drugs—even if he wanted to. But if the physician's interest in actually compounding drugs has lessened, this does not imply a lessening of his interest in what goes into those drugs. There has been no diminution of his interest in and professional responsibility toward
guaranteeing the quality of his prescriptions. Thus, the core of contemporary USP's great service to medicine is that it gives the physician his most effective instrument in specifying the quality of the drugs he prescribes. National Formulary Is Similar
Any discussion of USP must at least mention the National Formulary. They are so similar in format and purpose that reference to the one in ordinary parlance almost implies a reference to the other. Published by the American Pharmaceutical Association, the National Formulary is also one of the bases for FDA regulations and, like USP, appears at five-year intervals in revised form. The scope of the original USP, published in 1820, was restricted to drugs believed to have the greatest therapeutic value, regardless of the extent of use. Apparent duplication was avoided as much as possible by excluding secondary preparations of essentially equal medicinal value. That policy has never changed. Consequently, to provide coverage of those drugs not appearing in USP, but also possessing therapeutic merit, the American Pharmaceutical Association undertook publication of its National Formulary. The first edition came out in 1888, and the revision and publication programs of the two books have been carried on concurrently and harmoniously ever since. The two books do differ in respect In USP's New York headquarters hangs a 7- by 5-foot painting to sponsorship and financial strucdepicting the first United States Pharmacopeial Convention in 1820. ture. The United States PharmaThe artist, Robert Thorn, is famous for his series of paintings on the copeial Convention is an incorpodevelopment of pharmacy, sponsored by Farke, Davis & Co., rated organization run predomireproductions of which are seen in pharmacies throughout the nantly on the basis of voluntary incountry. Mr. Thorn, as is his custom, did considerable research dividual service. It has no formal on his subject prior to touching brush to canvas. Since the first relationship with any governmental meeting was held in the old Senate chamber, one of Mr. Thorn's first agency nor with any professional contacts was with the late Mr. Mitchell, Senate sergeant-at-arms. society, except that various agenUpon stating his business, during which he told of 11 physicians cies, societies, and institutions desholding their meeting in the Senate chamber, Mr. Thorn got a dis- ignated in the USP constitution concerting reaction from Mr. Mitchell, who demanded to know who and bylaws are entitled to appoint had given 11 doctors permission to use that room. Further research delegates; these constitute the Conrevealed that, of the 11 physician-delegates, one was also a Senator vention for the ten-year term of infrom the State of New York and two others were Congressmen from dividual membership. In passing it is noted that the American Chemithe State of Georgia. The gentleman with his back to the artist cal Society is one of the 277 organirepresents an ingeniously simple solution to one of Mr. Thorn's zations entitled to appoint a deleproblems—no contemporary portrait could be found from which gate each. The National Formuto copy the man's true facial features lary is produced under the author20 A
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REPORT FOR ANALYTICAL CHEMISTS ity of the American P h a r m a c e u t i cal Association, the principal organization of professional p h a r m a c y . A standing committee of A P h A is charged with revising the book periodically a t times coinciding with the appearance of each new P h a r macopeia. U S P C income derives only from the proceeds realized in the sale of the book and U S P Reference S t a n d ards, as well as from return on invested reserve. Yet the m o n e t a r y value of scientific contributions of the members of the Revision Committee and of the pharmaceutical industry as a whole is inestimable a n d cannot be disregarded in a p praising the whole worth of the program. I t is somewhat anomalous t h a t the organization, concerned as it is with establishing specifications and procedures of analysis, has no l a b oratory of its own. On the other hand, it does conduct extensive l a b oratory research through facilities available to the voluntary members of its Committee of Revision. Perhaps an even greater anomaly was the fact t h a t , until recently, the organization had no permanent headquarters. This existed in the office files of whoever happened to be the current chairman of the Revision Committee. A full-time Director of Revision first took over the duties of chairmanship a n d direction of the t T SP program in 1950.
published privately or on a limited regional basis, were written primarily for the physician himself as a concocter of remedies. As such they usually listed those medicines which were thought by the authors to be most effective in bringing about desired results. B u t , lack of uniformity with respect to composition, quality, usage, and even terminology was ever more plaguing the nation's physicians. An ailing traveler could not be sure of receiving the same medicine under a given n a m e from one place to another, much less rest confident that the quality and purity would be the same. Correction of these difficulties was the goal of the first United
States Pharmacopeia. This nationwide listing was designed to establish national uniformity in the awareness, preparation, compounding, and nomenclature of medicines. Because of this, and inasmuch as the formal analytical chemistry and pharmaceutical professions were practically nonexistent, the first Pharmacopeia was a document prepared essentially for physicians b y physicians. So the situation remained for the first two revisions of the book. Pharmacists did not help actively in preparing a revision until U S P I I I appeared in 1850, and professional analytical chemists weren't concerned until much later. After the Fifth Revision was p u b -
Enter A n a l y t i c a l Chemistry D r u g companies and those chemical firms producing items covered by the P h a r m a c o p e i a are of necessity vastly interested in its content. Moreover, since each revision of the compendium has dealt with a n a l y t i cal procedures to a greater extent t h a n its predecessors, it is among the analytical chemists in these firms t h a t such interest is concent r a t e d . I t is only in recent decades, however, t h a t analytical chemistry has been of any great pertinence to the book's objectives. T h e feeling in favor of a national pharmacopeia was originally inspired among physicians b y an awareness of the need for some organized list of legitimate drug p r e p arations. Early pharmacopeias,
Whether it be talcum or opium, the compound on the pharmacy shelf that bears the USP classification is backed by a USP monograph, and its purity is enforced by the United States Food and Drug Administration VOL. 32, NO. 10, SEPTEMBER 1960
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FREE DATA KIT
REPORT FOR ANALYTICAL CHEMISTS
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lished, in 1870, there was wide spread criticism to t h e effect t h a t little recognition was given to new and improved pharmaceutical and chemical processes which, on a large scale, were then coming into their own. As a result, the 1880 revision placed emphasis on standards and on providing test methods. This set t h e p a t t e r n for later revisions, and each succeeding period between editions found increased emphasis on specifications a n d procedures for testing. Even so, it was not until 1942 t h a t analytical chemists entered the scene in a more or less formal way, although they already were on hand informally as far back as 1920, when an agreement was loosely made to include 17 physicians and 33 pharmacists " o r other technical experts" among t h e Revision Com mittee's 50 members. This ratio, in which one third of t h e commit tee's members were to be physicians, was written into the Pharmacopeial Convention's revised bylaws in 1942. T h e other two thirds is now made up of pharmacists, analytical chemists, bacteriologists, and other scientific experts, and t h e Commit tee of Revision now totals 60 mem bers. The Committee of Revision is the backbone of t h e United States Pharmacopeial Convention. T h e Convention proper, consisting of u p to 277 members a t the present time, meets just once in each decade to authorize t h e publication of U S P and elect Revision Committee mem bers for t h e succeeding ten-year period. Committee members are usually appointed to one or more of the subcommittees, and these m a y meet repeatedly during t h e ten years. T h e Committee of Revision is charged with the duty of selecting the drugs to be admitted to t h e book and of preparing t h e required monographs on specifications and test procedures.
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One should bear in mind t h a t through t h e years and in spite of great changes in t h e book's format, the Convention's make-up, and t h e monographs' legal status, t h e fun damental objective has continued to be service t o the medical profession. I t is not surprising, then, t h a t phy sicians on t h e committee should re
tain responsibility for selecting t h e drugs to be recognized. I n this they are assisted by a small group of pharmacists, b u t t h e physicians do play the major p a r t in this phase. Selections having been made, it then falls to t h e other members of the committee to assume responsi bility for technical aspects of t h e monographs. T h e chemists and other scientific experts gather all the technical information concern ing t h e selected drugs and chem icals; and they devise suitable procedures for assay and for tests of strength and quality in both pure and dosage forms.
There Are Problems Setting reasonable specifications and standards for a given drug or medicinal is never an easy task. I n some cases it m a y be necessary t o define w h a t constitutes a material before such specifications can be considered, and a t t h e outset some disconcerting possibilities can occur. Illustrating this, U S P C was in volved in its own version of a whis key rebellion in t h e 1910-1920 period, arising from attempts to de fine whiskey. U S P standards for whiskey called for distillation from grain, followed by aging in charred barrels for at least four years. This was shortly after enactment of t h e Food and Drugs Act of 1906, which made U S P one of t h e bases for drug purity regulations. D r . H a r vey W. Wiley was director of t h e D e p a r t m e n t of Agriculture's Bureau of Chemistry which, a t t h e time, was charged with enforcing provi sions of t h e Food and Drugs Act. With due conscientiousness, D r . Wiley ruled t h a t all brands of blended whiskeys—those made partly with pure alcohol, or neutral spirits—should be labeled "imita tion whiskey." This decision, of course, w a s quite unpopular with the distillery interests and t h e r e sulting uproar brought USP publi cation activities to a halt for more than a year. Finally, after much discussion, the whole argument was settled simply by dropping whiskey standards from U S P . The U S P approach to specifica tions and test procedures reflects a philosophy t h a t h a s evolved over
the years. For example, USP de fines in minimum terms the purity required of the material concerned, taking account of the kind and amount of innocuous, unavoidable impurities that are likely to be pres ent. Needless to say, an effort is made to recognize all objectionable impurities and limit their content by specific tests. It is here that occasional conflict arises between the analytical chemist with his con cept of analytical purity of com pounds and the production chemist who, on the other hand, is concerned primarily with purity sufficient for medicinal purposes. Since the lat ter chemist's goal is therapeutic efficacy and safety, he sees the need to rule out only those impurities that are harmful in excessive amounts or that interfere with the action of the drug principle itself. Thus it seldom happens that a com pound of suitable medicinal quality is of a reagent or analytical grade of purity. Obviously, to require 100 per cent chemical purity in all medicinal compounds would be un realistic since, at best, it would generally greatly increase manu facturing costs. The concept of a minimum figure for purity also allows for some deterioration in storage and the inevitable differ ences in assays reported by different analytical chemists. General suitability of a given assay or test method is another problem encountered in setting up USP analytical procedures. In some cases the procedures used in the pharmaceutical manufacturer's control laboratory may not be suit able for pharmacopeial use. The individual manufacturer knows what goes into his product and he has a reasonable expectation of what will be found in his analysis; procedures in USP must be designed for testing products of many man ufacturers using dissimilar bulking agents, lubricants, disintegrating substances, preservatives, and colors. USP policy is one of not restrict ing the use of any suitable inactive ingredient in dosage forms simply because it might interfere with an assay. Rather, the assay should be devised so as not to be subject to such interference. In this respect
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REPORT FOR ANALYTICAL CHEMISTS USP XV was a bit weak, for example, in certain ultraviolet spectrophotometric assays. Recogniz ing the fact, U S P X V I ' s Revision Committee has developed, wherever possible, suitable extraction pro cedures whereby the active ingre dient of a dosage form will be sep arated from any inactive ingredients before quantitative determination is made.
Methods Are Modern
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So it is t h a t great skill is needed to separate quantitatively the often small, sometimes minute, amounts of active drug ingredient from rel atively large amounts of excipient. Then, devising a suitable procedure for measurement calls for consider ation of every tool at the analyst's disposal. These requirements might involve simple gravimetric proce dures on a readily isolated prin ciple; or they might involve chro matographic separation, followed by quantitative infrared spectro photometry. They might be too stringent for the use of any chemi cal-physical procedure—USP speci fies a microbiological assay for vitamin B l a activity in decavitamin tablets, whereby millimicrogram quantities are determined with sur prising accuracy. Since new editions of U S P appear only a t five-year intervals, an ap preciable time lag between an an alytical method's development and its use in U S P might seem reason able. Yet in the first place, a fiveyear publication interval need not in itself cause delay in the appear ance of a new and proven method. T h e policy of issuing supplemental procedures in the interim obviates criticism on t h a t score. More t h a n this, however, U S P cannot be said to lag in the use of proven methods. Just as the book is a compendium of medicinals shown to represent the best use in practice, so too should analytical procedures used in test ing them represent the best of an alytical practice. This is dictated by the very n a t u r e of U S P . Pos sibly the most rigorous require ment to be met by a U S P method is reliability with respect to ac curacy and precision. The same
requirement is usually dictated in industrial and research use, and from this point of view it will be found t h a t U S P takes up the newer methods about as rapidly as do other specification volumes. Use of Spectrophotometry Ultraviolet spectrophotometry had appeared in U S P XV, published in 1955. As is noted earlier, a feel ing existed t h a t in some cases the method was inadequate because of potential interferences due to the presence of inactive components. T h a t difficulty has been overcome to a large extent, but another limi tation of ultraviolet spectrophotom etry is its inherent inability to dis tinguish between closely related members of a given class of drugs or between structurally similar sub stances. T h u s , while ultraviolet methods were used for many of the antihistaininic agents in U S P ΧλΓ, their use for identification and as say of the more closely related members of this class was precluded because of the similarity of the compounds' ultraviolet spectra. Infrared spectra, on the other hand, generally enable identifica tion of closely related compounds that are indistinguishable by other methods. Particularly pertinent to USP, they will conclusively iden tify all the steroids, antihistaminic agents, and members of other struc turally similar groups admitted to the book. For this reason infrared identification procedures are used for the first time in no less t h a n 90 monographs in the newest edition of USP. This has its own interesting as pects. In developing details of pro cedures in identification by infra red, several approaches can be used. One of the more obvious things would be to publish the infrared spectra of the substances involved; but this is impractical from a pub lisher's standpoint. Another, less exact, method would be to spec ify wave lengths at which absorp tion bands are observed for indi vidual compounds and to character ize the bands by terms such as strong, moderate, weak, and shoul der. This is done in one case in which the alternative about to be mentioned could not be adopted be-
REPORT FOR ANALYTICAL CHEMISTS
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ANALYTICAL CHEMISTRY
cause no stable reference standard is available. This third alternative would be to specify t h a t the spec trum of the substance conform to t h a t of a reference standard of the same substance in a similar deter mination. There m a y be other pos sibilities, but these three were con sidered by the Revision Committee and the last one was chosen for use in 89 of the 90 monographs in volved.
sodium radio-iodides must show an iodide band having an Rt within five per cent of t h a t found for an iodine-131 of known purity, and the iodate band should not have more t h a n five per cent of the activity of the iodide band. Radioactive reference standards are not provided by USPC, since these are readily available on a commercial basis.
Radiochemical Methods
Chromatography and Other Methods
Admission of six radioactive com pounds to U S P X V I has brought on the necessity of including assay methods for radioactivity in the procedures. Geiger-Muller or scin tillation counting assemblies are specified for the assays and a vari ety of calibration standards are used for quantitative comparison. Identification of radiocyanocobalamin solution is effected by a requirement t h a t it show a gammaray scintillation spectrum identical with t h a t of a specimen of cobalt-60 of known purity. Radiogold solu tion must show a g a m m a - r a y scin tillation spectrum identical with t h a t of gold-198 of known purity, and sodium radiochromate injection must show a g a m m a - r a y scintilla tion spectrum identical with t h a t of chromium-51 of known purity. Sodium radiophosphate solution is required to emit beta radiation having a mass absorption coefficient in aluminum within five per cent of t h a t found for a sample of phosphorus-32 of known purity. Radioiodinated serum albumin must emit beta radiation having a mass ab sorption coefficient in aluminum within five per cent of t h a t found for a sample of iodine-131 of known purity. Sodium radio-iodide is specified in both capsule and solution form, but the means of identification of course is the same in both cases. Both forms are required to emit beta radiation having a mass absorption coefficient in aluminum within five per cent of t h a t found for a sample of iodine-131 of known purity. It will be noted t h a t this requirement is similar to t h a t for radio-iodinated serum albumin. B u t additionally, paper radiochromatograms of the
This reference to the use of radio chromatograms in identifying the radioactive compounds reflects by no means the only use of chroma tography in the Sixteenth Revision. In the assay of vitamin D , for ex ample, the methods of chromatog raphy and spectrophotometry are combined to replace a somewhat tedious and costly biological assay formerly used. In the new proce dure, interfering substances are re moved by passage of a solution of the vitamin through two chroma tographic columns, after which it is treated with antimony trichloride reagent. The latter gives a pink color which is evaluated spectrophotometrically. Another séparatory use of column chromatography is in the assay of the cardiotonic glycoside, digitoxin, where it is used to separate the pertinent glycoside from related glycosides. Chromatographic methods are used also for identification of several compounds in the new edition. Paper chromatography enables identification of another cardiotonic glycoside—digoxin—as well as of calcium leucovorin, an antidote for folic acid antagonists. I t is used also in identification of estradiol dipropionate injection and ethinyl estradiol tablets. Complexometric titrations, too, have proved valuable in some of the USP X V I procedures. Titration of calcium ion in this way has shown itself to be much better than the oxalate precipitation used previously. Since single indicators are not always entirely satisfactory in titrations of this type, U S P usually specifies the use of mixed indicators. Calcium carbonate, calcium chloride, calcium gluconate, and calcium
REPORT FOR ANALYTICAL
Acetylene at 13.7 microns, _ equivalent to 0.008 ppm at ~ 25 χ scale expansion and 10 — atmospheres cell pressure. -
