REPORT
FOR
ANALYSTS
Control of Fine Chemicals and Pharmaceuticals The ever-increasing output of complex, potent new drugs and pharma ceuticals has created problems of control undreamed of 50 years a g o . To ensure the identity and purity of fine chemicals and pharmaceuticals, the analyst has had to develop new methods and instrumentation. Much p r o g ress has been made. Much w o r k remains to be done. Some of the p r o b lems and their solutions are described in this month's Report for Analysts. The author presented this paper at the Symposium on Analysis of Fine Chemicals and Pharmaceuticals sponsored by the Division of Analytical Chemistry at the ACS meeting at Atlantic City last September.
the continuing activities of re WITH search chemists leading to the dis
W . B. F o r t u n e , 43-year-old analytical chemist, has been director of control of Eli Lilly & Co., Indian apolis, since 1949. In this capacity he is responsible for the quality and purity of more than 1 1 00 pharmaceu ticals and biologicals. He received his B. S. degree in chemistry from Mount Union College, Alliance, Ohio, in 1934 and his Ph. D. in analytical chemistry from Purdue in 1938. With the exception of the period 1941—1946, when he was with the army's military intelligence service, he has been associated with Eli Lilly. He started as a research chemist, became head of antibiotics development and produc tion, and then director of control. He has published many papers and holds several patents in the field of analytical chemistry. He is author of the chapter on visual comparators in "Analytical Spectroscopy." He is an active member of the ACS and was chairman of the Indiana Section, and is a member of the American Pharm aceutical Association.
covery of more and more complex, highly potent drugs a n d chemicals, the control of these fine chemicals and pharmaceuticals m a d e from t h e m has as sumed a stature undreamed of a half century ago. W i t h the tremendous ad vances in medicine which have occurred during the past 25 years has come a need for new methods and new instrumen tation to ensure the identity and purity of the drugs evolving from this research. One cannot fully appreciate the ex t e n t of control of fine chemicals and pharmaceuticals today without looking backward briefly to the history of writ ten control procedures. Written con trol procedures probably date back to the alchemist of the 16th century. Throughout the years there were minor booklets of specifications for chemicals, such as t h e crude European pharmaco peias, the small pharmacopeia used b y t h e A r m y hospital a t Lititz, Pa., in 1778, and t h a t drafted b y the Massa chusetts Medical Society in 1808. Such local tables of specifications m e t with resistance in other parts of the country. T h e first concrete action in the United States to establish control methods through the publication of a national pharmacopeia which would be accept able in all parts of the United States was initiated in 1817 b y the Medical Society of the C o u n t y of New York. A pharmacopeial convention was held in Washington, D . C , attended by rep resentatives from all four parts of the then existing United States, to discuss this proposal. The d a t a proposed were assembled into a single volume p u b lished in 1820, in both Latin and E n g
lish. This first "Pharmacopeia of the United States of America" (3) was chiefly a book of recipes for the medical profession. However, it provided spe cific directions for making various pharmaceutical formulations of the time and therefore might be considered the first national set of control specifica tions. As new revisions appeared, control procedures became more specific. B y 1880 (6th revision), chemical nomencla ture had been introduced, descriptions of crude drugs and chemicals were more comprehensive and exact, and constitu ents of pharmaceuticals were stated in " p a r t s b y weight." T h e first general tests for h e a v y metals a n d arsenic and the first purity rubric, t h a t relating to permissible innocuous materials, a p peared in 1905 (8th revision). T h e 1916 edition (9th revision) first gave of ficial methods for determination of ash, crude fiber, volatile and nonvola tile extractive, melting, boiling, and congealing points, and specifications for standard thermometers. I n 1906, Congress enacted " T h e Food and D r u g Act." Standards adopted un der this act were those of the United States Pharmacopeia and the National Formulary. T h u s the written national standards of the time acquired official status. Control increased throughout the next 20 years, in t h a t more and more pharmaceutical products were added to the pharmacopeia. I n the eleventh re vision period there appeared, for t h e first time, "reference s t a n d a r d s " to be used for comparison a n d official as says. Such standards were provided for vitamin A, vitamin D , vitamin Β χ , VOL. 29, NO. 1, JANUARY 1957
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REPORT FOR ANALYSTS
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vitamin C, ergot, digitalis, epinephrine, ouabain, pepsin, posterior pituitary, estrone, aconite, a n d trypsin. Respon sibility for distribution of these reference standards was delegated t o t h e Direc tor of Revision of t h e Pharmacopeia. Continuing new requirements for fine chemicals a n d pharmaceutical products is a p t l y illustrated in t h e fact t h a t U S P X V , which became effective in December 1955, a d d e d 242 monographs which h a d n o t been present in U S P X I V a n d deleted only 163, for a n e t gain of 79 monographs. Control standards and methods were required for each new monograph. A history of t h e National Formulary, from its original publication to its pres ent t e n t h revision, shows t h e same trend toward more specific a n d precise meth ods of control. Industrial vs. Fine Chemicals and Pharmaceuticals
I n a n y discussion of t h e control of fine chemicals a n d pharmaceuticals t h e question is raised as t o t h e difference be tween these products a n d so-called in dustrial chemicals. Fine chemicals, FISKE CONSTANT usually considered as raw materials TEMPERATURE BATHS intended for use in pharmaceuticals or •precision units on special quotation drug products, are required t o meet • * * rigid control standards, whereas t h e Send us your standards for most industrial chemicals specifications Today are relatively lenient. Technical grade zinc oxide, used in ADVANCED paints a n d tires, for example, m u s t have INSTRUMENTS, INC. a t least 9 0 % ZnO a n d m a y have a few t e n t h s of 1 % lead. T h e U S P grade, 15 Oakcrest Road used in lotions and ointments, m u s t have Needham 9 2 , Massachusetts a t least 9 9 % ZnO a n d must give a nega Circle Nos. IB A-1, 18 A-2, 18 A-3, 18 A-4 on Readers' tive reaction t o t h e test for lead. U S P Service Card, page 73 A
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glycerol has color standards which do not apply t o t h e industrial grades. Another striking example of t h e difference between industrial a n d fine chemicals is illustrated b y precipitated calcium carbonate. T h a t used for mineral feeds, according to standards of t h e Association of American Feed Control Officials (1), m u s t contain a t least 8 0 % C a C 0 3 compared to 9 8 % for t h e U S P grade. Unlike t h e feed grade, which has no additional standards for metals, U S P precipitated calcium car bonate has a limit of 30 p.p.m. for heavy metals a n d 1 % for magnesium and alkali salts. T h e differences in production proc esses required for t h e t w o grades result in substantially higher costs for t h e U S P grade. T h e same degree of tolerance exists between fine chemicals a n d industrial grade chemicals with respect t o tests for identity. General, nonspecific tests for identity, usually consisting of simply the analytical assay, are satisfactory for industrial chemicals whereas t h e iden t i t y tests for fine chemicals and pharma ceuticals are much more specific a n d stringent. Zinc oxide used in a p a i n t m a y have present appreciably large quantities of zinc carbonate without seriously affecting t h e final product; in a pharmaceutical product even small amounts of a foreign material m a y pro duce extremely serious side effects. Strychnine as a n impurity in saccharin is a good example. Because t h e y are used for h u m a n s a n d animals, t h e i d e n t i t y of pharmaceuticals a n d t h e fine chemicals going into t h e m m u s t be beyond question a n d identity methods established accordingly.
REPORT FOR ANALYSTS
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Classical Methods Limitations Let us consider briefly t h e old classi cal m e t h o d s which h a v e been used a n d in m a n y instances are still being used for the control of industrial chemicals a n d some of t h e older fine chemicals. I n our rapidly changing chemical world, these classical methods h a v e some limi tations. Melting Point. I n determining melting p o i n t , it should be relatively simple t o i n t r o d u c e a s m a l l a m o u n t of chemical m a t e r i a l i n t o a capillary m e l t i n g p o i n t t u b e , t o place t h i s alongside a t h e r m o m e t e r in a b a t h , and t o read a t e m p e r a t u r e on t h e t h e r m o m e t e r a t t h e point when t h e observer first notices a change in t h e physical characteristics of t h e prod uct in t h e capillary t u b e . I n view of the very complex fine chemicals on t h e m a r k e t today, however, such simplicity is u n a t t a i n a b l e . T h e U S P X V edition, describes no less t h a n five procedures for determining melting ranges or t e m p e r a t u r e s of fine chemicals. E v e n if t h e observer can select some melting point t e m p e r a t u r e or range of temperatures, t h e r e are still several pitfalls in interpreting this as a n absolute indication of identity. F o r every degree of melting tempera ture there are several, often widely differing, organic compounds which m a y be present. Likewise t h e use of a melt ing point as a single criterion of i d e n t i t y is subject to t h e pitfall of absolute pur ity. I t is conceivable t h a t t h e presence of only a small a m o u n t of i m p u r i t y might throw t h e melting point of t h e compound under test into those melting
ranges exhibited b y entirely different compounds. A n o t h e r factor n o t ordinarily noted in t h e consideration of t h e melting point determination as a n i d e n t i t y test, lies in t h e physical character of t h e material u n d e r test. T h e melting point of a substance in a very finely divided state m a y be significantly different from t h e melting point of a coarse crystalline form of t h e same product. T h u s , determination of melting point as a n i d e n t i t y test of a fine chemical is subject t o variations caused b y im purities, physical character, m e t h o d of determination, observed melting point, a n d interpretation. These same varia bles enter into t h e use of a melting point as a measure of p u r i t y of a product. W e m u s t conclude t h a t t h e use of t h e melting point as a m e t h o d for determin ing i d e n t i t y or p u r i t y of a compound should b e considered only a very small link in a v e r y long chain of circumstan tial evidence. Specific R o t a t i o n . S o m e control c h e m i s t s s w e a r b y specific r o t a t i o n as a m e a n s of identification a n d d e t e r m i n a t i o n of t h e p u r i t y of a c o m p o u n d , whereas o t h e r control c h e m i s t s swear a t t h i s m e t h o d . As long as t h e o b served o p t i c a l r o t a t i o n of a s u b s t a n c e is sufficiently large t o per m i t reading t h e angular scale with a high degree of precision, t h e m e t h o d has merit. We, however, frequently set it u p as a control procedure and place considerable emphasis upon it as a n i d e n t i t y test when t h e precision of t h e reading is so low as t o m a k e t h e deter mination almost valueless. As a m e m b e r of a collaborative s t u d y group set u p b y t h e U S P C o m m i t t e e
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ANALYTICAL CHEMISTRY
REPORT FOR ANALYSTS
of Revision, I well remember the com ments concerning the proposal to add "specific rotation" as a required test under the monograph on folic acid. The standards of the test for specific rotation of folic acid state that when determined in a solution in O.liV sodium hydroxide containing 50 mg. of folic acid in each 10 ml., the specific rota tion is between + 1 8 degrees and + 2 3 degrees. Calculating back to the for mula for specific rotation where [
