ba-1956-0016.ch020

Using the Literature on the Stability of Pharmaceutical RUDOLPH H. BLYTHE and MILDRED SHOWALTER

Ingredients ZIRKLE

Smith, Kline & French Laboratories, 1530 Spring Garden St., Philadelphia, Pa.

Downloaded by UNIV OF SYDNEY on May 17, 2013 | http://pubs.acs.org Publication Date: January 1, 1956 | doi: 10.1021/ba-1956-0016.ch020

Pharmaceutical manufacturers have become increasingly aware of the need for early introduction of their products to the physician. One development problem is the stability of the product, and one way of speeding the solution of this problem is use of the literature.

IN ew formulations constitute one of the great challenges to the pharmaceutical manufacturer, for problems a r i s i n g i n the development of new drugs must be solved quickly. This urgency stems from the need to provide the physician w i t h new drugs at the earliest moment and to maintain an advantageous position i n a highly com petitive field. One of the hurdles that bar the way to prompt introduction of a drug is product stability, which has become increasingly difficult to achieve as products have become more complex. When several therapeutically active drugs are combined i n one p r e p a r a t i o n — e.g., aspirin-phenacetin-caffeine, v i t a m i n B i 2 - i n t r i n s i c factor—the stability problems are multiplied because the medicaments may react chemically w i t h each other or i n directly affect the stability of other ingredients. E v e n when there is only one active ingredient, i t is rarely possible to prepare a stable product by simply dissolving the drug i n a solvent. How Literature Can Help

The a i m here is to describe the use of the literature as an aid to solving stability problems—the type of data available and where and how it may be found. In de veloping a new formula, f u l l utilization of published information helps reduce ex perimental work on stability. Suppose, for example, one is given the problem of developing an oral liquid multivitamin preparation. The skeleton formula might be something like that shown i n Table I. Table

Skeleton Multivitamin Formula 75.0 2.5 20.0 2.0 5 0.5 15.0

Ascorbic acid T h i a m i n e H C 1 or m o n o n i t r a t e Niacinamide Riboflavin Vitamin B Pyridoxine V e h i c l e to m a k e 1 2

mg. mg. mg. mg. γ mg. cc. (daily dose)

The finished preparation must ensure uniform dosage and optimal absorption of the active ingredients, be acceptable to the patient and physician, and remain stable for a shelf life of 2 to 3 years. In developing a suitable formulation for these drugs, some of the problems are selection of solvents and solubilizers to dissolve a l l components, buffers to regulate p H , antioxidants, preservatives to prevent bacterial and mold growth, sweetening and coloring agents, and aromatics. E a c h ingredient should itself remain stable, and not cause decomposition of the active ingredients or interfere w i t h their therapeutic efficacy. In short, stability is associated w i t h every stage of development. Stability problems may arise from a number of causes, which may be chemical, physical, or biological i n nature (Table I I ) . 198

In A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE; Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

BLYTHE and ZIRKLE—STABILITY OF P H A R M A C E U T I C A L Table II.

199

Causes of Drug Instability

Chemical

Physical

Oxidation Reduction Hydrolysis p H change Double decomposition Racemization


INGREDIENTS

Biological

Insolubility Separation Loss o r g a i n i n moisture content C h a n g e i n p h y s i c a l state

Bacter al and i u n g i contamination Insect c o n t a m i n a t i o n

The best approach to work on product stability is first to review the pertinent literature cn the behavior of each ingredient. One of the compounds i n the tentative formula of Table I, ascorbic acid, may be taken as an example. The stability prob lem he-e is decomposition caused by oxidation. This decomposition is accelerated by the presence of atmospheric oxygen, light, heat, and traces of copper, iron, and manganese. In reviewing the literature, then, one should look for any information on retarding or preventing the oxidation of ascorbic acid—effect of solvents, p H , temperature, different kinds of light, other compounds, etc. In approaching this problem, at least three literature sources should be con sidered: technical data from the manufacturer, journals, and patents. If the com pound, like ascorbic acid, can be obtained from a bulk manufacturer, technical data from the manufacturer may be especially valuable, as they may not be available else where. These three sources of stability information may be supplemented by other sources (Table I I I ) . Tabla M l . 1.

2. 3.

Sources of Pharmaceutical Information

J o u r n a l s a n d bulletins Journal of the American Pharmaceutical Journal of Pharmacy and Pharmacology Drug and Cosmetic Industry Pharmaceutical Journal

Association

5. 6.

Patents Books P h a r m a c e u t i c a l chemistry a n d p h a r m a c y texts " R e m i n g t o n ' s P r a c t i c e of P h a r m a c y " " U . S. D i s p e n s a t o r y " "Merck Index" " N e w a n d Nonofficial R e m e d i e s " Official pharmacopoeias "Martindale's E x t r a Pharmacopoeia" P a m p h l e t s a n d reports Government reports T e c h n i c a l i n f o r m a t i o n available f r o m i n d u s t r i a l firms Trade association scientific papers

7. 8.

Theses P e r s o n a l communications

4.

Proceedings

of

the

American

Drug

Manufacturers

Association

W h a t is the best way to search these sources? The reference tools most useful in this particular stability problem are Chemical Abstracts, Current List of Medical Literature, and patent abstract services. Additional ones appear i n Table I V . Table IV. 1. 2.

Quarterly

3.

Current

4. 5. 6. Chemical

Chemical

Reference Guides to Pharmaceutical Literature Abstracts

(1907-

Cumulative

List

of Medical

Index

J o u r n a l indexes Indexes to books P a t e n t abstract services

) Medicus

Literature

(Q.C.I.M.) (1942-

(1927-

)

)

Abstracts

Chemical Abstracts is the most comprehensive indexing and abstracting service, and by f a r the most useful for literature searches on pharmaceutical problems. Its abstract section on "Pharmaceuticals, Cosmetics, and Perfumes" is most pertinent. In the past few years, there has been greater specificity i n the indexing of pharma ceutical articles i n the subject indexes of Chemical Abstracts. U s u a l l y only general entries are made under such headings as " S t a b i l i t y , " "Pharmaceuticals/' etc.; articles on the stability of specific compounds are indexed under the compound—as " V i t a m i n C, stability of." In A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE; Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

A D V A N C E S IN CHEMISTRY SERIES


200

Headings are generally terms or names i n most common usage i n this country; for this reason, subject headings—especially drug names—may change through the years. Less frequently used terms or names are included as cross references. Gen eric names are used i n preference to trade names, although, i f a trade name is much more familiar, articles may be indexed under the trade name. Chemical compounds are named and entered alphabetically; organic compounds are usually entered under the "parent compound," the names of the substituent radicals following alphabeti cally. In the case of ascorbic acid one needs only to look under " V i t a m i n C , " but in many instances i t may be necessary to look under three headings to locate the entries on a specific compound—the chemical name, the generic name, and the trade name. To locate references pertinent to the stability of ascorbic acid one would search Chemical Abstracts under " V i t a m i n C . " The subheading " s t a b i l i t y o f " or variations of this should be checked first. Other subheadings to be carefully checked are " o x i d a tion of," "effect of," and "antioxidants f o r . " It is worth while to skim other sub headings and their modifying phrases under " V i t a m i n C " for references indirectly related—for example, "compounds compatible w i t h , " "pharmaceuticals contg.," and "poly-vitamin soin, contg." appear i n one annual index. Other pertinent references may be found under the main headings "Pharmaceuticals," " O x i d a t i o n , " " A n t i o x i dants," and "Reaction K i n e t i c s . " Index headings pertinent to oxidation and other causes of instability are shown in Table V . These headings or variations of them are especially helpful when searching Chemical Abstracts but are, of course, applicable to other indexes. It is also worth while to check the type compound (alkaloid, amine, ketone, etc.) as well as the type preparation (tablet, ointment, lotion, etc.) under study. Obviously, such general headings are of most value i f nothing can be found under the specific compound i n question. Table V.

Index Headings Pertinent to Stability Problems

Stability R e a c t i o n K i n e t i c s , " R a t e of K i n e t i c s " under " S o l u t i o n , K i n e t i c s " Oxidation, Antioxidants Reduction, O x i d i z i n g A g e n t s H y d r o l y s i s , H e a t of H y d r o l y s i s , L i p o l y s i s , I o n i z a t i o n Racemization Double Decomposition, Degradation, Reactivity, Decomposition, " E x c h a n g e " under " B a s e s " Hydrogen-Ion C o n c e n t r a t i o n , A c i d i t y , A l k a l i n i t y , Isoelectric P o i n t , Acid-Base Equilibrium Solubility, P r e c i p i t a t i o n , S o l u b i l i t y P r o d u c t , Solutions S e p a r a t i o n , " S e p a r a t i o n " under " E m u l s i o n s , M i s c i b i l i t y " Water, Absorption, Humidity, Vaporization, Evaporation Temperature, H e a t , F r e e z i n g , R e f r i g e r a t i o n L i g h t , " I n f r a r e d " a n d " U l t r a v i o l e t " under " L i g h t " Radiation, Ultrasonics S t e r i l i z a t i o n , B a c t e r i c i d a l A c t i o n or Bacteriostatic A c t i o n , F u n g i cides a n d F u n g i s t a t s , " P r e s e r v a t i o n " under " P h a r m a c e u t i c a l s " Current

List

of Medical

Literature

To locate articles too recent to be indexed i n Chemical Abstracts, one can ex amine the subject indexes of Current List of Medical Literature. This list is pub lished monthly by the A r m e d Forces Medical L i b r a r y and indexes articles of medical interest, but does not abstract articles. Its chief value is the fact that i t is pub lished monthly, as contrasted w i t h the annual indexes to Chemical Abstracts. Cumu lative indexes are published semiannually i n June and December. Chemicals and drugs are usually indexed under their most common function or action, unless the compound is i n wide usage. I n that case, the drug or chemical name is a main heading. F o r example, articles on actinomycin are indexed under " A n t i b i o t i c s , " whereas articles on streptomycin are indexed under "Streptomycin." A s i n Chemical Abstracts, generic names are given preference to trade names. The modifying phrases i n Current List are usually more general than those i n Chemical Abstracts. In searching Current List, time is gained by l i m i t i n g the search to indexes issued since the last Chemical Abstracts subject index. M a n y of the references indexed under " V i t a m i n C " which seem pertinent to ascorbic acid stability are i n journals that may not be readily available. Abstracts of those articles are usually published


BLYTHE and ZIRKLE—STABILITY OF P H A R M A C E U T I C A L INGREDIENTS

201

in Chemical Abstracts, as they are of chemical as well as medical interest. After selecting subject headings that seem pertinent and noting the authors of the refer ences i n Current List, the author indexes i n the current year's issues of Chemical Abstracts w i l l give the location of the abstract. The date of the issue containing the abstract roughly corresponds w i t h the date of the listing i n Current List. Because of the abundance of pharmaceutical data included i n the Journal of the American Pharmaceutical Association (Scientific Edition), Journal of Pharmacy and Pharmacology, and Drug and Cosmetic Industry, i t is a good idea to check recent issues. The abstracts sections of the two latter journals cover pharmaceutical articles, often foreign, which may contain helpful information.


Information on Patents

Recent patents can be covered best by using a patent abstract service. A l though some journals—for example, Drug & Cosmetic Industry—list by title recent patent issues of pharmaceutical interest, no journal other than Chemical Abstracts indexes and abstracts patents of this type. Services, such as Invention, Inc., w i l l prepare weekly abstracts of United States, B r i t i s h , and/or Canadian patents i n specified fields of interest w i t h i n 2 to 3 weeks of patent issue. Research Information Service prepares abstracts of German patent applications. In general, U n i t e d States, B r i t i s h , Canadian, and German patents are the most helpful i n studying phar maceutical problems. This company finds that the best way to handle patent data of potential help i n stability problems is to make reference cards as the patents and patent abstracts are read. F o r example, i f a patent describes an antioxidant for stabilizing ascorbic acid, cards are made to file under ascorbic acid and pharmaceutical stability. Refer ence cards from patents, brochures, technical data sheets, abstracts and proceedings of scientific meetings, some unpublished data, and about 200 journals, both foreign and domestic, are compiled by technical personnel i n the Literature Department. Such screening by literature specialists is a p a r t i a l solution to the ever-growing prob lem of keeping abreast of scientific developments. When studying the stability of ascorbic acid, Literature Department reference cards are checked and thereby the several named sources covered at once. A s the literature specialists prepare file cards only on information likely to be of interest to the company, these files are only supplemental to the published indexing services. Other Sources

There are other indexing guides besides those shown i n Table I V , both foreign and domestic, but none is known which covers only pharmacy. Pharmaceutical Abstracts, published from 1935 to 1947 by the American Pharmaceuticul Associa tion, was discontinued because such a high percentage of the articles abstracted were also covered i n Chemical Abstracts. F o r those who wish to find listings of indexing and abstracting services, volumes such as "Guide to Reference Books" by Constance M . Winchell, published i n 1951 by the A m e r i c a n L i b r a r y Association, are available. Ways to Improve Pharmaceutical Literature

Although many published reports may be found on the stability of ascorbic acid, few or no data are available on some other stability problems—because information is not indexed adequately from a pharmaceutical viewpoint or because such informa tion has not been published. To overcome this situation, there is a need f o r more publications i n better form, and more effective index systems to cover these publica tions. To this end, certain improvements are essential to increase the value of the literature on stability and other pharmaceutical subjects. More Data on Stability. Publication of more data on basic stability studies by those engaged i n research and development is desirable, especially i n industry. Per haps 75 to 8 5 % of such papers represent investigations carried on i n academic i n stitutions, although industrial grants support much of the work. That few publi cations of this type come from the pharmaceutical industries may perhaps be at tributed to their understandable unwillingness to reveal aspects of the development of their products to competitors. Obviously, no company is going to describe how all of the problems i n developing a complex product were overcome, and i t is not even In A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE; Advances in Chemistry; American Chemical Society: Washington, DC, 1956.


202

A D V A N C E S IN CHEMISTRY SERIES

desirable from a literature viewpoint. Instead, it is desirable to publish more data on the stability of each ingredient i n simple systems. Such publications might i n clude the nature of reaction, rate of reaction, and factors and compounds affecting the reaction. There is also a need for more publications on methods and conditions of stability testing, and comparisons of breakdown at exaggerated test conditions and " n o r m a l " conditions. Better Presentation of Data. In preparing material for publication, special attention should be given to clear, concise presentation of experimental details. Such a minute detail as the source of an ingredient may alter the stability of a preparation. Moreover, the terse economy of charts and graphs makes it possible to interpret data more readily. Descriptive Titles. Authors should select titles that describe the article, elim inating generalities where possible. A l l too often titles such as "Ascorbic A c i d " make it necessary to refer to the original article to determine the scope of the paper. Index headings are often chosen from the information i n the title of an a r t i c l e — so the more specific the title, the more specific the headings. Better Indexing. Indexing of material should be adequate from a pharma ceutical viewpoint. One of the major reasons the literature on stability is so little used is that it is often difficult to find. Indexer s must be made aware of the needs of academic and industrial investigators, so that better indexing of pharmaceutical data can be accomplished. Following are suggested ways of improving the index ing of journals and indexing services: D a t a pertinent to stability should be indexed under the heading " s t a b i l i t y " when ever possible. F o r example, an article on the deterioration of ascorbic acid solutions was indexed in Chemical Abstracts under " V i t a m i n C, deterioration of soins.," but not cross-indexed under " V i t a m i n C, stability, loss of." More emphasis on the use of the word " S t a b i l i t y " as a main heading would be valuable i n certain kinds of searching. F o r example, in making a literature search recently to find comparisons of drug breakdown under normal and exaggerated stor age conditions, the searcher had no specific compounds in mind, but wanted only to learn whether any generalizations could be made by type of preparations or type of compound. Because most information on stability was indexed under specific com pounds, it was impractical to do anything but a superficial search. Pharmaceutical information included in articles in which the primary interest is in another field should be indexed. Such information cannot be located i n a litera ture search unless it is indexed under the pharmaceutical aspect as well as headings related to the main aspect of the article. F o r instance, an article on the pharma cology of a new drug which includes compatibility and stability data should be i n dexed under "compatibilities" and " s t a b i l i t y of" as well as "pharmacology of." The Special Libraries Association has already recognized that existing services are not adequate from a pharmaceutical viewpoint. To help meet this deficiency it is planning to publish a weekly abstract bulletin, giving particular attention to such items as formulations and stability, especially when they appear in articles de voted to other basic interests. Articles from about 200 journals of medical, chem ical, and pharmaceutical interest w i l l be abstracted. It has not yet been decided whether the bulletin w i l l be indexed. Dissertations. Dissertations are a source of information not fully utilized. Although complete theses have not been available generally, scientific papers based on work carried out as part of graduate pharmacy programs are frequently pub lished in the Journal of the American Pharmaceutical Association. However, to ensure the widest use of dissertations, a central listing of all titles and abstracts, and copies available for use, is desirable. "Doctoral Dissertations Accepted by American Universities," published annually, contains a listing of titles, but apparently does not include dissertations from phar macy schools and colleges. Dissertation Abstracts hss been created recently to pub lish periodically abstracts of doctoral dissertations, title listings, and title and author indexes. Copies of the dissertations are available from University Microfilms, A n n Arbor, M i c h . Since participation of the universities granting degrees is voluntary, cooperation is essential if all dissertations are to be available. Hopefully, pharmacy schools and colleges w i l l cooperate, so that theses including information on stability of medicinal agents and other pharmaceutical problems may be freely available. In A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE; Advances in Chemistry; American Chemical Society: Washington, DC, 1956.


BLYTHE and ZIRKLE—STABILITY

OF P H A R M A C E U T I C A L

INGREDIENTS

203

Another possible reference is " F a c u l t i e s , Publications, and Doctoral Theses i n Chemistry and Chemical Engineering at United States Universities," printed by the Special Publications Department of the A M E R I C A N C H E M I C A L SOCIETY. Only one issue, the 1953 edition, has been published to date, and frequency of publication has not been established. Current publications and interests of professors are listed under the name of the faculty member, which i n t u r n is found under the alphabetical list of colleges and universities granting doctoral degrees i n chemistry and chemical engineering. One w i l l find i t most useful i f he knows that work is being done i n a given field i n a certain university or by a given professor. Translations. The translation of foreign publications is often a deterrent i n a literature review. To reduce the cost of translations, the Special Libraries Asso ciation has set up a pool to make available translations of articles from a l l lan guages, except Russian, at a nominal fee. This S L A Translations Pool is seeking translations of scientific articles from government agencies, technical societies, uni versities, and industries. The National Science Foundation has recently established a center for holding and photoduplicating scientific translations, w i t h special em phasis on Russian. In Great B r i t a i n , the A s l i b "Index of Translations i n the B r i t i s h Commonwealth" serves the same purpose. F u r t h e r information on these two domes tic translation pools may be obtained by w r i t i n g : S L A Translations Pool John Crerar Library 86 E a s t R a n d o l p h S t . Chicago 1, 111.

Scientific T r a n s l a t i o n Center Science D i v i s i o n L i b r a r y of Congress Washington, D . C.

Conclusions

A critical review of the literature on each ingredient is of great value i n solving pharmaceutical formulation problems. The most useful literature tool is Chemical Abstracts, because of its compre hensive coverage of patents, as well as pharmaceutical, chemical, pharmacological, and medical journals. A literature scientist who combines f a m i l i a r i t y w i t h the literature w i t h ex perience i n pharmaceutical work can make the search more productive because of his understanding of the relatively obscure titles under which pertinent information is indexed and his knowledge of journals i n which the stability information i s i n cluded as a minor interest, and which would otherwise escape indexing. The laboratory scientist needs to enlarge the literature by reporting more data derived from basic stability studies. Including the word " s t a b i l i t y " i n the title would make i t more likely to be found i n "index services" such as Chemical Abstracts. Emphasis on the word " s t a b i l i t y " both as a main heading and subheading i n indexing is desirable. . Because theses from pharmacy schools supply much useful information, they should be submitted to Dissertation Abstracts to make them generally available. RECEIVED

November

5, 1954.


ba-1956-0016.ch020

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