Role of the Compendia in Controlling Factors Affecting Bioavailability of Drug Products*

Role of the Compendia in Controlling Factors Affecting Bioavailability of Drug Products* By Martin I. Blake

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he generic equivalency of drug products enters into a number of current controversies including "brand vs generic drugs," repeal of antisubstitution laws, establishment of a federal drug compendium and others. In all of these debates the involvement of the official compendia must always be considered. This article discusses the role of the USP and NF in establishing standards for controlling factors affecting the bioavailability of drug products. Drug Product 'Equivalency' A drug may be defined as an agent employed in the diagnosis, mitigation, treatment or prevention of disease in man and in other animals. Generally, drugs are chemical compounds and are not administered to patients as such, but rather are combined as part of a formulation with one or more nontherapeutic agents referred to as excipients, pharmaceutical aids, additives or adjuncts. The final product is a dosage form or drug product. Typical dosage forms are tablets, capsules, ointments, suppositories, etc. The nontherapeutic agents are necessary in order to provide the active therapeutic agent in a form suitable for administration to a patient with assurance that the optimum therapeutic effects will result. The specific role of the additive may be to emulsify, stabilize, suspend, preserve, dilute, solubilize or to flavor. If it were not necessary to incorporate the active component in some type of formulation, then there generally would be no problem in assessing "equivalency" or "nonequivalency" of drugs. However, in comparing dosage forms, one must consider (a) the nature of the other components in the admixture, (b) the manufacturing procedure used in preparing the formulation and (c) the interaction of the other components with the active constituent. These factors o Presented at the 32nd Series of Lectures on Modern Pharmacy, Allerton Park, Monticello, Illinois, November 1970.

may affect the therapeutic efficacy of the dosage form. In the Second Interim Report of the HEW Task Force on Prescription Drugs l it is noted that considerable confusion exists over the term "generic equivalent" and in the report the term is not used. In its place the terms chemical equivalent, biological equivalent and clinical equivalent are used. Chemical equivalents are identical dosage forms which contain identical active ingredients in essentially identical amounts and which meet the physical and chemical standards in the official compendia. Biological equivalents are chemical equivalents which produce the same biological or physiological availability when administered in the same amounts as measured by blood, serum or plasma levels or from urinary excretion data. Clinical equivalents are chemical equivalents which provide essentially the same therapeutic effect when administered in the same quantities to patients suffering from the condition or disease for which the drug is intended. The current versions of the official compendia provide standards and specifications relating to the identity, purity, quality and strength of drugs and their dosage forms , thus assuring chemical equivalency where it exists. Future editions hopefully will contain protocols and standards for assuring optimum biological availability. Drug Standards and Enforcement Poor quality and the extensive adulteration of drugs at the turn of the century moved the U.S. Congress to pass the Pure Food and Drugs Act of 1906 which recognized the USP and NF as "official compendia" and as legal standards for strength, quality and purity of drugs. This authorization was reaffirmed by the 1938 Federal Food, Drug and Cosmetic Act which further elucidated the role of these books as legal standards for drug products. In essence, all drugs listed in the USP and N F must conform to the specifications

and standards of strength, quality and purity indicated in these books. The 1938 act was a direct result of the notorious "sulfanilamide elixir" incident which occurred in October 1937, and it required for the first time proof of safety before a drug product could be placed on the market. In addition, it required the disclosure of all active ingredients on the label of the container. In 1962 the Kefauver-Harris Amendments to the Federal Food, Drug and Cosmetic Act were prompted by the infamous "thalidomide" incident and required that both safety and efficacy be established before a drug product becomes marketable. Through these acts Congress entrusted the pharmaceutical and medical professions with the responsibility for establishing quality standards for drugs and their dosage forms. The NF andi USP were designated as the official compendia. It is noteworthy that these publications are prepared by completely private and independent organizations. The United States is essentially the only country in the world in which the compendia are under the control of private groups instead of being an instrument of the government. Practically all other pharmacopeias are published by an agency of the central government. Unfortunately over the years there ha ve been several exceptions to the principle stated in the previous paragraph. Since the turn of the century the U.S. Public Health Service has supervised production and has set purity and potency standards for all biologicals. The Food and Drug Administration sets standards and batch certifies most antibiotic preparations. Since 1939, when the patents on insulin expired, FDA has batch certified insulin products, although the official compendia have established the specifications and standards for most of these products. There appears to be no sound basis for this dichotomy in standards of responsibility. Setting of standards and batch certification of antiVol. NSll, No. 11 , November 1971

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Martin I. Blake is professor of pharmacy and head of the department of pharmacy at the University of Illinois college of pharmacy. He obtained his BS in pharmacy at Brooklyn College of Pharmacy, MS at Rutgers University and PhD at The Ohio State University. He has taught at North Dakota State University and Duquesne University colleges of pharmacy. In 1959 he was a research associate at Argu'me National Laboratory and has been a consultant and faculty associate since 1960. His memberships include APhA, Academy of Pharmaceutical Sciences, AAUP, ACS and AAAS. Blake is the author or co-author of over 80 scientific publications, two chapters and a textbook. His research interests include isotope effects, pharmaceutical analysis and biological effects of deuterium. He is currently a member oj the National Formulary Board and the USP Revision Committee.

biotics by a governmental agency has not resulted in fewer misfortunes with these products than with those for which standards are set by the nongovernmental compendia. Congress, through the acts mentioned previously, has delegated the authority of enforcement of compendial standards to the secretary of HEW and through him to FDA. Lloyd Miller, former director of revision of the USP, appearing before a senate subcommittee in 1967, accurately described 2 the situation, stating "that the U SP and the NF provide the yardstick against which the FDA measures the quality of drugs moving in interstate commerce." It is the primary responsibility of the pharmaceutical manufacturer to commercially produce drugs and drug products which comply with compendial standards and to adhere to good manufacturing practices and quality control procedures . At the local level, the community or hospital pharmacist must likewise apply good pharmaceutical techniques in compounding and dispensing prescriptions. This tripartite structure of activities is unique and constitutes an effective system of checks and balances on an important phase of health care in the United States. To summarize, the pharmaceutical and medical professions through private organizations prepare and publish the 6fficial compendia which contain standards for drugs; an agency of the government, FDA, enforces the standards adopted by the official compendia, and the pharmaceutical industry, including the practicing pharmacist, produces drug products of highest quality which must comply with compendial standards. As a result, the public and members of the health professions are assured that only safe and efficacious drugs and drug products reach the market. Official Compendia-Background The USP is presently in its 18th revision and is published by the u.S. Pharmacopeial Convention, Inc., which consists of representatives of the colleges of pharmacy and medicine, state medical and pharmaceutical associations and certain federal government 604

agencies. The convention has met decennially for the past 150 years, the last meeting having been in Washington, D.C., in April 1970, at which time the constitution and bylaws were revised and a new board of trustees and committee of revision were elected. Henceforth, the USPC will meet on a quinquennial basis. The revision committee is composed of 20 specialists in the medical sciences and 40 specialists in the pharmaceutical and allied sciences. The committee. is further supported in its revision activities by the appointment of a number of advisory boards and panels composed of distinguished medical and pharmaceutical scientists. The overall revision program is under the shared supervision of an executive director who is responsible for the drug selection program, and a director of revision who is responsible for the revision and preparation of the monographs and general tests chapters. The USP and NF were revised every ten years until 1940 and since then both books have been revised and expanded every five years. The NF is a publication of the American Pharmaceutical Association and is currently in its 13th edition. The revision work is conducted by specialists from various fields who serve on the eleven-member National Formulary Board or on one or more of the numerous committees and advisory panels composed of experts representing pharmacy, medicine and the physical and biological sciences. The revision activity is performed under the general supervision of the director of the National Formulary. The board develops procedures to be followed for admitting articles to the NF and establishes criteria for · standards and specifications for the drugs and drug products so admitted. The revision programs of the USP and NF are supported by the sale of the compendia and from the fees charged for reference standards which are used in laboratories performing the official tests. About two-thirds of the compendia are purchased by practicing pharmacists, while essentially all of the reference standards are used in governmental testing laboratories or by the pharmaceutical industry. Some 20 percent of

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USP Reference Standards are sold abroad indicating worldwide acceptance of the compendia. The admission of a drug or dosage form into U SP since the first edition ( 1820) has always been based on proven therapeutic value. The admission policy of the N F from the first publication (1888) up to NF XII was also based on frequency of use in addition to therapeutic value. However, commencing with NF Xll, admission has been based solely on therapeutic value. This policy change was adopted in 1961 , and it anticipated the 1962 drug amendments which require proof of efficacy, as well as safety, before a drug product can be marketed. This policy change on admissions does not place the NF in competition with the USP . There never has been, nor will there be now, duplication of identical drugs or dosage forms in concurrent editions of the USP and NF although closely related drugs may appear in both, e.g., ephedrine sulfate, USP, and ephedrine hydrochloride, NF. For combination dosage forms, USP3 maintains a conservative policy, "restricting it to the vitamins, electrolyte solutions, a triple sulfonamide mixture and the combinations of a local anesthetic with epinephrine." NF, 4 on the other hand, limits admission "to those combinations for which there is a therapeutic advantage to the patient as contrasted with administration of the separate individual therapeutically active ingredients." Through custom U SP has first option on the admission of items. Deletions from the U SP may be considered for possible inclusion into the subsequent NF and, also, promising new drugs are screened thoroughly for possible admission to the NF. Both compendia are now revised every five years and become official on the same date. This requires a close working relationship between the two groups involved in revision activities. It is not uncommon for an individual to become involved in the revision work of both comp'endia. Where appropriate, joint panels of experts function to advise on matters of common interest to both compendia. In recent years there has been an increased interest shown in a possible merger of the USP and NF; particularly in view of the complementary admission policies of the two books. At the 1970 meeting of the U.S. Pharmacopeial Convention a resolution was adopted urging "that the Board of Trustees and the Committee of Revision intensify efforts to coordinate the activities and programs of the United States Pharmacopeia and the Na tional Formulary , and to explore the advantages and feasibility of unification of these activities and programs with the

objective of producing a single compendium of standards and tests for official drugs and dosage forms." Merger talks pursuant to this resolution have already been undertaken, but it should be noted that a possible outcome of these negotiations could be simply a coordination of programs without necessarily the formulation of a single volume. In view of the considerable overlap of activities and duplication of efforts engaged in by the two revision bodies, such talks were apparently inevitable. At any rate no drastic changes in programs are anticipated during the present revision period which should culminate in the publications of USP XIX and NF XIV during 1975. Official CompendiaMonograph Information

A major portion of the compendia is devoted to monographs for drugs and dosage forms. Each drug and dosage form is treated separately. Monographs for the drug entities contain standards, specifications and other pertinent data concerning the particular drug. These include the name of the drug, structural and chemical formulas where applicable, definition, description, composition, tests for identity, limits tests for impurities, assay for active constituents, potency requirements, special precautions for handling, pharmacologic category or use and dosage information. Of particular import are those standards which are intended to establish the identity, purity, strength and quality of the drug entity. One or more simple tests are included for identification of the drug. These are not intended to characterize the compound, but rather to confirm its identity, and include color reaction tests, flame tests, spot tests and precipitation reactions. Tests in other categories within the monograph may also serve to establish and confirm the identity of the drug. These will be noted. Purity tests are included in the monograph and establish limits for a variety of impurities which may be of a general nature (heavy metals, halide ions) or they may be specific impurities (water, sulfate, selenium). Limits tests are generally included for contaminants which may be intermediates or byproducts resulting from the synthesis ' of the drug, such as p-chloroacetanilide in phenacetin, or impurities which may result from the breakdown of the molecule, for example, p-aminophenol in acetaminophen. Almost every drug monograph has an assay procedure for determining quantitatively the strength or potency of the drug. It is essential that the assay procedure be specific and selective in the presence of impurities arising from the decomposition

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of the active component or possible contaminants occurring through preparation or synthesis. Tests for establishing quality of the product may overlap with one or more of the categories already mentioned. These include mel ting ranges or boiling ranges, optical rotation, refractive index, infrared and ultraviolet spectral analysis, specific rotation and other tests dealing with physical measurements. Monographs for dosage forms differ somewhat from those of the individual drugs. Since, in general, all ingredients indicated for each dosage form are listed as individual monographs and since adequate standards and specifications are included there, only those tests and specifications are included in the dosage form monograph which pertain to the quality of the dosage form and are not otherwise listed in the individual drug monographs. Usually one or two identification tests for the active component are required, appropriately modified to take into account possible interference from excipients or other constituents which may be pres. ent in the dosage form . An assay is generally required more as a quality control check on the manufacturing procedure than for assessing the purity of the active constituent. A tablet dosage form may assay acceptably between 90 and 110 percent recovery of active constituent, while the purity rubric for the drug substance may require a purity of better than 99 percent. The assay procedure as noted for the drug must be specific for the active component in the presence of contaminants, decomposition products and excipients and additives used in the preparation of the dosage form . As a rule the compendia provide a preliminary isolation or extraction procedure for separation of the active constituent from the other components of the dosage form. For certain classes of dosage forms, for example, tablets and capsules, the monographs include a weight variation or a content uniformity test which controls dosage form homogeneity. A variety of other tests are designed to control the suitability of the dosage form for administration to patients. These may include sterility testing, tablet disintegration time and dissolution rate test, pH, particulate matter (ophthalmic ointments), acid-consuming capacity (antacid preparations) and others. Forms and sizes of dosage forms commonly available from commercial sources are generally included in these monographs. Standards pertaining to packaging, storage and labeling are provided. These are particularly important to the community and hospital pharmacist. Another relatively large section of the compendia deals with procedures, processes, techniques and special ap-

paratus employed in individual monographs. This is the general tests section of the compendia and includes such topics as spectrophotometry, chromatography, titrimetry, arsenic tests, sterility, refractive index measurements, to mention a few found in the USP and NF. In addition, the compendia have sections which generally provide specifications for every reagent and solution required to perform the official tests and assays. A detailed and comprehensive analysis of the content of the official compendia is presented by Edward G. Feldmann,5 former NF director. Therapeutic N onequivalency It is generally accepted by pharmaceutical and medical scientists that compliance with compendial standards assures chemical equivalency, as defined earlier, in drug products. However, the situation is quite different with regard to assurance of biological equivalency and clinical equivalency (therapeutic equivalency). The Task Force on Prescription Drugs 1 found "that lack of clinical equivalency among chemical equivalents meeting all official standards has been grossly exaggerated as a major hazard to the public health." The report also supports the view that compliance with compendial standards and specifications provides suitable presumptive evidence for the therapeutic equivalency of chemical equivalents. However, the report also avers that, "Even though such cases (instances of therapeutic nonequiva1ency) are few, and others may well be reported in the future, these cannot be ignored, and the problem deserves careful consideration because of the medical and economic policies which are involved." Feldmann 6 stated before a Senate subcommittee that "Information available in the published literature reveals only isolated case histories, and very few scientifically performed studies, which demonstrate substantial differences in 'therapeutic equivalence' between two comparable drug products (also referred to as generic or brand equivalence). Consequently, while we must recognize that this factor exists, currently available evidence indicates that only very seldom is there a difference in clinical performance if the official compendia standards are met by both drug products. . Undoubtedly, this problem has been grossly overstated by those who would benefit by clouding this issue." Miller 2 stated "that not more than a dozen drugs have presented problems with respect to physiHe further ological availability." points out that it is rare for a drug product to meet compendia standards and fail to produce the expected clinical effect. Feldmann, speaking at an American Society of Hospital PharVol. NSll, No. 11, November 1971

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macists meeting, 7 allowed that chemical equivalency alone does not constitute therapeutic equivalency, but if a product does meet the chemical and physical standards provided by the official compendia, then the product can be expected to be therapeutically equivalent. Lasagna8 reiterates the fact that "chemical equivalency" does not necessarily guarantee "therapeutic equivalency." Only a handful of drugs have thus far been shown to meet U SP and NF standards but proved therapeutically ineffective. There will probably be more examples in the future. He further states, "At the very least, the public deserves to have drugs that meet the current standards, whatever they may be-a label saying "USP" or "NF" should guarantee that the drug inside the package has indeed been shown to meet USP and NF standards." He reminds those who are responsible for establishing standards for drug quality that they should keep revising existing standards as new scientific and technological information comes to light. Reese in a review article 9 points out "that therapeutic equivalence is for practical purposes a fact for 3,000 single-entity and 4,000 combination drug products on the market that meet USP, NF or other appropriate standards. The exceptions would include perhaps 50 drugs for which therapeutic equivalence is usually a fact, but not always ." Much has been written in the past decade on the extent of therapeutic nonequivalency of drug products. Levy and Nelson 10 show with a number of examples where USP and NF standards do not assure therapeutic equivalency for generically identical drug products. They offer suggestions for improving the official standards in order to assure more adequately therapeutic efficacy of dosage forms. Slesserl l maintains that the official compendia do not contain therapeutic performance tests for drug products, nor can the compendial specifications or tests be used to evaluate therapeutic performance function. Sadove et al. 12 cite 24 factors which can affect markedly the pharmacologic activity of a drug and which may lead one to the conclusion that chemical equivalency of drug products does not assure therapeutic equivalency. Levy13 discusses at length the effect of physical, chemical and biological factors on the therapeutic efficacy of the active ingredient in dosage forms . Riegelman 14 and Schneller15 cite some 15 drugs or classes of drugs where dosage forms have been shown to elicit therapeutic nonequivalency primarily as a result of formulation factors. These reports were part of a symposium1 6 which dealt entirely with the subject of formulation factors affecting the therapeutic 606

TABLE I A Number of Drugs Whose Dosage Forms May Exhibit Differences in Bioavailability* Ampicillin Bishydroxycoumarin Chloramphenicol Diphenylhydantoin Erythromycin Griseofulvin Nitrofurantoin Novobiocin Oxytetracycline 0<

Phenylbutazone Prednisone Quinidine Spironolactone Sulfa drugs Theophylline Thyroid Tolbutamide

These are considered in refe rences 14, 15 and 16.

performance of drug products. In summation, it would appear that the controversy of nonequivalency of drug products is quantitative rather than qualitative in scope. There are two questions arising from this discussion which have not yet been answered. Do the instances of therapeutic nonequivalency thus far reported represent a serious hazard? How many additional instances of therapeutic nonequivalency will come to light as studies into this problem continue? AlI , however, seem to agree that the establishment of additional standards and specifications is essential in order to control c1inical or therapeutic equivalency of drug products. Table I (above) lists a number of drugs which have been cited as exhibiting bioavailability problems when administered in dosage forms . In general , these drugs are considered "critical" drugs (for control of a disease, rather than for the alleviation of a temporary symptom), they are usually administered as a solid dosage form (tablet or capsule) and the active component is generally relatively insoluble. CompendiaJ Standards and Therapeutic Activity As many as two dozen factors have been implicated as having an affect on the physiological or biological availability of the active component in drug products; thereby altering the therapeutic activity of the drug, rendering unpredictable the course of treatment of the disease and constituting an incidence of therapeutic nonequivalency of a drug product. Many, if not most of these factors are presently controlled by standards and specifications already established by the official compendia; others may be considered under partial control and rapidly developing to the point of offering complete control, and one (dissolution test) was the subject of intense study by a USP-NF Joint Panel on Physiological Availability and is showing positive signs of producing effective specifications and control procedures for physiological availability of dosage forms . The inclusion

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TABLE II Official Dosage Forms for Which Dissolution Test Specifications Are Incorporated Into the Monograph Acetohexamide Tablets NF Hydrochlorothiazide Tablets USP Indomethacin Capsules NF Meprobam ate Tablets USP Methanedrostenolone T ablets NF Methylprednisolone T ablets NF Nitrofurantoin Tablets USP Prednisolone Tablets USP Prednisone Tablets USP Sulfisoxazole Tablets USP Sulfamethoxazole Tablets NF Theophylline, Ephedrine Hydrochloride and Phenobarbital Tablets NF Tolbutamide Tablets USP

in the official compendia of an in vitro dissolution rate test which reflects the absorption rate (in man) of drugs contained in drug products has for some time been recognized as a major goal of the compendia revision committees. It may develop, however, that reliable standards can only be established through drug absorption studies in vivo, using human SUbjects. At present, specifications based on the in vitro test are included for seven USP tablet monographs and six NF dosage forms (Table II, above). Additional monographs will certainly be included through USP and NF supplements. Factors relating to formulation and manufacturing procedures are not subject to the establishment of specifications and standards by the official compendia, at least not at this time. They do, however, come under the purview and surveillance of FDA. Following are a number of factors affecting the therapeutic activity of drugs and the extent to which the compendial standards have been established for these factors. Isomeric Forms-Reference here is primarily to optical isomers. The structural formula of many organic medicinals indicates the presence of one or more asymmetric carbons (in simple terms, a carbon atom with four different groups attached) . The molecule does not possess a plane of symmetry and can exist in two forms which

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are referred to as D and L isomers and are mirror images of one another. They are also known as enantiomorphs. Because of the stereospecific nature of most biological interactions, one of the isomeric forms may demonstrate pharmacologic activity while the other form may be inactive or may even possess an activity which is different · from its isomer. Where more than one asymmetric carbon atom occurs in the molecule, a number of optical isomers are possible, but usually the pharmacologic activity resides only in certain stereoisomeric forms. This is of particular import with natural products including alkaloids and steroids. Where the form of the official drug is a specific optical isomer, the optical properties (specific rotation) are noted in the monograph and appropriate specifications are included to assure the isomeric integrity of the compound. Examples of such drugs are ergotamine tartrate, epinephrine and dextroamphetamine phosphate. Tablet Disintegration Test-Disintegration is an important attribute of tablet dosage forms and must take place before the active constituent of the tablet can dissolve and be ultimately absorbed. The test represents the first attempt to establish an indicator of the availability of a drug for allsorption into the body. Di~integration in this test dpes not imply complete solution of the tablet or its active component. As stated in the NF4 "Complete disintegration is defined as that state in which any residue of the tablet, except fragments of insoluble coating, remaining on the screen [ 10-mesh stainless steel wire cloth] is a soft mass having no palpably firm core." The time limit established in the particular monograph indicates the maximum time permitted for all of the test tablets to disintegrate. The test is conducted in a milieu resembling that of the gastrointestinal tract. The first official disintegration time limits for tablets appeared in the compendia which became official in 1950. The time limits have undergone major revisions over the years. Feldmann 7 has indicated that over half the tablets admitted from NF XI to NF XII had their disintegration time limits reduced in most cases by at least 50 percent. While the test has proven to be use- . ful as a quality control procedure for compressed tablets, it still suffers from certain shortcomings. Meeting the test only assures that the tablet will break up into small particles within an established time period, · and as such does preclude the possibility of the tablet passing through the entire gastrointestinal tract undisturbed. However, complying with the test requirements does not give assurances that the rate of solution of the active medicament

from the tablet is satisfactory. This may be an important consideration if the drug has a low solubility or is slowly soluble. The test does not take into account the possibility of an interaction occurring between the tablet excipients and the active constituent with the result that the active drug becomes complexed or bound in some other way so as to render the drug insoluble or inactive. Since drug must, in general, go into solution before it can be absorbed, such a tablet may prove ineffective clinically although it meets the disintegration test specification. Actually, USP3 does caution that "Meeting the requirements of the disintegration test is not necessarily indicative of therapeutic efficacy." The tablet disintegration test is a forerunner to the dissolution test discussed later. Crystalline Modification or Polymorphism-Many drugs have been shown to exist in two or more crystalline forms. This phenomenon is known as polymorphism and is studied with the aid of such analytical techniques as x-ray diffraotometry, optical crystallography, infrared spectroscopy and fusion behavior. Polymorphs exhibit differences in their physical properties including density, melting point and solubility. Only one form of a drug is stable, that possessing the highest melting point and lowest solubility; all other forms revert to it in time. It is possible to prepare individual polymorphs for study by using the appropriate crystallization conditions. It is the difference in solubility and dissolution rate which imparts to the polymorphs variable absorption rates and ultimately produces variations in therapeutic activity. Chloramphenicol exists in three polymorphic forms, only one of which is therapeutically active. Griseofulvin, prednisolone, novobiocin, sulfathiazole, sulfisoxazole, tolbuta~ide and many of the barbiturates and sex hormones are known to exist in polymorphic forms. Cortisone acetate may exist in at least five crystalline forms. It is important that the proper polymorph be used in pharmaceutical formulations in order to assure satisfactory, predictable and reproducible pharmacologic activity. NF XII contained a special chapter (which has been updated in the first supplement to NF XIII) in which optical crystallographic properties of virtually all NF drugs were listed. In addition, information was provided on apparatus and procedures employed in determining these characteristics. Specifications and standards for controlling crystallographic properties of drugs had not been made a requirement in NF XII monographs because, as Feldmann noted, 7 "such a standard in the National Formulary would not be reasonable, since it would seem to

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TABLE III

Drugs in NF XIII for Which X-ray Diffraction Data Are Included in the Monograph Acetohexamide Chlormadinone acetate Fluprednisolone Flurandrenolide Indomethacin Levopropoxyphene napsylate Magaldrate Paramethasone acetate

go beyond the general capability of even the major firms within the industry." This conclusion was a product of a survey conducted among the members of the Pharmaceutical Manufacturers Association concerning their ability and readiness to adapt to such a requirement if included in the NF monographs. Apparently only a minority of the drug firms rely on x-ray diffraction and optical crystallographic analysis of their drugs as part of their quality control program. Feldmann further stated that "the NF expects to expand its standards for crystalline structure by stipulating specifications in certain drug monographs where it is known that polymorphism plays an important role in the physiologic availability of the drug from its respective dosage forms." NF XII/ 4 has a chapter devoted to x-ray diffraction; theory, apparatus and procedure, and its application to the study of crystals and polymorphism. Table III (above) shows a number of NF drugs for which x-ray diffraction data are now listed in the monograph. Particle Size-The dissolution rate of a solid is directly related to the surface area or particle size of the crystal or powder. The smaller the particle size, the greater the surface area, the faster the dissolution process and the more rapid will be the absorption of drug from the gastrointestinal .tract. This assumes that the dissolution process is rate-limiting. Some 25 years ago it was demonstrated that the rate and extent of absorption of certain sulfonamides were increased markedly by reducing the particle size of the drug. Another popular example of this effect concerns griseofulvin which normally has a poor solubility and low dissolution rate. When the drug powder was micronized, it was possible to obtain the same blood levels with 250 mg of drug as was previously obtainable with 500 mg of drug form then commercially available. At present griseofulvin is marketed in a finely micronized or microcrystalline form which permits a 50 percent reduction in dosage. A smaller particle size doesn't necessarily assure faster and better absorption. Tetracycline hydrochloride, Vol. NSll, No. 11, November 1971

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for example, administered in two different particle sizes showed no difference in blood levels. This is to be expected because tetracycline hydrochloride is a soluble salt and the dissolution process in this case is not rate-limiting. Only several compendia monographs include specifications for particle size, for example, griseofulvin and bisacodyl. The compendia do not as yet have a well-defined method for particle size measurement. This matter is receiving the attention of several groups who are concerned with quality control of drug products. This appears to be an area where standards and specifications for an increasing number of drugs are sorely needed. Hydrates-Many dru~ form solvent addition products, the most common being the hydrates, which may involve one or more molecules of water tightly bound or associated with an ion or molecule. Water of hydration is frequently referred to as water of crystallization. Dissolution rate variability can be expected between the hydrated and anhydrous forms of a drug, and consequently differences in physiological availability and therapeutic activity can result. Higher dissolution rates have been reported for the anhydrous forms of caffeine, theophylline and glutethimide than for the corresponding hydrated form. In general, the amQrphous form of a drug is more soluble than the crystalline form. Novobiocin is not absorbed to any substantial degree when administered in the crystalline form and is therefore therapeutically inactive. Amorphous novobiocin is at least ten times more soluble initially than the crystalline modification and is therapeutically effective. The compendia do provide specifications for water of hydration for .the official hydrates. The determination is based on the Karl Fischer titration procedure. The problem here is not one of establishing standards but rather of determining the therapeutic efficacy of the different forms of the drug. Chemical Form-Drugs are commonly administered in the salt form, as an ester or in some type of complex rather than as the free compound. The purpose may be to increase solubility, to enhance stability, to improve the taste or possibly to reduce side effects and minimize toxicity. The chemical nature of the combination will affect the dissolution rate and control the physiological availability and therapeutic activity of the drug product. Sodium salts of weak bases are more soluble and more readily absorbed than the free compound, producing high blood levels more rapidly. The sodium salt of tolbutamide shows greater activity than the acid form as 608

measured in terms of in vitro dissolution rate and the effect on lowering of the blood sugar level. Erythromycin and chloramphenicol are administered in the ester form which is more stable and, in addition, reduces the unpleasantness of the taste. Erythromycin is also used in the salt form which is water soluble and has greater stability, but because of its solubility possesses a pronounced bitter taste. .fhe glucoheptonate, the lactobionate and the stearate are typical salt forms. The taste problem is obviated by using the ester in formulations, for example; the estolate, the ethylcarbonate and the ethylsuccinate. To be absorbed, the drug must first be hydrolyzed liberating the free drug which is the form involved in the absorption process. Morozowich et al. 17 prepared the phosphate ester of lincomycin, an unpleasantly bitter antibiotic. The 2phosphate ester was found to have a less bitter taste than the free drug presumably because the phosphate group imparts a net negative charge on a molecule which was originally positively charged. The authors postulate that this "might disturb or prevent the bitter taste receptor interaction." The "bioactivity" of the ester was also evaluated. The unhydrolyzed ester was inactive, but in vivo hydrolysis of the phosphate ester to the parent active compound occurred rapidly by the action of the widely distributed phosphatase enzymes. Both the ester and parent compound gave peak blood levels one hour after oral administration, with the blood levels for the ester slightly higher than those for the parent compound. The official compendia recognize the therapeutic and pharmaceutical advantages of various salt and ester forms of the same parent drug. An examination of the compendia reveals that a wide variety of therapeutically effective drugs in different chemical forms are provided to assure a suitable form of the drug for all routes of administration. Each, of course, is provided with an individual monograph containing the appropriate specifications and standards. Dissolution Test-With the possible exception of isomeric form, all of the factors thus far discussed influence the therapeutic activity of a drug product by affecting the solubility or dissolution rate of the drug. Except in a relatively few cases where the action of the drug is exerted locally within the gastrointestinal tract (succinylsulfathiazole, kaolin), the therapeutic activity of most drugs taken orally depends on the drug first dissolving in the gastrointestinal fluid to a sufficient extent. Once in solution, the drug must then be absorbed into the blood stream before its intended therapeutic effect can be re-

alized. An insoluble substance would not be absorbed and therefore could not exert systemic activity. Of course, it is also possible for a drug to be soluble and yet not be absorbed from the gastrointestinal tract once in solution. Examples of this type of drug include magnesium sulfate, streptomycin and polymyxin salts. The tablet disintegration test, as noted earlier, suffers from certain drawbacks as a general procedure for evaluating the availability of an active component from a solid dosage form. The recently official dissolution test is an alternative in vitro procedure to the tablet disintegration test and is actually a modification of it. The dissolution test indicates that a specified portion of the drug dissolves within a designated period of time in a given volume of fluid in which the dosage form is immersed and agitated under carefully controlled conditions. As mentioned previously a U SP-NF Joint Panel on Physiological Availability was appointed several years ago to examine the methodology currently described for physiological availability testing and to make recommendations on the suitability of test procedures for possible inclusion in the compendia. For the first time a dissolution test is official and is included in the monograph of the thirteen tablet and capsule dosage forms listed in Table II. For these drugs a correlation exists between satisfactory in vitro release from tablets or capsules and the safety and effectiveness of specific formulations, as demonstrated through appropriate in vivo studies and clinical evaluations. The dissolution test must be sensitive to small changes in drug product formulation in order to serve as a useful compendial test applicable as a control procedure for assuring batch-to-batch uniformity in routine manufacturing production and for comparing biological availability of similar dosage forms prepared in different laboratories. The dissolution test permits the evaluation of the biological equivalency of chemical equivalents, if it has been demonstrated that a positive relationship exists between in vitro data and data obtained from normal subjects through blood, serum, plasma level or urinary excretion studies. Ideally, in order to make valid comparisons of the therapeutic activity of chemical equivalents, one should determine the clinical equivalency by measuring the relative effects in human patients eliciting characteristic symptoms or suffering from the disease or condition for which the drug is intended. Such comparisons, except in unusual cases, appear impractical at the present time because it would be time-consuming, expensive and complicated by the variability in humans

Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION

d

and by difficulties in attempting to assess quantitatively dose and effect relationships. In adopting the dissolution test, the official compendia are providing specifications and standards for evaluating physiological availability reflective of the present state of the art, and as newer knowledge appears and modifications develop, they will be incorporated into the compendia where appropriate. Manufacturing and Formulation Factors-These factors relate to manufacturing processes and procedures involved in the preparation of dosage forms in an industrial plant or in the formulation of certain dosage forms in a community or hospital pharmacy. Of major concern are compressed tablets which are the most widely used of the dosage forms, and which offer the most problems with respect to the biologic availability of the active component. This is particularly true where the drug has a high dose, low solubility, low rate of solution, is unstable in the gastrointestinal media and is poorly absorbed. Other classes of dosage forms including solutions, suspensions, emulsions and capsules may also demonstrate manufacturing and formulation factors which could possibly alter the biologic availability of the therapeutic agent and result in the nonequivalency of drug products. Surfactants and viscosity-increasing agents may affect drug availability when employed in liquid formulations. Surface-active agents may increase or decrease the rate of absorption from the gastrointestinal tract, thereby altering the pharmacologic activity ·of the drug. Accelerated absorption may be attributed to the surface tension-depressing property of the surfactant which would promote greater contact between drug and absorbing membrane. Generally, this occurs when the surfactant concentration is below the critical micelle concentration (CMC). Where the surfactant concentration is above the CMC, the drug may interact or complex with ·the micelle thereby rendering the drug molecules unavailable for absorption. The drug is bound by some mechanism to the surfactant aggregate in which form its absorbability is reduced. Viscosity-increasing agents are frequently employed to modify the consistency of certain liquid preparations. In suspensions they impart greater physical stability. However, increased viscosity may retard drug absorption in the gastrointestinal tract and produce low blood levels. The viscosity effect results from the decreased rate of diffusion of the drug molecules from the gastrointestinal fluids to the absorption sites. Also, the viscosity-increasing agent may interact with the drug mole-

cule producing a complex which is less available for absorption. In adding adjuvants of these types to formulations, one must be aware of possible effects on the physiologic availability of the drug. Factors relating to manufacturing procedures and affecting the dissolution rate of drugs from tablet and capsule dosage forms have been noted by Wagner .18 These include such factors as the amount and type of diluent, filler, lubricant, binder or other adjuvants; granule size and size distribution; amount and type of disintegrant; effect of surfactants, if used; compression forces and speed of compression, and possible drug-excipient interactions. Starch, a commonly used disintegrant for tablets, generally increa~es the dissolution rate, the increase being proportional to the starch concentration. However, a number of qrugs including p-aminobenzoic acid interact with starch, affecting the availability of the drug. Polyethylene glycol, another tablet adjuvant, forms a rather insoluble complex with phenobarbital which shows a much slower rate of absorption than the pure drug. Levy13 notes that tablet binders tend to lower dissolution rate because they delay the disintegration process. If the granules are nondisintegrating, the dissolution rate is inversely proportional to the granule size. Tablet lubricants are generally hydrophobic in nature (water-insoluble and water-repelling) and may interfere with the contact between the dosage form and the dissolution medium. Magnesium stearate is a typical example of a hydrophobic lubricant ·showing dissolution-retarding effects. Sodium lauryl sulfate, a water-soluble lubricant, produces a pronounced dissolution-enhancing effect by promoting better contact between the drug solids and the medium. Fillers, which are generally inert, have been shown to produce drug availability problems. A wellknown example is dica1cium phosphate which was used as a filler in tetracycline capsules. This filler was found to reduce the dissolution rate markedly by forming a poorly soluble complex with the tetracycline. Alginic acid, wh.en used as a filler for a basic drug substance, has been shown to produce a less soluble product which demonstrated an undesirable therapeutic effect. On the other hand, tribasic sodium phosphate incorporated with weak acids (benzoic acid, phenobarbital, theophylline) increased the dissolution rate of the acid. Certain mucillaginous binders may interact with the active component in a tablet formulation and inhibit its release in a form which is suitable for absorption. These are but a few examples of ways in which the manufacturing process or formulation procedure may affect the

physiologic availability of a drug in a dosage form. Both the USP and N F in their respective sections on general notices 3 ,4 state that, "suitable substances such as carrIers, coatings, colors, flavors, preservatives, stabilizers, and vehicles may be added to an I official] dosage form to enhance its permanency, usefulness, or pharmaceutical elegance, or to facilitate its preparation. Such substances may be regarded as suitable only if they are harmless in the amounts used, if they do not exceed the minimum quantity required to provide their intended effect, if their presence does not impair the therapeutic efficacy of the dosage form, * and if they do not interfere with the assays and tests prescribed for determining compliance with the [official] standards." Also, in the same section in regard to capsules and tablets permission is granted for the use of "suitable diluents, colors, lubricants, disintegrants, and adhesives, such as starches, lactose, sucrose, and other innocuous materials," in their manufacture. The compendia provide standards and tests primarily for finished products and the ingredients used in their preparation. Protocols and specifications for manufacturing and formulation procedures, as well as quality control assurance, come under the purview of FDA and, to an extent, are left to the integrity of the manufacturer. According to a published statement in FDA Papers,19 "The Food and Drug Administration is convinced that most, if not all, of the problems of drug quality can be solved by compliance with the minimum requirements of the Current Good Manufacturing Practice regulations." The G MP regulations were promulgated in 1963 as one of the important provisions of the Kefauver-Harris Drug Amendments of 1962. These amendments also strengthened the regulatory authority of FDA over clinical testing of drugs and in assuring safety and therapeutic efficacy of drug products through the Investigational. Drug Regulations (lND) and the New Drug Aplication (NDA). It was noted earlier that the official compendia at this time do not include specifications and standards for controlling factors related to formulation and manufacturing procedures. Hodges, director, Office of New Drugs, FDA Bureau of Medicine, in discussing the role of FDA in the equivalency problem 2o lists the following as important factors influencing tablet disintegration-degree of compression; type of fillers, binders, lubricants and disintegrants, and the particle size of granulation. A correlation also must be established between disintegration specifications and the in vivo absorption o Italics

added by author.

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characteristics 'Of the active drug mDlecule. JfDdges emphasizes the fact that the details cDncerning many Df these factors are trade secrets and "a change in the attitude 'Of the manufacturers Dr in the law wDuldbe required to make them available to the ' public." Whether the drug manufacturer shDuld be required to' divulge such privileged "information i~ a subject for debate and b~YDnd the scope of this paper. However, the reader is referred to' a recent paper by Feldmann 21 for an interesting discussion Df this controversial tDpic and to' the CDmments of HDdges.20 Hodges makes the point that "If a firm licenses anDther manufacturer, discloses ' its full manufacturing process, and similar or identical equipment is used to make the formulatiDn , the chances are high that we will have a therapeutically equivalent product.-" Generic drug, according to Hodges, refers only to' the chemical entity, and not to the finished product. Thus, products referred to as generic equivalents are equivalent only in SO' far as the active ingredient is concerned and may vary 'cDnsiderably in 'methDd Df manufacture and the incorpDration of inactive non therapeutic additives. While manufacturing and fDrmulation factors may affect the physiolDgic availability of a drug in its dosage form, the testing of the final product Dn the basis of Dfficial compendia standards will determine whether or nDt quality has been built into the product. However, both final prDduct testing and an in-process quality control program are necessary to assure the clinical effectiveness and safety Df a drug product. Both are essential to assure that only the highest quality drug products reach the market. Other Factors-In additiDn to those described above, a number of Dther factors have been implicated as affecting the physiDlogical availability Df drug prDduct'S. While it is true that these factors may influence unfavorably the availability of a drug, in mDst cases the official compendia have specifications in the monograph for controlling the factDrs . One such factor which has been frequently referred to is the pH of the dosage form. This relates to the degree of acidity Df basicity Df a product. For numerDUS drugs the pH of the sDlution cDntaining the drug is an impDrtant factor which may CDntrol the therapeutic activity, the physical and chemical stability, and the SDlubility of the drug. FDr example, epinephrine bitartrate ophthalmic solutiDn USP according to the compendium must have a pH between 3.0 and 3.8. If the pH were alkaline, the epinephrine would be insoluble and very unstable; and if the solutiDn were mDre strDngly acidic, it wDuld be too irritating. Thiamine hydrDchl'Oride injectiDn 610

USP may be sterilized by autDclaving with nO' decDmpDsition if the pH is below five, while abDve five the thiamine hydrochlDride is unstable. The specifications call for a pH range of 2.5 and 4.5. Soluti'Ons cDntaining alkaloids are generally adjusted to an Clcidic pH to assure s'Olubility and stability. Where the pH is an impDrtant conditiDn fDr 4rug prDduct effectiveness, it is generally included as a specification in the monograph Df the product. Packaging and stDrage may affect the activity of a (lrug product, particularly over an extended period 'Of time. The decomposition 'Of a drug in a dO's age form not only reduces the potency of the drug product, but may also prDduce breakdown products which may be tDxic. The extent of deCompDsitiDn will increase with time. Shelf-life and storage c'Onditions may be impDrtant cDnsiderations in determining the biological availability of drugs. The Dfficial compendia do provide packaging and storage conditions for virtually all drugs and drug products. These generally include the appropriate containers and suitable temperature conditions which will assure maximum stability Df the drug over a reasonable periDd of time. Where a specific breakdDwn product has been identified, limits tests are usually included in the mon'Ograph for the product as means of cDntrolling the extent of decompositiDn. FDr example, there are limits tests for adrenalone in epinephrine and fDr m-aminophenol in p-aminosalicylic acid. The importance 'Of having an assay procedure which is stability-determining is apparent. The Dfficial cDmpendia require fDr a number of products (particularly those which are biDIDgic ' in origin) that the label bear an expiration date. The date is determined conservatively as the date beyond which the drug may be belDW the labeled pDtency. The product, of course, must be stDred according to the prescribed stDrage conditiDns. It is expected that more products will be required to' include an expiration date on the label as research on the shelf-life of drugs expands. A tablet-tD-tablet or capsule-tD-capsule variatiDn in active ingredient within the same IDt or batch of tablets or capsules could produce erratic therapeutic results. The assay prDcedure may not necessarily detect such a variatiDn since the assay is based on a sample consisting Df 10 to 20 tablets, or the contents remDved from a similar number of capsules or vials. The amount Df active ingredient in each unit dDsage form is calculated Dn the basis of the assay of the compDsite sample and is expressed in terms Df a unit-dosage form Df average weight. It is conceivable that there is a variatiDn in tablet (or capsule) weight and that there may be a variation in distribution

Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION

Df active ingredient thrDughout the entire batch or lot, despite the fact that the assay may be within appropriate limits; therefore tests fDr dosage form homogeneity are included in' mDnDgraphs fDr tablet and capsule dosage forms. A content unifDrmity test is provided in the tablet and capsule mDnographs where the active ingredient is present in relatively low amounts (50 mg or less of any ~trength available). Such a specificatiDn prDvides a greater degree Df assurance that uniformity of active ingredient exists within a single lot of a dosage form. The test is based Dn the assay of a predetermined number of individual dosage forms. AdditionaHy, the compendia include a weight variatiDn specification for tablets, capsules and certain creams, Dintments an~ powders. The test is based on the variatiDn in weight of a predetermined number of individual dosage forms. The content uniformity and weight variation tests, together with the assay of the composite sample, provide a satisfactory and adequate evaluation of dosage form hDmogeneity for quality control and enforcement purposes. A test procedure and apparatus fDr the in vitro testing of timed-release dosage forms (tablets and capsules) was described in the second supplement to NF XII and subsequently in the general tests section of NF XIII. This test provides suitable methodDlogy for establishing criteria to assure product unifDrmity for most types of timedrelease preparatiDns. Although at the present time there are nO' official preparations in the compendia which require such testing, it is described in the NF for its value as a routine test procedure which will assure uniformity and cDnsistency when applied on an inter-IaboratDry basis. This test procedure serves to prDvide general guidelines for develDping acceptable methDds of drug testing. This is an in vitro method and is nDt intended to evaluate the safety and effectiveness of a drug product, both Df which must be determined by in vivo studies and clinical evaluatiDn. By cDrrelating the in vivo test data and clinical evaluation studies with the in vitro tests, Dne may establish suitable release limits.

Summary It is generally accepted that the bioavailability (physiological availability or biolDgical availability) Df a drug in a dosage fDrm can be affected by a variety of factors. Also, chemical equivalency in drug prDducts based on active ingredient analysis does nDt necessarily assure biDlogical and clinical equivalency. However, it would appear that at the present time the number of case) where this situation exists is small and

restricted to those drugs possessing specific physical and chemical characteristics. It is probable that additional instances of biological or clinical nonequivalency will be revealed as studies in this area expand. A dozen or so factors which may contribute to nonequivalency in drug products have been cited here. The compendia provide a complete spectrum of tests, standards and specifications which are intended to assure the safety, efficacy, quality and purity of drugs and their dosage forms, and which are based on the most recent information, technology and methodology available to pharmaceutical and medical scientists. It has been noted earlier that except in rare instances, when a drug product meets compendial standards, therapeutic effectiveness can also be expected. The compendia3 •4 do recognize an urgent need for establishing suitable test procedures for assessing the bioavailability of drug products. Ideally, such tests should be performed on human patients suffering from the disease or exhibiting the symptom for which the drug is intended. This is impractical as a general test for medical and economic as well as for other reasons. Protocols will undoubtedly have to be developed utilizing blood levels and urinary excretion data obtained from normal human subjects. This has been mentioned before in connection with the evaluation of the biological equivalency of drug products. Bioavailability data are now required by FDA for the approval of both the New Drug Application and the Abbreviated New Drug Application. This was recently reaffirmed by Charles C. Edwards, MD, commissioner of foods and drugS. 22 In those cases where such a test may be inappropriate, as for example, where methodology based on

Conference Proceedings Available

blood level or urinary excretion data doesn't exist; in vitro dissolution test data will be required. A dissolution test procedure is currently included in the monograph of several tablet and capsule dosage forms. Such a test is meaningful as an indication of physiological availability where the dissDlution process is the rate limiting step in the overall absorption process and where a correlation has been demonstrated between dissolution test data and proper studies in human subjects. Ordinarily, once the drug is dissolved in the gastrointestinal fluids, absorption into the blood stream is immediate. Therefore, bioavailability studies will probably not be required for those drugs which are sufficiently soluble or which are in solution at the time of administration. Research in this area is fraught with a multitude of problems, and the dissolution test specification as presently described in the compendia is only the first attempt at quantifying bioavailability 'Of drugs. The official compendia recognize that through further studies correlating in vivo test data and clinical evaluation more precise in vitro dissolution limits might subsequently be established. Modifications, improvements and further applications will certainly be forthcoming. • Acknowledgment The m any helpful suggestions and constructive criticism offered by John V. B ergen, d irector of the N ational F onnulary, are gratefully acknowledged.

References 1. Second Interim Report and Recommendations, Task F orce on Prescription Dru gs, HEW, Washington, D.C . (Aug. 3 0 , 1968) 2 . Miller, L.C., "Statem e nt on the United States Pha rm acopeia," Hearings Before the Subcommittee on Antitrust and Monopoly of the C ommittee on the Judiciary, U.S. Senate, 90th C on gress (June 27, 1967) 3. United States Pharmacopeia 18th Revision, Mack Publishing Company, 'Easton, Pa., xv, xvii, 4 , 815 (1970)

4. National Formulary, 13th edition, Mack Publishing Company, Easton, Pa" xxii, xxiii, 7, 878, 902 (1970) 5. Feldmann, E .G., " The Official C ompendia - Analysis of Their Content," Am. J. Pharm. , 138, 183 (1966) 6. Feldmann, E .G ., " Stat em ent of the National F ormula ry," Hearings Before the Subcommittee on Monopoly of the Select Committee on Small Business, U.S. Sen ate, 90th Con g ress (June 8 , 1967) 7 . F eldmann, E .G ., " Biophannaceutics and Drug Standards," Second Annu al Clinical Midyear Meetin g of the American Society of Hospital Pharmacists, W ashington, D.C . ( D ec. 5, 1967) 8 . L asagna, L ., " The Pharmaceutical Revolution : Its Impact on Scien ce and Society," Scien ce, 166, 1227 ( 1969) 9. Reese , K.M., "Drug Prices," Ch em. Eng. N ew s, 62 (Jan. 29, 1968) 10. L evy, G., and Nelson, E ., " United States Pharmacopeia and Nation al F onnulary Stand ards, F ood and Dru g Administration Regulations, and the Quality of Drugs," N.Y. State J. M ed. , 61,4003 (1961) 11. Slesser, A.E., "The Myth of Dmg Product Equivalency," Presented t o the Hillsboro County Med. Assoc., T ampa , Fla . (June 1, 1965) 12. Sad ove, M .; Rosenberg, R; Helle r, F., and Shulman M., "What Is a Generic Equivalent ?," Amer. Prof. Pharm. (Feb., 1965 ) 13 . L evy, G., "Biopharmaceutical Con siderations in Dosage F orm Design and Evalu ation," Prescription Pharmacy, J .B. Sprowls Jr., ed ., Chapter 2, Lippin cott (1963) 14. Riegelm an, S. , " Critical Evaluation of the Effect of F ormul ation V ari ables on the Therapeutic Perform ance of Drugs," Drug Inf. Bu ll. , 3 , 59 (1969) 15. Schneller, G.H. , "The H az ard of Therapeutic N on-Equivalency of Dmg Products," Drug Inf. Bull. , 3, 100 (1969) 16 . " P roceedings of the Symp osium on F ormulation F a ctors Affectin g Therapeutic Perform ance of Drug Products," Drug Inf . Bull., 3 (1969) 17. Morozowich, W. ; Lamb, D.J.; Karnes, H .A. ; Mackellar, F.A.; L ewis, C .; Stern, K.F., and Rowe, E .L. , "Sy nthesis and Bioa ctivity of Lincomycin-2-Phosphate," J. Pharm. Sci., 58, 1485 (1969) 18. W agner, J.G. , "Biophann a ceutics 20. Rate of Dissolution in V itro and in Viv o," Drug Intell. and Clin t Pharm. , 4 , 13 2 ( 1970 ) 19. "Good Manufacturing Pra ctice," FDA Papers (April 1967) 20. H od ges, R.M., " Biopharma ceutic Equivalen cy and the Role of the F ood and Dru g Administration," Amer. J. H osp. Pharm., 25, 12 1 (1968) 2 1. Feldmann, E.G. , "Brand versus Generic Drugs," JA PhA, NS9, 8 (1969 ) 22. Edwards, C. C. , " The Need for a New Paradi gm to Assure Dmg Product Q uality, " presented to APhA Acad. of Pha nn. Sci. (April 15, 1970)

Daniel B. Smith Award

The full proceedings of the September

1970 Conference on Pharmacy Manpower are now available. Copie's are $3 each and may be obtained from-National Technical Information Service, 5285 Port Royal Road, Springfield, VA 22151. When ordering refer to: An Invitational Conference on Pharmacy Manpower (Challenge to Pharmacy in the 70's: HSRD 71-21). Checks should be made payable to National Technical Information Service. Single copies of a previously published companion document, Conference Highlights, are available free upon request from Drug-Related Studies Program, National Center for Health Services Research and Development, Room 15A-53, Parklawn Building, 5600 Fishers Lane, RockVille, MD 20852.

Pharmacy recognizes her distinguished citizens with many awards and medals, but none is reserved exclusively for her practitioners. I propose, then, that we now consider the establishment of the Daniel B. Smith Medal, in honor of the first president of th e Association . . . .. an award to be based on a single, or long-sustained, outstanding professional performance . ...

From address by George F. Archambault, May 12, 1963 Nominations are now being invited for the 1972 Daniel B. Smith Award. Deadline date for the nominations is December 15 and all community pharmacists are eligible. The award, the highest honor the Academy of General Practice of Pharmacy can bestow upon a community practitioner, will be awarded at the Academy luncheon during the APhA annual meeting in Houston, April 22-28. Past recipients include Wallace S. Klein Jr. (] 971) ; William F. Appel (1970) , and David J. Krigstein (1969). Nomination forms may be obtained from the Academy of General Practice of Pharmacy, 22]5 Constitution Avenue, N.W. , Washington, DC 20037. Vol. NSll, No. 11. November 1971

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