TMMar cel Dekker , Inc. New Yor k Baseledit ed byGilber t S. BankerUniversity of IowaIowa City, IowaChrist opher T. RhodesUniversity of Rhode IslandKingston, Rhode IslandModer nPhar maceut i csFour t h Edi t i on, Revi sed and ExpandedCopyright 2002 by Marcel Dekker, Inc. All Rights Reserved.Copyright 2002 Marcel Dekker, Inc.ISBN: 0-8247-0674-9This book is printed on acid-free paper.HeadquartersMarcel Dekker, Inc.270 Madison Avenue, New York, NY 10016tel: 212-696-9000; fax: 212-685-4540Eastern Hemisphere DistributionMarcel Dekker AGHutgasse 4, Postfach 812, CH-4001 Basel, Switzerlandtel: 41-61-261-8482; fax: 41-61-261-8896World Wide Webhttp:==www.dekker.comThe publisher oers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales=Professional Marketing at the headquarters address above.Copyright # 2002 by Marcel Dekker, Inc. All Rights Reserved.Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical,including photocopying, microlming, and recording, or by any information storage and retrieval system, without permission inwriting from the publisher.Current printing (last digit):10 9 8 7 6 5 4 3 2 1PRINTED IN THE UNITED STATES OF AMERICACopyright 2002 Marcel Dekker, Inc.DRUGS AND THE PHARMACEUTICAL SCIENCESExecutive EditorJames SwarbrickPharmaceuTech, Inc.Pinehurst, North CarolinaAdvisory BoardLarry L. AugsburgerUniversity of MarylandBaltimore, MarylandDavid E. NicholsPurdue UniversityWest Lafayette, IndianaDouwe D. BreimerGorlaeus LaboratoriesLeiden, The NetherlandsStephen G. SchulmanUniversity of FloridaGainesville, FloridaTrevor M. JonesThe Association of theBritish Pharmaceutical IndustryLondon, United KingdomJerome P. SkellyAlexandria, VirginiaHans E. JungingerLeiden/Amsterdam Centerfor Drug ResearchLeiden, The NetherlandsFelix TheeuwesAlza CorporationPalo Alto, CaliforniaVincent H. L. LeeUniversity of Southern CaliforniaLos Angeles, CaliforniaGeoffrey T. TuckerUniversity of SheffieldRoyal Hallamshire HospitalSheffield, United KingdomPeter G. WellingInstitut de Recherche JouveinalFresnes, FranceCopyright 2002 Marcel Dekker, Inc.PrefaceThe rst edition of Modern Pharmaceutics was published in 1980, the second in 1989, and the third in 1995. Duringthe more than 20 years since we developed the concept of this text we have been privileged to work with many of themost notable pharmaceutical scientists as chapter authors. Some of our original rst edition team are still with us.Others, for a variety of reasonsincluding change of career focus, retirement, and deathare no longer with us orable to cooperate in this endeavor. We place on record our gratitude to all our colleagues who have so unselshlyassisted us in any or all of our four editions.We are also grateful to all those readers of our book who have provided comments on their perceptions of thevalue of Modern Pharmaceutics and suggested to us ways in which the book might be improved. We have mostcarefully considered all such ideas and some of the changes that we have implemented in this edition derive fromadvice given to us by industrial pharmaceutical scientists, university faculty, and students.The fourth edition of Modern Pharmaceutics follows the same format and has the same goals as previous edi-tions. Chapter 1 sets the stage by reviewing the role of drugs and drug products in treating and preventing disease,while also summarizing their primary quality features. Chapters 2 through 6 provide background that is funda-mental to an understanding of drug action and the design of drug products. Chapter 7, on preformulation, isanother fundamentals chapter, describing the manner in which drugs are characterized for their physical, chemical,and pharmacokinetic properties to provide a rational and scientic basis for drug product design.Chapters 8 through 16 describe drug products and dosage forms, together with the routes of administration bywhich they are given. Chapters 17 through 28 also treat topics critical to drug product quality such as packaging,optimization, and food and drug laws, in addition to examining more specialized product classes and introducingseveral new chapters. As in previous editions, this book once again ends with a view to the future.In the planning of this edition, we identied certain areas of recent growth that seemed to merit increasedattention in this text, while attempting to further recognize pharmacy's international character. Also, we gaveattention to topics that are of relatively more importance than previously. Overall the book has grown in sizebecause there are a number of critical areas that justify signicant additional coverage. We have been fortunate inobtaining the services of a number of distinguished individuals to cover topics not allocated whole chapters inprevious editions.The growing importance of botanicals and other natural products has been recognized by devoting one of ournew chapters to this topic. Also, we have a new chapter on managed care since this is an area of great importanceand impacts all facets of pharmacy. Further, we expect this topic to gain additional recognition in parts of the worldwhere at present the implications of this discipline are not fully recognized. Also, appreciating the growing im-portance of generic products, especially in North America and the European Union, we have included in this editionCopyright 2002 Marcel Dekker, Inc.a chapter focused on bioequivalence. Finally, recognizing the impact of the information revolution, catalyzed bycomputers and the Internet, we have included a new chapter on drug information.With one exception, all the chapters from the third edition of Modern Pharmaceutics that appear in the fourthedition have been revised and updated. Many chapters were extensively updated, and some, such as the rst and lastchapters, were extensively rewritten. Due to the illness of Dr. Robinson, the chapter on sustained and controlledrelease drug delivery systems was updated with the assistance of Gil Banker, with Dr. Robinson's approval.Although Modern Pharmaceutics continues to evolve, our basic goals remain those which we developed in the1970s when we rst delineated the concept of this comprehensive and integrated treatment of pharmaceutics, with afocus on drug product quality and performance. We are committed to producing an up-to-date, authoritative,multiauthored treatise on pharmaceutics, which can be used by both students and practitioners.Gilbert S. BankerChristopher T. RhodesCopyright 2002 Marcel Dekker, Inc.ContentsPrefaceContributors1. Drug Products: Their Role in the Treatment of Disease, Their Quality, andTheir Status and Future as Drug-Delivery SystemsGilbert S. Banker2. Principles of Drug AbsorptionMichael Mayersohn3. PharmacokineticsDavid W. A. Bourne4. Factors Inuencing Drug Absorption and Drug AvailabilityBetty-ann Hoener and Leslie Z. Benet5. The Eect of Route of Administration and Distribution on Drug ActionSvein ie and Leslie Z. Benet6. Chemical Kinetics and Drug StabilityJ. Keith Guillory and Rolland I. Poust7. PreformulationJens T. Carstensen8. Cutaneous and Transdermal DeliveryProcesses and Systems of DeliveryGordon L. Flynn9. Disperse SystemsWandee Im-Emsap, Ornlaksana Paeratakul, and Juergen SiepmannCopyright 2002 Marcel Dekker, Inc.10. Tablet Dosage FormMary J. Kottke and Edward M. Rudnic11. Hard and Soft Shell CapsulesLarry L. Augsburger12. Parenteral ProductsJames C. Boylan and Steven L. Nail13. Design and Evaluation of Ophthalmic Pharmaceutical ProductsJohn C. Lang, Robert E. Roehrs, Denise P. Rodeheaver, Paul J. Missel, Rajni Jani, andMasood A. Chowhan14. Delivery of Drugs by the Pulmonary RouteAnthony J. Hickey15. Sustained- and Controlled-Release Drug Delivery SystemsGwen M. Jantzen and Joseph R. Robinson16. Target-Oriented Drug-Delivery SystemsVijay Kumar and Gilbert S. Banker17. Packaging of Pharmaceutical Dosage FormsThomas J. Ambrosio18. Optimization Techniques in Pharmaceutical Formulation and ProcessingJoseph B. Schwartz, Robert E. O'Connor, and Roger L. Schnaare19. Food and Drug Laws that Aect Drug Product Design, Manufacture, andDistributionGarnet E. Peck and Roland Poust20. European Aspects of the Regulation of Drug Products with Particular Referenceto Development PharmaceuticsBrian R. Matthews21. Pediatric and Geriatric Aspects of PharmaceuticsMichelle Danish and Mary Kathryn Kottke22. Biotechnology-Based PharmaceuticalsPaul R. Dal Monte, S. Kathy Edmond Rouan, and Narendra B. Bam23. The Pharmacist and Veterinary Pharmaceutical Dosage FormsJ. Patrick McDonnell and Lisa Blair Banker24. Dietary SupplementsTeresa Bailey Klepser25. BioequivalencyChristopher T. RhodesCopyright 2002 Marcel Dekker, Inc.26. Drug InformationHazel H. Seaba27. Managed Care and Pharmacotherapy ManagementJulie M. Ganther and William R. Doucette28. A View to the FutureGilbert S. Banker and Christopher T. RhodesCopyright 2002 Marcel Dekker, Inc.ContributorsThomas J. Ambrosio, Ph.D. Development Fellow, Package Development, Schering-Plough Research Institute,Kenilworth, New JerseyLarry L. Augsburger, Ph.D. Shangraw Professor of Industrial Pharmacy and Pharmaceutics, Department ofPharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MarylandNarendra B. Barn, Ph.D. Project Management and R&D Strategy, GlaxoSmithKline, Collegeville, PennsylvaniaGilbert S. Banker, Ph.D. Dean Emeritus and John L. Lach Distinguished Professor of Drug Delivery Emeritus,College of Pharmacy, University of Iowa, Iowa City, IowaLisa Blair Banker, D.V.M. Blair Animal Clinic, West Lafayette, IndianaLeslie Z. Benet, Ph.D. Professor of Biopharmaceutical Sciences, School of Pharmacy, University of California,San Francisco, CaliforniaDavid W. A. Bourne, Ph.D. Professor of Pharmacy, College of Pharmacy, University of Oklahoma, OklahomaCity, OklahomaJames C. Boylan, Ph.D. Pharmaceutical Consultant, Gurnee, IllinoisJens T. Carstensen, Ph.D. Professor Emeritus, School of Pharmacy, University of Wisconsin, Madison, WisconsinMasood A. Chowhan, Ph.D. Director of Consumer Products, Alcon Research Ltd., Fort Worth, TexasPaul R. Dal Monte, Ph.D. Project Management and R&D Strategy, GlaxoSmithKline, Collegeville, PennsylvaniaMichele Danish, Pharm.D. Clinical Manager, Department of Pharmacy, St. Joseph Health Services, Providence,Rhode IslandixCopyright 2002 Marcel Dekker, Inc.William R. Doucette, Ph.D. Associate Professor, Division of Clinical and Administrative Pharmacy, University ofIowa, Iowa City, IowaGordon L. Flynn, Ph.D. Professor of Pharmaceutical Science, Department of Pharmaceutical Sciences, College ofPharmacy, The University of Michigan, Ann Arbor, MichiganJulie M. Ganther, Ph.D. Assistant Professor, Department of Clinical and Administrative Pharmacy, University ofIowa, Iowa City, IowaJ. Keith Guillory. Ph.D. Professor Emeritus, Division of Pharmaceutics, College of Pharmacy, University of Iowa,Iowa City, IowaAnthony J. Hickey, Ph.D. Professor, School of Pharmacy, University of North Carolina, Chapel Hill, NorthCarolinaBetty-ann Hoener, Ph.D. Professor, Department of Biopharmaceutical Sciences, School of Pharmacy, Universityof California, San Francisco, CaliforniaWandee Im-Emsap College of Pharmacy, Freie Universita t Berlin, Berlin, GermanyRajni Jani, Ph.D. Senior Director, Department of Pharmaceutics, Alcon Research Ltd., Fort Worth, TexasGwen M. Jantzen, Ph.D. School of Pharmacy, University of Wisconsin, Madison, WisconsinTeresa Bailey Klepser, Pharm.D. Associate Professor, College of Pharmacy, Ferris State University, Big Rapids,MichiganMary Kathryn Kottke, Ph.D. Department of Regulatory Aairs, Cubist Pharmaceuticals, Inc., Lexington,MassachusettsVijay Kumar, Ph.D. Assistant Professor, Division of Pharmaceutics, College of Pharmacy, University of Iowa,Iowa City, IowaJohn C. Lang, Ph.D. Director of Emerging Technologies, Consumer Products Research and Development, AlconResearch Ltd., Fort Worth, TexasBrian R. Matthews, Ph.D. Senior Director of EC Registration, Alcon Laboratories (UK) Ltd., Hemel Hempstead,United KingdomMichael Mayersohn, Ph.D. Professor of Pharmaceutical Sciences, College of Pharmacy, University of Arizona,Tucson, ArizonaJ. Patrick McDonnell, B.S.Ph. Senior Compliance Auditor, Department of Biologics Quality Assurance, FortDodge Animal Health, Charles City, IowaPaul J. Missel, Ph.D. Principal Scientist, Department of Drug Delivery, Alcon Research Ltd., Fort Worth, TexasSteven L. Nail, Ph.D. Associate Professor, Department of Industrial and Physical Pharmacy, Purdue University,West Lafayette, IndianaRobert E. O'Connor, Ph.D. Pharmaceutical Sourcing Group Americas, a division of Ortho-McNeilPharmaceutical, Bridgewater, New Jerseyx ContributorsCopyright 2002 Marcel Dekker, Inc.Steven ie, Ph.D. Professor, Department of Biopharmaceutical Sciences, School of Pharmacy, University ofCalifornia, San Francisco, CaliforniaOrnlaksana Paeratakul, Ph.D. Assistant Professor, Pharmaceutical Technology, Faculty of Pharmacy,Srinakharinwirot University, Nakhonnayok, ThailandGarnet E. Peck, Ph.D. Professor and Director of the Industrial Pharmacy Laboratory, Department of Industrialand Physical Pharmacy, School of Pharmacy, Purdue University, West Lafayette, IndianaRolland Poust, Ph.D. Professor, Pharmaceutical Services Division, College of Pharmacy, University of Iowa, IowaCity, IowaChristopher T. Rhodes, Ph.D. Professor, Department of Applied Pharmaceutical Sciences, University of RhodeIsland, Kingston, Rhode IslandJoseph R. Robinson, Ph.D. Professor of Pharmacy, School of Pharmacy, University of Wisconsin, Madison,WisconsinDenise P. Rodeheaver, Ph.D., D.A.B.T. Assistant Director, Department of Toxicology, Alcon Research Ltd., FortWorth, TexasRobert E. Roehrs, Ph.D.* Vice President, Department of Drug Regulatory Aairs, Alcon Research Ltd., FortWorth, TexasS. Kathy Edmond Rouan, Ph.D. Vice President, Cardiovascular and Urology Project Team Leadership andManagement, Project Management and R&D Strategy, GlaxoSmithKline, Collegeville, PennsylvaniaEdward M. Rudnic, Ph.D. Advancis Pharmaceutical Corp., Gaithersburg, MarylandRoger L. Schnaare, Ph.D. Philadelphia College of Pharmacy, Philadelphia, PennsylvaniaJoseph B. Schwartz, Ph.D. Philadelphia College of Pharmacy, Philadelphia, PennsylvaniaHazel H. Seaba, M.S. Professor (Clinical) and Director, Division of Drug Information Service, College ofPharmacy, University of Iowa, Iowa City, IowaJuergen Siepmann, Ph.D. Assistant Professor, College of Pharmacy, Freie Universita t Berlin, Berlin, Germany*Retired.Contributors xiCopyright 2002 Marcel Dekker, Inc.Chapter 1Drug Products:Their Role in the Treatment of Disease, Their Quality, andTheir Status and Future as Drug-Delivery SystemsGilbert S. BankerUniversity of Iowa, Iowa City, IowaI. ROLE OF DRUGS AND DRUGPRODUCTS IN THE TREATMENTAND PREVENTION OF DISEASEThe methods of treating illness and disease as we enterthe twenty-rst century include the use of the followingforms of therapy: (a) surgery, including organ trans-plantation; (b) psychotherapy; (c) physical therapy;(d) radiation, and (e) chemo or pharmacotherapy. Ofthese various methods, pharmacotherapy (treatmentwith drugs) is the most frequently used technique fortreating disease, has the broadest range of applicationover the greatest variety of disease states, and is usuallythe most cost-eective and preferred treatment method.Although surgery is the preferred method of treatingsome ailments or disease states, when alternativemethods are available, these methods (usually phar-macotherapy) will be employed rst if feasible, in theinitial attempt to secure satisfactory relief or control ofthe condition or a complete cure. As pharmacotherapycontinues to improve, it is replacing other forms oftreatment as the preferred method of therapy. Phar-macotherapy is, for example, increasingly becoming thetreatment of choice in treating various forms of cancer,including breast cancer, replacing the use of radicalsurgery. Pharmacotherapy is now an eective option tosurgery in the treatment of some forms of prostatedisease. When cure rates or reliability of disease controlby pharmacotherapy can match surgical treatment(e.g., prostate surgery or radical mastectomy), mostpatients will strongly prefer the chemotherapeuticapproach or the use of chemotherapy combined withless radical surgical approaches.In some surgical procedures, such as organ trans-plantation, the success of that procedure will be onlyas great as the course of pharmacotherapy that fol-lows. Organ transplant recipients are required tocontinue drug therapy for the balance of their lives forcontrol of their immune systems and to prevent organrejection.Pharmacotherapy is also very important in theprevention of disease, since vaccines and other im-munizing agents are drug products. The impact ofvaccines in eliminating or reducing the incidence of sixdiseases is shown in Fig. 1. Some diseases that pre-viously killed or crippled tens of millions of peopleworldwide, often reaching epidemic proportions, arenow virtually unknown in most of the world. Table 1shows the average number of deaths in the UnitedStates per million people as a result of various diseasesin a nonepidemic situation over the last century. Thetable lists diseases that have been obliterated or nearlyobliterated in the United States through drug im-munology as shown in Fig. 1, together with diseasesthat have now been brought largely under control orgreatly reduced by the discovery and eective use ofanti-infective drugs than can combat bacterial infec-tions. Examples of diseases in this latter category areCopyright 2002 Marcel Dekker, Inc.Fig. 1 Impact of vaccines in reducing incidence of diseases.Table 1 Causes of Death in the United States per Million Population in Nonepidemic Years from Infectious and OtherIdentiable DiseasesYearDisease 1900 1920 1940 1960 1975 1985 1990 1999Influenza and pneumonia 2030 2080 700 310 370 250 3313 311Tuberculosis (all forms) 2020 1150 460 220 50 8 7 5Diarrheas and intestinal 1330 540 100 50 40 1 0 0Kidney diseases 890 890 820 210 110 85 83 95Bronchitis 460 130 30 20 30 16 1 1Diphtheria 430 260 10 3 0 0 0 0Typhoid and paratyphoid 360 80 10 0 0 0 0 0Syphilis 20 160 140 50 20 0 0 0Measles 120 90 5 3 0 0 0 0Whooping cough 120 120 20 7 0 0 0 0Appendicitis 100 130 100 20 0 2 1 0Scarlet fever 100 50 5 0 0 0 0 0Malaria 80 40 10 0 0 0 0 0Smallpox 20 6 0 0 0 0 0 0Source: Ofcial Statistics, U.S. Census Bureau.Copyright 2002 Marcel Dekker, Inc.pneumonia, tuberculosis, certain diarrheal and in-testinal disorders, and bronchitis.Yet other diseases have been largely controlled byimproved sanitation and public health procedures,alone or in combination with pharmacotherapy. Bu-bonic plague (the ``Black Death''), malaria, and typhusare in this category. Largely through pharmacother-apy, including the use of immunological agents, epi-demics of life-threatening diseases have been greatlyreduced and, until recently, were thought to have beeneliminated in all but the least developed regions of theworld. We now know that this is not the case.In past centuries epidemics swept entire countriesand continents. In one 8-year period in the fourteenthcentury when bubonic plague was epidemic through-out Europe, two thirds of the population were infected;half of these died, totaling 25 million deaths. In 19181919 an inuenza epidemic swept most of the world,causing 20 million deaths, with more than a half-mil-lion deaths occurring in the United States. Twenty or30 years ago we thought such pandemics could beprevented. A pandemic occurs when a disease occursover a wide geographic area and aects an excep-tionally high proportion of some populations. As weenter the third millennium we are in the midst of apandemic that is worse than anything the world hasknown before, based on numbers of human casualties.Acquired immunodeciency syndrome (AIDS) is avirally transmitted disease caused by HIV, a humanimmunodeciency retrovirus, whose genetic material isRNA. AIDS is an especially nasty, progressive, andcostly disease for which no cure currently exists. Whena cure is found it will be a drug cure. The virus uses theenzyme reverse transcriptase to incorporate its geneticmaterial into the infected host cell's genome. The pri-mary host target cells are T4 (T-helper) cells, which,after a signicant level of destruction, compromises thebody's immune system. A whole range of opportunisticinfections then attack, often in concert, until deathinevitably ensues.Table 2 lists the distribution of HIV=AIDS in var-ious regions of the world. The heavy infection level insub-Saharan Africa is the result of several factors.First, the disease probably originated there. The oldestHIV sample came from the Republic of the Congo in1959, but most researchers believe AIDS had beenkilling people many decades before then. Second, mostof the countries in sub-Saharan Africa are under-developed and have lacked the resources to ght thedisease or implement eective prevention plans. Thisregion of the world now has 70% of the global total ofHIV-infected people but only 10% of the world'spopulation. The epidemic in Africa has exploded in thelast 20 years. In 1982 only one African country had anHIV prevalence rate in adults above 2%. By 1998 itwas estimated that more than 7% of the adults living in21 African countries were HIV-positive or had AIDS.In two populations 25% of the adults were infected.Life expectancy has fallen to 30 years or less in some ofthese countries, making HIV an unprecedented cata-strophe in the world's history [1]. In addition to thenearly 35 million people estimated to have HIV=AIDSgoing into the new millennium, to date AIDS has killed20 million people [2]. It is clearly the most lethal pan-demic the world has ever known and represents one ofthe biggest challenges to public health and pharma-cotherapy today.Another challenge facing pharmacotherapy as weenter the twenty-rst century are diseases known aszoonoses. Zoonoses are animal-borne diseases, whichare transmitted to humans. They often develop in arelatively small region of the world initially and thenspread. They are often viral in origin and thus producea far greater challenge to humankind than did many ofthe bacterial diseases of the past. Although controversyexists, there is compelling evidence that HIV is a var-iant of viruses that infect nonhuman primates in cen-tral Africa and is thus a zoonose disease.Another recent example of a zoonose infection is theNipah virus, named after the town in Malaysia where itsrst known victimlived. The animal vector of this diseasehas been identied as several species of bats. The Nipahvirus has destroyed Malaysia's pig industry and it killed105 people in 1999. The virus produces a severe form ofencephalitis, and about 40% of infected individuals die.Table 2 Distribution of HIV=AIDS in Various Regions ofthe WorldRegion Number infectedaSub-Saharan Africa 22,500,000Southeast Asia 6,700,000Latin America 1,400,000North America 890,000Eastern Europe and Central Asia 560,000Western Europe 500,000Caribbean 330,000Northern Africa and Middle East 210,000Australia and New Zealand 12,000Total 34,400,000aAs of the end of 1998.Source: Ref. 1.Copyright 2002 Marcel Dekker, Inc.In the United States in recent years several diseaseswith animal hosts are now infecting humans. TheArena virus has as its host certain desert rodents.Rodent droppings when dry and airborne as dustparticles infect humans, often with lethal con-sequences. The West Nile virus appeared in the UnitedStates in 1999. Birds carry this virus, and mosquitoesare the vector to humans. In 1999 the virus was loca-lized in the New York City area. By 2000 it has spreadacross New York State and into New Jersey andMassachusetts. The West Nile virus is especially lethalwhen it infects children, the elderly, or those with acompromised immune system.The subject of zoonoses was extensively discussed atthe International Conference on Emerging InfectiousDiseases, July 1619, 2000 in Atlanta, Georgia [3]. Agroup of researchers from the University of Edinburghreported that humanity is currently challenged by 1709known pathogens, including viruses, bacteria, fungi,protozoa, and worms. Of these, 832, or 49%, arezoonotic. Of even greater concern is the fact that of the156 disease that are considered to be new or ``emer-ging,'' 114 are zoonoses, a staggering 73%. The dis-eases produced by these zoonoses often must primarilybe challenged by pharmacotherapy. It is clear thatmuch will remain to be done by pharmaceutical sci-entists in the years ahead, in addition to attacking theleading causes of death and disability.II. ROLE OF PHARMACOTHERAY INMORTALITY RATES, LIFEEXPECTANCY, AND QUALITY OF LIFEAnother impact of pharmacotherapy that is not gen-erally recognized has been its eect on life expectancyand on the health of the newborn, infants, and chil-dren. Some of the earliest valid historical statistics onthe death rates of children are found in parish recordsof London, England. One parish, St. Botolph's,``which was bordered by the city wall and eastern gate,the Tower of London and the Thames,'' has detailedrecords from 1558 to 1626, which have survived theyears intact [4]. The population of this region probablyenjoyed better medical care than did their ruralneighbors. The stillborn death rate in the parish uc-tuated between 40.8 and 133.4, averaging 71.6=1000births. The current overall average stillborn death ratein the United States is about 20=1000 births. Infantsdying in the rst month in Shakespeare's day in Lon-don were known as chrisoms. The average chrisomdeath rate from 1584 to 1598 was more than 162=1000(two to four times the average stillborn rate). Thus,about one child out of every three to four was stillbornor failed to survive the rst month. By contrast, in theUnited States today fewer than 10 deaths per 1000 livebirths occur during the rst year of life. Survival ratesof infants and older children were equally grim inShakespeare's England. Of every 100 children born inthe late sixteenth century, only about 70 survived tothe rst birthday, about 48 to their fth, and only 2730 survived to their fteenth birthday.The death rate statistics of newborns, infants, andolder children have greatly improved from the six-teenth, or even the twentieth century, to the opening ofthe twenty-rst century. An interesting exercise whennext you visit an old cemetery would be to readtombstones that predate 1900, or even 1940. You willnd that one grave marker out of every two or three isfor a newborn, infant, or a young child. This was lar-gely related to the inability of the medical and phar-maceutical professions of that day to eectivelycombat infectious and children's diseases. Many ofthese diseases aected children almost exclusivelyamong their fatality victims (see Table 1), includingmeasles, scarlet fever, polio, and whooping cough.Added to the infectious ``children's diseases'' problemwas the fact that these diseases often left their youngsurvivors with permanent physiological damage, suchas scarred heart valves, brain damage, poorly devel-oped limbs or paralysis, and other defects that re-mained for the balance of life. The dramaticimprovement in the infant mortality rate in the UnitedStates over the past 60 years is shown in Fig. 2 [5].Although great advances have been made, a number ofcountries in Western Europe have rates that are sub-stantially better than those of the United States.The increasing life expectancy and the growingnumber of the elderly in our citizenry over the lastcentury, and in recent decades, is well known (Figs. 3and 4) [5]. A person born in 1920 could expect to liveonly 54.1 years. Today we can expect to live over 76years (about 73 years for men and nearly 80 years forwomen). The life expectancy for women helps explainthe fact that octogenarians (persons over 80) are thefastest-growing segment of any age group in our po-pulation. Another interesting way to look at life ex-pectancy is shown in Fig. 5. Here we see the averageadditional life expectancy a person may have based ontheir current age. These gures, at all age levels, alsoshowa steady upward progression over the last 27 years.Figure 3 also shows what many experts predict. Lifeexpectancy is not expected to plateau, but by 20302040 the life expectancy for women will be at least 90,and for men will be approaching 85. However, theseCopyright 2002 Marcel Dekker, Inc.numbers could be negatively impacted in the UnitedStates by the current AIDS epidemic. Figure 4 showsanother result of our increasing life expectancythevery rapid growth in the over-65 population as a per-centage of the U.S. population from 1960 to the year2000. In a report of the National Institute on Aging [6]it was noted that there are 35 million people in theUnited States age 65 or older. This number will doubleby 2030, continuing the dramatic shift to a much largerpopulation of older Americans. Women currently ac-count for about 60% of those over 65, and nearly halfof these older women live alone. The percentage ofolder Americans living in poverty has dropped dra-matically in the last 40 years, from 35% to 11%, butthere is a disparity between races (8.2% for whites vs.26.4% for blacks). This dramatic shift in our elderlypopulation will have a large impact on social programssuch as Social Security, Medicare, and Medicaid, aswell as on the rapidly expanding growth and need forpharmaceutical services and pharmacy care in theyears ahead.The exact contribution of modern pharmaceuticalsto our increased longevity can be only estimated andweighed in comparison with improved diet and life-styles, sanitation, housing, and generally improvedpublic health. However, advances in chemotherapyhave certainly been the major factor in extending ourlife expectancy. Similarly, the contribution of phar-macotherapy to an improved quality of life in recentdecades can be only estimatedbut it has been a verymajor factor. It is clearly a leading factor in the well-being of the elderly, allowing them to remain activeand essentially healthy through more years and over agreater fraction of their total life span. The role ofpharmacotherapy in improving the quality of life of thementally ill is also clearly evident. Hundreds of thou-sands of mentally ill patients in the United States alonewho are currently being treated as outpatients can liveessentially normal lives and can remain with their fa-milies through the use of drugs to control their illness.Without the availability of eective psychotherapeuticdrug agents, many of these patients would require in-stitutionalization or at least short- to midterm hos-pitalization.Other diseases that formerly required long-termhospitalization or complete isolation include tubercu-losis and the dreaded leprosy. Only a generation or twoago, for patients to be told that they had such diseasesFig. 2 Infant (under 1 year) mortality rates in the United States, 19402000.Copyright 2002 Marcel Dekker, Inc.was equivalent to receiving a death sentence, or worse.These diseases are totally curable today by means ofchemotherapy, and the patient no longer needs to beisolated in a sanitarium. Other diseases, such as rheu-matoid arthritis, frequently drove patients to suicide.Today, even though we still lack cures for some ofthese diseases, we can contain and control them, per-mitting patients to lead nearly normal lives.Great strides have been made in chemotherapy sinceWorld War II (19391945) and in the decades followingthe war. Antibiotics and other anti-infective drugs,steroids, psychotherapeutic agents, many new im-munizing agents, important cardiovascular agents, an-tineoplastic agents, and numerous other drug classesand agents have appeared in the last four to ve dec-ades. Given the rapid advances in biotechnology, newdrug innovation is entering another period of revolu-tionary growth. Nevertheless pharmaceutical scientistshave no cause for complacency. We cannot yet cure thedebilitating diseases of cystic brosis or muscular dys-trophy. Many forms of cancer are treatable with onlylow to moderate success if detected early; that battle isfar from won. Over one-half million Americans aredying each year from cancer, the number 2 cause ofdeath in this country. Although death rates are con-sistently continuing to decline (Fig. 6), we must con-tinue the battle to eectively combat many degenerativediseases aecting our growing elderly population, no-tably heart disease, the number 1 killer, which killsthree-quarters of a million Americans a year. Thegrowing challenge posed by cardiovascular disease, asAmericans continue to age, is shown in Fig. 7. Thecurrent third leading cause of death also heavily af-fecting the elderly, is cerebrovascular disease, whichkills about 150,000 Americans a year. This prevalenceand estimated annual economic cost of some commondiseases as shown in Table 3, further documents someof our remaining challenges in pharmacotherapy andFig. 3 Expectation of life in years at birth in the United States.Copyright 2002 Marcel Dekker, Inc.health care. The challenge of the AIDS pandemic andother emerging diseases was discussed in the previoussection. Accidents are the fourth leading cause of deathat 90,00095,000=year. Pharmacotherapy is expected toprovide major answers to most, if not all of these andmany other disease challenges in the years to come.III. DRUG AND DRUG PRODUCTQUALITY AND ITS EVALUATIONA. Reasons for the Drug Product QualityQuestionThe quality of drugs, which used to be an importantdiscussion topic only for pharmaceutical manu-facturers and experts in education, compendial stan-dards, and regulatory enforcement, has now beenplaced in the spotlight of public attention. The reasonsfor the broadbased interest in drug product quality arebased on the following factors, at least in part: (a) aclear realization that drug products are dierent fromother consumer products; (b) rapidly increasing healthcare and drug product costs over the last several dec-ades; (c) increasing public advertising of prescriptiondrug products, with identication of price dierentialsamong chemically equivalent generic products; (d) in-creasing payment of health care costs by third parties;(e) promulgation of the federal ``maximum allowablecost'' (MAC) regulations; and (f) eects of health carereform and increasing pressure to provide a prescrip-tion drug benet under Medicare.The greatest dierence between drug products andother consumer products is that the principle of caveatemptor (``let the buyer beware'') cannot operate in theusual way when the layperson acquires prescriptiondrugs. In addition, laypeople lack the skills and so-phistication to evaluate the quality and appropriatenessof their prescription drug products, whereas they dohave some ability to evaluate most other consumerproducts. Furthermore, consumers do not select pre-scription products as they do nearly every other productthey purchase or use. A consumer is often compelled tobuy a specic drug product, whereas he or she has morefreedom of choice about when or if they buy otherproducts. In the process, the layperson must usuallytrust the physician who prescribes the medication andthe pharmacist who selects it (if a generic drug) and dis-penses it. Other dierences are that drug products areFig. 4 Percentage of the total U.S. population older than 65 years, 19602000. (From Ref. 5.)Copyright 2002 Marcel Dekker, Inc.typically more critical to the consumer's well-being thanare other products. A poor quality drug product canhave more serious consequences than a poor qualityconsumer product of nearly any other category. Drugproducts are also more complex than nearly any otherclass of consumer product. These last two factors arewhy drug products are subjected to many more tests andcontrols than are other types of products.In the last four to ve decades national health careexpenditures for all types of health-related transac-tions, including dental, medical, hospital, prescription,and over-the-counter (OTC) drugs, has grown fromabout 5% of the country's gross domestic product(GDP) (national expenditures on all goods and ser-vices) to nearly 14% of the GDP today. Total healthexpenditures in the United States are now well over $1trillion annually.There are many reasons for the cost increases inhealth care, in addition to ination, including the fol-lowing: (a) there are more and more older people,requiring more care; (b) new and additional types ofcare and treatment are available and they tend to bemore expensive, and (c) the quality of treatment hasbeen improving. Aggregate expenditures in thehealth sector, have been rising at 10% or more a yearover the last 1520 years. While per capita health careexpenditures for Americans are the highest in theworld, a recent report from the World Health Organi-zation (WHO) ranks the United States as only 37th outof 191 nations in terms of the health services providedto our citizens [7]. In this rst ever ranking of UnitedNations member countries' health systems, some of thefactors considered were life expectancy, health qualitybased on infant=child survival rates, system respon-siveness, system cost per population served, fairness ofnancial contributions, and overall health system per-formance. The top ranked countries were France, Italy,San Marino, Andorra, Malta, Singapore, Spain, Oman,Austria, and Japan. The bottom ranked countries wereall from sub-Saharan Africa plus Burma.Fig. 5 Additional years of life expectancy at various ages, 196519701997.Copyright 2002 Marcel Dekker, Inc.The WHO report noted that many countries arefalling far short of their potential and that ex-penditures per se do not necessarily produce the bestsystem. This is exemplied by the fact that the UnitedStates, which is ranked 37th, spends 13.7% of its grossdomestic product on health care, while the UnitedKingdom, which is ranked 18th, spends only 5.8%.While rankings are only as meaningful as the cri-teria on which they are based and the accuracy of theirassessments, there is undoubtedly some validity to theWHO study and its rankings. One analysis of the re-latively low U.S. ranking noted the large number ofAmericans who have no health insurance or othercoverage and the lower level of healthy life expectancyin the United States compared to other industrializednations. The WHO analysis also commented on thehigh rates of heart disease and tobacco-related cancersin the United States, together with the ``extremely poorhealth'' of minority groups, notably Native Americansand rural African Americans, as contributing to therelatively low ranking of U.S. health care.The great majority of health care expenditures arefor servicesmedical services, nursing services, orhospital services. While pharmacy (prescription pro-ducts and services) constitutes a relatively small per-centage of total health care expenditures (910% of thetotal), the pharmacy component has received a greatdeal of attention in recent years. There are severalreasons for this. A product is involved in the pharmacycomponent, and it is much easier to analyze and at-tempt to minimize product costs compared to medicalor hospital services. Second, a well-dened private in-dustry is involved with the drug component thepharmaceutical industry. Based in part on the relativelyhigh prots shown by this industry it is a target forcriticism by government and politicians. The pharma-ceutical industry, its relationships to pharmacy, andthe public are discussed in chapter 28. Lastly, theFig. 6 Age-adjusted death rates in the United States from all causes by sex and by race (white and all others), 19401996.(Courtesy of National Center for Health Statistics.)Copyright 2002 Marcel Dekker, Inc.pharmaceutical component has been the fastest grow-ing cost component of all health care expenditures,growing since 1993 at a steady 13.3 compound rate.The U.S. prescription drug market in 1999 increasedby 19%, totaling $2.7 billion, representing 2.7 billionprescriptions, a 9% increase over the prior year [8].Table 3 Prevalence, Cost, and Medicines in Development for Selected Major Diseases in the United StatesUncured diseaseApproximateprevalenceApproximateannualeconomiccost ($billions)Numberaofmedicines indevelopment SourceAlzheimer's disease 4,000,000 100.0 24 National Institute on AgingArthritis 43,000,000 54.6 28 Arthritis FoundationAsthma 14,000,000 6.2 17 National Heart Lung and Blood InstituteCancer 8,000,000 107.0 354 American Cancer SocietyCongestive heart failure 4,900,000 20.2 17 American Heart AssociationCoronary heart disease 13,900,000 95.6 38 American Heart AssociationDepression 17,600,000 53.0 17 National Institute on Mental HealthDiabetes 15,700,000 98.2 26 National Institute of Diabetesand Digestive and Kidney DiseasesHypertensive disease 50,000,000 31.7 10bAmerican Heart AssociationOsteoporosis 10,000,000 13.8 19 National Osteoporosis FoundationSchizophrenia 1,500,000 23.0 12 National Institute of Mental HealthStroke 4,000,000 43.3 19 American Heart AssociationNote: HIV=AIDS discussed separately in Chapter 1.aPhRMA data.bHypertension medicines.Source: PhRMA, 2000.Fig. 7 Aging of baby boomers will dramatically increase population potentially at risk from cardiovascular disease (CVD).Copyright 2002 Marcel Dekker, Inc.Of this total prescription market the federal govern-ment paid about 13% (Medicaid), third parties paid68%, and the individual paid about 19%[8]. The rapidgrowth of the prescription market in recent years is theresult of numerous factors, but it certainly includesgrowing managed care utilization which includes somelevel of drug coverage, the continuing aging of the U.S.population, new product approvals and introductions(which tend to be more expensive), direct to consumeradvertising by drug companies, ination of drug pro-duct costs, and a strong economy. The aging-of-America eect is documented by following statistics [9]:the 50-plus age group consume 74% of all prescriptiondrugs, 51% of all over-the-counter (OTC) drug pro-ducts, and represent 65% of all hospital bed days. By2005 30% of Americans will be 50 or older. The impactof the rapidly growing drug cost share of total operat-ing expenses for HMOs is discussed in Chapter 27.B. The Pharmacist's Responsibility and Rolein Drug Product SelectionThe pharmacist bears a heavy responsibility for thequality and appropriateness of the drug products thatshe or he dispenses. The Code of Ethics of the Amer-ican Pharmaceutical Association states (in Section 2):``The pharmacist should never condone the dispensingof drugs and medications which are not of goodquality or which do not meet standards required bylaw.'' Pharmacists are frequently obliged to makejudgments concerning the quality of individual drugproducts and the various dosage forms and possiblepresentations available for individual drugs. This oc-curs as pharmacists serve on formulary committees,therapeutics committees, and in other ``ocial'' roles,as well as on a day-to-day basis, in evaluating manu-facturers' and other data to select drug products fortheir patients that are not only cost-competitive, butare also safe and eective. The pharmacist's role indrug and drug product selection has increased dra-matically in recent decades with the evolution of clin-ical pharmacy and pharmaceutical care and with thegrowth of third-party payments for prescription drugs.Fortunately, the pharmacist is the most knowledgeableexpert on available drugs and drug products and cri-teria aecting drug product quality. Pharmacists arealso better qualied and more knowledgeable thanother health care professionals when it comes to drugproduct forms available, relative merits of dierentdosage forms, even within a given route of adminis-tration, and possible or most likely side eects within agiven population group such as children or the elderly.Furthermore, pharmacists are well acquainted with thestorage requirements for various drugs and drug pro-ducts and with the physical signs by which deteriora-tion may be detected. The pharmacist is the health careprofessional in the best position today to know thevarious drugs a given patient is taking and thus is bestable to avert adverse therapeutic eects that can arisefrom many sources. This is because many patients seemore than one physician, and they are increasinglytaking a broader range of OTC products, includingherbs, natural products, and nutriceuticals.The questions of drug quality, drug cost, drug se-lection and eectiveness, and proper drug utilizationhave become a matter of widespread public interest. Itis thus very important for pharmacists to be highlyknowledgeable concerning all aspects of drug productquality and optimal drug utilization on an individualpatient basis.C. History and Evolution of Drugs and DrugProductsEvery pharmacist and pharmacy student should readone of the many available books on the history of drugsand the drug industry [1014]. A pictorial history suchas Drugs [10] in the Life Science Library Series or one ofthe several illustrated books on the patent remedy era[11,12] is entertaining as well as educational reading.Several U.S. drug companies, on reaching the centurymark, have also written interesting histories that alsodocument U.S. pharmacy history [1517]. Severalpharmacy trade associations have written interestinghistories directed to pharmacy practice [18,19]. A his-tory of the U.S. Public Health Service also containsimportant bench marks for pharmacy [20]. These re-ferences are only a few of the many interesting histor-ical books on pharmacy that could be cited.When the history of drugs and drug products isexpressed as a time continuum, as shown in Table 4, itis very apparent that most drug and drug productadvancements have occurred over the last 50 years.Before the early twentieth century, the only puriedorganic chemical substances used in chemotherapywere aspirin, quinine, and morphine. For the preceding4000 years, drugs changed relatively little. EarlyEgyptian physicians recorded over 70 ``drugs'' in 800remedies administered in 14 dierent forms from pillsto ointments and salves and poultices. The drugs wereall from natural sources, ranging from spider webs, toanimal excretions, to packs of mud, to poppy seeds.Between the eighth and thirteenth centuries, Arabicalchemists greatly advanced pharmaceutical art byCopyright 2002 Marcel Dekker, Inc.introducing extraction and distillation processes toconcentrate and purify natural products. However,Arabic drugs did not reach Christian Europe until thelate Middle Ages (thirteenth to fteenth centuries).Pharmaceutical art in colonial America some 200 yearsago was little better than that of the Arabic alchemists1000 years earlier. The patent remedy era that our-ished in the second half of the nineteenth century was acolorful period in pharmaceutical history when ``cure-alls'' were marketed by pitchmen from the backs ofhorse-drawn wagons, often as a follow-up to some freeentertainment used to gather the locals. As depicted inthe advertised indications from the label of one pop-ular patent remedy of the day (Fig. 8), the only limit onclaims appeared to be the imagination of the labelwriters [10]. As noted on the advertising copy of Fig. 8,these remedies were expensive in the days when anaverage wage earner made 1520 dollars a week.Grandmother Pinkham used pictures of her grand-children on her advertising and label copy; others, suchas the medicinal syrups millionaire G. G. Green,placed on their advertising and labeling illustrations ofthe mansions that their high-prot ``cure-alls'' broughtthem. Most patent remedies contained common plantTable 4 Periods and Notable Events in the History of the Development of Drugs and Drug Products2000 B.C. First drug recordsAncient times toMiddle AgesAncient to medievalpharmacy and medicineWitch doctorsReligious healers1700 Natural products development1800 First compendium (U.S.)1850 First U.S. drug companies1900 Patent remedy era Development of analytical standards1906 Wiley Act first food and drug law1938 Second major FDA legislation19451965 Golden age of discovery Development of sulfa anti-infectives(antibiotics, steroids, etc.)1962 Kefauver-Harris AmendmentNew regulations Accelerating development of cancerchemotherapyNew drug-delivery systems1977 Additional drug regulatory legislationphaseIV testing, etc.1980s Pharmaceutics advances Full implementation of bioavailabilitystandardsAdditional new drug-delivery capabilities1980s2000s Mathematical optimization of drugproduct safety, effectiveness, and reliabilityBiotechnology era beginning First recombinant DNA productsHuman insulinHuman growth hormoneInterferons, etc.Monoclonal antibodiesNucleotide blockageGrowth in use of natural products andneutraceuticals2000 Pharmaceutical company megamergers con-tinueSequencing of the human geromeGene therapy developingUse of human tissues in medicineHigh throughput screening of potential drugsCombinatorial chemistry, biotechnology, andcomputers advance rational drug designCopyright 2002 Marcel Dekker, Inc.Fig. 8 Example of the advertised indication (cures) from the labeling of a widely used patent remedy, before Enactment of theFood, Drug and Cosmetic Act of 1906. (From Ref. 10.)Copyright 2002 Marcel Dekker, Inc.extracts, such as taraxicum (common dandelion weed),at least 15% alcohol, and occasionally opium or othernarcotic or addictive substances to help assure repeatsales. It is interesting to speculate on the number ofpersons in the temperance era who kept all thosearound them ``dry'' and then enjoyed their eveningtoddy of Lydia Pinkhams or stronger higher proofproducts before retiring. The Food, Drug, and Cos-metic Act of 1906 was intended to combat the abusesof the patent remedy era, at least in part by requiringlabeling of the active ingredients contained in allpharmaceuticals and by broadly limiting fraudulentpractices. The 1938 act went further, requiring that atleast some principles of rational therapeutics be ap-plied to all products and their claims. The 1962 actrequired many more proofs of safety and eectiveness.(See Chapter 19 for a more detailed description of theevolution of drug laws.)One interesting way of examining drug and drugproduct quality is to analyze the changes in drugs anddrug products over the centuries, especially the veryrapid changes in the last half-century (see Table 4).Anyone who imagines that current drug products areoptimal as to quality features or that we have reachedthe ultimate in chemotherapeutic capabilities is as-suming that the history of drugs is now standing still aswell as ignoring the science of pharmaceutics as wecurrently know it. Although the Middle Ages endedaround 1450, historically speaking, drugs and drugproducts did not progress substantially above thequality and knowledge level of the medieval perioduntil the late nineteenth and early twentieth centuries(Table 4). Drug and drug product advancements dur-ing the last 5060 years have surpassed the total ad-vancement in the eld over the entire 4000-year historyof drug development (see Chapter 28). As we enter thetwenty-rst century and the biotechnology scienticera, there is every likelihood that the rate of advance-ment in pharmacotherapy will overshadow everythingwe have known in the past.D. Criteria for Drug and Drug Product QualityCompendial standards and government regulationsrequire that all drug products, whether ethical pre-scription or OTC products, meet strict standards ofidentity, potency, and purity. From about 1900 (seeTable 4) until recent decades, standards of identity (theproduct is what it is actually labeled to be), potency(the active ingredient is present in the labeled amount),and purity [basically limiting nondrug materials as wellas describing the amount of active ingredient(s) innatural substances] were thought to dene drug qualityadequately and were enforced under evolving law andU.S. Food and Drug Administration (FDA) regula-tion. The addition of a few physical tests, such asweight variation and disintegration time to compendialproducts such as tablets and capsules, was thought toaccurately dene the quality of these products. We nowknow that drug products require very careful evalua-tion to accurately reect their quality and performancein clinical roles and that earlier concepts of evaluationrequired expansion. The designation ``quality,'' appliedto a drug product, according to a modern denition,requires that the product:Contain the quantity of each active ingredientclaimed on its label, within the applicable limitsof its specicationsContain the same quantity of active ingredient fromone dosage unit to the nextBe free from extraneous substancesMaintain its potency, therapeutic availability, andappearance until usedUpon administration, release the active ingredientfor full biological availabilityIn the contemporary denition of quality we seethat the concepts of identity, potency, and purity areretained in the rst three criteria, but that bioavail-ability potency maintenance (including maintenance ofpharmaceutical elegance and therapeutic availabilityor full biological availability) are added. The denitionrecognizes that drug products may undergo changeswith time that result in a loss of biological and ther-apeutic activity, even though the product compliescompletely with the original potency and purity stan-dards and no signicant drug decomposition has oc-curred. Such losses in therapeutic activity, without anychemical potency change, may occur as a result of avariety of causes, including:1. Physical changes in the dosage form (moistureloss or gain, crystal changes in excipients, tablethardening, loss of disintegration=deaggregationproperties, etc.)2. Physical changes in the drug (conversion of amore stable, less readily soluble polymorph,etc.)3. Chemical changes or interactions involving ex-cipients (such as esterication of coatings, ren-dering them less polar and less soluble)As noted in chapters that follow, in vitro testsmay not themselves be adequate to assure that aproduct possesses adequate or full bioavailability andCopyright 2002 Marcel Dekker, Inc.therapeutic activity. Whether or not in vitro tests areadequate quality-control indications depends on theirsensitivity to pick-up aging or environmental exposureeects that produce the type of changes noted in thepreceding paragraphs or other changes that are ofconsequence to therapy. The eects on drug potency ofenvironmental stress conditions (e.g., increased tem-perature, increased humidity, combinations of the two,or temperature cycling) are known for most drug pro-ducts. The eects of such stress conditions on bioa-vailability or therapeutic activity are much less wellknown currently, even for many commercial products.A drug product can be of no higher quality than thequality of the drug(s) and excipients (nondrug ad-ditives) from which the product is made. It is possible,however, for a product to be of much lower qualitythan its components, since quality and clinical per-formance are also related to:1. The rationale of the dosage form design (e.g., ifa drug is rapidly destroyed in solution at a pHof 2 or below, the design of an oral productmust enable the drug to get through the sto-mach without substantial dissolution)2. The method(s) of product manufacture3. In-process and nal quality-control proceduresto assure that the quality designed and manu-factured into the product is actually there4. Reasonable convenience and ease of productuse to assure patient compliance with prescribeddosagesSome of the factors and considerations in the designof high-quality drug products are shown in Table 5.Various physicochemical and pharmacokinetic prop-erties of drugs that aect dosage form design, and theirinuence on design of high-quality products, are de-Table 5 Factors in the Design and Production of High-Quality Drug ProductsInput factors Output factorsA sound development=design manufacturing base EffectivenessThe preformulation research database SafetyPhysicochemical properties of the drugPharmacokinetic characterization of the drug ReliabilityA rational dosage form design StabilityFormulation of a stable, reliable system PhysicalChemicalObjective preclinical and clinical testing MicrobiologicalBioavailabilityA precise, reproducible manufacturing processWell-controlled manufacturing steps PharmaceuticalCoordinated manufacturing sequences AppearanceEfficient, sanitary operation Organoleptic propertiesModern plant and equipmentKnowledgeable, well-qualified workersConvenienceA sensitive product control system Ease of useRaw material control Dosing frequencyProcessing controls Consumer acceptanceFinal product controlsChemical control standardsPhysical properties standardsBiological and microbiological standardsInformed, qualified, and responsible personnelManagementResearch and developmentQuality controlProductionServicesCopyright 2002 Marcel Dekker, Inc.scribed in Chapter 7 on preformulation. The criteriaand properties dening the quality of various dosageforms are discussed in the relevant chapters on dosageforms. The features of an optimized drug are discussedin the relevant chapters on dosage forms. The featuresof an optimized drug product and the concepts of truedrug-delivery systems are described in the next section.IV. THE DRUG PRODUCT AS A DELIVERYSYSTEMA. Drug Products, Drug-Delivery Systems,and Therapeutic SystemsDrug substances in their puried state usually exist ascrystalline or amorphous powders or as viscous li-quids. The majority of drug substances exist as whiteor light-colored crystalline powders. Although drugswere once commonly dispensed as such in powderpapers, this practice is virtually unknown in pharmacypractice today. With the possible exception of the an-esthetic gases, all drugs in legitimate commerce arenow presented to the patient as drug products. It isnow well recognized that the therapeutic ecacy andthe therapeutic index [ratio of LD50 (lethal dose in50% of the subjects) to ED50 (eective dose in 50% ofthe subjects)] of a drug product is not totally dened bythe chemical constitution of the drug and its inherentpharmacokinetic prole. The actual performance ofmany drugs in clinical practice is now known to begreatly aected by the method of presentation of thedrug to the patient. Factors aecting the presentationinclude:The portal of drug entryThe physical form of the drug productThe design and formulation of the productThe method of manufacture of the drug productVarious physicochemical properties of the drug andexcipientsPhysicochemical properties of the drug productControl and maintenance of the location of the drugproduct at the absorption site(s)Control of the release rate of the drug from the drugproductIn the late 1940s and early 1950s, sustained-releaseproducts appeared as a major new class of pharma-ceutical product, in which product design was intendedto modify and improve drug performance, by in-creasing the duration of drug action and reducing therequired frequency of dosing. In the mid- to late 1960s,the term ``controlled drug delivery'' came into being todescribe new concepts of dosage form design, whichalso usually involved controlling and retarding drugdissolution from the dosage form, but with additionalor alternative objectives to sustained drug action.These new objectives included improving safety,enhancing bioavailability, improving drug eciencyand eectiveness, enhancing reliability of performance,reducing side eects, facilitating patient use and com-pliance, or other benecial eects. In the 1970s, yetanother term and concept of drug product design andadministration appeared: the therapeutic system. Theobjective of the therapeutic system is to optimize drugtherapy by design of a product that incorporates anadvanced engineering systems control approach. Threetypes of therapeutic systems have been proposed, therst of which is already in use: (a) the ``passive pre-programmed'' therapeutic systemone containing acontrolling ``logic element,'' such as a membrane orseries of plastic laminates, which preprograms at thetime of fabrication or assembly a predetermined de-livery pattern (usually constant zero-order release) thatis ideally independent of all in vivo, physical, chemical,and biological processes; (b) the ``active, externallyprogrammed or controlled'' therapeutic systemwherein the logic element is capable of receiving andconverting a signal (such as an electromagnetic signal)sent from a source external to the body to control andproperly modulate drug release from the device withinthe body; and (c) the ``active, self-programmed'' ther-apeutic systemcontaining a sensing element thatresponds to the biological environment (such as bloodglucose concentration in diabetes) to modulate drugdelivery in response to that information. Before thesustained-release concepts of the 1940s and 1950s,which also included depot forms of parenteral pro-ducts, no signicant new oral drug-delivery conceptshad occurred in the preceding 75 years (since the en-teric-coating concept).B. The Concept of the Optimized Drug ProductThe optimized drug product may be viewed as a drug-delivery system for the one or more drugs that itcontains. The goal of this drug-delivery system is torelease the drug(s) to produce the maximum simulta-neous safety, eectiveness, and reliability, as depictedin Fig. 9. Various physicochemical product propertiesthat inuence the quality features of safety, eective-ness, and reliability are shown in Table 6. Some phy-sicochemical properties can aect two or all threequality features of Fig. 9. For example, considerchemical stability. As a drug decomposes, if theCopyright 2002 Marcel Dekker, Inc.decomposition product(s) are inactive, this is equiva-lent to a reduction of the drug dose remaining in theproduct in other words, a reduction in product re-liability and eventually eectiveness. If the decom-position products are toxic or irritating to the body,product safety is also reduced as the product degrades.In examining Table 6, the manner in which each phy-sicochemical, physiological, or therapeutic propertyaects the various quality features will generally beapparent. You will think of and read about many otherphysicochemical properties that inuence the qualityfeatures of drugs and drug products as you read var-ious chapters of this book. It should also be noted thatthe three basic quality features of Fig. 9 are connectedby double-headed arrows. Thus, as the pharmaceuticalformulator modies the design of a drug product or itsmethod of manufacture to improve one quality featureor one physicochemical property related primarily toone quality feature, the other properties or qualityfeatures may be, and usually are, altered. As an ex-ample, it may be our goal to increase the hardness of atablet by formulation (adding more binder) and=orprocessing (compressing the tablets harder) to improvetablet gloss and appearance or to reduce tablet fria-bility (powdering and chipping in the bottle). This is aFig. 9 Features of the optimized drug product.Table 6 Factors Affecting Drug Product Safety, Effectiveness, and ReliabilitySafety Eectiveness ReliabilityAcute safety quantification Clinical effectiveness Chemical stabilityTherapeutic index LD50=ED50Generic effectiveness Physical stabilityLong-range safety considerations Blood levelsOnset of side effects Urinary elimination Microbiological stabilityAccumulation Pharmacologicalresponse(s)Unit-dose precisionNature of side effects Bioavailability Patient acceptanceSeverity ConvenienceReversibility Pharmaceutical eleganceFrequency of side effects BioavailabilityHigh percentageUntoward and other reactions UniformityIdiosyncratic responses StabilityAnaphylaxisToleranceAddictionDrug interactionsNumber of drugs involvedProbability of interaction in therapySeverity of the interactionsFrequency of interactionsStability considerationsChemical stabilityPhysical stabilityMicrobiological stabilityBioavailability stabilityCopyright 2002 Marcel Dekker, Inc.worthy objective, but it may also reduce the rate andextent of drug dissolution from the tablet. This, inturn, could reduce the reliability of drug absorptionand drug performance from patient to patient, inu-ence transit rate and drug dissolution along the gas-trointestinal tract within a given patient, or evenreduce eectiveness if the dissolution rate now limits orreduces bioavailability. In the example just cited,maximizing tablet hardness and appearance is a``competing objective'' to maximizing drug dissolutionand bioavailability.In Fig. 9 we see the denition of the optimized drugproduct as the drug-delivery system that balances allthese factors against each other to produce the max-imum possible eectiveness as the primary objective,while producing the best possible simultaneous safetyand reliability as secondary objectives, with mathe-matical certainty. An alternative optimization ap-proach would be to produce the maximum possible(optimized) product safety as the primary objective,while producing the best eectiveness and reliability asthe secondary objectives. Yet a third approach wouldbe to optimize safety and eectiveness as equallyweighted primary objectives, while maximizing relia-bility as the secondary objective. Chapter 18 is devotedto the topic of optimization and treats the manner inwhich experiments may be designed to establish thenecessary factors and relationships between factors(independent and controllable processing, formulation,and other variables) as these inuence one another andthe product quality features (dependent or responsevariables). Optimization methods then treat this data-base to design and manufacture the best possibleproduct from an overall standpoint, consideringquality features, which may be competing (i.e., as youimprove one feature, another degrades), taking intoaccount primary versus secondary features and nu-merous possible trade-o decisions. Although it is truethat the vast majority of drug products on the markettoday are reasonably safe and eective, it is also truethat relatively few products have been designed asoptimized systems. Indeed, until about 25 years ago,formal optimization methods were unknown in thepharmaceutical and most other industries. The sig-nicance of drug products not being optimum systemsvaries with drug product class. For drugs and drugproduct classes with a high therapeutic index (ratio ofLD50 to ED50) and minimal dose-related side eects,maximizing safety is of less concern, and if the drug iswell absorbed, a good, stable, pure, and potent drugproduct that is reasonably reliable may be nearly op-timum. For drugs that have less of a safety margin, itmay be argued that the conventional, rapidly releasing,eective, stable, and typical reliable product that iscurrently marketed is not optimum.Figure 10 illustrates the types of blood level con-centration proles that are produced with dierentdoses of a rapidly releasing product versus a con-trolled-release product. This gure is representative ofthe oral route of administration but may be extra-polated to other routes of administration, with theblood-level time frame simply being shifted to reectchanges in absorption (and possibly distribution) pat-terns. For the rapidly releasing product, whether givenin a single 100-unit dose (curve A) or three divideddoses of 33 units (curve B), the inherent ability of theindividual to absorb the drug determines the rate ofabsorption and the peak blood level obtained. (At thepeak, the rate of absorption and elimination are equal.)The conventional rapidly releasing drug product is notcontrolling the blood level versus time proles; such aproduct is simply an uncontrolled ``dump system,''dumping the drug in the stomach for rapid dissolutionand uncontrolled absorption. The body's inherentability to absorb the drug under the patient's physio-logical state at a particular time point and the drug'spharmacokinetics dictate the shape of the blood levelversus time prole at any particular dosing level ordosing frequency. For the optimized controlled-releaseform (curve C in Fig. 10), the drug product, which isnow a drug-delivery system, is controlling the rate ofrelease of drug in solution for absorption, and the re-lease rate has been optimized to match drug inactiva-tion and elimination, so that nearly constant levels maybe maintained while the drug is in an absorption regionin the gut. It has been clearly demonstrated that con-trolled drug delivery can also substantially increase thetherapeutic index and safety margins of certain drugs,while retaining full therapeutic eectiveness. This isbecause many controlled-release systems produce morerounded blood level versus time proles, without sharppeaks (compare curves A and C in Fig. 10), so thatmuch larger doses of the controlled-release product arerequired to reach toxic levels. In one study [21], theeectiveness and duration of action of an anti-histamine was followed in animals using a histaminevapor challenge test. The drug as a rapidly solubledispersion or solution had a duration of action of 3.8hours, whereas the controlled-release form providedprotection to histamine vapor of 8.7 hours. Many an-tihistamines are depressant drugs and are dangerouson overdosage or in combination with other depressantdrugs. In the same study, the drug in conventionalform was lethal to 85% of the rats dosed within 30Copyright 2002 Marcel Dekker, Inc.minutes at a dose of 200 mg=kg. The same dose of drugwhen administered as the active controlled-releaseform killed none of the rats dosed (LD0 at 24 h) [21].Similar studies have demonstrated the ability to im-prove the safety of a barbiturate drug. In one suchstudy, conventional phenobarbital had an LD50 in ratsat a dose of 200 mg=kg. Twice the dose from an activecontrolled-release form had only an LD40 [22]. Thecost of developing, testing, and gaining approvalthrough the FDA of depressant or hazardous drugs asnew products, optimized from a safety as well as ef-fectiveness standpoint, is apparently currently too highto warrant much activity in this area. Nevertheless, wepredict that such products will be the rule, rather thanthe exception, at some point in the future. Not onlywould such products save lives as a result of the con-sequences of purposeful or accidental overdosing ofpotent, depressant, and low therapeutic index drugs,but they might also reduce the severity of some druginteraction eects (especially when alcohol is one of thedrugs). By eliminating the spikes in the blood prolesof immediate release dosage forms, sustained releasedosage forms have the ability to reduce the frequencyand severity of the side eects of some drugs. Anumber of cardiovascular and other drugs are designedas sustained release products for this reason. Othercontrolled-delivery forms have the potential ofreducing some drug abuse problems, since the for-mulations and slow drug dissolution from the formsmakes it more dicult to produce extemporaneous il-legal and hazardous injectable solution forms.Drug-delivery systems have been designed that areheld in the stomach or are bioadhesive at other ab-sorption sites for prolonged and controlled time peri-ods (610 h) while releasing drug at controlled rates.Such concepts are bringing us closer to being able toachieve the ideal attributes of drug-delivery systems(Table 7), including control of such factors as variableFig. 10 Blood level versus time prole simulations following: (A) a single dose representing 100 units of a drug from a rapidlyreleasing dosage; (B) Three divided ddoses of 33 units each from the same rapidly releasing product; and (C) a single 100 unitdose from an optimized controlled-release dosage form. A hypothetical eective level (80 units) and toxic level (160 units) aredepicted. The dosing units are typically in mg and the blood level concentration units in mg or ng.Copyright 2002 Marcel Dekker, Inc.and uncontrolled gastric emptying and transit alongthe gut, which currently cause the oral route ofadministration to be the least reliable route of drugadministration, even though it is the most popularmethod of achieving systemic drug eects. Futuredrug-delivery systems that have controlled, prolongedretention in the stomach (or accessible body cavities)with simultaneously controlled delivery rates will nodoubt improve drug eectiveness for some agents byenhancing absorption, reliability, and eciency. Theyalso oer new possibilities of truly optimizing drugsafety by prolonging the time over which the drug canbe recovered or neutralized, not only on overdosing,but in acute drug interaction episodes. Bioadhesivesystems that can retain drugs on mucosal surfaces forprolonged periods, while promoting drug absorptionand delivery, will play a growing role in developingfuture delivery systems and drug products for someproteins, peptides, and other biotechnology-generateddrugs. Such systems will also render the oral mucosal,nasal, vaginal, and rectal routes more useful and reli-able for drug delivery. During their working lifetimespharmacy students of today are certain to see manynew drug-delivery concepts reach the marketplace thatpermit true optimization of drug action and the at-tainment of the ideal attributes of drug delivery.REFERENCES1. HIV and Africa's future. Science 288: 21492178, 23June 2000.2. XIII International AIDS Conference, Durban, SouthAfrica, reported in Newsweek, July 24, 2000, and otherpublic press.3. Emerging diseases. Science 289: 518519, 28 July 2000.4. R. Forbes. Life and Death in Shakespere's London. AmSci 58: 511520 1970.5. Statistical Abstract. U.S. Dept. of Commerce,Washington, DC, 1999.6. Report of the National Institute on Aging. OlderAmericans 2000: Key Indicators of Well Being,Washington, DC, Aug. 10, 2000.7. World Health Report 2000. World Health Organiza-tion, Geneva, Switzerland.8. F. Deardor. Changes and Trends in the Rx Market.IMS Health, 1999.9. K. Dychtwald. Age Power, How the 21st CenturyWill be Ruled by the New Old. Putnam, New York,1999.10. W. Model and A. Lansing. Drugs. Time-Life Books,New York, 1969.11. A. Hechtlinger. The Great Patent Medicine Era.Galahad Books, New York, 1970.12. G. Carson. One for a Man, Two for a Horse. BramhallHouse, New York, 1971.13. W. Screiber and F. K. Mathys. Infectious Diseases inthe History of Medicine. Kreis and Co., Basel, 1987.14. P. Boussel, H. Bonnemain, and F. Bove. History ofPharmacy and the Pharmaceutical Industry. AsklepiousPress, Paris, 1983.15. R. Carlisle. A Century of CaringThe Upjohn Story.Benjamin Co., Elmsford, NY, 1987.16. W. D. Pratt. The Abbott Almanac. Benjamin Co.,Elmsford, NY, 1987.17. L. Galambos et al. Values and Visions. A MerckCentury. Merck and Co., 1992.18. C. F. Williams. A Century of Service and Beyond, 1898NARD-NCPA 1998. National Community PharmacyAssociation, Alexandria, VA 1998.19. J. Mobley. Prescription for Success, The Chain DrugStory. The Lowell Press, Kansas City, MO, 1990.Table 7 Ideal Attributes of a Drug-Delivery System1. Capable of controlled delivery rates to accommodate the pharmacokinetics of various drugs (flexibleprogramming)2. Capable of precise control of a constant delivery rate (precise programming)3. Not highly sensitive to physiological variables, such as:Gastric motility and emptying, pH, fluid volume, and contents of the gutPresence=absence or concentration of enzymesState of fasting and type of food presentPhysical position and activity of subjectIndividual variabilityDisease state4. Predicated on physicochemical principles (not pharmaceutical art)5. Capable of a high order of drug dispersion (the ultimate is molecular in scale)6. Drug stability is maintained or enhanced7. The controlling mechanism adds little mass to the dosage form8. Applicable to a wide range and variety of drugsCopyright 2002 Marcel Dekker, Inc.20. F. Mullan. Plagues and Politics, A Story of the UnitedStates Public Health Service. Basic Books Inc.,New York, 1989.21. H. Goodman and G. Banker. Molecular-scale drugentrapment as a precise method of controlled drugrelease I: Entrapment of cationic drugs by Polymericocculation, J. Pharm. Sci. 59: 11311137, 1970.22. J. Boylan and G. Banker. Molecular-scale drug en-trapment as a precise method of controlled drug releaseII: Entrapment of anionic drugs by polymeric gelation.J. Pharm. Sci. 62: 11771184, 1973.Copyright 2002 Marcel Dekker, Inc.Chapter 2Principles of Drug AbsorptionMichael MayersohnUniversity of Arizona, Tucson, ArizonaI. INTRODUCTIONDrugs are most often introduced into the body by theoral route of administration. In fact, the vast majorityof drug dosage forms are designed for oral ingestion,primarily for ease of administration. It should be re-cognized, however, that this route may result in in-ecient and erratic drug therapy. Whenever a drug isingested orally (or by any nonvascular route), onewould like to have rapid and complete absorption intothe bloodstream for the following reasons:1. Assuming that there is some relationshipbetween drug concentration in the body and themagnitude of the therapeutic response (whichis often the case), the greater the concentra-tion achieved, the greater the magnitude ofresponse.2. In addition to desiring therapeutic concentra-tions, one would like to obtain these con-centrations rapidly. The more rapidly the drugis absorbed, in general, the sooner the phar-macological response is achieved.3. In general, one nds that the more rapid andcomplete the absorption, the more uniform andreproducible the pharmacological response be-comes.4. The more rapidly the drug is absorbed, the lesschance there is of drug degradation or interac-tions with other materials present in the gas-trointestinal tract.In a broad sense, one can divide the primary factorsthat inuence oral drug absorption and thus govern theecacy of drug therapy into the following categories:physicochemical variables, physiological variables, anddosage formvariables. For the most part, these variableswill determine the clinical response to any drug ad-ministered by an extravascular route. Although oftenthe total response to a drug given orally is a complexfunction of the aforementioned variables interactingtogether, the present discussion is limited primarily tothe rst two categories involving physicochemical andphysiological factors. Dosage formvariables inuencingthe response to a drug and the eect of route of ad-ministration are discussed in Chapters 4 and 5.The vast majority of drugs in current use and thoseunder development are relatively simple organic mole-cules obtained from either natural sources or by syn-thetic methods. It is important to note, however, thevirtual revolution in development of new therapeuticentitiesthose based upon the incredible advancesbeing made in the application of molecular biology andbiotechnol