Table Of Content

PA RIOK J. SINKO P1: Trim:8.375in×10.875in LWBK401-fm-Dom LWW-Sinko-educational November30,2009 22:0 Dr. Murtadha Alshareifi e-Library i MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES Physical Chemical and Biopharmaceutical Principles in the Pharmaceutical Sciences SIXTH EDITION Editor PATRICK J. SINKO, PhD, RPh ProfessorII(Distinguished) Parke-DavisChairProfessorinPharmaceuticsandDrugDelivery ErnestMarioSchoolofPharmacy Rutgers,TheStateUniversityofNewJersey Piscataway,NewJersey Assistant Editor YASHVEER SINGH, PhD AssistantResearchProfessor DepartmentofPharmaceutics ErnestMarioSchoolofPharmacy Rutgers,TheStateUniversityofNewJersey Piscataway,NewJersey 1 P1: Trim:8.375in×10.875in LWBK401-fm-Dom LWW-Sinko-educational November30,2009 22:0 Dr. Murtadha Alshareifi e-Library Editor:DavidB.Troy ProductManager:MeredithL.Brittain VendorManager:KevinJohnson Designer:HollyMcLaughlin Compositor:Aptara®,Inc. SixthEdition Copyright(cid:2)c 2011,2006LippincottWilliams&Wilkins,aWoltersKluwerbusiness. 351WestCamdenStreet Baltimore,MD21201 530WalnutSt. Philadelphia,PA19106 PrintedinChina All rights reserved. This book is protected by copyright. No part of this book may be reproduced ortransmittedinanyformorbyanymeans,includingphotocopiesorscanned-inorotherelectronic copies,orutilizedbyanyinformationstorageandretrievalsystemwithoutwrittenpermissionfrom thecopyrightowner,exceptforbriefquotationsembodiedincriticalarticlesandreviews.Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employeesarenotcoveredbytheabove-mentionedcopyright.Torequestpermission,pleasecontact LippincottWilliams&Wilkinsat530WalnutStreet,Philadelphia,PA19106,viae-mailatpermis- [email protected],orviaWebsiteatlww.com(productsandservices). 987654321 LibraryofCongressCataloging-in-PublicationData Martin’sphysicalpharmacyandpharmaceuticalsciences:physical chemicalandbiopharmaceuticalprinciplesinthepharmaceutical sciences.—6thed./editor,PatrickJ.Sinko;assistanteditor, YashveerSingh. p.;cm. Includesbibliographicalreferencesandindex. ISBN978-0-7817-9766-5 1.Pharmaceuticalchemistry. 2.Chemistry,Physicalandtheoretical. I.Martin,AlfredN.II.Sinko,PatrickJ.III.Singh,Yashveer. IV.Title:Physicalpharmacyandpharmaceuticalsciences. [DNLM:1.Chemistry,Pharmaceutical. 2.Chemistry,Physical.QV744 M3862011] RS403.M342011 615(cid:2).19—dc22 2009046514 DISCLAIMER Carehasbeentakentoconfirmtheaccuracyoftheinformationpresentandtodescribegenerally accepted practices. However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty,expressedorimplied,withrespecttothecurrency,completeness,oraccuracyofthecontents ofthepublication.Applicationofthisinformationinaparticularsituationremainstheprofessional responsibility of the practitioner; the clinical treatments described and recommended may not be consideredabsoluteanduniversalrecommendations. Theauthors,editors,andpublisherhaveexertedeveryefforttoensurethatdrugselectionand dosagesetforthinthistextareinaccordancewiththecurrentrecommendationsandpracticeatthe timeofpublication.However,inviewofongoingresearch,changesingovernmentregulations,andthe constantflowofinformationrelatingtodrugtherapyanddrugreactions,thereaderisurgedtocheck thepackageinsertforeachdrugforanychangeinindicationsanddosageandforaddedwarnings andprecautions.Thisisparticularlyimportantwhentherecommendedagentisaneworinfrequently employeddrug. SomedrugsandmedicaldevicespresentedinthispublicationhaveFoodandDrugAdministration (FDA)clearanceforlimiteduseinrestrictedresearchsettings.Itistheresponsibilityofthehealth careproviderstoascertaintheFDAstatusofeachdrugordeviceplannedforuseintheirclinical practice. Topurchaseadditionalcopiesofthisbook,callourcustomerservicedepartmentat(800)638-3030 orfaxordersto(301)223-2320.Internationalcustomersshouldcall(301)223-2300. VisitLippincottWilliams&WilkinsontheInternet:athttp://www.lww.com.LippincottWilliams& Wilkinscustomerservicerepresentativesareavailablefrom8:30amto6:00pm,EST. 2 ii P1: Trim:8.375in×10.875in LWBK401-fm-Dom LWW-Sinko-educational November30,2009 22:0 Dr. Murtadha Alshareifi e-Library DedicatedtomyparentsPatriciaandPatrickSinko, mywifeRenee,andmychildrenPat,Katie(andMaggie) 3 iii P1: Trim:8.375in×10.875in LWBK401-fm-Dom LWW-Sinko-educational November30,2009 22:0 Dr. Murtadha Alshareifi e-Library DEDICATION ALFREDN.MARTIN(1919–2003) ThisfiftiethanniversaryeditionofMartin’sPhysicalPhar- focus,andphilosophyofpharmaceuticaleducationduringthe macyandPharmaceuticalSciencesisdedicatedtothemem- 1960sandthe1970sandpavedthewayforthespecialtydis- oryofProfessorAlfredN.Martin,whosevision,creativity, ciplines of biopharmaceutics and pharmacokinetics which, dedication, and untiring effort and attention to detail led to alongwithphysicalpharmacy,werenecessaryunderpinnings the publication of the first edition in 1960. Because of his ofascientificallybasedclinicalemphasisintheteachingof nationalreputationasaleaderandpioneerinthethenemerg- pharmacystudents,whichisnowpervasivethroughoutphar- ing specialty of physical pharmacy, I made the decision to maceuticaleducation. join Professor Martin’s group of graduate students at Pur- FromthetimeoftheinitialpublicationofPhysicalPhar- due University in 1960 and had the opportunity to witness macy to the present, this pivotal and classic book has been the excitement and the many accolades of colleagues from widely used both as a teaching textbook and as an indis- far and near that accompanied the publication of the first pensiblereferenceforacademicandindustrialresearchersin editionofPhysicalPharmacy.Thecompletionofthatwork thepharmaceuticalsciencesthroughouttheworld.Thissixth represented the culmination of countless hours of painstak- editionofMartin’sPhysicalPharmacyandPharmaceutical ingstudy,research,documentation,andrevisiononthepart Sciencesservesasamostfittingtributetotheextraordinary, of Dr. Martin, many of his graduate students, and his wife, heroic,andinspiredvisionanddedicationofProfessorMar- Mary,whotypedtheoriginalmanuscript.Italsorepresented tin. That this book continues to be a valuable and widely the fruition of Professor Martin’s dream of a textbook that usedtextbookinschoolsandcollegesofpharmacythrough- wouldrevolutionizepharmaceuticaleducationandresearch. out the world, and a valuable reference to pharmaceutical PhysicalPharmacywasforProfessorMartintrulyalaborof scientistsandresearchers,isamostappropriaterecognition love,anditremainedsothroughouthislifetime,asheworked ofthelife’sworkofAlfredMartin.Allwhohavecontributed unceasinglyandwithsteadfastdedicationonthesubsequent tothethoroughrevisionthathasresultedinthepublication revisionsofthebook. of the current edition have retained the original format and ThepublicationofthefirsteditionofPhysicalPharmacy fundamentalorganizationofbasicprinciplesandtopicsthat generatedbroadexcitementthroughoutthenationalandinter- werethehallmarksofProfessorMartin’sclassicfirstedition national academic and industrial research communities in ofthisseminalbook. pharmacyandthepharmaceuticalsciences.Itwastheworld’s ProfessorMartinalwaysdemandedthebestofhimself,his firsttextbookintheemergingdisciplineofphysicalpharmacy students,andhiscolleagues.Thefactthatthesubsequentand andhasremainedthe“goldstandard”textbookontheappli- current editions of Martin’s Physical Pharmacy and Phar- cation of physical chemical principles in pharmacy and the maceutical Sciences have remained faithful to his vision of pharmaceuticalsciences.PhysicalPharmacy,uponitspubli- scientificexcellenceasappliedtounderstandingandapply- cationin1960,providedgreatclarityanddefinitiontoadis- ingtheprinciplesunderlyingthepharmaceuticalsciencesis ciplinethathadbeenwidelydiscussedthroughoutthe1950s indeedamostappropriatetributetoProfessorMartin’smem- butnotfullyunderstoodoradopted.AlfredMartin’sPhysi- ory.Itisinthatspiritthatthisfiftiethanniversaryeditionis calPharmacyhadaprofoundeffectinshapingthedirection formallydedicatedtothememoryofthatvisionaryandcre- ofresearchandeducationthroughouttheworldofpharma- ativepioneerinthedisciplineofphysicalpharmacy,Alfred ceuticaleducationandresearchinthepharmaceuticalindus- N.Martin. tryandacademia.Thepublicationofthisbooktransformed pharmacy and pharmaceutical research from an essentially empirical mix of art and descriptive science to a quantita- JohnL.Colaizzi,PhD tiveapplicationoffundamentalphysicalandchemicalscien- Rutgers,TheStateUniversityofNewJersey tificprinciplestopharmaceuticalsystemsanddosageforms. Piscataway,NewJersey Physical Pharmacy literally changed the direction, scope, November2009 iv 4 P1: Trim:8.375in×10.875in LWBK401-fm-Dom LWW-Sinko-educational November30,2009 22:0 Dr. Murtadha Alshareifi e-Library PREFACE EversincetheFirstEditionofMartin’sPhysicalPharmacy moved to the Web (see the “Additional Resources” section waspublishedin1960,Dr.AlfredMartin’svisionwastopro- laterinthispreface). videatextthatintroducedpharmacystudentstotheapplica- tionofphysicalchemicalprinciplestothepharmaceuticalsci- SIGNIFICANT CHANGES FROM THE FIFTH EDITION ences.ThisremainsaprimaryobjectiveoftheSixthEdition. Martin’sPhysicalPharmacyhasbeenusedbygenerationsof pharmacyandpharmaceuticalsciencegraduatestudentsfor ImportantchangesincludenewchaptersonPharmaceutical 50 years and, while some topics change from time to time, Biotechnology and Oral Solid Dosage Forms. Three chap- the basic principles remain constant, and it is my hope that ters were rewritten de novo on the basis of the valuable eacheditionreflectsthepharmaceuticalsciencesatthatpoint feedback received since the publication of the Fifth Edi- intime. tion. These include Chapter 1 (“Introduction”), which is nowcalledInterpretiveTools;Chapter20(“Biomaterials”), which is now called Pharmaceutical Polymers; and Chap- ORGANIZATION ter 23 (“Drug Delivery Systems”), which is now called DrugDeliveryandTargeting. Aswithprioreditions,thiseditionrepresentsanupdatingof mostchapters,asignificantexpansionofothers,andtheaddi- ADDITIONAL RESOURCES tionofnewchaptersinordertoreflecttheapplicationsofthe physicalchemicalprinciplesthatareimportanttothePhar- maceuticalSciencestoday.AswastruewhenDr.Martinwas Martin’sPhysicalPharmacyandPharmaceuticalSciences, at the helm, this edition is a work in progress that reflects SixthEdition,includesadditionalresourcesforbothinstruc- the many suggestions made by students and colleagues in torsandstudentsthatareavailableonthebook’scompanion academia and industry. There are 23 chapters in the Sixth Websiteatthepoint.lww.com/Sinko6e. Edition,ascomparedwith22intheFifthEdition.Allchap- ters have been reformatted and updated in order to make Instructors thematerialmoreaccessibletostudents.Effortsweremade to shorten chapters in order to focus on the most important Approved adopting instructors will be given access to the subjectstaughtinPharmacyeducationtoday.Carehasbeen followingadditionalresources: taken to present the information in “layers” from the basic ■ Practiceproblemsandanswerstoascertainstudentunder- tomorein-depthdiscussionsoftopics.Thisapproachallows standing. theinstructortocustomizetheircourseneedsandfocustheir course and the students’ attention on the appropriate topics andsubtopics. Students With the publication of the Sixth Edition, a Web-based Students who have purchased Martin’s Physical Pharmacy resource is also available for students and faculty members andPharmaceuticalSciences,SixthEdition,haveaccessto (seethe“AdditionalResources”sectionlaterinthispreface). thefollowingadditionalresources: ■ A separate set of practice problems and answers to rein- FEATURES forceconceptslearnedinthetext. Inaddition,purchasersofthetextcanaccessthesearchable EachchapterbeginswithalistingofChapterObjectivesthat Full Text Online by going to the Martin’s Physical Phar- introduceinformationtobelearnedinthechapter.KeyCon- macyandPharmaceuticalSciences,SixthEdition,Website ceptBoxeshighlightimportantconcepts,andeachChapter at thePoint.lww.com/Sinko6e. See the inside front cover of Summary reinforces chapter content. In addition, illustra- this text for more details, including the passcode you will tive Examples have been retained, updated, and expanded. needtogainaccesstotheWebsite. Recommended Readings point out instructive additional sourcesforpossiblereference.PracticeProblemshavebeen PatrickSinko Piscataway,NewJersey v 5 P1: Trim:8.375in×10.875in LWBK401-fm-Dom LWW-Sinko-educational November30,2009 22:0 Dr. Murtadha Alshareifi e-Library CONTRIBUTORS GREGORYE.AMIDON,PhD TERUNAJ.SIAHAAN,PhD ResearchProfessor Professor DepartmentofPharmaceuticalSciences DepartmentofPharmaceuticalChemistry CollegeofPharmacy UniversityofKansas UniversityofMichigan Lawrence,Kansas AnnArbor,Michigan YASHVEERSINGH,PhD CHARLESRUSSELLMIDDAUGH,PhD AssistantResearchProfessor DistinguishedProfessor DepartmentofPharmaceutics DepartmentofPharmaceuticalChemistry ErnestMarioSchoolofPharmacy UniversityofKansas Rutgers,TheStateUniversityofNewJersey Lawrence,Kansas Piscataway,NewJersey HOSSEINOMIDIAN,PhD PATRICKJ.SINKO,PhD,RPh AssistantProfessor ProfessorII(Distinguished) DepartmentofPharmaceuticalSciences Parke-DavisChairProfessorinPharmaceuticsandDrugDelivery CollegeofPharmacy ErnestMarioSchoolofPharmacy NovaSoutheasternUniversity Rutgers,TheStateUniversityofNewJersey Ft.Lauderdale,Florida Piscataway,NewJersey KINAMPARK,PhD HAIANZHENG,PhD ShowalterDistinguishedProfessor AssistantProfessor DepartmentofBiomedicalEngineering DepartmentofPharmaceuticalSciences ProfessorofPharmaceutics AlbanyCollegeofPharmacyandHealthSciences DepartmentsofBiomedicalEngineeringandPharmaceutics Albany,NewYork PurdueUniversity WestLafayette,Indiana vi 6 P1: Trim:8.375in×10.875in LWBK401-fm-Dom LWW-Sinko-educational November30,2009 22:0 Dr. Murtadha Alshareifi e-Library ACKNOWLEDGMENTS The Sixth Edition reflects the hard work and dedication of IwouldliketoacknowledgeDr.MayurLodayaforhiscon- manypeople.Inparticular,IacknowledgeDrs.GregoryAmi- tributionstothecontinuousprocessingsectionofChapter22 don (Ch 22), Russell Middaugh (Ch 21), Hamid Omidian onOralDosageforms. (Chs 20 and 23), Kinam Park (Ch 20), Teruna Siahaan (Ch Numerous graduate students contributed in many ways 21),andYashveerSingh(Ch23)fortheirhardworkinspear- to this edition, and I am always appreciative of their in- headingtheeffortstowritenewchaptersorrewriteexisting sights,criticisms,andsuggestions.ThanksalsotoMrs.Amy chapters de novo. In addition, Dr. Singh went beyond the Grabowski for her invaluable assistance with coordination call of duty and took on the responsibilities of Assistant effortsandsupportinteractionswithallcontributors. Editor during the proofing stages of the production of the To all of the people at LWW who kept the project mov- manuscripts.Throughhisefforts,Ihopethatwehavecaught ingforwardwiththehighestlevelofprofessionalism,skill, manyoftheminorerrorsfromthefourthandfiftheditions.I andpatience.Inparticular,toDavidTroyforsupportingour alsothankHaiAnZheng,whoeditedtheonlinepracticeprob- vision for this project and Meredith Brittain for her excep- lemsforthisedition,andMissXunGong,whoassistedhim. tionaleyefordetailandherpersistenteffortstokeepuson The figures and experimental data shown in Chapter 6 track. were produced by Chris Olsen, Yuhong Zeng, Weiqiang And to my wonderful wife, Renee, who deserves enor- Cheng, Mangala Roshan Liyanage, Jaya Bhattacharyya, mous credit for juggling her hectic professional life as a JaredTrefethen,VidyashankaraIyer,AaronMarkham,Julian pharmacistandherexpertskillasthefamilyorganizerwhile KissmannandSangeetaJoshioftheDepartmentofPharma- maintaining a sense of calmness in what is an otherwise ceuticalChemistryattheUniversityofKansas.Thesection chaoticlife. ondryingofbiopharmaceuticalsisbasedonaseriesoflec- turesandoverheadspresentedbyDr.PikaloftheUniversity PatrickSinko ofConnecticutinAprilof2009attheUniversityofKansas. Piscataway,NewJersey vii 7 P1: Trim:8.375in×10.875in LWBK401-fm-Dom LWW-Sinko-educational November30,2009 22:0 Dr. Murtadha Alshareifi e-Library CONTENTS 1 INTERPRETIVETOOLS 1 13 DRUGRELEASEANDDISSOLUTION 300 2 STATESOFMATTER 17 14 CHEMICALKINETICSANDSTABILITY 318 3 THERMODYNAMICS 54 15 INTERFACIALPHENOMENA 355 4 DETERMINATIONOFTHEPHYSICALPROPERTIES 16 COLLOIDALDISPERSIONS 386 OFMOLECULES 77 17 COARSEDISPERSIONS 410 5 NONELECTROLYTES 109 18 MICROMERITICS 442 6 ELECTROLYTESOLUTIONS 129 19 RHEOLOGY 469 7 IONICEQUILIBRIA 146 20 PHARMACEUTICALPOLYMERS 492 8 BUFFEREDANDISOTONICSOLUTIONS 163 21 PHARMACEUTICALBIOTECHNOLOGY 516 9 SOLUBILITYANDDISTRIBUTIONPHENOMENA 182 22 ORALSOLIDDOSAGEFORMS 563 10 COMPLEXATIONANDPROTEINBINDING 197 23 DRUGDELIVERYANDTARGETING 594 11 DIFFUSION 223 Index 647 12 BIOPHARMACEUTICS 258 viii 8 Dr. Murtadha Alshareifi e-Library 1 Interpretive Tools Chapter Objectives At the conclusion of this chapter the student should be able to: 1. Understand the basic tools required to analyze and interpret data sets from the clinic, laboratory, or literature. 2. Describe the differences between classic dosage forms and modern drug delivery systems. 3. Use dimensional analysis. 4. Understand and apply the concept of significant figures. 5. Define determinant and indeterminant errors, precision, and accuracy. 6. Calculate the mean, median, and mode of a data set. 7. Understand the concept of variability. 8. Calculate standard deviation and coefficient of variation and understand when it is appropriate to use these parameters. 9. Use graphic methods to determine the slope of lines. 10. Interpret slopes of lines and how they relate to absorption and elimination from the body. Introduction “One of the earmarks of evidence-based medicine is that the practitioner should not just accept the conventional wisdom of his/her mentor. Evidence-based medicine uses the scientific method of using observations and literature searches to form a hypothesis as a basis for appropriate medical therapy. This process necessitates education in basic sciences and an understanding of basic scientific principles.”1,2 Today more than ever before, the pharmacist and the pharmaceutical scientist are called upon to demonstrate a sound knowledge of biopharmaceutics, biochemistry, chemistry, pharmacology, physiology, and toxicology and an intimate understanding of the physical, chemical, and biopharmaceutical properties of medicinal products. Whether engaged in research and development, teaching, manufacturing, the practice of pharmacy, or any of the allied branches of the profession, the pharmacist must recognize the need to rely heavily on the basic sciences. This stems from the fact that pharmacy is an applied science, composed of principles and methods that have been culled from other disciplines. The pharmacist engaged in advanced studies must work at the boundaries between the various sciences and must keep abreast of advances in the physical, chemical, and biological fields in order to understand and contribute to the rapid developments in his or her profession. You are also expected to provide concise and practical interpretations of highly technical drug information to your patients and colleagues. With the abundance of information and misinformation that is freely and publicly available (e.g., on the Internet), having the tools and ability to provide meaningful interpretations of results is critical. Historically, physical pharmacy has been associated with the area of pharmacy that dealt with the quantitative and theoretical principles of physicochemical science as they applied to the practice of pharmacy. Physical pharmacy attempted to integrate the factual knowledge of pharmacy through the development of broad principles of its own, and it aided the pharmacist and the pharmaceutical scientist in their attempt to predict the solubility, stability, compatibility, and biologic action of drug products. Although this remains true today, the field has become even more highly integrated into the biomedical aspects of the practice of pharmacy. As such, the field is more broadly known today as the pharmaceutical sciences and the chapters that follow reflect the high degree of integration of the biological and physical–chemical aspects of the field. Developing new drugs and delivery systems and improving upon the various modes of administration are still the primary goals of the pharmaceutical scientist. A practicing pharmacist must also possess a thorough understanding of modern drug delivery systems as he or she advises patients on the best use of prescribed medicines. In the past, drug delivery focused nearly exclusively on pharmaceutical 9