Table Of ContentPA RIOK J. SINKO
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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
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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
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consideredabsoluteanduniversalrecommendations.
Theauthors,editors,andpublisherhaveexertedeveryefforttoensurethatdrugselectionand
dosagesetforthinthistextareinaccordancewiththecurrentrecommendationsandpracticeatthe
timeofpublication.However,inviewofongoingresearch,changesingovernmentregulations,andthe
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thepackageinsertforeachdrugforanychangeinindicationsanddosageandforaddedwarnings
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DedicatedtomyparentsPatriciaandPatrickSinko,
mywifeRenee,andmychildrenPat,Katie(andMaggie)
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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
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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
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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
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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
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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
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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
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