PHARMACEUTICS We dedicatethis text to our teachersand professors who inculcated inus a love of scientificprinciples and pharmaceutics. PHARMACEUTICS Basic Principles and Application to Pharmacy Practice Edited by A K. D , RP , P D LEKHA ASH H H CreightonUniversity,Nebraska,USA S S , P D OMNATH INGH H CreightonUniversity,Nebraska,USA J T , P D, P D USTIN OLMAN HARM H CreightonUniversity,Nebraska,USA AMSTERDAM(cid:129)BOSTON(cid:129)HEIDELBERG(cid:129)LONDON NEWYORK(cid:129)OXFORD(cid:129)PARIS(cid:129)SANDIEGO SANFRANCISCO(cid:129)SINGAPORE(cid:129)SYDNEY(cid:129)TOKYO AcademicPressisanimprintofElsevier AcademicPressisanimprintofElsevier 525BStreet,Suite1900,SanDiego,CA92101-4495,USA 32JamestownRoad,LondonNW17BY,UK 225WymanStreet,Waltham,MA02451,USA Copyrightr2014ElsevierInc.Allrightsreserved Nopartofthispublicationmaybereproduced,storedinaretrievalsystem,ortransmittedin anyformorbyanymeanselectronic,mechanical,photocopying,recordingorotherwise withoutthepriorwrittenpermissionofthepublisher. PermissionsmaybesoughtdirectlyfromElsevier’sScience&TechnologyRights, DepartmentinOxford,UK:phone(144)(0)1865843830;fax(144)(0)1865853333; email:[email protected],visittheScienceandTechnologyBooks websiteatwww.elsevierdirect.com/rightsforfurtherinformation. Notice Noresponsibilityisassumedbythepublisherforanyinjuryand/ordamagetopersons, orpropertyasamatterofproductsliability,negligenceorotherwise,orfromanyuseor,operation ofanymethods,products,instructionsorideascontainedinthematerialherein.Becauseof rapidadvancesinthemedicalsciences,inparticular,independentverificationofdiagnosesand drugdosagesshouldbemade. BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress ISBN:978-0-12-386890-9 ForinformationonallAcademicPresspublications visitourwebsiteatelsevierdirect.com PrintedandboundintheUnitedStatesofAmerica 14 15 16 17 10 9 8 7 6 5 4 3 2 1 Contents Preface ix 3. Physical Properties, Their Determination, Acknowledgments xi and Importance in Pharmaceutics List of Contributors xii SOMNATHSINGHANDALEKHAK.DASH 3.1. Introduction 51 I 3.2. SurfaceandInterfacialTension 52 3.3. Adsorption 53 PHYSICAL PRINCIPLES AND 3.4. Solubilization 59 3.5. Rheology 61 PROPERTIES OF PHARMACEUTICS 3.6. ColligativeProperties 65 3.7. OsmolarityandOsmolality 68 3.8. SolubilityandSolutionsofNonelectrolytes 71 1. Introduction: Terminology, Basic 3.9. Spectroscopy 73 Mathematical Skills, and Calculations 3.10. Conclusions 83 EMANATEFANDSOMNATHSINGH CaseStudies 82 References 84 1.1. Introduction 3 1.2. ReviewofBasicMathematicalSkills 3 1.3. GraphicalRepresentation 11 4. Equilibrium Processes in Pharmaceutics 1.4. DimensionsandUnits 12 SUNILS.JAMBHEKAR 1.5. Conclusions 14 CaseStudies 14 4.1. Introduction 85 References 15 4.2. GastrointestinalPhysiology 87 4.3. Ionization 90 4.4. PartitionCoefficient:Lipophilicity 93 2. Physical States and Thermodynamic 4.5. EquilibriumSolubility 96 Principles in Pharmaceutics 4.6. TheEffectofpH 98 4.7. UseofCo-solvents 99 VIVEKS.DAVE,SEONHEPBURN ANDSTEPHENW.HOAG 4.8. DrugDissolutionandDissolutionProcess 100 4.9. FactorsInfluencingtheDissolutionRate 102 2.1. Introduction 17 4.10. PassiveDiffusion 104 2.2. CompositionofMatter 17 4.11. BiopharmaceuticsClassificationSystem(BCS) 105 2.3. ForcesofAttractionandRepulsion 18 4.12. Conclusions 106 2.4. StatesofMatter 22 CaseStudies 106 2.5. Thermodynamics 33 References 107 2.6. BasicConceptsandDefinitions 35 SuggestedReadings 108 2.7. TheFirstLawofThermodynamics 37 2.8. EnthalpyandHeatCapacity 39 5. Kinetic Processes in Pharmaceutics 2.9. TheSecondLawofThermodynamics 41 2.10. TheThirdLawofThermodynamics 44 RAMPRAKASHGOVINDARAJAN 2.11. FreeEnergyandThermodynamicFunctions 44 2.12. ChemicalEquilibrium 46 5.1. Introduction 109 2.13. OpenSystems 46 5.2. Thermodynamicsvs.Kinetics 109 2.14. Conclusions 47 5.3. ChemicalReactionKineticsandDrugStability 110 CaseStudies 47 5.4. Diffusion 127 Appendix2.1CalculusReview 48 5.5. Dissolution 130 References 49 5.6. Conclusions 136 v vi CONTENTS CaseStudies 136 9. Liquid Dosage Forms References 137 HARIR.DESU,AJITS.NARANG,LAURAA.THOMA ANDRAMI.MAHATO 6. Biopolymers 9.1. Introduction 181 SOMNATHSINGHANDJUSTINTOLMAN 9.2. SelectionofLiquidDosageForms 181 9.3. TypesofLiquidDosageForms 183 6.1. IntroductiontoPolymers 139 9.4. GeneralAspectsofLiquidDosageForms 207 6.2. IntroductiontoPeptidesandProteins 142 9.5. ManufacturingProcessesandConditions 210 6.3. IntroductiontoOligonucleotides 146 9.6. Packaging 214 6.4. Conclusions 149 9.7. Labeling 217 CaseStudies 149 9.8. QualityAssuranceandQualityControl 217 References 150 9.9. RegulatoryConsiderations 219 SuggestedReadings 150 9.10. Conclusions 221 ListofAbbreviations 221 II CaseStudies 221 References 222 PRACTICAL ASPECTS OF PHARMACEUTICS 10. Aerosol Dosage Forms JUSTINA.TOLMANANDMEGANHUSLIG 7. Drug, Dosage Form, and 10.1. Introduction 225 Drug Delivery Systems 10.2. LungAnatomy 226 ALEKHAK.DASH 10.3. LungPhysiology 227 10.4. PulmonaryDrugTargets 228 7.1. Introduction 153 10.5. PulmonaryDrugDeposition 228 7.2. PharmaceuticalIngredients 154 10.6. TherapeuticGases 230 7.3. PreformulationStudies 154 10.7. InhaledAerosols 232 7.4. PhysicalDescription 154 10.8. Conclusions 237 7.5. LiquidDosageForms 154 CaseStudies 238 7.6. SolidDosageForms 156 Acknowledgments 238 7.7. PartitionCoefficientandpKa 157 References 238 7.8. Solubility 157 7.9. Dissolution 157 7.10. Polymorphism 157 11. Semisolid Dosage Forms 7.11. Stability 158 SHAILENDRAKUMARSINGH,KALPANANAGPAL 7.12. Conclusions 158 ANDSANGITASAINI CaseStudies 158 11.1. Introduction 241 References 159 11.2. ClassificationofSemisolidDosageForms 243 11.3. PercutaneousAbsorption 249 8. Solid Dosage Forms 11.4. TheoryofSemisolidDosageForms 253 ALEKHAK.DASH 11.5. MethodsofEnhancementofPercutaneous Absorption 255 8.1. Introduction 161 11.6. CharacterizationandEvaluationofSemisolid 8.2. Powders 161 DosageForms 260 8.3. Capsules 165 11.7. ProcedureandApparatusforDiffusionExperiment 263 8.4. Tablets 168 11.8. Conclusions 269 8.5. ManufactureofCompressedTablets 170 CaseStudies 269 8.6. MethodsUsedforManufactureofCompressed References 270 Tablets 172 8.7. TabletCompressionandBasicFunctionalUnits 12. Special Dosage Forms and ofaTabletPress 173 8.8. QualityControlofTabletDosageForm 175 Drug Delivery Systems 8.9. TabletCoating 178 SARATK.MOHAPATRAANDALEKHAK.DASH 8.10. Conclusions 179 CaseStudies 179 12.1. Introduction 273 References 180 12.2. SpecialDosageForms 274 vii CONTENTS 12.3. ParenteralDrugDelivery 275 14.5. EvaluationofOralAbsorption 324 12.4. OsmoticDelivery 277 14.6. DrugDisposition 325 12.5. NanotechnologyforDrugDelivery 280 14.7. Conclusions 327 12.6. ImplantableDrugDelivery 292 CaseStudies 327 12.7. Prodrugs 299 References 329 12.8. Conclusions 301 CaseStudies 302 15. Routes of Drug Administration References 303 MOHSENA.HEDAYAANDJUSTINA.TOLMAN III 15.1. Introduction 333 15.2. ParenteralDrugAdministration 334 BIOLOGICAL APPLICATIONS 15.3. TransdermalDrugAdministration 337 OF PHARMACEUTICS 15.4. OphthalmicDrugAdministration 338 15.5. Auricular(Otic)DrugAdministration 340 15.6. NasalDrugAdministration 341 13. Membrane Transport and Permeation 15.7. PulmonaryDrugAdministration 341 JUSTINA.TOLMANANDMARIAP.LAMBROS 15.8. OralDrugAdministration 342 15.9. RectalDrugAdministration 346 13.1. Introduction 307 15.10. VaginalDrugAdministration 347 13.2. CellMembranes 307 15.11. Conclusions 347 13.3. MembraneTransport 309 References 348 13.4. PharmacologicallyRelevantMembrane TransportProcesses 311 13.5. Conclusions 315 16. Bioavailability and Bioequivalence CaseStudies 315 AJITS.NARANGANDRAMI.MAHATO References 315 16.1. Introduction 349 16.2. Bioavailability 349 14. Factors Affecting Drug Absorption 16.3. FactorsAffectingBioavailability 352 and Disposition 16.4. Bioequivalence 359 CHONG-HUIGU,ANUJKULDIPKUMAR 16.5. Conclusions 362 ANDHARSHCHAUHAN CaseStudies 362 References 362 14.1. Introduction 317 14.2. DrugAbsorption 317 14.3. OralDrugAbsorptionProcesses 318 Index 365 14.4. FoodEffectsonOralDrugAbsorption 323 This page intentionallyleftblank