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Access to the electronic materials is limited to the first individual who redeems the PIN, located on the inside cover of this book, at studentconsult.inkling.com and may not be transferred to another party by resale, lending, or other means. 2020_ME_IE ’ Aulton s Pharmaceutics ’ Aulton s Pharmaceutics The Design and Manufacture of Medicines Sixth Edition Edited by Kevin M.G. Taylor BBPPhhaarrmm,, PPhhDD,, FFRRPPhhaarrmmSS Professor of Clinical Pharmaceutics UCL School of Pharmacy London, UK Michael E. Aulton BBPPhhaarrmm,, PPhhDD,, FFAAAAPPSS,, FFSSPP,, FFRRPPhhaarrmmSS Emeritus Professor De Montfort University Leicester, UK Elsevier (cid:2)2022,ElsevierLimited.Allrightsreserved. Firstedition1988 Secondedition2002 Thirdedition2007 Fourthedition2013 Fifthedition2018 Sixthedition2022 Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicormechanical,including photocopying,recording,oranyinformationstorageandretrievalsystem,withoutpermissioninwritingfromthepublisher.Detailson howtoseekpermission,furtherinformationaboutthePublisher’spermissionspoliciesandourarrangementswithorganizationssuch astheCopyrightClearanceCenterandtheCopyrightLicensingAgency,canbefoundatourwebsite:www.elsevier.com/permissions ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher(otherthanasmaybenoted herein). Notices Practitionersandresearchersmustalwaysrelyontheirown experienceand knowledgeinevaluating andusingany information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumedbyElsevier,authors,editorsorcontributorsforanyinjuryand/ordamagetopersonsorpropertyasamatterofproducts liability,negligenceorotherwise,orfromanyuseoroperationofanymethods,products,instructions,orideascontainedinthe materialherein. ISBN:9780702081545 9780702081552 PrintedinChina Lastdigitistheprintnumber:987654321 ContentStrategist:AlexMortimer ContentDevelopmentSpecialist:LouiseCook ProjectManager:AndrewRiley Design:MaggieReid IllustrationManager:NarayananRamakrishnan MarketingManager:DebWatkins Contents Preface....................................................................... vii Contributors............................................................. ix Part 3: Pharmaceutical microbiology Acknowledgements.................................................. xiii and sterilization What is ‘pharmaceutics’?......................................... xv KevinM.G.TaylorandMichaelE.Aulton 13. Fundamentals of microbiology...................184 1. Design of dosage forms.................................. 1 Lara-MarieBarnesandGeoffreyW.Hanlon PeterYork 14. Pharmaceutical applications of microbiological techniques..........................208 Part 1: Scientific principles of Lara-MarieBarnesandNormanA.Hodges 15. Action of physical and chemical agents dosage form design on microorganisms.......................................229 Lara-MarieBarnes,GeoffreyW.Hanlonand 2. Dissolution and solubility............................. 13 NormanA.Hodges MichaelE.Aulton 16. Principles of sterilization.............................247 3. Properties of solutions................................... 30 SusannahE.Walsh,KatieLairdandJean-Yves MichaelE.Aulton Maillard 4. Surfaces and interfaces................................... 39 17. Sterilization in practice................................257 GrahamBuckton Jean-YvesMaillard,KatieLairdandSusannahE. 5. Disperse systems.............................................. 50 Walsh DavidAttwood 6. Rheology........................................................... 81 Part 4: Biopharmaceutical principles ChristopherMarriott of drug delivery 7. Kinetics.............................................................101 GarethR.WilliamsandJohnP.Malkinson 18. Introduction to biopharmaceutics..............275 Part 2: Particle science and powder MarianneAshfordandKevinM.G.Taylor 19. Gastrointestinal tract e physiology and technology drug absorption.............................................279 MarianneAshfordandKevinM.G.Taylor 8. Solid-state properties....................................114 20. Bioavailability e physicochemical, GrahamBuckton dosage form and formulation factors........297 9. Particle size analysis.....................................126 MarianneAshford,KevinM.G.Taylorand KevinM.G.Taylor HalaM.Fadda 10. Particle size reduction and size 21. Assessment of biopharmaceutical separation.......................................................143 properties.......................................................320 MichaelE.Aulton MarianneAshfordandKevinM.G.Taylor 11. Mixing.............................................................156 22. Dosage regimens...........................................343 AndrewM.Twitchell SorayaDhillonandNkirukaUmaru 12. Powder flow...................................................172 MichaelE.Aulton v Contents 42. Otic drug delivery.........................................701 Part 5: Dosage form design and XuLiu,HughSmythandFengZhang 43. Topical and transdermal drug delivery......713 manufacture AdrianC.Williams 44. Rectal and vaginal drug delivery.................735 23. Pharmaceutical preformulation..................360 KalliopiDodou SimonGaisford 45. Preparation and delivery of 24. Solutions........................................................386 biopharmaceuticals.......................................752 SudaxshinaMurdan IjeomaF.UchegbuandAndreasG.Schätzlein 25. Clarification...................................................397 46. Pharmaceutical nanotechnology and AndrewM.Twitchell nanomedicines..............................................768 26. Suspensions...................................................407 YvonnePerrie SusanA.Barker 47. Radiopharmaceuticals...................................789 27. Emulsions and creams.................................424 NeilHartmanandMargaretCooper GillianM.Eccleston 48. The formulation and manufacture of 28. Ointments, pastes, gels, cutaneous plant medicines.............................................805 patches and topical sprays...........................453 G.BrianLockwood MajellaE.Lane 49. Design and administration of medicines 29. Powders, granules and granulation............463 for paediatric and geriatric patients............818 MichaelE.Aulton CatherineTuleu,MineOrluandDavidWright 30. Drying.............................................................483 MichaelE.AultonandSatyanarayanaSomavarapu Part 6: Packaging, stability and 31. Tablets and compaction...............................501 GöranAlderbornandGöranFrenning pharmaceutical regulation 32. Modified-release oral drug delivery............542 EmmaL.McConnell,ChristineM.Madlaand 50. Packaging.......................................................833 AbdulW.Basit SudaxshinaMurdan 33. Coating of tablets and multiparticulates...558 51. Chemical stability in dosage forms............848 StuartC.Porter AndrewR.BarnesandMarkSantillo 34. Continuous manufacturing of tablets........574 52. Microbial contamination, spoilage and AkthamAburubandHalaM.Fadda preservation of medicines............................860 35. Hard capsules................................................586 NormanA.HodgesandLara-MarieBarnes BrianE.Jones 53. Product stability and stability testing.........871 36. Soft capsules..................................................599 PaulMarshall StephenTindal 54. Pharmaceutical quality: the application 37. Dissolution testing of solid dosage of pharmaceutics in medicines forms...............................................................612 regulation.......................................................894 AnaCristinaFreire,FrancescaK.H.Gavinsand KevinM.G.Taylor,MajellaE.Laneand AbdulW.Basit KhalidA.Sheikh 38. Parenteral drug delivery...............................626 RobertLowe Self-assessment questions 39. Pulmonary drug delivery.............................641 KevinM.G.Taylor SudaxshinaMurdan 40. Nasal drug delivery.......................................658 Please check your eBook at https://studentconsult. GaryP.MartinandAlisonB.Lansley inkling.com/ for self-assessment questions. See inside 41. Ocular drug delivery.....................................677 cover for registration details. HalaFadda,AshkanKhalili,PengTeeKhawand SteveBrocchini Index..........................................................................915 vi Preface This is the sixth edition of Aulton’s Pharmaceutics: The Design and Manufacture of Medicines. The first editionwaspublishedin1988andthefifthin2018.Thepedigreeofthebookis,however,actually mucholder.ItwasoriginallyknownasTutorialPharmacy(whichitselfalsowenttosixeditions)andwas initiallyeditedbyJohnCooperandColinGunn,andlaterbySidneyCarter. ProfessorMikeAultonandProfessorKevinTaylorcontinuetheireditingroleandhaveidentified newauthorsandfreshsubjectmatterforthisnewedition.Thephilosophyofthissixtheditionremains unchangedfromthatofpreviouseditions,i.e.itisintentionallydesignedandwrittenfornewcomersto thedesignofdosageforms(drugproducts).Otherexperttextscantakeyouintomuchgreaterdetailfor eachofthesubjectareasconsideredhere,onceyouhavemasteredthesebasics. Thesubjectmattercoveredbythebookremains,inessence,thesamebutthedetailhaschanged significantly,becausepharmaceuticshaschanged.Sincethelasteditiontherehavebeenchangesinthe waythatdosageformsaredesignedandmanufacturedanddrugsaredelivered.Thesedevelopmentsare reflectedinthisnewedition. Theinvolvementofawiderangeofauthorscontinuesinthisedition,allauthorsbeingarecognized expert in the field on which they have written. Just as importantly, each author has experience of imparting that information to undergraduate pharmacy and pharmaceutical science students, to practitionersinthepharmaceuticalandassociatedindustries,andtothoseworkingintechnicalservices withinhospitalpharmacywhoarenewtothesubject.Mostauthorsfromthepreviouseditionremainas theyarestillworldleadersintheirfield.Otherchaptershavebeenwrittenbyanewgenerationofexperts. Thenewauthorshipreflectscontemporaryknowledgeandthinkinginpharmaceutics. Everychapterhasreceiveddetailedattentionandhasbeenrevisedandupdatedappropriatelyto reflectmodernthinkingandcurrentuniversitycurriculaworldwide.Someofthebasicscienceremains virtuallyunchangedeandwillalwaysdosoebutotherareas,suchasbiopharmaceuticsandsome areasofdrugdelivery,havechangedsignificantlyinrecentyears. Several new authors and new subject areas have been included in this edition to ensure thecomprehensivenatureandcurrencyofthistext.Thefollowingnewchaptershavebeenaddedtothe sixthedition. l The design and preparation of dosage forms applied to the skin, including ointments, pastes, gels,cutaneouspatchesandtopicalspraysarenowgatheredtogetherinasinglechapter. l Continuous manufacturing is a relatively new concept in the manufacture of pharmaceutical products.Itisconsideredhereinanewchapterwithaparticularfocusontabletmanufacturing. l Theformulationandplaceintherapyofdrops,semisolids,injectionandimplantsfordelivering drugstoandviatheear(oticdelivery)formthesubjectmatterofanothernewchapter. l There is a new chapter on radiopharmaceuticals used for diagnostic and therapeutic purposes coveringtheirformulation,preparation,purification,qualitycontrolanddelivery. l Thebookendswithanewchapteronpharmaceuticalqualityandtheapplicationofpharmaceutics inmedicinesregulation.Itoutlineshowmedicinesareregulatedandhowtheirqualityisassured.It showshowtheapplicationofthetheoriesandpracticesdescribedintheprecedingchaptersofthe bookenablequalitytobebuiltintoamedicinalproduct. vii Preface Allpurchasersoftheprintversionofthisneweditionreceivetheenhancedebook,whichcanbe usedonlineordownloadedtotheirmobiledeviceforconvenient,anytimeaccess.Theebookincludes morethan400self-assessmentquestions,basedonthecontentofthisbook,tocheckunderstanding andtohelpwithanyexaminationpreparation. Wewishyouwellinyourstudiesifyouareanundergraduatestudent,orwithyourcareerifyou areworkinginindustry,thehospitalserviceormedicinesregulation.Wesincerelyhopethatthis bookhelpswithyourunderstandingofpharmaceuticsethescienceofthedesignandmanufacture ofmedicines. K.M.G.Taylor M.E.Aulton viii