DRUGS AND THE PHARMACEUTICAL SCIENCESVOLUME 199Pharmaceutical Preformulation and Formulationedited byMark GibsonA Practical Guide from Candidate Drug Selection to Commercial Dosage FormS E C ONDE DI T I ON Pharmaceutical Preformulation and FormulationDRUGSANDTHEPHARMACEUTICALSCIENCESASeriesofTextbooksandMonographsExecutiveEditorJamesSwarbrickPharmaceuTech,Inc.Pinehurst,NorthCarolinaAdvisoryBoardLarryL.AugsburgerUniversityofMarylandBaltimore,MarylandJenniferB.DressmanUniversityofFrankfurtInstituteofPharmaceuticalTechnologyFrankfurt,GermanyAnthonyJ.HickeyUniversityofNorthCarolinaSchoolofPharmacyChapelHill,NorthCarolinaAjazHussainSandozPrinceton,NewJerseyJosephW.PolliGlaxoSmithKlineResearchTriangleParkNorthCarolinaStephenG.SchulmanUniversityofFloridaGainesville,FloridaYuichiSugiyamaUniversityofTokyo,Tokyo,JapanGeoffreyT.TuckerUniversityofSheffieldRoyalHallamshireHospitalSheffield,UnitedKingdomHarryG.BrittainCenterforPharmaceuticalPhysicsMilford,NewJerseyRobertGurnyUniversitedeGeneveGeneve,SwitzerlandJeffreyA.HughesUniversityofFloridaCollegeofPharmacyGainesville,FloridaVincentH.L.LeeUSFDACenterforDrugEvaluationandResearchLosAngeles,CaliforniaKinamParkPurdueUniversityWestLafayette,IndianaJeromeP.SkellyAlexandria,VirginiaElizabethM.ToppUniversityofKansasLawrence,KansasPeterYorkUniversityofBradfordSchoolofPharmacyBradford,UnitedKingdomForinformationonvolumes1149intheDrugsandPharmaceuticalScienceSeries,pleasevisitwww.informahealthcare.com150. LaboratoryAuditingforQualityandRegulatoryCompliance,DonaldSinger,Raluca-IoanaStefan,andJacobusvanStaden151. ActivePharmaceutical Ingredients:Development,Manufacturing,andRegulation,editedbyStanleyNusim152. Preclinical DrugDevelopment,editedbyMarkC.RoggeandDavidR.Taft153. Pharmaceutical StressTesting:PredictingDrugDegradation,editedbyStevenW.Baertschi154. HandbookofPharmaceutical GranulationTechnology:SecondEdition,editedbyDilipM.Parikh155. PercutaneousAbsorption:DrugsCosmeticsMechanismsMethodology,FourthEdition,editedbyRobertL.BronaughandHowardI.Maibach156. Pharmacogenomics:SecondEdition,editedbyWernerKalow,UrsA.MeyerandRachel F.Tyndale157. Pharmaceutical ProcessScale-Up,SecondEdition,editedbyMichael Levin158. Microencapsulation:MethodsandIndustrial Applications,SecondEdition,editedbySimonBenita159. NanoparticleTechnologyforDrugDelivery,editedbyRamB.GuptaandUdayB.Kompella160. SpectroscopyofPharmaceutical Solids,editedbyHarryG.Brittain161. DoseOptimizationinDrugDevelopment,editedbyRajeshKrishna162. Herbal Supplements-DrugInteractions:ScientificandRegulatoryPerspectives,editedbyY.W.FrancisLam,Shiew-Mei Huang,andStephenD.Hall163. Pharmaceutical PhotostabilityandStabilizationTechnology,editedbyJosephT.Piechocki andKarl Thoma164. Environmental MonitoringforCleanroomsandControlledEnvironments,editedbyAnneMarieDixon165. Pharmaceutical ProductDevelopment:InVitro-InVivoCorrelation,editedbyDakshinaMurthyChilukuri,GangadharSunkara,andDavidYoung166. NanoparticulateDrugDeliverySystems,editedbyDeepakThassu,MichelDeleers,andYashwantPathak167. Endotoxins:Pyrogens,LALTestingandDepyrogenation,ThirdEdition,editedbyKevinL.Williams168. GoodLaboratoryPracticeRegulations,FourthEdition,editedbyAnneSandyWeinberg169. GoodManufacturingPracticesforPharmaceuticals,SixthEdition,editedbyJosephD.Nally170. Oral-LipidBasedFormulations:EnhancingtheBioavailabilityofPoorlyWater-solubleDrugs,editedbyDavidJ.Hauss171. HandbookofBioequivalenceTesting,editedbySarfarazK.Niazi172. AdvancedDrugFormulationDesigntoOptimizeTherapeuticOutcomes,editedbyRobertO.WilliamsIII,DavidR.Taft,andJasonT.McConville173. Clean-in-PlaceforBiopharmaceutical Processes,editedbyDaleA.Seiberling174. FiltrationandPurificationintheBiopharmaceutical Industry,SecondEdition,editedbyMaikW.JornitzandTheodoreH.Meltzer175. ProteinFormulationandDelivery,SecondEdition,editedbyEugeneJ.McNallyandJayneE.Hastedt176. AqueousPolymericCoatingsforPharmaceutical DosageForms,ThirdEdition,editedbyJamesMcGinityandLindaA.Felton177. Dermal AbsorptionandToxicityAssessment,SecondEdition,editedbyMichael S.RobertsandKennethA.Walters178. PreformulationSolidDosageFormDevelopment,editedbyMoji C.AdeyeyeandHarryG.Brittain179. Drug-DrugInteractions,SecondEdition,editedbyA.DavidRodrigues180. GenericDrugProductDevelopment:BioequivalenceIssues,editedbyIsadoreKanferandLeonShargel181. Pharmaceutical Pre-Approval Inspections:AGuidetoRegulatorySuccess,SecondEdition,editedbyMartinD.HynesIII182. Pharmaceutical ProjectManagement,SecondEdition,editedbyAnthonyKennedy183. ModifiedReleaseDrugDeliveryTechnology,SecondEdition,Volume1,editedbyMichael J.Rathbone,JonathanHadgraft,Michael S.Roberts,andMajellaE.Lane184. Modified-ReleaseDrugDeliveryTechnology,SecondEdition,Volume2,editedbyMichael J.Rathbone,JonathanHadgraft,Michael S.Roberts,andMajellaE.Lane185. ThePharmaceutical RegulatoryProcess,SecondEdition,editedbyIraR.BerryandRobertP.Martin186. HandbookofDrugMetabolism,SecondEdition,editedbyPaul G.PearsonandLarryC.Wienkers187. Preclinical DrugDevelopment,SecondEdition,editedbyMarkRoggeandDavidR.Taft188. ModernPharmaceutics,FifthEdition,Volume1:BasicPrinciplesandSystems,editedbyAlexanderT.FlorenceandJuergenSiepmann189. ModernPharmaceutics,FifthEdition,Volume2:ApplicationsandAdvances,editedbyAlexanderT.FlorenceandJuergenSiepmann190. NewDrugApproval Process,FifthEdition,editedbyRichardA.Guarino191. DrugDeliveryNanoparticulateFormulationandCharacterization,editedbyYashwantPathakandDeepakThassu192. Polymorphism of Pharmaceutical Solids, Second Edition, edited by Harry G. Brittain193. Oral DrugAbsorption:PredictionandAssessment,SecondEdition,editedbyJenniferJ.Dressman,hansLennernas,andChristosReppas194. BiodrugDeliverySystems:Fundamentals,Applications,andClinical Development,editedbyMarikoMoristaandKinamPark195. Pharmaceutical ProcessEngineering,SecondEdition,editedbyAnthonyJ.HickeyandDavidGanderton196. Handbook of Drug Screening, Second Edition, edited by Ramakrishna Seethala andLitaoZhang197. Pharmaceutical PowderCompactionTechnology,SecondEdition,editedbyMetinCelik198. HandbookofPharmaceutical GranulationTechnology,DilipM.Parikh199. Pharmaceutical PreformulationandFormulation:APractical GuidefromCandidateDrugSelectiontoCommercial DosageForm,SecondEdition,editedbyMarkGibsonPharmaceutical Preformulation and FormulationSecond EditionA Practical Guide from Candidate Drug Selection to Commercial Dosage Formedited by Mark Gibson AstraZeneca R&D Charnwood Loughborough, Leicestershire, UKInformaHealthcareUSA,Inc.52VanderbiltAvenueNewYork,NY10017# 2009byInformaHealthcareUSA,Inc.InformaHealthcareisanInformabusinessNoclaimtooriginalU.S.GovernmentworksPrintedintheUnitedStatesofAmericaonacid-freepaper10 9 8 7 6 5 4 3 2 1InternationalStandardBookNumber-10:1-4200-7317-6(Hardcover)InternationalStandardBookNumber-13:978-1-4200-7317-1(Hardcover)Thisbookcontainsinformationobtainedfromauthenticandhighlyregardedsources. Reprintedmaterial isquotedwithpermission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publishreliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materialsorfortheconsequenceoftheiruse.Nopartofthisbookmaybereprinted,reproduced,transmitted,orutilizedinanyformbyanyelectronic,mechanical,orother means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any informationstorageorretrievalsystem,withoutwrittenpermissionfromthepublishers.For permissiontophotocopyor usematerial electronicallyfromthiswork, pleaseaccesswww.copyright.com(http://www.copyright.com/)orcontacttheCopyrightClearanceCenter,Inc.(CCC)222RosewoodDrive,Danvers,MA01923,978-750-8400. CCCis a not-for-profit organizationthat provides licenses andregistrationfor a varietyof users. FororganizationsthathavebeengrantedaphotocopylicensebytheCCC,aseparatesystemofpaymenthasbeenarranged.TrademarkNotice: Product or corporate names maybe trademarks or registeredtrademarks, andare usedonlyforidentificationandexplanationwithoutintenttoinfringe.LibraryofCongressCataloging-in-PublicationDataPharmaceutical preformulation and formulation: A practical guide from candidate drugselectiontocommercialdosageform/editedbyMarkGibson.2nded.p.;cm.(Drugsandthepharmaceuticalsciences;199)Includesbibliographicalreferencesandindex.ISBN-13:978-1-4200-7317-1(hb:alk.paper)ISBN-10:1-4200-7317-6(hb:alk.paper) 1. DrugsDosageforms.I. Gibson,Mark,1957-II. Series:Drugsandthepharmaceuticalsciences;v.199.[DNLM: 1. DrugCompounding. 2. Biopharmaceuticsmethods. 3.DosageForms. 4. DrugDiscovery. 5. DrugEvaluation. W1DR893Bv.1992009/QV778P535352009]RS200.P42520096150.1dc222009012458For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Avenue,16thfloor,NewYork,NY10017.VisittheInformaWebsiteatwww.informa.comandtheInformaHealthcareWebsiteatwww.informahealthcare.comPrefaceThe first edition of this book published in 2001 has been more successful than I ever imagined,asindicatedbytheexcellentreviewsithasreceived,thecontinueddemand, andimpressivesales!Ibelievethatthemainreasonsforitspopularityarethattherewasasignificantgapinthe literature and also that the information presented was based on the extensive experiencesof the various contributors who were all actively working in the industry and were willing tosharebest practicefromtheirknowledgeandexperiences. Thebookisintendedtobeapractical guidetopharmaceutical preformulationandformulationtobeusedasareferencesource or a guidance tool to those working in the pharmaceutical industry or relatedindustries,suchasbiopharmaceuticalsormedicaldevices,oranyonewantinganinsightintothe subject area. Indeed, this book has also proved to be a valuable text for undergraduate andpostgraduate courses in industrial pharmacy and pharmaceutical technology. A second editionis required because preformulation and formulation technology continues to develop and alsobecausethereareboundtobesomegapsandimprovementstobefilled.Thesecondeditionstillmeetsthemainobjectivesofthefirstedition,thatis,tolprovidealogical andstructuredapproachtoproduct development, withkeystagesidentifiedandthepreformulation, biopharmaceutics, andformulationactivitiesandtypical issues at each stage discussed, wherever possible with real or worked examples,lemphasizewhatpracticalstudiesneedtobeundertakenforwhatreasonsandduringwhatkeystagesofthedrugdevelopmentprocess,andlprovideseparatechaptersontheformulationdevelopmentofeachrouteandtypeofdosageforms.The pressure to accelerate the drug development process, shorten the development timelines,andlaunch newpharmaceutical products is even more intense than before, with fewerregistrations year on year. Having a structured approach and doing the right things first timeare essential elements for achievingthis. The chapters onproduct designandproductoptimizationarestill veryrelevantbut havebeenupdatedtoincludethequalitybydesign(QbD) andInternational Conference onHarmonisation(ICH) Q8 (product development),ICH Q9 (quality risk management), process analytical technology (PAT), and leanmanufacturingprinciplesthataimtolinkregulatoryexpectationstogoodscience.Anothersignificant changesincethefirsteditionisthegrowthofbiopharmaceuticals,comparedwithsmallmolecules,thatdeservesmoreattention.Pharmaceuticalcompaniesareshiftingfromdevelopingsmall moleculestodevelopingbiopharmaceuticalstotreat awiderangeofdiseases, andtodayapproximatelyoneinfourdrugsintroducedtothemarketisabiopharmaceutical.Sincethemajorityofbiopharmaceuticalswillbedeliveredbyinjectionorinfusion, thechapteronparenteraldosageformshasbeenupdatedtoreflectthis. Focushasbeengiventothestepsafterpurification, formulation, andsubsequent fill-finish. Consider-ation has also been given in the other chapters for handling and developing biopharmaceuticaldosage forms where there is some potential for drug delivery,for example, intranasaldosageforms.Elsewhereinthesecondedition, thereareupdatesthroughout thebooktoreflect onsome omissions and developments since the first edition and make it up-to-date; for example,toreflect emergingcutting-edgetechnologies suchas polymorphandsalt selectionandprediction,molecularmodelingandautomationinpreformulationstudies, andmoreconsider-ation forpackagingtechnologyduringdevelopmentofthevariousdosageforms.OnceagainIamindebtedtoallthecontributorsforgivinguptheirtimeandenergyinproducing this updated version. I am also indebted to my wife, Alison, and my family for theirsupportandunderstandingduringthetimeIhavebeenbusyworkingonthisbook.MarkGibsonviii PrefaceContentsPreface viiContributors xi1. IntroductionandPerspective 1MarkGibson2. AidingCandidateDrugSelection:IntroductionandObjectives 11MarkGibson3. PreformulationInvestigationsusingSmallAmountsofCompoundasanAidtoCandidateDrugSelectionandEarlyDevelopment 17GerrySteeleandTalbirAustin4. BiopharmaceuticalSupportinCandidateDrugSelection 129Anna-LenaUngellandBertilAbrahamsson5. EarlyDrugDevelopment:ProductDesign 172MarkGibson6. PreformulationasanAidtoProductDesigninEarlyDrugDevelopment 188GerrySteele7. BiopharmaceuticalSupportinFormulationDevelopment 247BertilAbrahamssonandAnna-LenaUngell8. ProductOptimization 289MarkGibson9. ParenteralDosageForms 325JoanneBroadheadandMarkGibson10. InhalationDosageForms 348PaulWright11. OralSolidDosageForms 367PeterDavies12. OphthalmicDosageForms 431MarkGibson13. AqueousNasalDosageForms 456NigelDay14. TopicalandTransdermalDelivery 475KennethA.WaltersandKeithR.BrainIndex 527x ContentsContributorsBertilAbrahamsson AstraZeneca,Mo lndal,SwedenTalbirAustin AstraZenecaR&DCharnwood,Loughborough,Leicestershire,U.K.KeithR.Brain CardiffUniversity,Cardiff,U.K.JoanneBroadhead AstraZenecaR&DCharnwood,Loughborough,Leicestershire,U.K.PeterDavies ShirePharmaceuticalDevelopmentLtd.,Basingstoke,U.K.NigelDay AstraZenecaR&DCharnwood,Loughborough,Leicestershire,U.K.MarkGibson AstraZenecaR&DCharnwood,Loughborough,Leicestershire,U.K.GerrySteele AstraZenecaR&DCharnwood,Loughborough,Leicestershire,U.K.Anna-LenaUngell AstraZeneca,Mo lndal,SwedenKennethA.Walters An-eXAnalyticalServicesLtd.,Cardiff,U.K.PaulWright AstraZenecaR&DCharnwood,Loughborough,Leicestershire,U.K.1Introduction and PerspectiveMark GibsonAstraZeneca R&DCharnwood, Loughborough, Leicestershire,U.K.INTRODUCTIONThis book is intended to be a practical guide to pharmaceutical preformulation and formulation.It can be used as a reference source and a guidance tool for those working in the pharmaceuticalindustry or related industries, for example, medical devices and biopharmaceuticals, or anyonewantingan insightinto this subjectarea. The information presentedisessentially based ontheextensive experiences of the editor and various other contributors who are all actively working intheindustryandhavelearnedbestpracticefromtheirexperiences.Therearevarious excellent books alreadyavailablethat cover thetheoretical aspects ofdifferent types of pharmaceutical dosage forms and processes. A variety of books are also availablethatfocusonthedrugdevelopmentprocess, business, andregulatoryandprojectmanagementaspects. The popularity of the first edition of this book, Pharmaceutical Preformulation and Formulation:A Practical Guide from Candidate Drug Selection to Commercial Formulation, confirms my opinion thatthereisaneedforapragmaticguidetopharmaceuticalpreformulationandformulationwithanemphasis on what practical studies need to be undertaken, for what reasons, and during what keystages of the drug development process. Preformulation, biopharmaceutics, and formulation are allimportant for candidate drug selection and through the various stages of product development asshown in Figure 3. This book has been written to try and address this need.A logical approach to product development is described in the book, with the key stagesidentifiedandthepreformulation,biopharmaceuticals,andformulationactivitiesandtypicalissuesateachstage discussed.Wherever possible,thebook isillustratedwith realorworkedexamples fromcontributors whohaveconsiderablerelevant experienceof preformulation,biopharmaceuticals,andformulationdevelopment.JimWellsbookonpreformulation(Wells,1988)madeastrongimpactontraineesandpharmaceutical scientists (including myself) working in this field of the pharmaceuticalindustrywhenit was introducedtwoyears ago. It describes the important concepts andmethods used in preformulation with the underlying theory. To his credit, Wells book is stilluseful today, but sadly, the book is now out of print, and existing copies are hard to obtain. Italsorequires updatingtoinclude the abundance of modernpreformulationinstrumentaltechniquesthathaveemerged, suchasthermogravimetricanalysis(TGA), hot-stagemicros-copy(HSM),X-raypowderdiffraction(XRPD),Ramanandinfraredspectroscopy,andsolid-statenuclearmagneticresonance(NMR). Thesetechniquescanbeusedtoprovidevaluableinformationtocharacterizethedrugsubstanceandaidformulationdevelopment usingtheminimalamountsofcompound.Pharmaceutical Preformulation and Formulation: APractical Guide fromCandidate DrugSelection to Commercial Formulation covers a wider subject area than just preformulation. Topicsincludebiopharmaceutics, drugdelivery, formulation, andprocessdevelopment aspectsofproduct development. The bookalso describes a logical andstructuredapproachto theproduct development process, recommendingat what stages appropriate preformulation,biopharmaceutics,andformulationworkarebestundertaken.DRUGDEVELOPMENTDRIVERS,CHALLENGES,RISKS,ANDREWARDSIt is important that the reader is aware of the nature of pharmaceutical research anddevelopment (R&D) toappreciatetheimportanceofpreformulationandformulationintheoverallprocess.In simple terms, the objective of pharmaceutical R&D can be defined as converting ideas intocandidate drugs for development and the objective of product development as converting candidatedrugs into products for registration and sale. In reality, these goals are extremely challenging anddifficult toachievebecauseof themanysignificant hurdlesapharmaceutical companyhastoovercome during the course of drug development. Some of the major hurdles are listed in Table 1.Thehighriskof failureindrugdiscoveryanddevelopment throughout thepharma-ceuticalindustrystatisticallyshowsthat, onaverage, only1in5000compoundsscreenedinresearch will reach the market. For those that are nominated for development, the failure ratewill vary from one in five to one in ten compounds that will achieve registration and reach themarketplace. Most failuresinearlydevelopment areduetodrugtoxicityor safetyissues,whereas alackof efficacyis theprimaryreasonfor late-stageattrition(Lowe, 2008). Therelatively high attrition rates of new medicines is a major challenge, particularly when they areexpensivephaseIIIclinical failuresthathaveoccurredinrecentyears. Regulatorsarebeingmore selective in what they approve, and they are demanding more data on efficacy and sideeffects. Only about 20 new drugs are now approved every year, down from 40 or 50 a decadeago and despite an approximate 70% increase in R&D investment over the last 10 years. On topof this, there is a significant commercial risk from those that are marketed; only 3 out of 10 arelikely to achieve a fair return on investment. The products that give poor return on investmentare often the result of poor candidate drug selection (the compound does not have the desiredproperties of safety, selectivity, efficacy, potency, or duration) and/or poor productdevelopment (thedevelopment programdoesnot establishthevalueof theproduct). Thelatter scenario should, and can be, avoided by careful assessment at the product design stageofdevelopment.Productdesignisdiscussedfurtherinchapter5.Therehasbeenarecentworryingtrendofmarketedproductsbeingwithdrawnafewyears after launch. This may be because once it is used by many thousands, or even millions, ofpeople, rare but significant side effects can emerge. For example, Mercks blockbuster arthritisdrug,Vioxx, wasapprovedin1999butwithdrawnfiveyearslaterwhenlinkedtoincreasedcardiovascular risks. Another example is the surprise announcement by Pfizer when itwithdrewthe worlds first inhalable insulin product, Exubera, fromthe market in 2007followingdisappointingsales. Itwouldseemthatthecompanyhadfailedtoappreciatethecustomerrequirementswellenoughduringtheproductdesignphaseofdevelopment.Table1 MajorHurdlestoSuccessfulProductRegistrationandSaleActivity RequirementsResearch Novel compound(Isitpatentable?)Novel biological mechanism(Isitpatentable?)Unmetmedical needsPotentandselectiveSafety HighmarginofsafetyNontoxic(notcarcinogenic,tetratogenic,mutagenic,etc.)Clinical TolerablesideeffectsprofileEfficaciousAcceptabledurationofactionDrugprocess Bulkdrugcanbesynthesized/scaledupPharmaceutical Acceptableformulation/pack(meetscustomerneeds)Drugdelivery/productperformanceacceptableStable/acceptableshelflifeRobustclinicaltrial process,whichcanbescaledupandtransferredintooperationsRegulatory Qualityofdata/documentationManufacturing ManufacturableAcceptablecostofgoodsAbletopasspreapproval inspectionMarketing/commercial CompetitiveMeetscustomerneedsValueformoneyCommercial return2 GibsonTo be successful and competitive, research-based pharmaceutical companies mustensure that new discoveries are frequently brought to the market to generate cash flow. This isrequired to fund the next generation of compounds to meet the therapeutic needs of patients,and of course, to benefit the shareholders. This cycle of events is sometimes referred to as theproductlifecycleandisfurtherillustratedinFigure1.Theoverall costsof drugdiscoveryanddevelopment tobringanewmedicinetothemarket are increasing at an alarming rate. It is currently estimated that US$1 billion is requiredtorecoupthecosts of research, development, manufacturing, distribution, marketing, andsales for a newchemical entity (NCE). Cost estimates are even higher for a newbiopharmaceutical product at US$1.2billionandtakelonger todevelopthanaNCE, buttend to enjoy much greater success rates (DiMari and Grabowski, 2007). Asignificantproportionof this total is for the cost of failures, or inother words, the eliminationofunsuccessfulcompounds.R&Dexpendituretendstoincreasesubstantiallyasthecompoundprogresses fromdrug discovery research through the various clinical trial phases ofdevelopment.ThepivotalphaseIIIpatienttrialsareusuallythelargest,involvingthousandsof patients, andhencethemost expensive. Toreducedevelopment costs, somecompaniesselectivelyscreenandeliminatecompoundsearlierinthedrugdevelopmentprocessonthebasisofresultsfromsmall-scale, lessexpensivestudiesinhumanandprogressfewer, morecertaincompoundstolaterclinicalphases.Inspite of the highrisks andhighcosts involved, there is still a huge incentive forpharmaceutical companiestoseekthefinancial rewards fromsuccessful marketedproducts,especially from the phenomenal success of the rare blockbuster (reaching sales of >US$1 billionperyear). Thiscanearnthecompanysignificant profitstoreinvest inresearchandfundtheproduct developmentpipeline.Anotherfactor, theriskofdelaytoregistrationandlaunch, canalsohaveasignificantimpact on the financial success of a marketed product. McKinsey & Company, a managementconsultancy, assessedthataproductthatissixmonthslatetomarketwillmissoutonone-thirdof thepotential profit over theproducts lifetime. Incomparison, theyfoundthat adevelopment cost overspend of 50% would reduce profits by just 3.5%, and a 9% overspend inproductioncostswouldreduceprofitsby22%(McKinsey&Co., 1991). ThelossofproductFigure1 Productlifecycle.Introduction and Perspective 3revenueisoftenduetocompetitor companiesbeingfirst tomarket, capturingthemarketshare, and dictating the market price, in addition to the loss of effective patent life. Hence, theimportanceofacceleratingandoptimizingdrugdiscoveryanddevelopment, andgettingtothe market first with a new therapeutic class of medicinal product, cannot be underestimated.Thesecondproduct tomarket inthesameclasswill usuallybecomparedwiththemarketleader,oftenunfavorably.The average time from drug discovery to product launch is currently estimated to be 10to12years.Severalfactorsmayhavecontributedtolengtheningdevelopmenttimesovertheyears,includinganincreaseinthepreclinicalphasetoselectthecandidatedrugandalsoanincrease in the duration of the clinical and regulatory period required for marketing approvalbecauseregulatoryagenciesarerequestingcomparatorefficacystudiesandextensivesafetyprofiling. Benchmarking studies showwide gaps between industry average or worstperformancecomparedwithwhatisachievableasbestpracticeperformance(Spence, 1997).Onaverage, thepreclinical phasecurrentlytakesfourtosixyearstocomplete, whereasthetimefromcandidatedrugnominationtoregulatorysubmissiontakesonaveragesixtoeightyears,andlongerfortreatmentsofchronicconditions.Mostforward-lookingpharmaceuticalcompanies are aiming to reduce these times by reevaluation and subsequently streamlining thedevelopment process, for example, by introducing more effective clinical programs and moreefficient data reporting systems, forwardplanning, andconducting multiple activities inparallel. However, this in turn may put formulation development and clinical supplies on thecritical path, with pressures to complete these activities in condensed time scales. Suggestionsare offered throughout this book on how preformulation, biopharmaceuticals, and formulationcanbeconductedinthemostefficientwaytoavoiddelaysindevelopmenttimes.Anyreductioninthetotaltimeframeofdrugdiscoverytomarketshouldimprovethecompanysprofitability. Inahighlycompetitivemarket, product lifetimesarebeingerodedbecauseofthepaceofintroductionofcompetitorproducts,therapidintroductionofgenericproducts when patents expire and move to over-the-counter (OTC) status. Successfulpharmaceutical companies are focusing on strategies for optimumproduct life cyclemanagement tomaximize the earlygrowthof the product onthe market, sustainpeaksales for as long as the product is in patent, and delay the post-patent expiry decline for as longaspossible. Thisshouldmaximizethereturnoninvestment duringaproduct lifecycletoenablethecompanytorecover development costs andmakefurther investments inR&D.Figure2showsaclassiccashflowprofileforanewdrugproductdevelopedandmarketed.Figure2 Productlifecyclemanagement.4 GibsonDuring development there is a negative cash flow, and it may be some time after launch beforesales revenue crosses fromloss to profit because of manufacturing, distribution, andadvertisingcosts. Profits continue toincrease as the market is establishedtoreachpeaksales, after whichsales decrease, especiallyafter the primarypatent expires andgenericcompetitionisintroduced.Throughoutthelifespanofaproduct, itisinacompanysinteresttoensurethebestpatent protection to achieve the longest possible market exclusivity. Prior to the primary patentexpiring (normally for the chemical drug substance), it is imperative to introduce newindications, formulations, manufacturingprocesses, devices, andgeneral technology, whichare patent protected, to extend the life of the product and maintain revenue. A patent generallyhasatermof about 20years, but asdevelopment timesaregettinglonger, therewill bealimiteddurationofprotectionremainingoncetheproduct ismarketed(theeffectivepatentlife). Acomparisonof effective patent life for pharmaceutical NCEs invarious countriesaroundtheworldshowsthesamedownwardtrendbetweenthe1960sandthe1980s(Kariaet al., 1992; Lis andWalker, 1988). IntheEU, products typicallyenjoy10years of patentexclusivity,whereasintheUnitedStates,itistypicallyonly5years.Gettingtothe market quicklyis a major business-drivingforce, but this has tobebalancedwiththedevelopment of aproduct of theappropriatequality. Thereisaneedtogenerate sufficient information to enable sound decisions on the selection of a candidate drugfordevelopment,aswellastodevelopdosageformsthatarefitforpurposeatthevariousstages of development. Anything more is wasting precious resources (people and drugsubstance), addingunnecessarycost totheprogram, and, moreimportantly, extendingthedevelopment time. Perfect quality should not be the target if good qualityis sufficientfor theintended purpose. This can only be achieved if there is a clear understanding of the customerrequirements.Forexample,ifasimple,non-optimizedformulationwitharelativelyshortshelflifeisacceptableforphaseIclinical studies, anyfurtheroptimizationorstabilitytestingmightbeconsidered wasteful, unless the data generated can be used later in the development program.There can be a significant risk associated with doing a minimum development programandcuttingcornerstofasttracktomarket.Postlaunch,thecostofaretrospectivefixduetopoor product/process designand/or development canbe extremelyhigh. The additionalfinancial cost fromworkinproduct/processredevelopment, manufacturingandvalidation,technical support, regulatorysubmission, andsalesandmarketing(duetoaproductrecall)can easily wipe out the profit from an early launch. This can have several unpleasant knock-oneffects; it mayaffect themarket shareandthecompanysrelationshipwiththeregulatoryauthorities, andits credibility with customers (both externally andinternally withinthecompany) maybethreatened. Thesefactorsneedtobetakenintoaccount whenplanningpreformulation/formulation studies, which can directly influence the progress of a product tomarketandfinalproductquality.CURRENTTRENDSINTHEPHARMACEUTICALINDUSTRYIncreasing competition and threats to the pharmaceutical industry with respect to maintainingcontinuedsalesgrowthandincomemeanthat successful companiesgoingforwardwill bethose that have a portfolio of products capable of showing volume growth. However, to showvolume growth, innovative newproducts are required. The cost of drug discovery anddevelopmentisescalatingbecausetherearenoeasytargetsleftandthecostofdevelopmentandthe cost of goods (CoG) soldare increasing. There have beenseveral mergers andacquisitions of research-based pharmaceutical companies since the 1980s, and increasedcollaborations and inward licensing of products and technologies, in attempts to acquire newleads, tosharecosts, toreducethetimetolicense, andtomaintaingrowth. Unfortunately,mergersandacquisitionsalsoresultinstreamliningandjoblosses,whichimproveefficiencyanddecreaseoverheadcostsatthesametime.There is a changing trend in the nature of the candidate drug emerging frompharmaceutical R&D, froma low molecular weight chemical to a more complexIntroduction and Perspective 5macromolecule (biopharmaceuticals). Biopharmaceuticals comprise biologics such asvaccinesandbloodandplasmaproducts, andproductsderivedusingbiotechnologysuchas monoclonal antibodies or recombinant proteins that are engineered or derived frommammalian or other cells. Some of these compounds have been derived from biotechnologicalprocessestoproducebiotechnologicalmedicinalproductsthatfightinfectionanddisease. Atypical biotechnologyprocess consists of threemajor phases toproducethepurifiedbulkactivepharmaceutical ingredient (API): (i) fermentationof cells(generallymammaliancelllinesforantibodymanufacture), (ii) downstreamprocessingtoclearupanycontamination,and(iii) characterizationandtestingof impurities. ThebulkAPI is theneither processedfurtherorjustfilledinvialsorampoulestoproducethedrugproduct.Itisestimatedthattodaytherearemorethanonehundredbiotechnologicalmedicinalproducts on the market, and many more in clinical trials are being developed to treat a widevarietyofdiseases. Thosecurrentlyonthemarketaccountfor60%ofabsoluteannualsalesgrowth in major pharmaceutical companies, with the remaining 40%being fromsmallmolecules (Mudhar, 2006). Biopharmaceuticals possess some advantages over smallmolecules, for example, somecanaffect humandrugtargets, whichis not possiblewithsmall molecules. Theyarealsodifficult tocopywhenthepatent expires, thuskeepingthegenerics at bay. However, there are also some significant disadvantages of usingbiopharmaceuticals, suchasthealmost unavoidablelossof anyoral dosingroutebecausethey tend to be denatured in the gastrointestinal tract or are too large to be absorbed. It can beamajor challengefor theformulator todevelopself-administeredformulationstodelivermacromoleculessuchasproteinsandpolypeptidesintothebody. Evenifadministeredbyinjection, thepharmacokinetics of biopharmaceuticals can becomplicated becauseofbuilt-inclearancemechanisms.For bothsmall molecules andbiopharmaceuticals, more sophisticateddrugdeliverysystems are beingdevelopedto overcome the limitations of conventional forms of drugdelivery systems [e.g., tablets and intravenous (IV) solutions], problems of poor drugabsorption, noncomplianceof patients, andinaccuratetargetingof therapeuticagents. Oneexample of emerging drug delivery technology is the use of low-level electrical energy to assistthetransport of drugsacrosstheskininaprocessknownaselectrophoresis. Thismethodcould be particularly useful for the delivery of peptides and proteins, which are not adequatelytransported by passive transdermal therapy. The drug absorption rate is very rapid and morecontrolled compared with passive diffusion across the skin. Another example is the pulmonarydelivery of proteins and peptides. The recent successful delivery of insulin using a dry-powderinhalerisimpressivesinceithadtopasssomanyhurdlesincludingthenarrowtherapeuticindexofinsulinandtheneedfortightparticlesizecontroltoreachthealveolarsurface.Thisprovidesencouragementforthedeliveryofotherproteinandpeptideproductsdeliveredbythis route. A third example is the use of bioerodable polymers that can be implanted or injectedwithin the body to administer drugs from a matrix, which can be formulated to degrade over along duration from one day to six months and do not require retrieval. Some of these specificdeliverysystemsareexplainedinmoredetailinlaterchaptersonthevariousdosageforms.Futuristicdrugdeliverysystemsarebeingdeveloped,whicharehopedtofacilitatethetransportofadrugwithacarriertoitsintendeddestinationinthebodyandthenreleaseitthere. Liposomes, monoclonal antibodies, and modified viruses are being considered to deliverrepairgenesbyIVinjectiontotargettherespiratoryepitheliuminthetreatmentofcysticfibrosis. These novel drug delivery systems not only offer clear medical benefits to the patient,but canalsocreateopportunitiesforcommercial exploitation, especiallyuseful if adrugisapproachingtheendofitspatentlife.Therearepressuresonthepharmaceuticalindustry,whichaffectthewayproductsarebeingdeveloped. For example, thereisatrendfor morecomprehensivedocumentationtodemonstrate compliance with current good manufacturing practice (cGMP) and goodlaboratory practice (GLP) and to demonstrate that systems and procedures have beenvalidated. Thelatest trendisfor moreinformationrequiredonthedesignspaceforthemanufacturingprocess prior toregulatorysubmission, as discussedlater inchapter 8onproductoptimization.Abenefitofdoingthisistoprovidemoreflexibilityforchangestotheprocess within the design space limits once submitted. However, the pressure is for a company6 Gibsontosubmitearlyanddeveloptheproductrightfirsttimewithathoroughunderstandingoftheproductandmanufacturingprocess.Inspite of efforts to harmonize tests, standards, andpharmacopoeias, there is stilldiversitybetweenthemajorglobal marketsEurope, theUnitedStates, andJapanwhichhavetobetakenintoaccount inthedesignof preformulationandformulationprograms(Anonymous,1993).Thisisdiscussedfurtherinchapter5onproductdesign.Other pressures facingthe pharmaceutical industryare of apolitical/economical orenvironmental nature. Some governments are trying to contain healthcare costs by introducinghealthcarereforms, whichmayleadtoreducedpricesandprofitmarginsforcompanies, orrestricted markets where only certain drugs can be prescribed. Although the beneficial effect ofdrugs is not questionedingeneral, the pressure tocontainthe healthcare costs is acute.Healthcarecostsareincreasingpartlybecausepeoplearelivinglongerandmoretreatmentsare available. This may influence the commercial price that can be obtained for a new productentering the market and, in turn, the CoG target. The industry average for the CoG target is5% to 10% of the commercial price, with pressure to keep it as low as possible. This may impactonthechoiceandcostofrawmaterials,componentsandpackagingfortheproduct,andthedesignandcostofmanufacturingthedrugandproduct.Environmentalpressuresaretouseenvironmentallyfriendlymaterialsinproductsandprocesses and to accomplish the reduction of waste emissions from manufacturing processes.Agoodexampleisthereplacement of chlorofluorocarbon(CFC)propellantsinpressurizedmetered-doseinhalers(pMDIs)withhydrofluorocarbons(HFAs).TheproductionofCFCsindeveloped countries was banned by the Montreal Protocol (an international treaty) apart fromessential uses, such as propellants in pMDIs, to reduce the damage to the earths ozone layer.However,there isincreasingpressure tophase out CFCsaltogether. Thetransition from CFCto HFA products involves a massive reformulation exercise with significant technicalchallenges and costs for pharmaceutical companies involved in developing pMDIs, asdescribedinchapter 10 InhalationDosage Forms. However, this canbe turnedintoacommercial opportunity for some companies, which have developed patent-protected deliverysystemstoextendthelifecycleoftheirCFCpMDIproducts.LESSONSLEARNTANDTHEWAYFORWARDToachievethebestchanceofafastandefficientdevelopmentprogramtobringacandidatedrug to market, several important messages can be gleaned from projects that have gone wellandfromcompanieswithconsistentlygoodtrackrecords.There are benefits for pharmaceutical development to get involved early with preclinicalresearchduring thecandidatedrug selection phase.This isto moveawayfrom anover-the-wall handover approach of the candidate drug to be developed fromresearch todevelopment. The drug selection criteria will be primarily based on pharmacologicalproperties such as potency, selectivity, duration of action, and safety/toxicology assessments.However, if all these factors are satisfactory and similar, there may be an important differencebetweenthepharmaceuticalpropertiesofcandidatedrugs.Acandidatedrugwithpreferredpharmaceutical properties, for example, good aqueous solubility, crystalline, nonhygroscopic,andgoodstability, shouldbeselectedtominimizethechallengesinvolvedindevelopingasuitableformulation.Thisisdiscussedfurtherinchapter2.Another important factor is goodlong-termplanning, ideally fromcandidate drugnomination to launch, with consideration for the safety, clinical and pharmaceuticaldevelopment, manufacturingoperations, andregulatorystrategiesinvolvedtodeveloptheproduct. There is a need for one central, integrated company project plan that has been agreedon by all parties with a vested interest in the project. Needless to say, the plan should containdetails of activities, timings, responsibilities, milestones, reviews, and decision points. Reviewsand decision points are required at the end of a distinct activity to ensure that the project is stillmeetingitsobjectivesandshouldprogresstothenextstageofdevelopment.However,thesereviews should not cause any delays to the program, rather, they should ratify what is alreadyprogressing. Thetraditional sequential phasesof product development (chapter2) must beIntroduction and Perspective 7overlappedtoacceleratetheproducttomarket. Inreality, planswillinevitablychangewithtime; they should be living documents, which are reviewed and updated at regular intervalsandthencommunicatedtoallparties.Theremaybeseveralmoredetailed,lower-levelplansfocusing on departmental activities, for example, pharmaceutical development, but these plansmustbelinkedtothetop-levelcentralprojectplan.Forwardplanningshouldprovidetheopportunityfor awell thought out andefficientapproachtoproductdevelopment, identifyingrequirementsupfront soastoavoidtoomuchdeliberation and backtracking along the way. It should also provide a visible communication tool.Goodplanning is supportedby adopting a systematic andstructuredapproachtoproduct development. The development process can be broken down into several key definedstagesproduct design, process design, product optimization, process optimization, scale-up,andsoon. Eachstage will have inputs andoutputs as showninFigure 3, a simplifiedframeworkfor product development. Theappropriatedefinitionandrequirementsat eachstagearedescribedinchapters5and8.Asproductdevelopmentcantakeseveralyearstocomplete, itisimportanttohaveaneffectivedocumentmanagementsysteminplacetorecordthework. Theprimaryreferencesource for recordingexperimental workwill usuallybe a laboratorynotebook(paper orelectronic). The work should be checked, dated, and countersigned to satisfy GLP andintellectualpropertyrequirements.Experimentalprotocolsaresometimesusefulfordefiningprograms of work, explaining the rationale for the studies, and defining the acceptance criteria.When the studies are completed, the results can be reported with reference to the protocol andacceptancecriteria. Laboratorynotebooksarereferencedintheprotocolsandreportssothattherawdatacanberetrievedintheeventofanaudit.At the completion of key stages of the work, summary reports can be written, referencingallotherprotocolsandreportsrelevanttothatstageandhighlightingthemajorrecommenda-tionsandconclusions. Inthisway, aproductdevelopmentdocumentfilecanbebuiltupfortransferof informationandtechnology, includingthedevelopment historyandrationaleforprogression.The file willalsobevitalfordata retrievalin theeventofaregulatoryinspection.Finally, successful product development isoftenassociatedwithgoodteamwork. Theprocess is multidisciplinary, relying on people with different specialist skills working togethertomakeit happen. This is particularlyimportant at thekeyinterfaces suchas preclinicalresearch with pharmaceutical development and pharmaceutical development withFigure3 Frameworkforproductdevelopment.8 Gibsonmanufacturing operations at the final production site. It is therefore useful to haverepresentationontheprojectteamsfromall thekeyspecialistfunctionstoensurebuy-intotheplans,strategies,anddecisions,andtohaveagoodprojectmanagementsysteminplace.SCOPEOFTHEBOOKThis book is structured in a logical order to cover the various stages of drug development fromcandidatedrugselectiontodevelopmentoftheintendedcommercialdosageform.Inchapter2, thekeystagesoftheR&Dprocessareexplainedinsomedetail, withtheoutputs expected fromeach stage, to afford an appreciation of the entire process. Theremainder of the book concentrates on candidate drug selection for development anddevelopment of thecommercial dosageformwherepreformulation, biopharmaceutics, andformulation play a vital role. Initial emphasis is on candidate drug selection and theimportance of preformulation, formulation, and biopharmaceutics input at this stage.Traditionally, not all pharmaceutical companies operate inthis way, andthe result fromexperienceisoftenthatpharmaceuticaldevelopmenthastoacceptwhatevercandidatedrugcomes out of researchandaddress any unforeseendifficulties during development. Thedisadvantages of this approach, and the opportunities and benefits of pharmaceutical input tothecandidateselectionprocess,areclearlyexplainedintheearlychapters.Available drug substance for preformulation and biopharmaceutics studies at thecandidate drug selection stage can be a major challenge. Chapter 3 describes thepreformulationstudies that canbe undertakentomaximize the informationgainedfromsmall amounts of drugsubstancetoselect thepreferredcandidatedrugfor development.Various modern preformulation techniques that use minimal amounts of drug are described toevaluatethephysicochemicalpropertiesofcompounds,saltsandpolymorphs.Chapter 4 describes the importance of drug delivery and biopharmaceutical factors in thecandidate drug selection phase. Consideration is given to the intended route of administration,what predictions can be made, and useful information gained frombiopharmaceuticalassessmentofthecandidatedrug.Followingcandidateselection, usually, onecandidatedrugisnominatedfordevelop-ment.Theimportanceofestablishingtheproductdesignattributesisdiscussedinchapter5.Thevalueofthisexerciseisoftenunderestimatedintherushtodevelopproductsquickly.However, thequalityoftheproductdesigncanofteninfluencethesuccessofdevelopingacommerciallyviableproductwithadesiredproductprofileinatimelymannertomarket.Chapters 6 and 7 focus on preformulation and biopharmaceutics, respectively, as an aidtoproduct design. Theemphasisisongeneratingtheappropriatedatatocharacterizethecandidatedrugandaidproduct designanddevelopment. Theobjectiveat thisstageistodetermine the physicochemical properties of the candidate drug, which are consideredimportant inthedevelopment of astable, effective, andsafeformulation. Useof alimitedamountofavailabledrugsubstanceandthespeedandprogramofworkdependingontheintended dosage form and route, are all carefully considered here and illustrated with the aidof workedexamples. Moderninstrumental techniques andpersonal computer (PC)-basedexpertsystemsarediscussedasusefultools.Todevelopaproduct frominceptiontomarket, theproduct andprocesshavetobeoptimizedandtheprocessscaledupandtransferredtocommercial production. Definitionsanddescriptions of therequirements for all thesestages of development arediscussedinchapter 8, although the major discussion is on the preformulation/formulation input toproductoptimization.Themanyfactorsthataformulatorshouldconsiderintheselectionofpharmaceutical excipientsandpackagingarediscussed. Useful sourcesof informationandtechniquesforselectionsuchasexpertsystemsandexperimentaldesigntoolsareincluded.Drugs are generally administered via the mouth, eyes, nose, or skin or by inhalation orinjection, andso these routes are coveredin more detail in separate chapters. Specialconsiderations and issues for the formulation development of each route and type of dosageformare discussed on the basis of considerable relevant experience of the variouscontributors.Introduction and Perspective 9REFERENCESAnonymous.Globaldifferencesinregistrationrequirements.PharmJ1993;251:610611.DiMari JA, Grabowski HG. The cost of biopharmaceutical R&D: is biotech different? Manage Decis Econ2007;28:469479.Karia R, Lis Y, Walker SR. The erosion of effective patent lifean international comparison. In: Griffin JP, ed.Medicines,Regulation,Research andRisk. 2nded. Belfast:QueensUniversityPress,1992:287301.Lis Y, Walker SR. Pharmaceutical patent termerosiona comparisonof the UK, USAandFederalRepublicofGermany(FRG).PharmJ1988;240:176180.Lowe D. Opininion in the pipeline. Its been a rough year, but the future looks bright. Chem World 2008;January:23.McKinsey&Co. In: Burall P, ed. ManagingProduct Creation, aManagement Overview. London: TheDesignCouncilfortheUKDepartmentofTradeandIndustry,1991.Mudhar P. Biopharmaceuticals:insight intotodays market and a lookto thefuture. Pharm Technol Eur2006;9:2025.SpenceC, ed. ThePharmaceuticalR&DCompendium: CMRInternational/SCRIPsGuidetoTrendsinR&D.Surrey,UK:CMRInternational/SCRIPPublication,1997.Wells JI. Pharmaceutical Preformulation. The Physicochemical Properties of Drug Substances. Chichester:EllisHorwood;andNewYork:Wiley,1988.10 Gibson2Aiding Candidate Drug Selection:Introduction and ObjectivesMark GibsonAstraZeneca R&DCharnwood, Loughborough, Leicestershire,U.K.STAGESOFTHEDRUGDISCOVERYANDDEVELOPMENTPROCESSThe development of a new medicinal product from a novel synthesized chemical compound, achemical extracted froma natural source or a compound produced by biotechnologicalprocesses,isalongandcomplexprocedureandinvolvesmanydifferentdisciplinesworkingtogether. The drug discovery and development process for a typical research-basedpharmaceutical companycanbebrokendownintofivedistinct stagesasdescribedbrieflybelow. At eachstage, therewill beseveral activities runninginparallel, withtheoverallobjective of discovering a candidate drug and developing it to market as efficiently as possible.It shouldbe notedthat different companies may use slightly different terminology andperformsomeactivitiessoonerorlater,buttheoverallprocessisessentiallythesame.StrategicResearchFeasibility studies are conducted to demonstrate whether interfering in a particular biologicalmechanismhasaneffectthatmightbeoftherapeuticvalue.Thestrategicresearchofaparticularcompanyisusuallyguidedbyfactorssuchasitsinherent researchcompetenceandexpertise, therapeuticareasof unmet medical need, andmarket potential/commercial viability. Companies often wish to develop a portfolio ofproducts within a specific therapeutic area to capture a segment of the market. By focusing ona particular therapeutic area, a company can build on its existing expertise and competence inall of its functions with the aim of becoming a leading company in that field. Product life cyclemanagementisimportantinachievingthisaim.ExploratoryResearchExploratoryresearchisaninvestigationofthebiological mechanismandidentificationofachemicalorbiologicalleadthatinterfereswithit.Duringtheexploratoryresearchstage,diversecompoundsarescreenedforthedesiredbiological activity. Theaimistofindachemical ormolecularentitythatinterfereswiththeprocess and to provide a valuable probe of the underlying therapeutic problem. Traditionally,thishasbeenachievedbytheorganicchemistsynthesizingcompoundsoneatatimeforthebiologist to test in a linear fashion. Over the last two decades, there has been a rapiddevelopment in the technologies for creating very large and diverse quantities of synthetic andbiosynthetic molecules and for testing large numbers of activity in less time. Thesetechnologieshavebeenlabeledcombinatorial chemistryandautomatedhigh-throughputscreening(HTS), respectively. Thekeyimpact hasbeentoacceleratethesynthesisof newcompoundsfrom,say,50compoundsperchemistyeartomanytensofthousandsandtobeabletotest theseagainst manybiological targets (e.g., biological receptors or biochemicalpathways)veryquickly(Doyleetal.,1998).TherateoftechnologydevelopmentspecificallyassociatedwithHTSforpharmaceuticaldrug discovery has increased markedly over recent years, with automated techniques involvingminiaturization, toallowassaysonverysmall samples(e.g., 1mLvolume), andtheabilitytoanalyzethousands ofsamples adayusingwellmicroplates(Burbaum,1998).Inadditiontotheuse of HTS for pharmacological activity, HTS tests have been developed for assessing metabolismand pharmacokineticandtoxicityfactors tospeedupthedrugdiscoveryprocess.Insimple terms, a biologically active compoundcanbe consideredto consist of asupportiveframeworkwithbiofunctional groupsattachedthat bindtoatarget toinduceabiological response. Eachcompound is, ineffect,a unique combinationofnumerouspossiblegroups.Combinatorialtechniqueshavereplacedtraditionalsyntheticapproachestogeneratemanypossiblecombinationsrapidlyforbiologicaltesting.Approaches to lead generation during exploratory research often depend on how muchisalreadyknownaboutthetherapeutictargetunderconsideration.Forexample,ifthethree-dimensional structure of the target (such as an enzyme-inhibitor complex) is known, chemicalleads could be found and optimized through combinatorial chemistry and HTS. Alternatively,in some cases, the only available biochemical knowledge might be the structure of a ligand fortheenzyme. Iftherewerenoinformationatall, thentheonlyapproachmightbelimitedtoHTSofbatchesofcompoundsfromcombinatoriallibraries.Even with combinatorial chemistry and HTS, lead generation can be extremely laboriousbecauseof thevast number of different molecules possible(frameworkandbiofunctionalgroup combinations). To ease this burden, some rational drug design and quantitativestructure activity relationships (QSARs) are often introduced to direct the program and utilizeacompanysfinitescreeningresourceasefficientlyaspossible.Representative libraries of compounds, where each member is selected to giveinformation about a larger cluster of compounds, are designed and used to reduce the amountofcompoundsthathavetobemadeandtested.There have beenrecent advances tocreate diverse biopharmaceutical molecules forevaluation, for example, through antibody engineering to produce anticancer treatments(Morrow, 2007). Protein and glycosylation engineering can be employed to generate antibodieswith enhanced effector functions. The presence or absence of one sugar residue can result in atwo-orders-of-magnitudedifferenceintheabilitytokill cancercellsbyantibody-dependentcellcytotoxicity,whichcouldresultinreduceddoseandcost.Togetherwithcombinatorial chemistryandrational drugdesign, genomicsisrapidlyemergingasauseful techniquetoenablecompaniestosignificantlyincreasethenumberofdrugtargetsandimproveoncandidateselectionsuccess.Anumberofcompanieshaveseenthe potential in defining patient groups based on their genotypes and are now investing lots ofmoney to gain a clearer understanding of the genes that are important to drug action. Personalmedicinehasbeenindevelopment sincethe1980s: Personalizedtreatmentiswherethedoctorprescribes thebesttreatmentforapatientbased onhisorhergeneticprofile,whereaspersonalizedproducts involve drugs that are actuallymade for anindividual patient. Apatients DNAcanbe rapidlysequencedandrecombinant proteincanbe produced. Forexample, it is possible to look at the DNA sequences (biomarkers) of cancer patients, which tellthe doctor what the best treatment would be for that patient. If personalized products are notavailable yet, the doctor can identify which general therapy, such as chemotherapy, antibodies,or radiation, would be the most statistically effective for a particular cancer type based on thegeneticscreening.CandidateDrugSelectionThechemical or biological leadisusedtogeneratespecificchemical compoundswiththeoptimal desired characteristics, for example, potency, specificity, duration, safety, andpharmaceuticalaspects.Oneormorecandidatedrugsarenominatedfordevelopment.Duringthecandidatedrugselectionstage,themolecularleadisoptimizedbytestingarange of selected compounds in in vitro and in vivo (animal) studies. The objective is to selectone or more candidate drugs for development with the most desired characteristics.Pharmacological characteristics might include acceptable absorption, potency, durationofaction, andselectivity forthe receptor orenzyme. Safetycharacteristicswill normallyincludenoncarcinogenicity, nonteratogenicity, nonmutagenicity, andgeneral nontoxicity. Thepoten-tial for these characteristics can be predictedfromrelatively short-termpreclinical toxi-pharmacologicalanimalstudiesandinvitrotests.TheU.S. FoodandDrugAdministration(FDA) hasrecentlyrecommendedthat drugdevelopers conduct phase 0 studies, a designation for exploratory, first-in-human microdosingstudies. These are conducted prior to phase I studies and intended to speed up the12 Gibsondevelopment of promising drugs or imaging agents by establishing very early on whether thedrugoragentbehavesinhumansubjectsaswasanticipatedfrompreclinical studies(FDA,2006). Phase0studiesinvolvetheadministrationof single, subtherapeuticdoseof thenewdrug candidate to a small number of human subjects (1015) to gather preliminary data on thepharmacokinetics(howthebodyprocessesthedrug)andpharmacodynamics(howthedrugworksinthebody).Aphase0studygivesnodataonsafetyorefficacy,butdrugdeveloperscancarryout thesestudiestorankdrugcandidatestodecidewhichtotakeforward. Theyenable decisions to be made based on human data instead of relying on animal data, which canbe unpredictive and vary between species. The potential advantages of phase 0 studies are toaid candidate drug selection by getting an insight into the human pharmacokinetics, but also tohelptoestablishthelikelypharmacological doseandalsothefirst doseforthesubsequentphaseI study. Theymayalsoidentifyearlyfailuresandsavethecompanycostsoffurtherdevelopment.In the interests of rapid drug development, it is also important to select a chemical leadwith preferredpharmaceutical andchemical synthesis properties at this stage. Alist ofpreferredcharacteristicsforacompoundintendedfororalsoliddosageformdevelopmentisgiveninTable1.Higherpriorityintheselectionprocesswill, inmostcases, begiventoacompoundsoptimalpharmacologicalandsafetycharacteristics.However,intheeventofhavingachoicefrom a range of compounds all possessing similar pharmacological and safety properties, theremay be a significant advantage for formulation development in selecting a compound with themost preferred pharmaceutical development properties. It is useful to conduct preformulationstudiesandbiopharmaceuticsstudiesatthecandidatedrugselectionstagetodeterminethemost relevant physicochemical and biopharmaceutical properties of potential candidate drugstoaidcandidateselection.Biopharmaceuticsisthestudyofhowthephysicochemicalpropertiesofthecandidatedrugs, theformulation/deliverysystem, andtherouteofadministrationaffect therateandextent of drug absorption. Appropriate biopharmaceutical information generated at this stagecanalsobeveryimportantindirectingthecandidateselectionprocessandforfuturedosageformdesignduringdevelopment.The benefits of providing preformulation and biopharmaceutics input during thecandidate drug selection stage, to characterize the candidate drug and provide usefulinformationtosupport theselectionof theoptimal compoundforpharmaceutical develop-ment, are emphasizedinchapters 3 and4. Generally, anypharmaceutical issues canbediscoveredearlier,beforethecandidatedrugreachesdevelopment,andanyimplicationsforproductdesignanddevelopmentconsideredinadvance.Theinvolvementofpharmaceuticaldevelopment inthe selectionprocess andbuy-in tothe nominationdecisioncanoftenenhancetheteamsworkingrelationshipwiththeirresearchcolleagues. Theobjectiveistoachieveaseamlesstransitionfromresearchtodevelopment, asopposedtothetraditionalover-the-wall approachthat many pharmaceutical companies experience to their costs.Table1 PreferredDrugSynthesisandDosageFormPharmaceutical PropertiesforChemical CompoundsIntendedforOral SolidDevelopmentDrugsynthesisfactors Formulation/drugdeliveryfactorsLeastcomplexstructure(none/fewchiral centers) ExistsasastablepolymorphicformFewsynthesisstepsaspossible NonhygroscopicHighyieldsaspossible CrystallineNonexplosiverouteorsafetyissues Acceptablesolid-statestabilityofcandidatedrugCommercial availabilityofbuildingblocksandcontractmanufacturersAcceptableoral bioavailabilityLowcostofgoodscomparedwithoverall costofproductonmarketNothighlycoloredorstrongodor(toensurebatchreproducibility and reduce problems with blinding inclinical studies)Nopredictedproblemsinscale-upofmanufacturingprocessNopredictedproblemsinscale-upofbatchsize CompatiblewithkeyexcipientsAiding Candidate Drug Selection 13Earlier involvement by the pharmaceutical development group at the preclinical stage shouldalsoresultinbetterplanningforfulldevelopment.In spite of all these potential advantages of early pharmaceutical involvement tocandidatedrugselection, theremaybeseveralbarrierswithinacompany,whichcanhinderthis way of working. Distance between the research group and the development group shouldnot reallybe considereda barrier, althoughthis canbe the case for groups ondifferentcontinents with different cultures and languages. The important factor for success seems to bethedevelopmentofaformalmechanismforinteraction,supportedbyseniormanagementinthe company. This often takes the form of a joint project team with regular meetings to reviewprogress. However, there may still be a lackof appreciationof what input or expertisepharmaceutical development can offer at the candidate drug selection stage. Opportunities todemonstrate what can be done and to educate research colleagues should be sought to try andovercomethisattitude.Another potential barrier is anyoverlappingexpertisetheremaybeinresearchanddevelopment groups. Forexample, overlapmayoccurbetweenpreformulationinpharma-ceutical development andphysical chemistryinresearch, or betweenbiopharmaceutics indevelopmentanddrugmetabolisminresearch. Inthesecases, itisimportanttoclarifyandagreewhichgroupdoeswhatactivity.Acommonperceivedbarriertoprovidingearlypreformulationandbiopharmaceuticsinput canbethequantityof compoundrequiredforevaluationat thisstage. Theresearchgroupmaybelievethatsignificantlymorecompoundisrequired;withmoderninstrumentaltechniques;however,thisisoftennotthecase.Otherpotentialbarriersthatcaninfluencethesuccessof therelationship with researchatthecandidatedrugselectionstagearethepharmaceuticaldevelopmentresponsetimenotbeing fast enough to support research and the lack of resources that pharmaceuticaldevelopmentcangivetosupportthecandidatedrugselectionprogram.Severalcompoundsmayhavetobeevaluatedsimultaneouslytogeneratecomparativedatatoaidtheselectionprocess. Preformulationandbiopharmaceuticshavetokeeppacewiththepharmacologicalandsafetytesting;otherwisethereisnopointingeneratingthedata.Onewayofachievingthis is to allocate dedicated resources to these projects using people trained to rapidly respondtothepreformulationandbiopharmaceuticsrequirements. Fit-for-purpose, simpleformula-tions can be usedat this stage, andrank order information is often acceptable, ratherthandefinitive quantitative information. Analytical methods shouldnot require rigorousvalidationat thisstagetoprovidethesedata. Excessivedocumentationandrigidstandardoperatingproceduresthatcanslowdowntheworkarenotusuallynecessaryandshouldbeavoided.ExploratoryDevelopmentTheaimof exploratorydevelopment istogaugehowthecandidatedrugisabsorbedandmetabolized in healthy human volunteers before studying its effect on those actually sufferingfrom the disease for which it is intended. Occasionally, it is necessary to conduct further small-scalestudiesinpatientstomakeadecisionwhethertoprogressthecandidatedrugintofulldevelopment. This stage is often referred to as phase I clinical studies or concept testing (proofof concept). Usually a small number of healthy volunteers (2080 who do not have theconditionunderinvestigationoranyotherillness)receivethedrugcandidateprovidedasasimpleformulation, whichcanbedifferent fromtheintendedcommercial formulation. Forexample, a simple aqueous oral solution or suspension may be used, rather than a capsule ortablet,tominimizetheformulationdevelopmentworkatthisearlystage.PhaseIstudiesarethe first stage of testing in human subjects to assess the safety (pharmacovigilance), tolerability,pharmacokinetics, and pharmacodynamics of a new drug. The trials are usually conducted inan inpatient clinic where the subjects can be observed by full-time medical staff. These studiesoften include dose ranging or dose escalation so that the appropriate dose for therapeutic usecanbefound.TherearedifferentkindsofphaseItrials.SAD: Single ascending dose studies where human subjects are given a single dose of thedrug. If there are no adverse side effects, the dose is escalated until intolerable side effects starttobeobserved.Thisiswherethedrugreachesitsmaximumtolerateddose(MTD).14 GibsonMAD: Multiple ascending dose studies are conducted to better understand thepharmacokinetics andpharmacodynamics of multiple doses of the drug. Patients receivemultiple low doses of the drug, and then the dose is subsequently escalated to a predeterminedlevel.Food effect: A short trial designed to investigate any differences in absorption of the drugby the body caused by eating before the drug is given. These are usually designed as crossoverstudies, with volunteers being given two identical doses of the drug on different occasions, onewhilefastedandoneafterbeingfed.If the candidate drug does not produce the expectedeffects inhumanstudies, orproduces unexpected and unwanted effects, the development program is likely to be stoppedat this stage. Since the introduction of the EU Clinical Trial Directive 2001/20/EC in 2001, thereisnowarequirementforallEUcountries,includingtheUnitedKingdomwhenitcameintoforceinMay2004,tomakeasubmissiontothelocalregulatoryauthoritiesforpermissiontoconductthetrialsinhumanvolunteers.FullDevelopmentCompletionoflonger-termsafetyandclinicalstudies(phasesIIandIII)inpatientssufferingfrom the disease are accomplished at this stage. Phase II studies are dose-ranging studies in areasonable patient population (several hundred) to evaluate the effectiveness of the drug andcommon side effects. During phase II, the intended commercial formulation should bedeveloped, andthe product/process optimizedandeventually scaledupto commercialproduction scale. The candidate drug should ideally be in the intended commercialformulationforthephaseIIItrials. AfterthesatisfactorycompletionofphaseIItrials, largepatient populations (several hundred to thousands) are involved to statistically confirmefficacy and safety. Some patients will be given the drug, some a placebo product (required tobe identical in appearance), and some may be given a known market leader (with all productsappearing identical). The doctors and patients in the study will not know whether the patientsare getting the test drug, placebo, or market leader; by switching the medication in a controlledway (double -blind trials), objectivity and statistical assessment of the treatment underinvestigationareassured.Mostregulatoryauthorities,includingtheFDA,theMedicinesandHealthcareproductsRegulatoryAgency(MHRA)intheUnitedKingdom,andtheEuropeanAgency for the Evaluation of Medicinal Products (EMEA), require three phases of clinical trialsand sufficient data to demonstrate that the new product can be licensed as safe, effective, andof acceptable quality. Once these clinical studies are complete, the company candecidewhether it wishes to submit a marketing authorization application to a regulatory authority foramedicinaldrugproduct.Approvalisusuallyfollowedbyproductlaunchtomarket.There are also phase IV trials, also known as post-marketing surveillance trials,conductedtoevaluatethesafetysurveillance(pharmacovigilance)ofadrugafteritreceivespermissiontobesold. This maybearequirement of theregulatoryauthorities or maybeundertakenbyadrug-developingcompanytofindanewmarket forthedrugorforotherreasons. For example, the drug may not have been tested for interactions with otherdrugs oron certain population groups such as pregnant women or pediatrics. The objective of phase IVstudies is to detect any long-term or rare adverse effects over a much larger patient populationand longer time period than phases I to III trials. If harmful effects are discovered, it may resultinadrugnolongerbeingsoldorarestrictiontocertainuses.SUMMARYPharmaceutical companies with the best track records for drug discovery and rapid developmenttomarket tendtohaveaseamless transfer fromresearchtodevelopment. Therearemanyopportunities andbenefits tobegainedbytheinvolvement of pharmaceutical developmentgroups, such as preformulation and biopharmaceutics, during the candidate drug selection stage.Itmaybesurprisingwhatvaluableinformationcanbeobtainedusingmodernpreformulationinstrumental techniquesandbiopharmaceutical techniquesfromrelativelysmall quantitiesofcompound.Thesetopics arediscussedfurther in chapters3and4 of thistext.Aiding Candidate Drug Selection 15REFERENCESBurbaumJ.Enginesofdiscovery.ChemBr1998;6:3841.DoylePM,BarkerE,HarrisCJ,etal.CombinatorialtechnologiesarevolutioninpharmaceuticalR&D.PharmTechnolEur1998;4:2632.Food and Drug Administration (FDA). Guidance for Industry, Investigators, and ReviewersExploratoryINDStudies. Available at: http://www.fda.gov/cder/guidance/7086fnl.htm. AccessedJanuary2006.MorrowJMJr.Glycosylationandthedemandsofantibodyengineering.BioPharmInt2007;10:126129.16 Gibson3Preformulation Investigations using SmallAmounts of Compound as an Aid to CandidateDrug Selection and Early DevelopmentGerry Steele and Talbir AustinAstraZeneca R&DCharnwood, Loughborough, Leicestershire,U.K.INTRODUCTIONIn recent years, there has been a significant increase in pressure on pharmaceutical companiestodiscoveranddevelopnewmedicineseverfastertoreplacethosecomingoffpatentandtocounter genericmanufacturer competition(Frantz, 2007). Despitetheexpenditureof manybillonsofdollars, Joshi(2007)reportsthatsince1990anaverageofonly28drugshavebeenapprovedeachyear, withtheFoodandDrugAdministration(FDA)approvingonly17newchemical entities(NCEs)in2002, thelowestnumberofnewdrugapprovalsforthedecadeleadinguptothat year (KolaandLandis, 2004). Indeed, thesuccessrateachievedbytheindustry of bringing a candidate drug (CD) to market is no more than 10% (Schmid and Smith,2006), andit isestimatedthat of 30,000compoundssynthesizedonly0.003%of discoverycompounds will show a satisfactory return on investment (Federsel, 2003). The majority of theattrition occurs in phase II and phase III of development, with approximately 62%ofcompoundsenteringphaseIIundergoingattrition(KolaandLandis,2004).So,notonlydoesthe number of compounds being brought through from discovery phase need to increase, butthe amount of effort expended on them needs to reflect the attrition that will occur as they areprogressed through early development. One idea being mooted to increase the productivity ofthe drug discovery process is the concept of lean thinking, which has been used inpharmaceutical manufacturingfor process improvement (Petrillo, 2007). Simplyput, leanconcepts aim to eliminate those steps in the process that do not add value to the process chain.It has been estimated that utilizing lean concepts in the discovery phase, combined with othermethods of increasingproductivity, wouldleadtoanincrease(from1in5to1to3) incompoundsenteringclinicaltrials.Drugdiscoveryanddevelopmentischaracterizedbyanumberofdistinctstages, andtypically,thedrugdiscoveryprocessfallsintotwophases,leadgeneration(LG)followedbylead optimization (LO) (Davis et al., 2005). The LG period is further subdivided into the active-to-hit (AtH) and the hit-to-lead (HtL) phases (Baxter et al., 2006). The HtL phase utilizes high-throughput screening (HTS) and generates actives, hits, and leads: leads are those compoundsthatmeetpredefinedchemicalandbiologicalcriteriatoallowselectionofthechemistrythatprovidesmoleculeswithdrug-likeproperties(Leesonetal.,2004).Drug-likecompoundscanbe defined as those with pharmacokinetic and pharmacodynamic properties that areindependent of the pharmacological target (Viethet al., 2004). LeesonandSpringthorpe(2007) have discussed how drug-like concepts can influence decision making in the medicinalchemistry arena. In this paper, they argue that the wave of molecules presently beingsynthesizedpossess significantlydifferent physicochemical properties tothose alreadyinclinicaldevelopment.One important aspect of the HTS and HtL approach is that it provides multiple chemicalseries tode-riskfutureLOwork. Thus, theaimof this phaseis toincreasethedrug-likeproperties (e.g., improve potency, selectivity, pharmacokinetic properties, and decreasetoxicity) of leadcompounds against a CDtarget profile (CDTP). During the LOphase,structure-activityrelationships(SARs), whichcorrelatemolecularpropertieswithbiologicaleffects, arederived. WhenSARscanbemeasuredquantitatively, theybecomequantitativeSARs (QSARs) (Andricopula and Montanari, 2005). Two specific examples of LO programs forthesystematicoptimizationofcompoundseriesaregivenbyGuileet al. (2006)andBaxteretal.(2006).The iterative assessment of optimized leads against selection criteria allows identificationofthemostpromisingleadcandidates. Oncetheleadcandidateshavebeenidentified, thenassessment of the material characteristics by the development scientists can be initiated(Venkatesh and Lipper, 2000). This phase has traditionally been termed prenomination andtypically lasts around three to six months. It encompasses investigations into thephysicochemicalcharacterizationofthesolidandsolutionpropertiesofCDcompoundsandhas been the subject of the books by, for example, Wells (1988) andCarstensen (2002).Essentiallytheaimof this phaseistoprovideaninitial evaluationof compoundsfromadevelopmentperspectiveandsupportthetolerabilitystudiesofcompounds.Thescopeof prenominationandearlydevelopment studiestobecarriedout largelydepends on the expertise, equipment, and drug substance available, and also on anyorganizational preferences or restrictions. Insome organizations, detailedcharacterizationstudiesareperformed, whileother companiesprefer todotheminimumamount of workrequired to progress compounds as quickly as possible into development. There areadvantages anddisadvantages to bothapproaches, but animportant consideration is tobalancethestudiesthat allowanappropriateunderstandingoftheCDwiththesignificantpossibility of attrition. However, for the smoothprogressionof compounds throughthepreformulationphase, acloseinteractionbetweenMedicinal Chemistry, SafetyAssessment,Pharmaceutical Sciences, Analytical Chemistry, and Process Research and Developmentdepartments is essential to assess the physicochemical properties and toxicology ofcompoundsandtheirprogressiontothefirst humandoseasquicklyaspossible(Li, 2004).Ifthecompoundpassestheseassessments,itcanthenpassintothelate-phasedevelopment,whichwillbedealtwithinsubsequentchapters.In the case of development studies that can be undertaken to support the nomination of acompound for development, Balbach and Korn (2004) have proposed the 100 mg approach fortheevaluation of early developmentCDs. However, as pointed outbyTicehurst and Docherty(2006), if a complete package of work is carried out too early, it may lead to much wasted effort.Ontheotherhand,if insufficient workis performed,then it mayleadto increasedpressuretocharacterizethecompoundtomeetacceleratedprojectdemands.Thus,theyrecommendafitfor purpose solid form in the early studies, followed by selection of solid form for a commercialdevelopment. For convenience, these phases can be termed early and late development,respectively. Thegoal of earlydevelopment canbedefinedasthat tosecureaquick, risk-managed processesfortesting theCDin animalsandhumanvolunteersforphaseIstudies.During prenomination, compounds needto be evaluatedinanimals for exposure/toxicitypurposes [7-daytoxand28-daysingle andmultiple ascendingdoses (SADs andMADs)] (Krameret al.,2007).Thecompound,inasuitableform toensure systemicexposure(Gardneretal.,2004),needstobeformulatedintoanappropriateformulationfordeliveryinthefirst goodlaboratorypractice(GLP) dosetypicallyas either asuspensionor solution.ReferenceismadetoChaubal(2004)forareviewofthisareaandManskyetal. (2007)foramethodforrapidlyscreeningpreclinicalvehiclesthatenhancethesolubilityoflowsolubilitycompounds. HitchinghamandThomas(2007) havedevelopedasemiautomatedsystemtodeterminethestabilityofthedosingformulations.During this stage, there may be a number of compounds with sufficient activity to meritconsideration, and so studies must be designed appropriately to allow efficient assessment andselection of suitable compounds for development. Clear differences in in vivo activity may besufficienttodeterminewhichof thecandidatesare selected.However, otherfactorsthatmaybe important froma pharmaceutical and drug synthesis point of viewshould also beconsidered if there is a choice. For example, physicochemical and biopharmaceuticalcharacteristics of the compound(s), easeof scale-upfor compoundsupply, cost of goods,andthenatureoftheanticipateddosageformshouldalsobepartofthedecisionprocess.Ideally, for an oral solid dosage form, a water-soluble, nonhygroscopic, stable, and easilyprocessed crystalline compound is preferred for development purposes; however, otherformulation types will have their own specific requirements. For example, inhalationcompoundsneedtobemicronizedfor formulationintoapressurizedmetereddoseor dry18 Steele and Austinpowder inhaler. This is an energy-intensive process and can change the crystallinity ofcompounds, andthus their subsequent interactionwithmoisturemaybe important. For asolution formulation, however, the stability of the compound will be paramount, and ifinstabilityisamajorissue, thenalternativemeasuressuchasfreeze-dryingmayberequired.Table1summarizestheprenominationstudiesthatcouldbecarriedout onaCD. Theseareconsideredtobetheminimumteststhat shouldbeundertaken, recognizingthat duringtheprenomination phase only a limited quantity of compound, for example, 50 to 100 mg is typicallyavailable to the pharmaceutical scientist for characterization. However, it should be emphasizedthat this is a critical decision period that can profoundly affect the subsequent development of aCD. Thus, the tests shown are considered to be those important for making a rational decision asto which compound, salt, or polymorph to proceedwith into development. A poor decision atthispoint maymeansomerevisionarywork, suchas, achangeof salt orpolymorphbeingnecessarylaterandapossible delaytothedevelopmentof thedrugforthemarket.Table1 SuggestedPhysicochemical TestsCarriedOutDuringPrenominationTier1Test/activity Guidancetoamount Timing/commentsElementalanalysis 4mg LOInitial HPLCmethodology 2mg LONMRspectroscopy 5mg LOMassspectroscopy 5mg LOGeneral,e.g.,MW,structural andempirical formulae LOIR/UV-visiblespectroscopy 5mg LOKarl Fischer 20mg LOPKa10mg LOLogP/logD 10mg LOInitial solubility 10mg LO/prenominationInitial solutionstability Doneonabovesamples LO//prenominationCrystallinityinvestigations 2030mg LO/prenominationHygroscopicity 510mg LO/prenominationInitial solidstability 10mg PrenominationSaltselectionDecide/manufacturesalts PrenominationCharacterizesaltsuseDVS,Xray,DSC,solubility/stabilitytests1050mgeachsalt PrenominationInitial polymorphismstudies,etc.Investigationsofselectedsaltorneutralcompound.Productionusedifferentsolvents,coolingrates,precipitation,evaporationtechniques,etc100mg PrenominationAlsoincludedisthepropensity of the CD toformhydrates,solva-tes,andamorphsPolymorphism,etc. PrenominationInvestigationsofselectedsaltorneutral compound.CharacterizationDSC/TGA/HSM 2mgpertechnique/sample PrenominationX-raypowderdiffraction,includingtemperatureandRH10mg/sample,0backgroundholderPrenominationFTIR/Raman 2mg/sample PrenominationCrystal habitmicroscopy,light,andSEM 10mg PrenominationStability-stresswrttemperature/humidity 100mg PrenominationChoosepolymorph,amorph,orhydrate PrenominationAbbreviations: LO, lead optmization; CD, candidate drug; HPLC, high-performance liquid chromatography; NMR,nuclear magneticresonance; MW, molecular weight; IR/UV, infrared/ultraviolet; DVS, dynamicvapor sorption;DSC, differential scanning calorimetry; TGA, thermogravimetric analysis; HSM, hot-stage microscopy; RH, relativehumidity;FTIR,Fouriertransforminfrared;SEM,scanningelectronmicroscopy;wrt,withrespectto.Preformulation Investigations 19After first-time-in-human (FTIH) studies in early development, if the compoundprogressesintofull development, amorecompletephysicochemical characterizationof thechosen compound(s), with particular emphasis on the dosage form, should be carried out, thusallowingarational,stable, andbioavailableformulationtobeprogressedthroughtolaunch.Thisisdiscussedinmoredetailinchapter6.Fromadevelopmentpointofview, perhapsthebiggestchangeinthelastdecadehasbeen the introduction and utilization of HTS technologies, whereby large number ofcompoundscanbeassessedinparallel toallowefficient physicochemical profilingaswellassalt andpolymorphscreening(Desrosiers, 2004; Storeyet al., 2004; Seadeeket al., 2007;Wyttenbachetal.,2007).MOLECULARPROPERTIESInitialPhysicochemicalCharacterizationInitial physicohemical characterizationexplores the two-dimensional structural properties.Manyof thetests carriedout, suchas proof of structure, arenormallyperformedbytheDiscoverydepartment, forexample, nuclearmagneticresonance(NMR), massspectra, andelemental analysis. Although important froma physicochemical point of view, thesemeasurementswillnotbediscussedinthischapter.Rather,thetextwillfocusonthosetestscarriedoutduringprenominationthat will haveanimportant bearingontheselectionofapotentialCDinrelationtotheproposedformulation/dosageform.pKaDeterminationsPotential CDs that possess ionizable groups, as either weak acids or bases, can be exploited tovary biological and physical properties such as binding to target enzyme or receptor, bindingto plasma proteins, gastrointestinal (GI) absorption, central nervous system (CNS) penetration,solubility, andrateof dissolution(as willbediscussedlaterin thechapter).Therefore,oneofthe most important initial determinations carried out prior to their development is the pKa orionizationconstant(s). Avdeef (2001)andKerns(2001) havecomprehensivelyreviewedthisaspectofdiscoverywork,andthereaderisreferredtothesepapersforadetailedaccount.Strong acids such as HCl are ionized at all relevant pH values, whereas the ionization ofweak acids is pH dependent. It is essential to know the extent to which the molecule is ionizedat a certain pH, because it affects the properties noted above. The basic theory of the ionizationconstantiscoveredbymostphysical chemistrytextbooks, andamostuseful textisthatbyAlbert andSargeant (1984). Fundamental toour appreciationof thedeterminationof thisparameter, however, is the Brnstead and Lowry theory of acids and bases. This states that anacid is a substance that can donate a hydrogen ion, and a base is one that can accept a proton.Foraweakacid,thefollowingequilibriumholds:HA HAFor the sake of brevity, a detailed discussion and derivation of equations will be avoided;however,itisimportantthatthewell-knownHendersonHasselbachequationisunderstood(equation 1). This equation relates the pKato the pHof the solution and the relativeconcentrationsofthedissociatedandundissociatedpartsofaweakacid(equation1).pH pKalogA

HA1where [A] is the concentrationof the dissociatedspecies and[HA] the concentrationof theundissociatedspecies. Thisequationcanbemanipulatedintotheformgivenbyequation(2)toyieldthepercentageofacompoundthatwillbeionizedatanyparticularpH.%Ionization 1001 pH pKa220 Steele and AustinOne simple point to note about equation (1) is that at 50% dissociation (or ionization) thepKa pH. It should also be noted that usually pKa values are preferred for bases instead of pKbvalues(pKw pKa pKb).MeasurementofpKaTable2summarizessomemethodsusedinthedeterminationofionizationconstants.Ifacompound ispoorlysolubleinwater,theaqueous pKamay bedifficulttomeasure.Onewaytocircumvent thisproblemistomeasuretheapparent pKaof thecompoundinsolvent-water mixtures, and then extrapolate the data back to a purely aqueous medium usingaYasudaShedlovskyplot.Theorganicsolventsmostfrequentlyusedaremethanol,ethanol,propanol, dimethylsulfoxide(DMSO), dimethyl formamide(DMF), acetone, andtetrahydro-furan (THF). However, methanol is by far the most popular, since its properties bear the closestresemblancetowater. Takacs-Novaketal. (1997)havereportedavalidationstudyinwater-methanolmixtures, andthe determinationof thepKasofibuprofen andquinine in a rangeoforganicsolvent-watermixtureshasbeendescribedbyAvdeefetal.(1999).If the compound contains an ultraviolet (UV) chromophore that changes with the extentofionization, thenamethodinvolvingUVspectroscopycanbeused. ThismethodinvolvesmeasuringtheUVspectrumofthecompoundasafunctionofpH.Mathematicalanalysisofthespectralshiftscan thenbeusedtodeterminethepKa(s)ofthecompound.Thismethodismost suitable for compounds where the ionizinggroupis close toor actuallywithinanaromatic ring, whichusuallyresults inlarge UVshifts uponionization. The UVmethodrequires only 1 mg of compound, and the potentiometric method around 3 mg of compound.Another method of determining pKa is the pH indicator titration described by Kong et al.(2007).ThisappearstobequiteanovelapproachinsofarthatitutilizesauniversalindicatorsolutionwithspectrophotometricdetectionforthedeterminationofthepKainsteadofapHelectrode. ThemethodworksbycalculatingthepHfromtheindicatorspectrainthevisibleregion and then obtaining the spectra in the UV. Favorable results were obtained from a test setoffivecompounds.ThescreeningofpKascanbecarriedoutbyusinganinstrumentationknownasgoodlaboratorypracticepKa(GLpKa), socalledbecauseitconformstothecriterialaiddownforinstrumentsperforminganalyzestothecodeofGLP.However,oneofthelimitationsofthistechniqueisthatasolutionconcentrationofatleast5 104MisneededforthepKatobecalculated from the amount of titrant versus pH data. Alternatively, the UV method appears toworkat lower concentrations (