Amorphous Solid Dispersions: Theory and Practice PDF
Preview Amorphous Solid Dispersions: Theory and Practice
Advances in Delivery Science and Technology SeriesEditor MichaelJ.Rathbone Forfurthervolumes: http://www.springer.com/series/8875 Navnit Shah • Harpreet Sandhu (cid:129) Duk Soon Choi Hitesh Chokshi (cid:129) A. Waseem Malick Editors Amorphous Solid Dispersions Theory and Practice 2123 Editors NavnitShah HiteshChokshi KashivPharmaLLC RochePharmaResearch&EarlyDevelopment Bridgewater RocheInnovationCenter NewJersey NewYork USA NewYork USA HarpreetSandhu A.WaseemMalick Merck&Co.,Inc. PharmaceuticalandAnalyticalR&D Summit Hoffmann-LaRocheLtd. NewJersey Nutley USA NewJersey USA DukSoonChoi KashivPharmaLLC Bridgewater NewJersey USA ISSN2192-6204 ISSN2192-6212(electronic) ISBN978-1-4939-1597-2 ISBN978-1-4939-1598-9(eBook) DOI10.1007/978-1-4939-1598-9 SpringerNewYorkHeidelbergDordrechtLondon LibraryofCongressControlNumber:2014947686 © ControlledReleaseSociety2014 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartofthe materialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation, broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformation storageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology nowknownorhereafterdeveloped.Exemptedfromthislegalreservationarebriefexcerptsinconnection withreviewsorscholarlyanalysisormaterialsuppliedspecificallyforthepurposeofbeingenteredand executed on a computer system, for exclusive use by the purchaser of the work. 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Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) ToextraordinaryscientistsatHoffmann-La Rochewhoadvancedthefieldofamorphous sciencetotransformpoorlysoluble“sand-like” compoundsintoimportantmedicines Preface The idea of writing this book was triggered by the development ofASD utilizing microprecipitated bulk powder (MBP) technology at Hoffmann-La Roche and the successfulapplicationofthistechnologytopoorlysolublemolecules,suchasvemu- rafenib.Thistechnologywasinstrumentalintransformingthisnovelmoleculeinto a medicine (Zelboraf®) for malignant melanoma patients. It was a gratifying and fulfillingexperienceforallofuswhenZelboraf®becameakeydrugforthisdeadly diseaseandmadeadifferenceinthelivesofmanypatients.Webelievethatmany pharmaceuticalscientistsfacesuchachallenge,andabookcoveringthetheoryand practiceofamorphoussoliddispersiontechnologieswouldbeveryusefultoindus- trialandacademicscientistsaswellasstudentsinunderstandingandhandlingthe challengesassociatedwithdevelopingsuchmolecules. Poorly water soluble drug molecules emerging from contemporary discovery programsoftenhaveinadequateand/orvariableinvivoexposure, presentingphar- maceuticalscientistswithconsiderablechallengesduringdevelopment.Drugswith poor and variable oral absorption often have suboptimal therapeutic performance andsignificantfoodeffect,therebyraisingsafetyconcerns,particularlyfornarrow therapeuticwindowdrugs.Asaresult,promisingmoleculescanbeterminatedpre- maturely if these issues are not adequately addressed. A number of formulation strategieshavebeendevelopedtoenhancethebio-performanceofsuchmolecules. Amongthesetechnologies,particlesizereductionbymicronizationornanomilling improvestherateofdissolution;however,thisstrategyhasresultedinlimitedsuc- cessforpoorlywatersolublemoleculeshavingasolubilityoflessthan10mcg/mL. Solubilizationinlipidvehiclesandself-emulsifyingdeliverysystemshavecertainly addedvalue,buttheirutilityhasbeenlimitedbydrugloading,whichremainsamajor issue.Similarly,saltsofweakacidsandbaseshavemetwithlimitedsuccessdueto precipitationofthesesaltsinphysiologicalfluidsresultinginsignificantvariability. Co-crystallizationhasbeenrecentlyexplored,butitsutilityhasyettoberealizedfor poorlysolublemolecules. The amorphous form of a drug offers high free energy and therefore higher ki- netic solubility, which provides an opportunity for overcoming solubility-related absorption and bioavailability challenges. The amorphous form, however, is ther- modynamically unstable, and stabilization of molecules in this physical state still vii viii Preface remainsaformidabletask.Agreaterunderstandingofthescientificprinciplesgov- erning these systems and the development of amorphous solid dispersion (ASD) formulationsforstabilizingamorphousmoleculeshavecreatedtremendousoppor- tunitiesforthepharmaceuticalscientisttoaddressissuesrelatingtothebioavailability ofpoorlysolublemolecules.ASDtechnologyhasbecomeoneofthemostpowerful andversatiletechnologyplatformsinrecentyears.Thedesignanddevelopmentof successfulASDformulationsrequirestheintegrationofscientific,technologicaland biopharmaceuticalaspectstoarriveatarobustdrugproduct.Amorphousformulation technologies and our understanding of amorphous systems have advanced signifi- cantlyinthelastdecade.Agreaterappreciationoftheunderlyingphysicalscience and thermodynamics, the emergence of newer technologies for the preparation of amorphousformulations,andtheavailabilityofnewerexcipientsandpolymersfor stabilizingASD have vastly expanded the opportunities for pharmaceutical scien- tiststoestablishstabilizationstrategiesforthesesystems.Theinterestindeveloping amorphousformulationshasincreasedmorethaneverduetothesuccessfulmarket introductionofsuchproductsoverthelastdecade. Writtenbyexpertsfromindustry,academiaandgovernment,thisbookprovides an excellent reference for pharmaceutical research scientists in the understanding, preparation and stabilization of ASD. In this book, we present the three primary factors for the stabilization and successful development of ASD, namely (a) the physicalandchemicalpropertiesofthedrugsubstance,(b)polymersandtheirimpact onthestabilityofthefinalproduct,and(c)processingtechnologiestoputASDinto practice.Theseaspectsareextensivelycoveredbytheinclusionofcasestudies. Thefirstfewchaptersofthebookcoverthefundamentalsandtheoreticalaspects ofamorphoussystems,anoverviewofASDtechnologies,anddetailsonexcipients andpolymersusedinASD,alongwiththeirsafetyaspects.“FundamentalsofAmor- phous Systems” discusses the theoretical aspects of thermodynamics and kinetics withrespecttotheenergybarrier.Alsoaddressedaretheactivepharmaceuticalin- gredient(API)propertiesandpolymercharacteristicsnecessaryforpreparingstable ASD,involvingsolubilityandmiscibility, interactionparametersanddrugloading impact. “Overview ofAmorphous Solid Dispersion Technologies” provides a de- tailedpresentationofeachtechnologyanditslimitations.Thechapteronexcipients presentsdifferentclassesofexcipients,theirphysico-chemicalpropertiesandtheir interrelationship with different processes; the safety and stability of excipients are alsodescribedatlength. LaterchapterspresentdetailsofASDmanufacturingtechnologies,includingspray drying, hot melt extrusion, and a breakthrough novel solvent-controlled micro- precipitation technology (MBP). Each technology is illustrated with processing fundamentals and scale up factors along with specific case studies, which provide the scientist with approaches for handling challenges presented by different types ofmoleculesaswellasbuildingprocessflexibility.Inaddition,adedicatedsection covers the miniaturization of technologies for screening polymers and processes with small amounts of API, particularly during the discovery and early develop- ment phases addressing preclinical needs. Since all of the technologies used in preparingASDsystemsrequiredownstreamprocessingfordevelopingviabledrug Preface ix products,thechapterondownstreamprocessingcoversthephysicalandmechanical factorsimpactingproductperformance.Theanalyticaltoolsforthecharacterization ofamorphoussoliddispersions,predictionoflongtermstability,evolvingsuitable dissolutionmethodsparticularlyaddressingsupersaturationkinetics,aswellasregu- latoryaspectsgermanetoamorphoussoliddispersionformulationsandtechnologies arealsoextensivelycovered. This volume explores technologies on the horizon, such as supercritical fluid processing,mesoporoussilica,KinetiSol®,andtheuseofnon-saltformingorganic acids and amino acids for the stabilization of amorphous systems. It presents a comprehensiveoverviewofthetheoryandpracticeofamorphoussoliddispersions in overcoming the challenges associated with poorly soluble drugs, and it in- cludespracticalexamplesbasedoncommerciallysuccessfulproductsusingdifferent manufacturing technologies and stabilization strategies. Amorphous Solid Disper- sionsprovidespharmaceuticalscientistswithup-to-dateknowledgeonamorphous solid dispersions that will further enhance their ability to handle more challeng- ing molecules and will pave the way for future innovation to bring cutting-edge therapeuticstopatientsinneed. Sincerely NavnitShah HarpreetSandhu DukSoonChoi HiteshChokshi A.WaseemMalick Acknowledgement Theeditorswanttothankalltheindividualswhoprovidedscientificinputandcri- tiqueaswellasofferedvaluablechangesandsuggestions.Thesecontributionstruly enhancedthequalityofthebook.Weacknowledgeandexpressoursincereanddeep appreciationfortheirefforts. ItishardtoexpressourgratitudeinwordstoHoffmann-LaRocheInc.forsupport- inghighqualityresearchandcreatinganatmospherethatwasconducivetoexploring newideasandinnovation.Theinspirationalandcollaborativeenvironmentenabled ustopursueoriginalresearchandcontributetotheadvancementofamorphoussys- tems.Theseeffortsledtocuttingedgeinnovationsthatinturnenableddevelopment ofeffectivenewmedicines.Noneofthiswouldhavebeenpossibleifitwerenotfor the dedication and enormous effort of many outstanding scientists from the Phar- maceutical andAnalytical R&D Department, strong partnership of scientists from otherdisciplinesaswellasunwaveringmanagementsupport.Inreality,gettingthese differentiatedmedicinestothepatientsinneedisthetrueinspirationforwritingthis book. We do not have enough words to express our earnest thanks to all the authors and co-authors for accepting our request for contributing to this effort and most importantlyforprovidinghighqualitycontentstoenablethetimelycompletionof thebook.Wearehighlyappreciativeoftheirpatienceinrespondingtoournumerous requeststhroughoutthisprocess.Itindeedhasbeenaprivilegetoworkwithpeople ofsuchhighscientificcaliberandintegrity. WewanttoexpressoursincerethankstoSpringerfortheinvitationforwriting this book. Our special thanks to Ms. Carolyn Honour and Ms. Sarah McCabe for theirvaluablesuggestions,helpfulcommentsandespeciallyforputtingupwithour slighttardinessincompletionofthebook. TheeditorswanttoacknowledgethevaluablecontributionsofMr.DineshShah andDr.MartinInfeldforreviewingdocumentsandprovidingconstructivecomments forenhancingthequalityofthebook.OurthankstoMs.LisaMitchellforhandling thelogisticsandallthesupportforarrangingthebookcontents,formatting,preparing tables,andvaluableedits.AspecialthankyoutoMs.VickyPacholecforkeepingus togetherduringchallengingtimes. xi xii Acknowledgement Most importantly, our heartfelt thanks are owed to our families. Our spouses, Gita,Farooq,Kwanghee,SonalandAneezaandourchildrenfortheirpatienceand sacrifice during the last two years, for tolerating our long hours away from them and encouraging us to undertake this mission. Without their support, the timely completionofthisbookwouldnothavebeenpossible. Sincerely NavnitShah HarpreetSandhu DukSoonChoi HiteshChokshi A.WaseemMalick
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