Table Of ContentAdvances 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
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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
