Innovative dosage forms : design and development at early stage

462 Pages·2020·9.29 MB·english

by  Yogeshwar Bachhav

InnovativeDosageForms
MethodsandPrinciplesinMedicinalChemistry
EditedbyR.Mannhold,H.Buschmann,JörgHolenz
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Innovative Dosage Forms
DesignandDevelopmentatEarlyStage
EditedbyYogeshwarG.Bachhav
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v
Contents
Preface xvii
1 ImpactofthePolymorphicFormofDrugs/NCEs
onPreformulationandFormulationDevelopment 1
MHDBashirAlsirawanandAnantParadkar
1.1 Introduction 1
1.1.1 Background 1
1.1.2 TypesofPolymorphism 2
1.1.2.1 ConformationalPolymorphism 2
1.1.2.2 PackingPolymorphism 4
1.1.3 Thermodynamic-BasedClassificationofPolymorphism 4
1.1.3.1 EnantiotropicPolymorphism 4
1.1.3.2 MonotropicPolymorphism 5
1.1.4 ConcomitantPolymorphism 6
1.1.5 DebatablePolymorphismCases 7
1.1.5.1 TautomericPolymorphismorTautomerism 7
1.1.5.2 Enantiomerism/Stereoisomerism 7
1.1.5.3 Pseudopolymorphism 8
1.2 PolymorphismImpactonDrug/ExcipientProperties 9
1.2.1 PhysicochemicalProperties 10
1.2.2 MechanicalProperties 11
1.2.3 ImpactofPolymorphismonInVivoPerformance 13
1.2.3.1 EffectofPolymorphismonSolubility 14
1.2.3.2 EffectofPolymorphismonDissolutionRate/SolubilityKinetics 17
1.2.3.3 EffectofPolymorphismonBioavailability 20
1.3 CriticalImpactofPolymorphicFormofAPIonProcessingand
Formulation 22
1.3.1 Process-inducedTransformationTypes 23
1.3.1.1 Grinding-inducedTransitions 23
1.3.1.2 Granulation-inducedTransitions 25
1.3.1.3 Tableting-inducedTransition 30
1.3.1.4 Freeze-drying-inducedTransition 32
1.3.1.5 Spray-drying-inducedTransitions 33
1.3.1.6 Supercritical-fluid-inducedTransitions 35
1.4 Conclusion 37
References 38
vi Contents
2 StrategiesfortheFormulationDevelopmentofPoorlySoluble
DrugsviaOralRoute 49
SanketShah,AbhijitDate,andRenèHolm
2.1 Introduction 50
2.2 QualitybyTesting(QbT)andQualitybyDesign(QbD) 50
2.3 LinkingtheFormulationtotheClinicalPhase 52
2.4 DefiningtheFormulationStrategy 55
2.5 Nanosuspensions 58
2.5.1 Description 58
2.5.2 MethodofManufacturing 59
2.5.2.1 Top-DownMethods 59
2.5.2.2 WetMediaMillingTechnology 60
2.5.2.3 High-pressureHomogenization 61
2.5.2.4 Bottom-UpMethods 62
2.5.2.5 MethodsUtilizingaHybridApproach 63
2.5.3 CharacterizationofNanosuspensions 63
2.5.3.1 ParticleSize,PolydispersityIndex,andParticleMorphology 63
2.5.3.2 SurfaceCharge 63
2.5.3.3 ParticleMorphology 64
2.5.3.4 Solid-stateProperties 64
2.5.3.5 SaturationSolubilityandDissolutionVelocity 64
2.6 SolidDispersion 64
2.6.1 Description 65
2.6.2 MethodofManufacturing 66
2.6.2.1 Melting/Fusion 66
2.6.2.2 SolventEvaporation 67
2.6.2.3 Coprecipitation 67
2.6.3 Characterization 68
2.6.3.1 InvestigationofCrystallinity 68
2.6.3.2 InvestigationofMolecularArrangement 69
2.7 Lipid-BasedDrugDeliverySystems 69
2.7.1 Description 70
2.7.2 MethodofManufacture 71
2.7.3 Characterization 75
2.7.4 RoleofAPIPropertyonLipid-BasedDDS 76
2.8 MicellarSystem 76
2.8.1 Description 76
2.8.2 FormulationDevelopmentandOptimization 80
2.8.3 Characterization 81
2.9 MesoporousSilicaParticles 81
2.9.1 Description 82
2.9.2 MethodofManufacturingandCharacterization 83
2.9.3 CaseStudyontheinVivoEfficacyofMesoporousSilicaParticles 84
2.10 Conclusion 84
References 85
Contents vii
3 EffectofResidualReactiveImpuritiesinExcipients
ontheStabilityofPharmaceuticalProducts 91
AnkitSharma
3.1 Introduction 91
3.2 ReactiveImpuritiesintheExcipientsandTheirImpactonDrug
Stability 92
3.3 ImpactofReactiveImpuritiesonDrug–ExcipientCompatibility 93
3.3.1 PhysicalInteractions 93
3.3.2 ChemicalInteractions 94
3.3.3 OxidativeDegradation 94
3.3.4 Peroxides 95
3.3.5 TransitionMetalImpurities 96
3.3.6 CondensationReactions 99
3.3.7 AldehydeImpurities 99
3.3.8 ReducingSugars 102
3.3.9 OrganicAcids 103
3.3.10 HydrolyticDegradation 105
3.4 RiskAssessmentforAPIIncompatibilitiesandMitigation
Strategies 107
3.5 AssessmentofIncompatibilitiesofAPIwithExcipients 108
3.6 DesignandSelectionofDrugSubstance 109
3.7 FormulationStrategiestoCircumventAPIDegradation 110
3.8 InhibitionofOxidativeDegradation 110
3.8.1 InitiationInhibitors 111
3.8.2 PropagationInhibitors 111
3.8.3 SelectionofAntioxidant 112
3.9 Super-RefinedExcipients 113
3.9.1 PolyethyleneGlycols(PEG) 114
3.9.2 Polysorbates 114
3.9.3 FattyAcids 115
3.10 PackagingandStorage 115
3.11 ConcludingRemarks 116
References 116
4 PreclinicalFormulationAssessmentofNCEs 119
RajuSaka,PriyadarshiniSathe,WahidKhan,andSachinDubey
4.1 Introduction 120
4.2 SignificanceofVariousPropertiesofNCEsinEarlyDrug
Discovery 122
4.2.1 Solubility 123
4.2.2 Permeability 124
4.2.3 Stability 125
4.3 FormulationStrategiestoImprovePropertiesofNCEs 125
4.3.1 pHModification 127
4.3.2 Cosolvents 127
viii Contents
4.3.3 Cyclodextrins 128
4.3.4 Surfactants 128
4.3.5 SuspensionsandNanosuspensions 129
4.3.6 EmulsionsandMicroemulsions 130
4.3.7 SolidDispersions 130
4.3.8 Liposomes 131
4.4 PreclinicalFormulationAssessmentofOral,Parenteral,andTopical
DosageForms 131
4.4.1 OralFormulations 131
4.4.1.1 FormulationDevelopment 132
4.4.2 ParenteralFormulations 134
4.4.3 TopicalFormulations 135
4.4.3.1 StructureofSkinandEffectonPermeation 136
4.4.3.2 FormulationEffect 136
4.4.3.3 SkinMetabolism 136
4.4.3.4 FormulationDevelopment 136
4.4.3.5 FormulationApproaches 137
4.4.4 Excipients 138
4.4.5 CharacterizationandStabilityofPreclinicalFormulations 140
4.4.6 FormulationSelectionforPharmacokineticStudies 141
4.4.7 FormulationSelectionforPharmacodynamicStudies 142
4.4.8 FormulationDevelopmentforToxicityStudies 142
4.5 CaseStudies 143
4.5.1 Case1:UseofSurfactanttoPreventPrecipitationofAPIin
Cosolvent-BasedFormulations 143
4.5.2 Case2:TopicalGelMicroemulsionFormulationofLipophilicDrug
WHI-07 144
4.5.3 Case3:SaltApproachtoImprovetheBioavailabilityofthePoorly
SolubleDrug 144
4.5.4 Case4:UseofSMEDDSDosageFormtoImproveBioavailability 145
4.5.5 Case5:MicronizedSuspensionofPoorlySolubleLeadCompounds
UsingWetMillingTechnique 145
4.5.6 Case6:PolymerAdditioninCyclodextrin-BasedFormulationsandpH
Adjustment 146
4.5.7 Case7:CyclodextrinComplexationtoImproveTopicalDeliveryofa
PoorlySolubleCompound 146
4.5.8 Case8:UseofSolublizersandTheirEffectonPKofPreclinicalLead
Candidates 147
4.5.9 Case9:Self-nanoemulsifyingDrugDeliverySystems(SNEDDS)to
ImproveSolubilityandBioavailability 147
4.6 ConclusionandFuturePerspectives 148
References 148
5 RegulatoryAspectsforFormulationDesign–withFocusonthe
SolidState 155
MichaelGruss
5.1 TheUnderstandingof“Regulatory” 156
5.2 FormulationDesign 157
Contents ix
5.3 AnExtendedTimescale 158
5.4 SolubilityData 158
5.5 ImpactofSolubilityandDissolutionRateonFormulationDesign 162
5.6 SingleandMulticomponentSystems 163
5.6.1 Introduction 163
5.6.2 ScientificPointofView 164
5.6.2.1 Polymorphism 164
5.6.2.2 Polyamorphism 165
5.6.2.3 MulticomponentCompounds–Salt,Co-crystal,Solvate,and
Hydrate 165
5.6.3 FateandPathwayofaCompoundDuringDevelopment 166
5.6.4 RegulatoryPointofView 167
5.6.4.1 Patents 167
5.6.4.2 Pharmacopeias 168
5.7 AnalyticalTechniquesfortheCharacterizationoftheSolidState 168
5.7.1 ScientificLiterature 168
5.7.2 Pharmacopeias 169
5.8 ControlofSolid-stateConstitution 171
5.8.1 TheProcess–fromSynthesistoPatient 171
5.8.2 ChangeofPropertiesandConstitution 173
5.8.3 NeedforControlofSolid-StatePropertiesDuringtheProcessand
SupplyChain 173
5.9 RegulatoryConsiderationofSolidCompounds 174
5.9.1 DefinitionsforSolidCompounds 174
5.9.1.1 Co-crystalsandSolvates 174
5.9.1.2 SaltsandCo-crystals 174
5.9.1.3 Polymorphism 175
5.9.2 CommonTechnicalDocument(CTD)–M4Q 175
5.9.2.1 CTD–Section3.2.S–DrugSubstance 175
5.9.2.2 CTD–Section3.2.P–DrugProduct 177
5.9.3 GuidelineontheChemistryofActiveSubstances 178
5.9.4 GuidelineonQualityofTransdermalPatches 180
5.9.5 QualityGuidelines 181
5.9.5.1 ICHQ1A(R2)StabilityTestingofNewDrugSubstancesand
Products 182
5.9.5.2 ICHQ1BPhotostabilityTesting 182
5.9.5.3 ICHQ1CStabilityTesting:RequirementsforNewDosageForms 183
5.9.5.4 ICHQ6ASpecifications:TestProceduresandAcceptanceCriteriafor
NewDrugSubstancesandNewDrugProducts:Chemical
Substances 183
5.9.6 EMA–ConsiderationandPerspective 188
5.9.6.1 AbridgedApplications 188
5.9.6.2 NewActiveSubstance(NAS)Status 188
5.9.6.3 MarketingAuthorizationApplication(MAA) 189
5.9.6.4 Co-crystalsandGMPManufacturing 189
5.9.6.5 ActiveSubstanceMasterFile(ASMF) 190
5.9.6.6 PharmaceuticalAcceptance 190
5.9.6.7 CompoundsContainingMorethanOneTherapeuticMoiety 190
x Contents
5.9.7 FDA–ConsiderationandPerspective 190
5.9.7.1 SourcesforInformation 190
5.9.7.2 NamingofDrugSubstancesandDrugProducts 191
5.9.7.3 InvestigationalNewDrugApplication(IND) 192
5.9.7.4 MarketingAuthorizationApplication–NewDrugApplication
(NDA) 194
5.9.7.5 ANDA–AbbreviatedNewDrugApplications 194
5.9.7.6 RegulatoryClassificationofPharmaceuticalCo-crystalsand
Salts 196
5.9.8 SimilaritiesandDifferencesBetweentheRegulativeSystemsintheEU
andUnitedStates 197
5.10 ConclusionsandRecommendations 198
Disclaimer 198
References 198
6 InsightintoInnovativeApplicationsofParenteral
Formulations 209
ClaraFernandes
6.1 Introduction 209
6.2 FactorsAffectingDevelopmentofSustained-/Controlled-Release
Formulations 209
6.3 OverviewofSustainedandControlledReleaseParenteral
Formulations 213
6.3.1 SuspensionBasedFormulations 213
6.3.1.1 NanosuspensionBasedFormulations 213
6.3.1.2 MicrosuspensionBasedFormulations 214
6.3.2 ParticulateSystemBasedFormulations 215
6.3.2.1 PolymerNanoparticlesBasedFormulations 215
6.3.2.2 LipidNanoparticlesBasedFormulations 217
6.3.2.3 InorganicNanoparticlesBasedNanoparticles 217
6.4 CaseStudies 219
®
6.4.1 NanosuspensionFormulationofPaclitaxel–Abraxane 219
®
6.4.2 PLGADepotBasedFormulationofTriptorelin–Trelstar 219
6.4.3 MicroemulsionFormulationofPropofol 220
6.4.4 InorganicMetalNanoparticleBasedFormulationforParenteral
Applications 220
6.4.5 PolymericFormulationofGlatiramer 221
6.5 Conclusion 222
6.6 FutureProspects 222
References 222
7 AssessingPharmacokineticsofVariousDosageFormsatEarly
Stage 227
SusanneBonsmannandJoachimOssig
7.1 Introduction 227
7.2 DefinitionofPharmacokinetics 229