制藥學(xué)課件(英文版)

Capsules

Capsules-CapsulaeEP5.01‘Capsulesaresolidpreparationswithhardorsoftshellsofvariousshapesandcapacities,usuallycontainingasingledoseofactivesubstance.Theyareintendedfororaladministration’.Thecapsuleshellsaremadeofgelatin…..HardCapsules Relativelyeasyproduction. Capsuleshellsavailablefrommanymanufacturers.OftenfilledinDispensary/HospitalSoftCapsules

Specificrooms(humidity&temperature)andequipmentnecessaryforproductionOnlyveryfewContractManufacturersGelatinmanufacture/html/rawmaterials.htmlGelatinmanufactureResult:

Differentiso-electricalpointTypeAratheralkaline(pH6.0–9.5)TypeBratheracidic(pH4.7–5.6)Reason:Hydrolysisofglutamine/asparagineoccursonlyduringthealkalineprocessPropertiesofGelatinAppearance Faintlyyelloworlightyellowish-brown,solid,usually occurringastranslucentsheets,shreds,granulesor powder.Solubility –Swellsincoldwaterandgivesonheatingacolloidal solution –Goodsolubilityinglycerol,propyleneglycol,sorbitol solutionandaceticacid –PartiallysolubleinEtOH-water-mixtures –Insolubleinethanol,etherandotherorganicsolventsSoftCapsules?Multipurposedosageform:eg,oral,rectal,vaginal?Swallow,breakwiththeteeth,suckon(Gelsolets)?Fillingvolumefrom0.1-20mlSoftGelatinCapsules Thethickshellcontainsglyceroland/orsorbitolasplasticiserWatercontent7-8%Higherhygroscopicitythanhardgelatincapsules(plasticiser)HugediversityinformsandcoloursUsedfornonaqueoussolutionsandsuspensionsSize/shapemanufacture1.Swellingofthegelatin2.Additionofplasticisers,antimicrobialpreservatives,sweeteners,colouringmatter3.Castingofgelatinribbons4.Shapingtothedimensionofthedie5.FillingfromdosingpumpdirectlybeforesealingRotary-DieMethod

(Scherer,1933)

AContinuousprocess…/Rotary-Diemethod1Gelatinribbons2Rotarydies3V-notchfiller4Finishedcapsules5Gelatinribbonwithpunchedholes6FeedmaterialOthermethodsTheScherermethodisnottheonlyprocess…..SomemethodsusevacuumfillingSomecanproduceseamlesscapsulesThebasicprinciplesareshownmosteasilyintheScherermethod….Incookingtermsitislikemakingravioli!Advantages/DisadvantagesofSC

SuitablefornonaqueousfillingsExclusionofair(oxygen)assuresstabilityforsensitivedrugs(eg,vitamins)HughdiversityofcoloursandshapesCompliance,drugsafetySurfactants(seams!)andwatercontainingmaterialsnotencapsulatableProductionrequiresspecificenvironmentalconditions(20-30%rH,22°C)SpecialisedcontractmanufacturersreleaseSoftcapsulesgenerallyshowexcellentreleasecharacteristics.Thestomachisdesignedtodigestsoftproteinmateriallikecapsuleshellssothefillingisaccessedveryrapidly.HardGelatinCapsulesInventedin1846CapsuleshellsconsistingoftwoprefabricatedcylindricalsectionsWatercontent10-12%Ingredients: –Gelatin, –colouringagents –opacifiers(TiO2,Fe-oxides)HCmanufactureCommonfaultssizesCapsuleFillingCapsuleFillingofSolidsCapsuleFillingofPelletsCapsuleFillingofPellets

CapsuleFilling–

LiquidFormulationsCapsuleFillingofLiquidsSomePointsonHGC1.Compatibilitywithgelatin Drugswithreactivealdehydegroupsareincompatiblewithgelatin(cross-linking).Hightemperatures,humidityandlightshouldalsobeavoided.

2.Dose Shouldbebetween100–600mg…continued

3.Particlesizeandshape Isometricparticleshavebetterflow properties Particlesizebetween10-150m4.Hygroscopicity Hygroscopicexcipients/drugswillabsorb waterfromthegelatin=>brittleness…continued6.ChoiceoftheCapsule Size:preferablysmall Choiceofcolour: -Identification -Psychologicaleffects:BLUE:cool,calmingRED,ORANGE:stimulating,arousingTabsv.CapsExcipientsforFastReleaseHC

1.Diluents Mannitol Lactose Starch(maize) microcrystallinecellulose2.Lubricants Magnesiumstearate Stearicacid Glycerolmono-stearate3.Flowregulatingagents Aerosil? TalcObjectivesWiththepossibleexceptionofanaestheticgases,medicinalsubstancesaredeliveredtothebodyasformulatedproducts.Aformulatedsubstancecouldalsobecalledadosageform,andconsistsofanActivePharmaceuticalIngredient(API)andvariousexcipients.DosageFormsDosageformsvaryfromrelativelysimplemixtures(asinapowderblendorasolution)totechnologicallycomplexdevicessuchaspatches.Youshouldinsertheresomereferencetoacomprehensivelistingofdosageforms(partofyourpost-lecturestudy).CommonfeaturesDespitethewiderangeofdosageformsthereareseveralcommonfeatures:Shouldbestable–hencecompatibilitybetweentheAPIandtheexcipientsShouldbecapableofconsistentmanufacture(quality–adherencetoaspecification)ShoulddeliveraconsistenteffecttothepatientStabilityDosageformsaremixturesofchemicals–hencetheyareinherentlyunstable.Thequestionisnot‘whetherthesubstancewilldegrade?’but‘Cantherateofdegradationbecontrolled?’StabilityismonitoredbyobservingboththereductionintheAPIcontent,andtheincreaseofadegradationproduct.ControlofstabilityThedosageformhastobeformulatedcorrectlysothatthemaximumshelf-lifeisattained.Degradationoccursthroughacombinationofchemical,physical,andmicrobiologicalprocesses.Theseeffectsarecontrolledbycorrectprocessingandbyselectionofsuitableexcipients.QualityAdherencetoaspecificationisthekeyfeatureinaqualitysystem.Thespecificationisgeneratedduringformulationtrialsandmustreflectaveragemanufacturingconditions.Formulationworkstartsonagram-scale,movesthroughtokilo-scaleandthento100sofkilosortonnes.TechnologicaltransferAsthescaleofworkingisincreasedfromthelabtothepilotplantandthentoproductionscaletheprocessesinvolvedhavetobetransferred.Thereisawealthofdifferencebetweenstirringsomethingina250mLbeakeranddoingthesameoperationto100kgproductThenatureoftheproductaltersasthescaleofworkingchanges.Finalformulationcannothappenuntilthereisstabilityinthemethodsofworking,butthedevelopmentdoesn’tstandstill–clinicaltrialsaretakingplaceatthesametimeastheformulationisbeingdeveloped.Whatarewemaking?Theselectionofadosageformisnoteasy.Itbecomessimplerwhentheintendedproductisanextensionofanexistingline.ThisisverycommonintheOTCmarket(Over-the-Counter).YearsagoAnadin(orsimilarbrands)existedasonlyoneform.OTCItisnowcommontohaveco-existencebetweentablets,capsules,caplets,solubleforms,extended/modifiedreleaseformsofthesamebrandname.Formulationworktoextendintoanewareaisstillhard,butmuchlessdemandingthanformulatingatotallynewAPIintothefirstproduct.FactorsrelatingtochoiceofdosageformClinicalconcerns…whatisbeingtreated?,self-administeredproduct?Orforhospitaluse?Hospitalsmightuseinfusionsorivinjections.Physico-chemicalaspects…solubility,partitionbehaviour,pK/pHBioavailabilityMarketingaspectsmarketingMedicinesareproductsandaremadeinordertomakeprofitsforthecompany.Itisthussensibleformarketingconcernstohaveasayintheselectionofthedosageformforanewproduct.MarketingexpertslookattrendsinsalesandtheactivitiesofcompetitorsRoutes/propertiesSotheselectionofaproductisablendofdifferentdrivingforces.Evenwhenadosageformhasbeenselected,thereisstillthequestionofpotency.Theeffectivenessoftheproductwillhavebeentestedinclinicaltrials,andthesewillhaveshowntheneedforsay50,100,and250mgstrengthtablets,togetherwithsay,anoralsuspension.transportAgeneralfeatureisthatdrugsmustcrossepitheliallayerstoreachgeneralcirculation.Thisabilityisincreasedbyalargeconcentrationgradient,butalsobythecorrectphysico-chemicalproperties.Therateisthusaffectedbytheionizationstateofthedruganditslipid/aqueoussolubility.Reviselastterm’snotesAspectssuchtheHenderson-HasselbalchandlogPwerediscussedlastterm.ParticlesizeWeallknowsimplethingssuchasifwewanttodissolvesugaritisquickertouseicingsugarthancrystallisedlumpsugar.Themaindifferenceisparticlesize.Smallerparticlespresentalargerareatothesolventandhencedissolvemorerapidly.Whenusingaerosols(suchasinhalers)theparticlesizeisvital,toolargeandtheparticlesdonotreachthelungs–toosmallandtheyreach,butarealmostimmediatelyexhaled.micronization..meansreducingparticlestomicronsize(10-6m).Thisisoftenabrutalprocessandcaninduceotherphysicalchangesinthesubstanceorincreasethechanceofachemicalreactiontakingplace.Thisisanexampleofwherethefactorsrelatingtotheconductofaprocesshastobeinvestigated.Anotherexamplewouldbedrying.Removalofwatercanbedonebymanymethods,anditisalwayspossiblethatthemethodsusedinduceotheralterations.ThepatientThepatienthasaconsiderableinfluenceonthechoiceofroute.Localorsystemicaction?Rapidactionormediumtermaction?Complicatedregimen?Orasimpleonce-per-day?Age….childrenmayhaveswallowingproblems…h(huán)encemanysyrups(niceflavours)insteadofcapsules.3/12/202451RelatedChapters8:Physicochemicalproperties9:SolidStateProperties10:ParticleSizeAnalysis11:ParticleSizeReduction12:ParticleSizeSeparation13:PowderFlow24:PowdersandGranules25:Granulation26:Drying27:TabletandCompaction28:CoatingofTabletsandMultiparticulates29:HardGelatinCapsule30:SoftGelatinCapsule3/12/202452OralSolidDosageFormsPhysicochemicalCharacteristicsBiologicalCharacteristicsPharmaceuticalExcipientsPharmaceuticalManufacturingProcessStabilityProblemsofOralSolidDosageFormsBiopharmaceuticalConsiderations3/12/202453PhysicalCharacteristicsAppearanceTabletsCapsulesPowdersPhysicochemicalCharacterizationRapidReleaseSustained/ControlledReleaseEntericCoatingOtherCoating3/12/202454PhysicochemicalCharacteristicsThermodynamicallyStablePowderLessThermodynamicallyStableTabletCapsuleWhensomethingisthemodynamicallystable,itusuallymaintainsitsphysicalform.3/12/202455PhysicalCharacteristicsPowderSolidcoarsedispersionCapsulesPowdersGranulesCoatedgranulesTabletsSingleLayerMultipleLayers3/12/202456PhysicalCharacteristicsPowderApparenttasteApparentsmellCapsulesSlowerdrugreleaseLesstasteorsmellTabletsVariabledrugreleaserateSignificanttasteorsmell3/12/202457BiologicalCharacteristicsPowderRapidonsetofactionComplianceproblemCapsulesSloweronsetofactionSustaineddrugreleaseEasiertodosedrugswithbadtaste/smellTabletsComplianceproblemSloweronsetofaction3/12/202458PharmaceuticalExcipientsExcipientsdonothavepharmacologicalactivitiesthemselvesandshallnotenhanceordiminishthepharmacologicalactivitiesoftheactivespecies.Excipientsareusedinthemanufacturingorthecompoundingprocessforthepurposesof:MaintainingtheappearanceProtectingtheactivespeciesDisguisingtheunpleasanttaste/smellChangingthedissolutionratesofactivespecies3/12/202459PharmaceuticalExcipientsforPowdersMaintainingtheappearanceColorProtectingtheactivespeciesPreservativesAntioxidantsDisguisingtheunpleasanttaste/smellSugarFlavoringagentsMaintainingthevolumeDiluents3/12/202460PharmaceuticalExcipientsforCapsulesMaintainingtheappearanceColorCapsuleShellSealantsProtectingtheactivespeciesAntioxidantCoatingDisguisingtheunpleasanttaste/smellSealantsChangingthedissolutionratesofactivespeciesCoatingManufacturingDiluentsLubricantsGlidant3/12/202461TypesofCapsulesRegularCapsulesHardGelatinSoftGelatinControlledReleaseSystemsCoatedgranulesCoarsedispersion3/12/202462HardGelatinCapsule3/12/202463HardGelatinCapsule3/12/202464HandMadeGelatinCapsuleFillloadingtraywithemptycapsules.Placetrayinbed.Operatecamhandletoseparatecapsulescapfrombody.Placepowdertrayinposition,fillwithaccuratequantityofpowderandspreadwithscraper.Operatepinplatetocompressandfill.Operatelevertolockcapsulescapandbody.Removetrayandemptyfilledcapsules.3/12/202465HardGelatinCapsuleMachine/main.html3/12/202466SoftGelatinCapsule3/12/202467WorkingofSoftgelGelatinCapsuleMachine/softgel_manufacturing_process.htm3/12/202468SoftGelatinCapsuleMachine3/12/202469PharmaceuticalExcipientsforTabletsMaintainingtheappearanceColorConsistencyProtectingtheactivespeciesAntioxidantsDisguisingtheunpleasanttaste/smellSugarFlavoringagentsChangingthedissolutionratesofactivespeciesCoatingMatrixManufacturingDiluentsLubricantsGlidant3/12/202470TypesofExcipientsFiller/DiluentDisintegrantSolutionBinderDryBinderGlidantLubricantAntiadherentColorCoatingProtectiveAgents3/12/202471TabletManufacturingProcessMillingandGranulationProcess:Powdersand/orGranulesDrying:Reducemoisture/solventcontentEstablishstrongbondbetweensolidparticleswithinthegranulesSizingProcess:Maketheparticlesmoreuniform3/12/202472TabletManufacturingProcessMixingProcess:AddalltheexcipientstothemixersotheproducthasconsistencyandgoodflowcharacteristicsTablettingFillCompactionEjectionCoating:ProtectivecoatingPalatablecoating3/12/202473WeighingMixingGranulationTablettingCoatingDissolutionQAcheckQCCheckfrom:/tableting.htmTheTablettingProcess3/12/202474HandCrankedTabletMachine3/12/202475TabletMachine3/12/202476TabletPunchesandDies3/12/202477QualityAttributesofTabletsCorrectdoseConsistentweight,sizeandappearanceExpectedandreproduciblerateofdrugreleaseBiocompatible/SafeStrengthChemical,physically,andmicrobiologicallystableInvitecomplianceSafelypacked3/12/202478TabletCompactionGranulation:WetgranulatingDirectCompaction3/12/202479MakingTabletsviaGranulation

3/12/202480DirectCompaction3/12/202481RationaleforGranulationIncreasebulkdensityImproveflowabilityImprovehomogeneityImprovecompactabilityEnsurehomogenouscolorControldissolutionrate3/12/202482Tabletting

Process3/12/202483TablettingProcess3/12/202484MachineTablettingProcess3/12/202485TypesofExcipientsFiller/DiluentDisintegrantSolutionBinderDryBinderGlidantLubricantAntiadherentColorCoatingProtectiveAgents3/12/202486TabletExcipients-FillerFillerFunctions:Increasethebulkvolumesothatthefinalproducthasthepropervolumeforpatienthandling.FillerRequirements:inert,compatible,non-hydroscopic,soluble,cheap,compactable,tasteful(?)Fillers:Lactose,Sucrose,Glucose,Mannitol,Sorbitol,Calciumphosphate,Calciumcarbonate,Cellulose3/12/202487TabletExcipients-DisintegrantDisintegrantFunctions:Toensurethatwhentabletsareincontactwithwater,theyarerapidlybreakingintosmallerfragments,facilitatingtheirdissolutionDisintegrantTypes:

FacilitatewateruptakeRupturethetabletsDisintegrants:Starch,Cellulose,Crosslinkedpolyvinylpyrrolidone,SodiumStarchGlycolate,Sodiumcarboxymethylcellulose3/12/202488TabletExcipients-BinderBinderFunctions:ToensurethattabletsandgranulescanbeformedwithrequiredmechanicalstrengthBinderTypes:

DrypowderaddedtothemixturepriortothewetgranulationprocessSolutionthatisusedinthewetgranulationprocessAddrightbeforethetablettingprocessBinders:

Wet/SolutionBinders:Gelatin,Cellulose,Cellulosederivatives,Polyvinylpyrrolidone,Starch,Sucrose,PolyethyleneglycolDryBinders:Cellulose,Methylcellulose,Polyvinylpyrrolidone,PolyethyleneglycolNotlast……Itisfairlyobviousthatthechoiceofpackagingisamajorpartoftheproductdesign.Thepackagingistheexternalfaceoftheproductandisresponsibleforensuringtheintegrityoftheproduct.Thechoiceofthepackagingcomesearlyonintheproductdevelopmentcycle.Primaryetc…Primarypack–isindirectcontactwiththeproducte.g.ablisterpack.Secondarypack–holdstheprimarypacke.g.acardboardpack.Tertiarypack–holdsmultiplesecondarypackse.g.alargecardboardbox.PrimaryPackContainstheproduct.Givesimmediateprotectiontotheproduct.Reducesmechanicaldamage.Aidscompliance(calendarpacks)Reducesmaliciousdamage(tamper-proof)Stopsaccidentaluse(child-proof)BlisterpackTheblisterpackisoneofthemostcommonformsofprimarypackaging.Itcanofferprotectionfromlight,moisture,andmechanicalshock.Blistersarenotimperviousandmoisturecancross.Thenatureofthematerialsusedtoformthepackwillbeselectedaccordingtocompatibilitywiththeproduct.stabilityThestabilityofaproductisofmajorconcerntothemanufacturerandtothepharmacist.Allproductsdegrade–theissueisatwhatspeedandhencewhatistheshelf-life?Allstabilitytrialsonaproductareconductedwiththeproductinitsprimarypacking.CounterfeitproductsGenuineViagracomesinpacksoffour.Thecounterfeitproductshownherehasfiveperpack.CounterfeitinghereisquitesophisticatedandmakesprominentuseofthePfizerlogo.CalendarpacksThecontraceptive‘pill’isprobablythemainproductthatusescalendarpacksasanaidtotheuseoftheproduct.ChildproofprimarypackAblisterpackisnotchild-proof,Butmanyproductsdocomewithfeaturesthatmakeithardforyoungfingerstogainaccesstowhatmaylooklikesweets.Akeyfeatureofthedesignofchild-proofsystemsisthatvulnerableadultsarestillabletousetheproduct.Tamper-proofpacksTylenolwastheproductthatintroducedtamper-proofingtothepharmacy.TherewasanotoriouscaseintheUSwherepacksofTylenol(paracetamol)werecontaminatedwithapoisonandreplacedonsupermarketshelves.Theaimwasblackmail.Peopledied.Thefirmshrink-wrappingisagoodsigntotheuserthatthepackisinthesamestatethatitleftthefactory.VialsVialsareusedforsterileproducts.Specialconditionsareusedinthefillingofthesesystems.tubesTubesmaybemadeofplasticoraluminium.Theymustbeflexiblesothattheproductcanbeextruded.SecondarypackThesecondarypackhasanumberofobjectives:Oneimportantpointisthatitenablesauniformsizetobeproducedforeaseofputtingintothetertiarypack.Thesecondpointisthatitprovidesrecognitioninformationforthepharmacistandforthepatient.Itisalsoanimportantvehiclefordisplayofthecompanyimageandlogo.PackinsertsThesecondarypackistheidealplacetoaddothervitalpartsoftheprescribedmedicine.TheInformationLeafletismandatoryandcontainsessentialinformationforthepatient,suchastheingredients,whatconditiontheproductisdesignedtotreat,contra-indications,howtousetheproduct,warnings(‘donotdriveoroperatemachinery’etc.),storageadvice,expirydateetc.Otheritemsthatmaybeincludedcouldincludespoons,applicators,syringesetc.TertiarypackagingThesecondarypackswillbeputintosmallcartonsofasuitablesizeforuseinapharmacy.Thesetertiarypackswillbefurtherpackedintolargerunitssuitableforhandlingatthewarehouseandwholesalers(useofforklifttrucks).Theselargerunitswillbeshrink-wrappedinplasticandmayhavefurtherpackingtoensuresafetransportbyairetc.PackagingattheplantPackagingistheendoftheproductionprocess.Greatcarehastobetakentoensurethatthecorrectpackisusedsothatitmatchestheproductinallrespects.Asaprocessthisconcerns:PeopleEquipmentmaterialsPeopleAllstaffneedappropriatetrainingandmotivationtogetthisimportantworkdonecorrectly.Staffinvolved:OperatorsEngineers(mechanicalandelectrical0QCEquipmentPointstoconsider:Toobig?Toosmall?Easytoservice?Adaptable?Expensivecapitalcost?Expensivespareparts?WhyPK/PD?

?Provideasimplifieddescriptionoftheobservations?Importantindecisionmakingfordrugregulation?Canhelpsetdose,dosingintervalandclinicalefficacy?Complementclinicalendpointdatainmodifyingdosingregimes?Usefulinansweringresearchquestions(allADME)PK/PDmodels:Antibiotics?PD/PKdataisimportantindecidingwhicharetheimportantfactorsforefficacy/safetyissues?Eachdrugmayhavetobemodelledinadifferentway–Timedependent?T([plasma]>MIC)fora-lactams,macrolideantibiotics–Concentrationdependent?AUC/MICpredictiveforfluoroquinones?Cmax/MICforaminoglycosides–Canbeacombination!?GlycopeptidesFactors

referenceAulton‘Pharmaceutics’Secondedition(2002)pp113-138.PreformulationprogrammeWiderangeofpotentialdosageforms(addsomeexampleshere….Allwithsimilaraims StabilityReleaseofactiveDosageuniformityPurposeofprogrammeTomeasurephysicalandchemicalpropertiesoftheactiveagentinordertoguideTypeofformulationRouteofadministrationManufacturingprocessesTopicareasUVassay(spectroscopy)SolubilityPartitionMeltingbehaviourStability(heat/light/pHetc)MicroscopyPowderflowCompressionbehaviourExcipientcompatibilityLimitedquantitiesPreformulationisdonefairlyearlyintheproductdevelopmentcycle.Onlylimitedamountsofmaterialmaybeavailable.Veryaccuratemeasurementsarenotrequiredatthisstage.Manyprocesseshavebeenautomated.UVspectroscopyAlthoughthemajorityofactivepharmaceuticalsubstancesarewhitepowders,theymainlyhavespectroscopicactivityintheUVregionofthespectrum.Thisareacorrespondsinenergytovaluessimilartochemicalbondstrengths.Bestresultsareobtainedfrommoleculeswithdoublebonds.UVspectroscopyThespectrumhasapeakofmaximumabsorbance(inthiscaseat230nm).TheheightofthispeakisdirectlyproportionaltotheconcentrationofthesubstanceUseoftheUVspectrumAlthoughatypicalUVspectrumisofonlylimiteduseintheidentificationofasubstance,ithasgreatutilityasanassaymethod.SolubilitymeasurementThesolubilityofasubstanceisanimportantpropertythatdependsonthreefactors:ThenatureofthesubstanceThesolventThetemperaturesolubilityItisnormaltokeepthetemperatureconstantandforpharmaceuticalsubstancestousewaterasthesolvent–althoughthepHisalsorelevantandsometimestheionicstrengthofthesolutionaswell.Thebasicprincipleistoshakethesubstancewithwateruntilnomorewilldissolve.ThentheclearsolutionisfilteredoffandtheconcentrationmeasuredbyUVanalysis.Thiswillnormallyonlyworkifthesolutionisfirstdiluted.Thisisrelativelyeasywork–buttimeconsuming.Micro-titreplatesThepictureisofa96-well(12x8)micro-titreplate.ThewellscanbefilledbyroboticsandscannedbyalaserSolubilitybyroboticsStartwithasolutionofthesubstanceina‘super-solvent’(usuallydimethylsulfoxide).Addanamountofthissolutiontoeachwell.Thenaddincreasingamountsofwater(atafixedpH)tothewells.AtsomepointthesubstancewillcomeOUTofsolution.laserAlaserisshoneupthroughthesolution.Allthetimethereisasolutionthelightpassesstraightupwards.Whenthesubstancecomesoutofsolutionthelightwillbescatteredbytheparticles.Hencethesolubilitypointshowsup.HighthroughputscreeningSolubilitymeasurementasdescribedaboveisanexampleofhigh-throughputscreening.Themethodisreadilyadaptabletoproduceasolubilityprofile(asafunctionofpH)ofthedrugsubstanceItisalsopossibletousethesametechnologytomeasurethepKofweakacids.DeductionsfromsolubilitymeasurementsIdeallyadrugneedsabout1%aqueoussolubility(10mg/mL)ifpoorbioavailabilityproblemsaretobeavoided.Saltformationcanincreasesolubility.Or,formulateasaliquid-fillinsoftgelatincapsuleswiththedrugdissolvedinPEG400,glyceryltriacetate,orcoconutoil.SaltformationSaltsoftenhavegreateraqueoussolubilitythantheparentneutralmolecule.Butwhichsalttopick?ThisiswhereroboticsandHTScanhelp.Withsuitablechemistry,thedifferentpotentialsaltscanbeformedinawell-plateandtheirsolubilitymeasuredwithoutactuallymakingasolidsampleofthesalt.PartitionThefunnelshownhereisusedtoseparatetwolayers.Waterisnormallythelowerlayerandthelighterhydrocarbon-richsolventthetoplayer.Substancespartitionbetweenthetwolayersaccordingtotheirhydrophobiccharacter.Pharmaceuticallyweareinterestedinpartitionbetweenwater(atdifferentpHs)andoctanol.Themeasurementscanbemadebythe‘shake-the-flask’method(Aultonpp119-120)orbyanadaptationofthehigh-throughputsolubilitymethod.partitionPartitionisacrucialmeasurementforasubstance.Itrecordsthehydrophobic/hydrophilictendencyofthemolecule.Toohydrophobicanditwillhaveverylowaqueoussolubility.Toohydrophilicanditwillbeunabletocrossthemainlyhydrophobicmembranebarriersinthebody.MeltingbehaviourThemeltingpointofasubstanceisacharacteristicpropertythatisalsoanindicatorofpurity.Meltingisanexampleofaphase-change.Heatingcanalsoinducereactionsanddecomposition.MeltingpointmeasurementTheuseofstandardlaboratorymeasurementofthemeltingpointisquitetimeconsuming.Thereisalotofskillneededtogetreproducibleresults.Theenergychangethataccompaniesmeltingcanbeusedasamorereliablemethod.Italsorecordsanyotherphasechangesandanyreactions.DifferentialScanningCalorimetryThedifferentialscanningcalorimeterhastwocompartmentsthatareheatedseparately.Circuitryisusedtokeepthesametemperature.Whensomethinghappensinthesamplecompartmentthathasanenergychangethenthiscanbeprintedout.DSCtraceDSCTheDSCrecordsthermaleventsasthetemperatureisgraduallyraised.Itshowsphasechanges,reactionsandalleventsthatinvolveenergychanges.TheDSCtraceofadrugandmixtureswithpotentialexcipientswillshowwhethertherearelikelyreactionsbetweenthesubstances.Similartracescanberunoftheproductwithpotentialpackagingmaterials.PolymorphismPoly(‘many’)morphic(‘shape’)hencemanyshapes.Mostsubstanceshaveonlyonestablesolidform.Somesubstance