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PharmaceuticalEquipmentFundamentalsCrystallizationCrystallization陈慧萍chenhuiping@ncu.edu.cnCrystallizationCrystallizationisthe(naturalorartificial)processofformationofsolidcrystalsprecipitatingfromasolution,meltorgas.SynthesizedbovineinsulincrystalsCrystallizationinNatureGeologicaltimescaleprocessexamplesinclude:9Natural(mineral)crystalformation9Stalactite/stalagmiteformationUsualtimescaleprocessexamplesinclude:9Snowflakesformation9HoneycrystallizationCrystallizedhoneyCrystallizationCrystallizationisalsoachemicalsolid-liquidseparationtechnique,inwhichmasstransferofasolutefromtheliquidsolutiontoapuresolidcrystallinephaseoccurs.Crystallizationoccursinacrystallizerthroughavariationofthesolubilityconditionsofthesoluteinthesolvent.Precipitationoccursduetochemicalreaction.eg.AgNO3+NaCl=AgCl↓+NaNO3Crystallization+solventseparation+washing+dryingAkeyoperationinthefreeze-concentrationoffruitjuices;thedesalinationofseawater;therecoveryofvaluablematerials(eg.metalsaltsfromelectroplatingprocesses);theproductionofmaterialsfortheelectronicindustries;biotechnologicaloperationssuchastheprocessingofproteinsCrystallizationFeaturesLessenergyrequirementsEnthalpiesofcrystallizationEnthalpiesofvaporizationOperatingatambienttemperatureLowcostSimpleequipmentEasytooperate.Goodselectivity:Onlycongenericelementsandionscanbearrangedincrystal,mostoftheimpuritiesremaininthesolvent.SeparationTechnology49%,20%,11%physicalproperty-basedoperations(suchasfloatationandscreening)high-energyintensityprocesses,wellestablishedinindustrialpractice.thermallydriven(basedontheheatsofExperimentalSetupCrystallizationMethodsForcrystallization(seealsorecrystallization)tooccurfromasolutionitmustbesupersaturated.Inindustrialpractice,themostcommonmethods:(1)solutioncooling,(2)additionofasecondsolventtoreducethesolubilityofthesolute----antisolventordrown-out,(3)chemicalreaction(4)changeinpHOthermethods,suchassolventevaporation,canalsobeused.Thesphericalcrystallizationhassomeadvantages(flowabilityandbioavailability)fortheformulationofpharmaceuticaldrugsPurificationProblemsImpuritieswouldnormallynotfitaswellinthelattice,andthusremaininsolutionpreferentially.Hence,molecularrecognitionistheprincipleofpurificationincrystallization.Thereareinstanceswhenimpuritiesincorporateintothelattice,hence,decreasingthelevelofpurityofthefinalcrystalproduct.Insomecases,thesolventmayincorporateintothelatticeformingasolvate.Thesolventmaybe'trapped'(inliquidstate)withinthecrystalformed,andthisphenomenonisknownasinclusion.CrystallizationFactorsThenatureofacrystallizationprocessisgovernedbyboththermodynamicandkineticfactors,whichcanmakeithighlyvariableanddifficulttocontrol.impuritylevelmixingregimevesseldesigncoolingprofileImpactonthesize,number,andshapeofcrystalsproducedProcessThecrystallizationprocessconsistsoftwomajorevents:Nucleationisthestepwherethesolutemoleculesdispersedinthesolventstarttogatherintoclusters,onthenanometerscale(elevatingsoluteconcentrationinasmallregion),thatbecomesstableunderthecurrentoperatingconditions.Thesestableclustersconstitutethenuclei.Crystalgrowthisthesubsequentgrowthofthenucleithatsucceedinachievingthecriticalclustersize.CrystallizationProcessNucleationandgrowthratesarebothfunctionsofsupersaturation.Thenucleationratetendstoexhibitahigherorderexponentialrelationship,soasthesupersaturationincreasesthenucleationtendstodominate.PromotingcrystalgrowthrequiresoperationwithinalimitedrangeofsupersaturationCrystallizationProcessNucleationandgrowthcontinuetooccursimultaneouslywhilethesupersaturationexists.Supersaturationisthedrivingforceofthecrystallization,hencetherateofnucleationandgrowthisdrivenbytheexistingsupersaturationinthesolution.Dependingupontheconditions,eithernucleationorgrowthmaybepredominantovertheother,andasaresult,crystalswithdifferentsizesandshapesareobtainedControlofcrystalsizeandshapeconstitutesoneofthemainchallengesinindustrialmanufacturing,suchasforpharmaceuticals.Oncethesupersaturationisexhausted,thesolid-liquidsystemreachesequilibriumandthecrystallizationiscomplete,unlesstheoperatingconditionsaremodifiedfromequilibriumsoastosupersaturatethesolutionPolymorph•Manycompoundshavetheabilitytocrystallizewithdifferentcrystalstructures,aphenomenoncalledpolymorphism.•Eachpolymorphisinfactadifferentthermodynamicsolidstate•Crystalpolymorphsofthesamecompoundexhibitdifferentphysicalproperties,suchasdissolutionrate,shape(anglesbetweenfacetsandfacetgrowthrates),meltingpoint,etc.•Forthisreason,polymorphismisofmajorimportanceinindustrialmanufactureofcrystallineproducts.CrystalSystemsSnowflakesSnowflakesareaverywellknownexample,wheresubtledifferencesincrystalgrowthconditionsresultindifferentgeometriesPolymorphExampleBenzamide:oncoolingthebenzamideinitiallycrystallisedassilkyneedlesbutonstandingthesewereslowlyreplacedbyrhombiccrystals.Threepolymorphsforbenzamide:1)theleaststableone,formedbyflashcoolingistheorthorhombicformII.2)followedbythemonoclinicformIII3)themoststableformismonoclinicformI.Thehydrogenbondingmotifisthesame