11 PEF-Crystallization

PharmaceuticalEquipmentFundamentalsCrystallizationCrystallization陈慧萍[e-mail]lizationisthe(naturalorartificial)processofformationofsolidcrystalsprecipitatingfromasolution,meltorgas.SynthesizedbovineinsulincrystalsCrystallizationinNature™Geologicaltimescaleprocessexamplesinclude:9Natural(mineral)crystalformation9Stalactite/stalagmiteformation™Usualtimescaleprocessexamplesinclude:9Snowflakesformation9HoneycrystallizationCrystallizedhoneyCrystallization™Crystallizationisalsoachemicalsolid-liquidseparationtechnique,inwhichmasstransferofasolutefromtheliquidsolutiontoapuresolidcrystallinephaseoccurs.Crystallizationoccursinacrystallizerthroughavariationofthesolubilityconditionsofthesoluteinthesolvent.Precipitationoccursduetochemicalreaction.eg.AgNO3+NaCl=AgCl↓+NaNO3Crystallization™+solventseparation+washing+drying™Akeyoperationinthefreeze-concentrationoffruitjuices;thedesalinationofseawater;therecoveryofvaluablematerials(eg.metalsaltsfromelectroplatingprocesses);theproductionofmaterialsfortheelectronicindustries;biotechnologicaloperationssuchastheprocessingofproteinsCrystallizationFeatures™LessenergyrequirementsEnthalpiesofcrystallizationEnthalpiesofvaporization™Operatingatambienttemperature™Lowcost™Simpleequipment™Easytooperate.™Goodselectivity:Onlycongenericelementsandionscanbearrangedincrystal,mostoftheimpuritiesremaininthesolvent.SeparationTechnology49%,20%,11%physicalproperty-basedoperations(suchasfloatationandscreening)high-energyintensityprocesses,wellestablishedinindustrialpractice.thermallydriven(basedontheheatsofExperimentalSetupCrystallizationMethods™Forcrystallization(seealsorecrystallization)tooccurfromasolutionitmustbesupersaturated.™Inindustrialpractice,themostcommonmethods:(1)solutioncooling,(2)additionofasecondsolventtoreducethesolubilityofthesolute----antisolventordrown-out,(3)chemicalreaction(4)changeinpH™Othermethods,suchassolventevaporation,canalsobeused.Thesphericalcrystallizationhassomeadvantages(flowabilityandbioavailability)fortheformulationofpharmaceuticaldrugsPurificationProblems™Impuritieswouldnormallynotfitaswellinthelattice,andthusremaininsolutionpreferentially.Hence,molecularrecognitionistheprincipleofpurificationincrystallization.™Thereareinstanceswhenimpuritiesincorporateintothelattice,hence,decreasingthelevelofpurityofthefinalcrystalproduct.™Insomecases,thesolventmayincorporateintothelatticeformingasolvate.™Thesolventmaybe'trapped'(inliquidstate)withinthecrystalformed,andthisphenomenonisknownasinclusion.CrystallizationFactorsThenatureofacrystallizationprocessisgovernedbyboththermodynamicandkineticfactors,whichcanmakeithighlyvariableanddifficulttocontrol.™impuritylevel™mixingregime™vesseldesign™coolingprofileImpactonthesize,number,andshapeofcrystalsproducedProcessThecrystallizationprocessconsistsoftwomajorevents:™Nucleationisthestepwherethesolutemoleculesdispersedinthesolventstarttogatherintoclusters,onthenanometerscale(elevatingsoluteconcentrationinasmallregion),thatbecomesstableunderthecurrentoperatingconditions.Thesestableclustersconstitutethenuclei.™Crystalgrowthisthesubsequentgrowthofthenucleithatsucceedinachievingthecriticalclustersize.CrystallizationProcessNucleationandgrowthratesarebothfunctionsofsupersaturation.Thenucleationratetendstoexhibitahigherorderexponentialrelationship,soasthesupersaturationincreasesthenucleationtendstodominate.PromotingcrystalgrowthrequiresoperationwithinalimitedrangeofsupersaturationCrystallizationProcess™Nucleationandgrowthcontinuetooccursimultaneouslywhilethesupersaturationexists.™Supersaturationisthedrivingforceofthecrystallization,hencetherateofnucleationandgrowthisdrivenbytheexistingsupersaturationinthesolution.™Dependingupontheconditions,eithernucleationorgrowthmaybepredominantovertheother,andasaresult,crystalswithdifferentsizesandshapesareobtained™Controlofcrystalsizeandshapeconstitutesoneofthemainchallengesinindustrialmanufacturing,suchasforpharmaceuticals.™Oncethesupersaturationisexhausted,thesolid-liquidsystemreachesequilibriumandthecrystallizationiscomplete,unlesstheoperatingconditionsaremodifiedfromequilibriumsoastosupersaturatethesolutionPolymorph•Manycompoundshavetheabilitytocrystallizewithdifferentcrystalstructures,aphenomenoncalledpolymorphism.•Eachpolymorphisinfactadifferentthermodynamicsolidstate•Crystalpolymorphsofthesamecompoundexhibitdifferentphysicalproperties,suchasdissolutionrate,shape(anglesbetweenfacetsandfacetgrowthrates),meltingpoint,etc.•Forthisreason,polymorphismisofmajorimportanceinindustrialmanufactureofcrystallineproducts.CrystalSystemsSnowflakesSnowflakesareaverywellknownexample,wheresubtledifferencesincrystalgrowthconditionsresultindifferentgeometriesPolymorphExample™Benzamide:oncoolingthebenzamideinitiallycrystallisedassilkyneedlesbutonstandingthesewereslowlyreplacedbyrhombiccrystals.™Threepolymorphsforbenzamide:1)theleaststableone,formedbyflashcoolingistheorthorhombicformII.2)followedbythemonoclinicformIII3)themoststableformismonoclinicformI.Thehydrogenbondingmotifisthesame