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crystals Article The Effect of Ultrasound on the Crystallisation of Paracetamol in the Presence of Structurally Similar Impurities ThaiT.H.Nguyen1 ID,AzeemKhan1,LaylaM.Bruce1 ID,ClarissaForbes1,2,3, RichardL.O’Leary2andChrisJ.Price1,3,* ID 1 DepartmentofChemical&ProcessEngineering,UniversityofStrathclyde,GlasgowG11XQ,UK; [email protected](T.T.H.N.);[email protected](A.K.);[email protected](L.M.B.); [email protected](C.F.) 2 TheCentreforUltrasonicEngineering,DepartmentofElectronic&ElectricalEngineering, UniversityofStrathclyde,GlasgowG11XW,UK;[email protected] 3 EPSRCCentreforContinuousManufacturingandCrystallisation,UniversityofStrathclyde, GlasgowG11RD,UK * Correspondence:[email protected] AcademicEditor:JudyLee Received:17August2017;Accepted:26September2017;Published:30September2017 Abstract: Sono-crystallisationhasbeenusedtoenhancecrystallineproductqualityparticularlyin termsofpurity,particlesizeandsizedistribution.Inthiswork,theeffectofimpuritiesandultrasound on crystallisation processes (nucleation temperature, yield) and crystal properties (crystal size distributiondeterminedbyFocusedBeamReflectanceMeasurement(FBRM),crystalhabit,filtration rate and impurity content in the crystal product by Liquid Chromatography-Mass Spectroscopy (LC-MS))wereinvestigatedinbulksuspensioncrystallisationexperimentswithandwithoutthe useofultrasound. Theresultsdemonstratethatultrasonicinterventionhasasignificanteffecton both crystallisation and product crystal properties. It increases the nucleation rate resulting in smallerparticlesandanarrowerParticleSizeDistribution(PSD),theyieldhasbeenshowntobe increaseashastheproductpurity. Theeffectofultrasoundistoreducethelevelacetanilideimpurity incorporated during growth from a 2 mol% solution of the selected impurity from 0.85 mol% to 0.35mol%andlikewiseultrasoundreducestheuptakeofmetacetamolfrom1.88mol%to1.52mol%. Keywords: suspension crystallisation; impurities; crystal size distribution; filtration rate; optical microscopy;imageanalysis;crystalmorphology;purification;HPLC;ultrasoundintensity 1. Introduction Crystallisationistheprincipalpurificationtechniqueinthepharmaceutical,finechemical,paint, pigmentsandagrochemicalsector. Itallowsthedesiredproducttobeobtainedinapurestateleaving unwantedorhazardousimpuritiesinsolutionwheretheycanberemovedeffectivelybyfiltration and washing. During crystallisation, molecules of the product assemble together to form crystals witharegular3Dpackingarrangementknownasacrystallattice. Purificationoccursbymolecular recognitionatthesolution-latticeinterface. Themismatchbetweensomeimpuritymoleculesandthe crystallatticeissosignificantthattheimpuritymoleculecannotbeincorporatedinthelatticeandis rejected. However,ifthemolecularmismatchissmallenough,theimpuritymoleculecanbecome incorporatedintothecrystallattice. Iftheportionoftheimpuritymoleculeprojectingoutfromthe crystalsurfaceisdifferentfromtheadjacentmoleculesinthesurfacelayerofthecrystalthisislikely todisruptandretardsubsequentgrowthatthatgrowthsiteandadjacentsitesonthatcrystalface. Crystals2017,7,294;doi:10.3390/cryst7100294 www.mdpi.com/journal/crystals Crystals2017,7,294 2of24 Increasingthecrystallisationdrivingforce,i.e.,increasingsupersaturationlevel,reducesselectivity allowingeasierincorporationoftheimpurityintothecrystallatticeandsubsequentovergrowth.Inone oftheauthor’sindustrialexperience,typicalfeedstreamstoindustrialcrystallisationcontainseveral mole%ofimpuritiessointeractionsbetweenimpuritymoleculesandthegrowingcrystalsurfaceare veryfrequentandcanhaveundesirableconsequences. Impuritypoisoningofgrowingcrystalfaces increases processing time and slows the approach to equilibrium. In some instances, a significant amountofproducthastobeleftinsolutionandlostinthewastestreaminorderfortheprocesstobe runwithaplausiblebatchduration. Sometimestheproductissoimpurethatithastobere-crystallised tomeettherequiredspecification. Mostimpuritiesthatarereadilyincorporatedintothegrowingcrystallatticeandactascrystal growth inhibitors are close analogues of the active pharmaceutical ingredient and are produced inadvertentlyasby-productsordegradantsduringthesyntheticprocess. Aswellasretardingcrystal growththeyalsomodifycrystalhabit. Asaconsequence,otherattributesoftheisolatedcrystalssuch asbulkdensityandpowderflowaremodifiedandcaninfluenceboththesubsequentformulation processanddrugproductperformance. Severalrouteshavebeenidentified[1]bywhichimpurities becomeentrappedinfinalcrystallineproduct: (i)Depositiononcrystalsurfacesduetotheincomplete removalofimpuremotherliquorduringfiltrationandwashing;(ii)incorporationwithinthecrystal latticebymolecularrecognition/substitutionor(iii)entrapmentofmultipleimpuritymoleculeswithin inclusionsorbetweenindividualcrystallitesinagglomerates. Theimpactofspecificimpuritieson crystallisationprocessesdependson;thestructureoftheimpurity,itsconcentration,thecrystallisation solvent, the supersaturation and the temperature of the crystallising solution. The presence of impurities during the crystallisation process can significantly modify the kinetics of nucleation, the growth rate of specific crystal faces, crystal morphology (habit) and the polymorphic phase crystallized. Theseundesiredeffectscancausecostlydelaysduringtheresearchanddevelopment processwithinthepharmaceuticalindustry.Therearemanycasestudiesofimpurityeffectsreportedin thecrystallisationliterature[2–5].Theeffectofincreasingamountsoftheimpurityp-acetoxyacetanilide on paracetamol nucleation is to increase the metastable zone width and lengthen the induction time[3,6,7]. Ithasbeenreportedthatthisduetoitsabilitytodisrupttheformationandgrowthofthe criticalnucleus[3,8]. Impuritieshavebeenreportedbothtosuppressandoccasionallytoaccelerate crystalgrowthprocesses[9]. N-phosphonomethylphosphoricacid(PMG)crystallisationisreported tobeaffectedbytheimpurities,iminobismethylenephosphonicacidandaminomethylphosphoric acidbyselectiveabsorptionontothe(100)faceinhibitingthegrowthofthisface;whiletheimpurity N-phosphonomethyliminodiaceticacid(PIDA)doesnotchangecrystalhabitnoticeably[10]. Also, animpurityhasbeenreportedtoaffectthesolution-mediatedphasetransformationofthemetastable AformtothestableBformofanactivepharmaceuticalingredient[11]. Thepresenceofimpurities iswidelyreportedtoinfluencecrystalgrowthandcrystalmorphology[9,12–15]. Thisisthecasefor aminoacidsonthehabitofglycinecrystals[16],orureacrystallisationinthepresenceofbiuret[15]. Thechangeofcrystalhabitisduetoadifferenceintheextentofadsorptionandmagnitudeofbinding energiesondifferentcrystalfaces[16]. Forthisreason,identification,quantificationandreductionof impuritiesintheearlystagesofsyntheticprocessdevelopmentcanavoidproblemsincrystallisation development,enhanceproductperformanceandreducedevelopmenttime[17]. Ultrasound(US)hasbeenusedinthechemicalandfoodindustriestoenhancecrystallineproduct quality in terms of particle size, size distribution and impurity and is termed sono-crystallisation. Ultrasound has been widely reported to influence the primary nucleation process accelerating nucleation kinetics, this is typically expressed in terms of reducing the induction time and MSZW [18–33]. Ultrasound can also increase the rate of secondary nucleation, this is manifested as a reduction on the product crystal size distribution [20,22,24,31,32,34–43]. Ultrasound can also influence crystal growth [20,25,26,36,40,44–46] although the effect on crystal growth is not as dramatic as on nucleation and arises largely from enhanced mass transfer [46] and can influence crystal morphology. Other reported outcomes of ultrasonic intervention include influencing; Crystals2017,7,294 3of24 which polymorph nucleates [23,47,48], crystal structure [30], crystal properties [49] and reaction crystallisation[45]. Severalproposedmechanismsoftheeffectofultrasoundoncrystallisationhave beenpublished.Theseincludetheformationoflocalhotspotswhicharisefromthelargeenergyrelease onthecollapseofcavitationbubblescreatinghighlylocalisedregionsofextremelyhightemperature and pressure [50,51], or due to rapid cooling which follows; shockwaves released from cavitation bubbles[52,53],promotingmasstransferandcollisionsbetweencrystalsandadjacentsurfaces[54]. These effects of ultrasound on crystallisation have been demonstrated on pharmaceuticals and commoditychemicalsincluding;lactose[35,39,42,55],alpha-dextrosemonohydrate[20],glycine[48], p-aminobenzoic acid [47], adipic acid [28], benzoic acid [31], acetylsalicylic acid [27], protein [19] variousfoodproducts[30,56,57]andinthecrystallisationofinorganicmaterialssuchaspotassium sulphate[26],potassiumdihydrogenphosphate[32]andcalcite[34]. Ultrasoundhasalsobeenutilized incontinuouscrystallisation[28,58–60]. Whilesomeauthorsmentionthatultrasoundcanimprove crystal purity [54]; there is very limited data on the effect of ultrasound on the purity of the final crystallineproduct. Thisworkfocusesontheuseofultrasoundinsuspensioncrystallisationprocesses to improve product purity, yield and crystal size distribution. The objective is to develop a bulk suspension sonocrystallisation process at lab scale which exploits ultrasound to improve product purity, yield and crystal habit. The research hypothesis is that through active intervention in the molecularprocessesoccurringatgrowingsurfacesitmaybepossibletoremoveimpuritymolecules fromthesurfacesandreducetheentrapmentofimpuritiesinsideagglomeratesformedduringgrowth. Thesemeasurementsaimtoincreaseunderstandingofhowultrasonicinterventionsaffectproduct puritybothdirectlythroughinfluencingimpurityincorporationduringgrowthandindirectlythrough influencingnucleationkinetics,crystalsizedistributionandagglomeration,whichallinfluencethe purityoffinalproductsbymodifyingtheextenttowhichimpuritiesareremovedduringfiltration andwashing. Paracetamol(Acetaminophen)hasbeenusedasamodelcompoundforthisstudybecauseits crystallisationbehaviouriswellcharacterised[2–5]andmultiplestructurallyrelatedimpuritiesare readilyavailable. Threepolymorphsofparacetamolhavebeenreported[61–63]butsofaronlyforms IandIIhavebeenobtainedassinglecrystalswhichhaveallowedthecrystalstructuretobesolved. PolymorphI(monoclinic,P21/n)isthethermodynamicallystableformatroomtemperature,thiscan bepreparedaslargesinglecrystalsfromsolutionsinvarioussolvents. PolymorphII(orthorhombic, Pcab) is metastable at ambient conditions. Crystals of paracetamol form I exhibit three dominant crystal habit faces; {100}, {001} and {110}. Individual paracetamol crystals exhibit different crystal habits,forexamplesignificantchangesofthegrowthrateandresultantmorphologyofparacetamol singlecrystalsareobservedinpure[64]andimpuresystems[4]. 2. MaterialsandMethodology 2.1. Materials Paracetamol (BioXtra grade, purity ≥ 99.0%, Lot number 637515L263) was obtained from Sigma-Aldrich(St. Louis,MO,USA).TheimpuritiesinvestigatedwereAcetanilide99.0%Lotnumber STBD0193VandMetacetamol97.0%LotnumberMKBX4643VbothalsoobtainedfromSigma-Aldrich, all three samples were analysed on receipt to confirm the reported assay. The basis for selecting acetanilideisthatitisstructurallysimilartoparacetamolbutlacksthehydroxylgroupandsowhile it may be incorporated into the crystal lattice it is deficient in a hydrogen bonding opportunity. Metacetamol was selected as a positional isomer which is also likely to be incorporated into the crystallattice;however,themisplacedhydroxylgroupislikelytodisruptthelocalhydrogenbonding arrangement. Importantlybotharemoresolublethanparacetamolin3-methyl-1-butanol,theselected solventensuringlittleriskofthemcrystallizingindependentlyduringtheexperiments. The crystallisation solvent 3-methyl-1-butanol (isoamyl alcohol) was selected because the solubility relationship with temperature for paracetamol is appropriately steep over the chosen Crystals2017,7,294 4of24 temperature range and the product crystals tend not to form agglomerates. 3-methyl-1-butanol wasobtainedfromSigma-Aldrich98%,n-heptane99%fromAlfaAesar(WardHill,MA,USA)usedfor filtercakewashingfollowingfiltration. HPLCgrademethanolandwaterusedfortheanalysiswere purchasedfromSigma-Aldrich. 2.2. EquipmentApparatus 2.2.1. SolubilityMeasurements GravimetricMethod In order to evaluate the effect of impurities on the crystallisation of paracetamol it was first necessarytomeasuretheextenttowhichtheimpuritiesaffectthesolubilityofparacetamolinthe crystallisationsolvent. SolubilitymeasurementswereperformedbyequilibrationusingaStuartSI60D Incubator(Stuart,Staffordshire,UK).AgitationoftheequilibratingsampleswasprovidedbyaThermo scientific submersible telesystem 15.20 magnetic stirrer plate (Thermo Fisher Scientific, Waltham, MA,USA).ThetemperaturewasrecordedusinganOmegaHH800SWtemperaturesensor(Omega, Manchester, UK).SamplesweretakenusinganEppendorfpipetteweighedonanA&DGRseries balance(A&DInstrumentsLimited,Manchester,UK)andevaporatedtodrynessinaMemmertGmbH vacuumovenV0200(MemmertGmbH+Co. KG,Schwabach,Germany)at55◦C. DetectionoftheDissolutionTemperatureMethodUsingCrystalline-TechnobisCrystallisationSystems Solubility measurements of acetanilide and metacetamol were also conducted in a Technobis Crystalline system, a multi-reactor crystallisation platform which has eight independent Peltier heater-coolers able to maintain temperatures from −15 ◦C to 150 ◦C. Each 8 mL (34 × 10 mm) crystallizerisequippedwithathree-blademarineimpellerwithoverheadstirring.Eachvesselposition isequippedwithaturbiditysensorandacameraallowingturbidityandimagestoberecordedand synchronisedwiththetemperaturetimeprofile. 2.2.2. Sono-CrystallisationStudies Aschematicdiagramoftheexperimentalequipmentusedtoevaluatetheeffectofultrasoundon crystalpurityisshowninFigure1. Thesystemcomprisedtwocellcultureflasks,doublesidearm, Celstir® 125mLplacedontoasubmersibleTelesystem15.20stirrerfromThermoScientific(Waltham, MA,USA)immersedinaXUB25ultrasonicbathfromGrantInstruments(Cambridge,UK)operatingat 35±3kHz. ThetemperatureofthewaterintheultrasonicbathandhencethesolutionsintheCelstir® flaskswascontrolledusinganImmersionCompactThermostat(ICC)fromIKA(StaufenimBreisgau, Germany)whichwasconnectedtoaHaileaHC-150Achiller(GuangDong,China). Additionalcooling capacity was provided by a stainless-steel dip coil running around the base of the ultrasonic bath andconnectedtoaLauderLCK1913,ECORE420Gthermocirculator(LaudaBrinkmann,NJ,USA). ThetemperatureofsolutionswasmonitoredusingaprecisePPL-GMH-3750thermometerandPt100 probe(±0.03◦C)(GHMMesstechnikGmbHStandortGreisinger,Regenstauf,Germany). Thepoint ofnucleationwasdeterminedbyvisualobservation,initiallyafewparticleswereobservedandthe solution gradually became cloudy. On completion of the crystallisation (~3–3.5 h after nucleation processoccurs)theproductcrystalsizedistributionwasmeasuredinsitubyFocusedBeamReflectance (FBRM)(MettlerToledo,Greifensee,Switzerland). TheproductsuspensionwasfilteredusingaVac Master10system(BiotageLtd.,Uppsala,Sweden)whichhadbeenmodifiedtoaccommodate50mL graduatedcylinderswhichallowedthefiltrationratetobemeasured,filtrationtobehaltedatdryland, andthemotherliquorandindividualwashliquorstobesegregatedforsubsequentassay.Thefiltration drivingforcewasmonitoredandcontrolledusingaBüchiV800vacuumcontroller(BüchiUKLtd., Oldham,UK). Crystals2017,7,294 5of24 Crystals 2017, 7, 294 5 of 24 Figure 1. (a) Schematic diagram and (b) Annotated photograph showing the experiment setup for Figure1. (a)Schematicdiagramand(b)Annotatedphotographshowingtheexperimentsetupfor suspension cooling crystallisation of paracetamol in the presence of impurities using an ultrasonic suspensioncoboatlhin. gcrystallisationofparacetamolinthepresenceofimpuritiesusinganultrasonicbath. 2.3. Experimental Method Chemicalanalysisofproductcrystals,motherliquorsandwashliquorswasperformedusingan AgilentHigh2P.3e.1r. fSoorlumbialintyc eLiquidChromatography6130dualsourcemodel(Agilent,SantaClara,CA, USA)providedwithathermostatedautosampler,athermostatedcolumncompartmentandasingle Gravimetric Method wavelengthultraviolet(UV)detectoranda2.7µmPoroshell120EC-C18Column: 4.6×75mmto Solubility measurements were performed by equilibration using a Stuart SI60D Incubator determinetheopcerraytsedta olvlienr ethpe rtoemdpuecrattuprue rriatnyg.e 25 to 50 °C. The sample size employed to prepare saturated solutions to determine solubility was 15 mL. The effect of impurities on solubility was determined by 2.3. ExperimenditsaslolMvinegt hao dknown target amount of metacetamol and/or acetanilide in the solvent prior to the addition of paracetamol. Individual vials were prepared with specific impurity loadings and then equilibrated with an excess of paracetamol. The vials were placed onto a Thermo scientific 2.3.1. Solubility submersible telesystem 15.20 magnetic stirrer plate and agitated at 190 rpm. The temperature was kept within ±0.2 °C of the desired temperature which was recorded with an Omega precise GravimetricMethod thermocouple. After equilibration for 24 h, the excess solid paracetamol was allowed to settle for 1 h without agitation. A 2 mL sample of the clear saturated solution was withdrawn using an Eppendorf SolubilitymeasurementswereperformedbyequilibrationusingaStuartSI60DIncubatoroperated pipette taking great care not to disturb the settled solids. The samples were then transferred into a overthetemplaeberlaletdu raendr awnegiegh2ed5 tvoia5l. 0T◦hCe .sTamhpeles avmialp cloenstaiizneinge mthpe losaytuerdatetdo psorleuptioanr ewsaas tuwreaigtheedd solutionsto determinesoilmumbeildiitaytewly. aTshi1s 5sammpLl.inTg hperoecefsfse cwtaso freipmeapteud rfiotri eeascho neqsuoililburbatieldit vyiawl aansd dtheet searmmpilense wderbey dissolving placed in a fume hood and allowed to evaporate to dryness for 24 h, after evaporation the samples, a known target amount of metacetamol and/or acetanilide in the solvent prior to the addition of were then transferred to a vacuum oven and allowed to dry for a further 48 h at 55 °C. The dry residue paracetamol. Individualvialswerepreparedwithspecificimpurityloadingsandthenequilibrated withanexcessofparacetamol. ThevialswereplacedontoaThermoscientificsubmersibletelesystem 15.20magneticstirrerplateandagitatedat190rpm. Thetemperaturewaskeptwithin±0.2◦Cofthe desiredtemperaturewhichwasrecordedwithanOmegaprecisethermocouple. Afterequilibrationfor 24h,theexcesssolidparacetamolwasallowedtosettlefor1hwithoutagitation. A2mLsampleofthe clearsaturatedsolutionwaswithdrawnusinganEppendorfpipettetakinggreatcarenottodisturb thesettledsolids. Thesampleswerethentransferredintoalabelledandweighedvial. Thesample vialcontainingthesaturatedsolutionwasweighedimmediately. Thissamplingprocesswasrepeated foreachequilibratedvialandthesampleswereplacedinafumehoodandallowedtoevaporateto drynessfor24h,afterevaporationthesamples,werethentransferredtoavacuumovenandallowed todryforafurther48hat55◦C.Thedryresiduemass,wasdeterminedandthesolubility,expressed inmgofsolute/gofsolvent,wascalculatedwithsubtractionoftheknownamountofimpurityinthe Crystals2017,7,294 6of24 drysamplesbasedonthepresumptionthattheimpurityremainedevenlydistributedthroughoutthe Crystals 2017, 7, 294 6 of 24 liquidphase. mass, was determined and the solubility, expressed in mg of solute/g of solvent, was calculated with DissolutionTemperatureDetectionMethod subtraction of the known amount of impurity in the dry samples based on the presumption that the Aimspeurriietsy orefmsuaisnpeedn esvioennlsy odfisktrniobuwtendc tohnrocuenghtroautti othneo lifqmuiedt apcheatsaem. ol(50–130mg/g)andacetanilide (80–200mg/g)in3-methyl-1-butanolwerepreparedin8mLvials. Thevialswereheatedfrom5◦Cto 70◦CDaitsshoeluattiinong Traemtep0e.1ra◦tuCr/e mDiente.cTtihoen tMemetphoedra tureofdissolutionwasdeterminedatthepointatwhich alltheparAti cselersiews oefr esucsopmenpslieotnesl yofd kisnsoowlvne cdo.nBceynmtraatkioinn gofm meeatsauceretammeonl t(s50a–c1r3o0s smagr/ga)n agnedo afcceotamnpiliodsei tions theso(8lu0–b2i0li0t ymcgu/gr)v ienw 3-amsedtheytel-r1m-biunteadnoal nwderteh eprseoplaurbedil iitny 8a mtsLp veicailfis.c Ttheem vpiaelrsa wtuerree shewaittehdi fnrotmhi s5 r°aCn tgoe can 70 °C at heating rate 0.1 °C/min. The temperature of dissolution was determined at the point at which beinterpolated. all the particles were completely dissolved. By making measurements across a range of compositions 2.3.2.thUel tsroalusobniliitcyI cnutrevnes iwtyasM deetaesrumrienmede nantsd the solubility at specific temperatures within this range can be interpolated. ThesonomechanicalactivityfromtheXUB25ultrasonicbathwascharacterisedbymeasurement of aco2.u3.s2t.i cUlitnrtaesnonsiicty Inutesninsigtya MNeaHsu4r0e0m0ePnVts DF needle hydrophone (Precision Acoustics Ltd., Dorset, UK).TheexperimentalarrangementwasasshowninFigure1exceptthelidoftheCelstirvesselwas The sonomechanical activity from the XUB25 ultrasonic bath was characterised by measurement replaocfe dacwouitshtica ipntleungsimtya unsuinfagc atu NreHd40fr0o0m PVPDVFC nteheadtlea lhloydwreodphtohneen (ePerdecliesihoynd Arocopuhsotincse Ltotdb.,e Dpoorsseitti,o ned 25 mUmKf)r. oTmhe tehxpeebriamseenotafl tahreraCngeelmsteirntv wesasse als, sahliogwnne din wFiigtuhret h1e excceenpttr tahlea lixdi sofo tfheth Ceelssatimr vee.ssIenl worads er to makerempleaacseud rwemithe na tpolufga mcoaunsutfiaccitnutreedn sfirtoymw PiVthCi nthtahte alCloewlsetdir tvhee snseeeld,lteh heytdimroephdoonme atoin bew paovseitfioornmed from theN2H5 m40m00 frhoymd trhoep bhaosne eofw thaes Creelcsotirrd veedsswel,i tahligannedA wgiiltehn tthTe eccehntnroall oagxiise osfI tnhfien snamiVei.s Iino norXde2r0 t2o4 m-Aakdei gital measurement of acoustic intensity within the Celstir vessel, the time domain waveform from the oscilloscope(AgilentTechnologies,SouthQueensferry,UK).Atimingtriggerforthemeasurement NH4000 hydrophone was recorded with an Agilent Technologies InfinniVision X2024-A digital wasprovidedviaasubmersiblepiezoelectrictransducer,sensitiveattheoperatingfrequencyofthe oscilloscope (Agilent Technologies, South Queensferry, UK). A timing trigger for the measurement XUB25bath,andpositionedonthetopsurfaceofthestirrerplate. was provided via a submersible piezoelectric transducer, sensitive at the operating frequency of the Priortostartingthemeasurements,theNH4000hydrophonewaswettedandsoakedfor1hour XUB25 bath, and positioned on the top surface of the stirrer plate. indeionisedwater. AswasdescribedinSection2.3.3,thecrystallisationwasundertakenusingorganic Prior to starting the measurements, the NH4000 hydrophone was wetted and soaked for 1 hour solveinnt dwehioicnhiseisd inwcaotemr.p Aatsi bwleasw ditehsctrhibeePdV iDn FSehcytidorno p2.h3.o3n, ethteip c.rIynstoarlldiseartitoon pwroatse cutntdheerthakyednr oupshinogn etip durinogrgtahneicm seoalsvuenret mwehnictho fist hiencaocmoupasttiibclien wteinthsi ttyhei nPtVhDeFc rhyystdarlolpishaotinoen tmip.e dIniu omrd,ethr etoh ypdrorotepcth othnee was placehdyidnrsoipdheonane t8ipm dmuridngia tmhee mteeralsautreexmreunbt boef rthseh aecaotuhsfiticll eindtewnsiitthy dine tihoen icsreydstawlliastaetrio.nT mheedCiuelmst, itrhve essel usedhfoyrdrsoupshpoennes iwonasc prylascteadll iisnastiidoen aenx p8 emrimm edniatmswetears lfialtleexd ruwbibthera snheaalitqhu foiltleodf wthiethc dryesiotanliisseadt iwonatseor.l vent; The Celstir vessel used for suspension crystallisation experiments was filled with an aliquot of the thehydrophone,completewithprotectivesheath,wasimmersedintothecrystallisationmediumas crystalisation solvent; the hydrophone, complete with protective sheath, was immersed into the showninFigure2. Measurementsofacousticintensitywerethenundertakenwiththecrystallisation crystallisation medium as shown in Figure 2. Measurements of acoustic intensity were then vesselplacedinsidetheXUB25bath,itwaslocatedaroundthedefinedpositionsonthestirrerplateat undertaken with the crystallisation vessel placed inside the XUB25 bath, it was located around the thebottomoftheultrasonicbath—allmeasurementswererecordedat30◦C.Thepeakinstantaneous defined positions on the stirrer plate at the bottom of the ultrasonic bath—all measurements were acousticintensityoftherecordedwaveformwasdeterminedatboth50%and100%powersettingon recorded at 30 °C. The peak instantaneous acoustic intensity of the recorded waveform was theXdUeBte2r5mbinaetdh .at both 50% and 100% power setting on the XUB25 bath. Figure 2. Photograph of the hydrophone arrangement within the Celstir vessel set-up for ultrasonic Figure2.PhotographofthehydrophonearrangementwithintheCelstirvesselset-upforultrasonic intensity measurement. intensitymeasurement. Crystals2017,7,294 7of24 2.3.3. Sono-Crystallisation A 150 mL suspension containing 12.65 g of paracetamol and 1% or 2% mol of metacetamol and/oracetanilidein115g3-methyl-1-butanolwaspreparedincellcultureflasks,Celstir®125mL. Theparacetamolsuspensionin3-methyl-1-butanolwiththepresenceofimpurities,wasimmersedand sonicatedintheultrasonicbath,XUB25,operatingat35±3kHzandwascontinuouslystirredata rateof~150rpmusingasubmersibleTelesystem15.20. Thesolutionwasheatedto65◦Candheldat 65◦Cfor15mintoensurecompletedissolutionwhichwasverifiedbyvisualinspectionbeforeslow coolingto15◦Cover2h. Duringthecoolingcrystallisationprocess,thenucleationtemperatureofthe solutionswasrecorded. Attheendofthecrystallisation(3hafternucleation)andimmediatelyprior toisolation,thecrystalsizedistributionwasmeasuredinsituusinganFBRMtodeterminethemean chordlengthdistribution. Thentheproductcrystalswereseparatedfromthemotherliquorsusing themodifiedVacMaster10systematpressuredrivingforceof200mbarusinga70mLIsolutefilter tubewithapolyethylenefilterwithanominalporesizeof10µm(BiotageLtd.,Uppsala,Sweden). Thetimerequiredtocollectfiltratevolumesof5mL,10mL,15mLetc. wererecorded. Thefiltration was halted at “dry land” the point where the filter cake surface is first exposed above the mother liquors. Themassofthesolventwetcakewasmeasured. Fromthefiltrationdata,thefiltrationrate andfiltercakeresistancewereobtainedusingDarcy’sequation[65]. dt µαC µR = V+ m (1) dV ∆PA2 A∆P where: tistime(s); V isvolume(m3); αiscakeresistance(m/kg); µisthemotherliquorviscosity (kg/s.m);∆Pispressuredifference(Pa);Cisconcentrationofsolids(kg/m3);Aisareaofcake(m2); R isresistanceoffiltermedium(m−1). m Inthiswork,filtrationwascarriedoutatconstantpressuredifference,∆P=200mbar. Integration Darcy’sequationgives: t µαC µR = V+ m (2) V 2∆PA2 A∆P Plottingt/VversusVwillallowthecakeresistanceαtobedetermined. Theratiooftheconcentrationofimpurityintheproductcrystalstotheconcentrationofimpurity relativetoparacetamolinthemotherliquorswasalsodeterminedbydissolutionofproductcrystals andHPLCAnalysis. 2.3.4. ImpurityAnalysisUsingHPLC TheseparationofanalyteswasachievedusinganAgilentPoroshellcolumnoperatedat40◦C with an isocratic elution of 1 mL/min, the mobile phase composition was 80% water and 20% methanol. Thedetectionwavelengthwas243nm,whichrepresentsthemaximumabsorbanceforboth paracetamolandmetacetamol[66]whilestillremainingclosetothelambdamaxforacetanilideat 242nm[67]. Thematerialcorrespondingtoeachpeakinthechromatogramwasidentifiedusingmass spectroscopy. Theanalyticalsampleusedtodeterminethepurityoftheproductcrystalswasprepared byweighing14mgofdryproductcrystalsintoa100mLvolumetricflaskanddissolvingthemina 5%methanol/95%watermixturetoprepareasolutionwithaconcentrationwhichwaswithinthe concentrationrangeusedtocalibratetheinstrument. Motherliquorsweresimilarlydilutedbymassto ensureappropriatecompositionforassay. 3. Results 3.1. Solubility Thesolubilitycurvesofparacetmol,metacetamolandacetanilidein3-methyl-1-butanolprepared usingtheisothermalequilibrationandgravimetricanalysisandpolythermaldissolutiontemperature detection method are shown in Figure 3. These data are summarised in Table 1. Full details of Crystals2017,7,294 8of24 Crystals 2017, 7, 294 8 of 24 the gravimetric studies and dissolution temperature detection are given in Section S1 within the ESI†dmetaaitlesr oiaf ltsh.e gravimetric studies and dissolution temperature detection are given in Section S1 within tTheh eESsIo†l umbaitleitryiaolsf. paracetamol,metacetamolandacetanilideincreasewithincreasingtemperature. ParacetamThoel issotlhuebilleiatys tsoof lupbalreacinet3am-moel,t hmyle-t1a-cbeutatamnool laanndd aacecetatanniilliiddee isinthcreeamseo stwsiothlu binlecraenadsinegx hibits the stetrmopnegreastutrde.e pPearnadceetnacmyolo nis ttehme pleearsat tusorleub(Flei ginu r3e-m3)e.thEyxl-a1-mbuintainnogl tahned daacteatapnirleidsee niste tdhei nmFoisgt ure 3, soluble and exhibits the strongest dependency on temperature (Figure 3). Examining the data therewasadiscrepancyinsolubilityofmetacetamolobtainedbyisothermalequilibrationfollowedby presented in Figure 3, there was a discrepancy in solubility of metacetamol obtained by isothermal gravimetricanalysisandbyobservingthedissolutiontemperatureduringheatingusingtheTechnobis equilibration followed by gravimetric analysis and by observing the dissolution temperature during Crystalline. Determining the dissolution temperature using the Crystalline involves identifying a heating using the Technobis Crystalline. Determining the dissolution temperature using the clearpointatwhichdissolutionispresumedtohaveoccurred. Theclearpointwasdeterminedusing Crystalline involves identifying a clear point at which dissolution is presumed to have occurred. The bothtransmissivitymeasurementandexaminingimagesfromthecrystallinecamera. Thedissolution clear point was determined using both transmissivity measurement and examining images from the kinetcircysstdaellpineen dcaomnertah.e Tshize edaisnsdolushtiaopn ekoinfetthices cdreypsetanlds odnis tshoel vsiinzeg aanndd sthhaepier aobf itlhitey ctroysitmalps eddisesothlveinpga ssage ofligahntd( tthraeinr sambiilsitsyiv tiot yim)opredtoe tbhee cplaesasralgyer oefs olilgvhetd (tirnanasnmiimssiavgitey()c oarm toe rbae bclaesaerdly mreesaoslvuerde mine annt )i.mAaglteh ough them(ceaamsuerrae mbaesnedtw maesapsuerrefmoremnte)d. Aalttahomuogdh etshteh meaetaisnugrermateenot fw0a.1s ◦pCer/fomrmine,dth aet pao mssoidbeilsitt yheoaftoinvge rrsahteo oting thedoifs 0s.o1l °uCti/monint,e tmhep peorsastiubirleityre omf oavineresdh.oMotientga ctheet mdiosslohluatsioanv teemryptehraintunree eredmlea-ilnikede. cMryetsatcaeltmmoolr hpahso logy; a very thin needle-like crystal morphology; the crystals appear to persist some while after they could thecrystalsappeartopersistsomewhileaftertheycouldhavedissolvedinanisothermalexperiment. have dissolved in an isothermal experiment. As a result complete dissolution is detected at slightly Asaresultcompletedissolutionisdetectedatslightlyhighertemperaturethanseeninthegravimetric higher temperature than seen in the gravimetric method. Interestingly, there is no similar discrepancy method. Interestingly,thereisnosimilardiscrepancyinthedatacollectedusingthetwomethods in the data collected using the two methods for acetanilide, this is believed to be due to the higher foracetanilide,thisisbelievedtobeduetothehighersolubilityofacetanilideandthemorerapid solubility of acetanilide and the more rapid dissolution which may be linked to the thin plate-like dissolutionwhichmaybelinkedtothethinplate-likecrystalhabit. crystal habit. 300 250 Paracetamol (Gravimetric) ) g g/ m200 Metacetamol n ( (Gravimetric) o ti150 Metacetamol (Crystalline) a r t n e Acetanilide (Gravimetric) c100 n o C Acetanilide (Crystalline) 50 0 0 10 20 30 40 50 60 Temperature (°C) FiguFriegu3.reS o3.l uSobliulibtiylitoyf opfa praarcaecteatmamool,l,m meettaacceettaammool laanndd acaecteatnainlidileid ine i3n-m3e-mthyelt-h1y-blu-1ta-bnuolt aonbotalinoebdt abiyn edby isothiseormthearlmeqaul ileiqburialtibiorantifoonll ofwolelodwbeydg rbayv imgraevtriimceatnriacl yasnisalaynsdis baynodb sbeyrv ionbgsetrhveindgi sstohleu tdioisnsotelumtiponer ature duritnegmhpeearattiunrge udsuirninggt hheeaTtiencgh unsoibnigs tCher yTsetcahlnlionbei.s Crystalline. Table 1. Molecular weights, melting points, enthalpy of fusion and measured solubilities of Table 1. Molecular weights, melting points, enthalpy of fusion and measured solubilities of paracetamol, metacetamol and acetanilide determined using the gravimetric method. paracetamol,metacetamolandacetanilidedeterminedusingthegravimetricmethod. Measured Solubility in Compounds Molecular Weight (g/mol) Melting Point (K) ΔHfusion (kJ mol-1) 3-meMtheyals-1u-rbeudtSanoolul b(miligty/gi)n ComPaproaucentdasmol MolecularW1e5i1g.1h6t (g/mol) M44e3l.t6in [g68P];o 4in42t.(9K [)69] ∆2H7.f1u s[i6o8n](; k3J0.m72o l[-619)] 2255543 °.-◦8CmC ethy4l70-41 4°.-3Cb0 u ◦tCano51l52(4°m.C35g 5/g◦)C Metacetamol 151.16 420 [70,71] 26.0 [71]; 28.8 [70] 81.4 116.7 162.6 ParaAcceetatamnoillide 15113.156.17 443.6[6388]7;.454 [26.99][ 69] 27.1[6280].;3300 [.6792][ 69] 16524..88 241.784 .3 - 124.3 Metacetamol 151.16 420[70,71] 26.0[71];28.8[70] 81.4 116.7 162.6 Acetanilide 135.17 387.5[69] 20.30[69] 162.8 241.8 - The solubility of a crystalline organic material typically depends on the lattice structure (polymorph), melting point, molecular weight and solvent choice. The measured solubility of pTahraecestoamluobli alintdy moeftaacectarmysotla allrien reelaotrigvealnyi scimmilaatre irni acolmtypparicisaolnly wdithe paecentdansiloidne, tthhies ilsa ctotincseistsetnrut cture (poly morph), melting point, molecular weight and solvent choice. The measured solubility of paracetamolandmetacetamolarerelativelysimilarincomparisonwithacetanilide,thisisconsistent Crystals2017,7,294 9of24 withtheirrelationshipaspositionalisomerscontainingthesamefunctionalgroups. Theparacetamol crystalstructureisdominatedbyhydrogen-bondedmolecularchainspackedina‘herringbone’pattern. Similarly,Cmryesttalas c20e1t7a, 7m, 29o4l crystalsareboundtogetherbyanetworkofhydrogenbondin9g ofi 2n4t eractions. Acetanilidehoweverhasnohydroxylgroupinthepara-positionsolacksaprotondonor. Inaddition, with their relationship as positional isomers containing the same functional groups. The paracetamol the melting point and the enthalpy of fusion decrease in the order Paracetamol > Metacetamol > crystal structure is dominated by hydrogen-bonded molecular chains packed in a ‘herring bone’ Acetanilidpeat(tseerne. TSiambillearl1y), .mFeotarceatcaemtoaln cirlyidstealst haere cbroyusntda ltosgtreuthcetru brye ais nseutwcohrkt hoaf thmydorolegecnu lbeosndairneg boundby weakerforicnetesratchtaionnsi.n Apceatraanicleidtea mhoowledveure hatso nloa hckydorofxtyhl egrhoyupd rino txhyel pgarrao-upopsirteiodnu scoi lnacgkst ha eprooptopno drotnuonr.i tytoform In addition, the melting point and the enthalpy of fusion decrease in the order Paracetamol > ahydrogenbondingnetwork. Acetanilidehasasubstantiallylowerheatoffusionandalowermelting Metacetamol > Acetanilide (see Table 1). For acetanilide the crystal structure is such that molecules pointthanparacetamolandmetacetamol. Therelativesolubilityispresumedtoaffecttheimpurity are bound by weaker forces than in paracetamol due to lack of the hydroxyl group reducing the segregatioonppoofrtthuneitfiyn tao lfcorrmys ata hllyidnreogperno bdouncdti.ng network. Acetanilide has a substantially lower heat of The dfuastiaonp arneds ean tloewderi nmFelitginugr epo4init ntdhainc aptearatcheatatmtohle anpdr emseetnacceetaomfo1l. –T4h%e roeflattihvee ssoelulebciltietyd isi mpurities doesnotspigrensiufimceadn ttol yaffaefcfte tchte tihmepusroitlyu sbeiglrietygaotifonp oafr tahcee ftinaaml coryl.stAaltlin2e5 p◦rCoduacntd. 40◦C,itwasshownthatthe The data presented in Figure 4 indicate that the presence of 1–4% of the selected impurities does solubilityissimilarorincreasesslightlywiththepresenceoftheselectedimpurities. At55◦C,thedata not significantly affect the solubility of paracetamol. At 25 °C and 40 °C, it was shown that the showsincrsoelausbeilditys cisa stitmerilaarn odr itnhceretarseesn dsligishtlleys wsipthr othneo purnesceendce. oIft tchaen sebleectceodn imclpuudreitdiest. hAatt 5t5h °eCe, fthfeec tof1–4% metacetamdoatla/ sahcoewtas ninilcirdeaeseodn sctahteters oanludb thilei ttyrenodf pisa lersasc pertoanmouonlciesd.m Ito cdane sbte. concluded that the effect of 1–4% metacetamol/acetanilide on the solubility of paracetamol is modest. Figure 4. Solubility of paracetamol in 3-methyl-1-butanol with the presence of impurities Figure4.Solubilityofparacetamolin3-methyl-1-butanolwiththepresenceofimpurities(metacetamol (metacetamol and acetanilide) obtained by equilibration and gravimetric assay. andacetanilide)obtainedbyequilibrationandgravimetricassay. 3.2. Ultrasonic Intensity Measurements 3.2. UltrasonicTIhnet eunltsriatsyouMndea isnuternemsiteyn mtseasurements reveal that the local ultrasonic field is highly chaotic and intensities range from 0.12 to 0.25 mW/cm2 at 50% ultrasonic power and from 0.9 to 1.68 mW/cm2 Theultrasoundintensitymeasurementsrevealthatthelocalultrasonicfieldishighlychaoticand at 100% power (see Table 2). It is clear from this data that the % ultrasound power is not a linear intensitiesdreasncrgipetofrr.o Cmry0st.a1l2listaotio0n.2 e5xmpeWrim/ecnmts 2waetre5 0co%nduulcttreads oatn picospitoiownse r1 aanndd 2fr oanmd 0th.9e tuoltr1a.s6o8unmd W/cm2at 100%poweinrte(nsesietyT aapbplelie2d) .dIutriisngc lethaersefr oexmpetrhimisendtas tcaatnh baet tchhear%actuerlitsreads oasu; nzderpo o(0w merWis/cnmo2)t laowlin, e50a%r descriptor. ultrasound power (0.19 ± 0.06 mW/cm2) and high, 100% ultrasound power (1.45 ± 0.21 mW/cm2). Crystallisationexperimentswereconductedatpositions1and2andtheultrasoundintensityapplied during these experiments can be characterised as; zero (0 mW/cm2) low, 50% ultrasound power Table 2. The ultrasonic intensity was measured at four positions within the ultrasonic bath. (0.19±0.06mW/cm2)andhigh,100%ultrasoundpower(1.45±0.21mW/cm2). Ultrasonic Intensity (mW/cm2) Positions on the Stirrer plate at the Bottom of the Ultrasonic Bath 50% Ultrasonic Power 100% Ultrasonic Power Table2.Theultrasonicinte1 nsitywasmeasuredatfourpo0s.i1t3i ±o 0n.0s2 withintheu1l.2t5r a± s0o.1n3 icbath. 2 0.25 ± 0.03 1.68 ± 0.25 3 0.24 ± 0.02 1.32 ± 0.09 4 0.12 ±U 0l.t0r4a sonicIntensity0.9(m ± W0.0/7c m2) PositionsontheStirrerplateattAhveeBraogteto vmaluoefs theUltrasonicBath 50%U0l.t1r9a ±so 0n.0i7c Power 110.209% ± 0U.3l2t rasonicPower 1 0.13±0.02 1.25±0.13 2 0.25±0.03 1.68±0.25 3 0.24±0.02 1.32±0.09 4 0.12±0.04 0.9±0.07 Averagevalues 0.19±0.07 1.29±0.32 Crystals2017,7,294 10of24 3.3. Sonocrystallisation The data comprise 11 suspension crystallisation experiments designed using the Design of Experiments software MODDE. (Umetrics Modde, Version 11, MKS Instruments, Umea, Sweden) to facilitate multivariate analysis. A full factorial (2 level) method was used to create a data set that was then analyzed using multiple linear regression (MLR) methods to measure effects of the three independent variables on the experimental responses. The parameters investigated were; theconcentrationsofthetwoimpuritieswheretheparameterrangewasselectedas0–2mol%and ultrasonicpowerwheretheparameterrangewas0%to100%powersettingsontheultrasonicbath. Whentheultrasonicpowerwasmeasuredthecenterpoint(50%ultrasoundpower)theintensitywas foundtobe0.19±0.06mW/cm2andat100%ultrasoundpowertheintensitywas1.45±0.21mW/cm2. Theresponsesanalyzedwerenucleationtemperature,particlesize,filtrationrate,productyieldand thepercentageofimpuritiesintheproductcrystals. Theeffectofthepercentageofimpuritiespresentinsolutionatthestartofcrystallisationand ultrasonicpoweron;nucleationtemperature,crystalsizedistribution,filtrationrateandprocessyield atadefinedcrystallisationendpointaresummarisedinTable3. Table3. Summaryofcrystallisationtemperature,crystalsizedistribution,filtrationtime(for50mL suspensionsolution),filtrationrate,cakeresistanceandprocessyieldasafunctionofthepercentageof impuritiesandultrasonicpower. Experiments Tcrys(◦C) PSLDenMgethan(µCmho)rd FTiilmtraeti(os)n RFaitletr(amtio3/ns) Cake(mRe/ksigs)tance Yield Pureparacetamol 41.3 47–55 209 1.90×10−7 7.03×1011 57.7% (100%powerUS) Pureparacetamol 36.0 85–100 95 4.29×10−7 2.62×109 54.3% (noUS) 2mol%Metacetamol 36.4 47 361 1.07×10−7 1.52×1010 45.5% (100%powerUS) Aftermaintaining 2mol%Metacetamol at15◦Cfor 100–109 45 1.06×10−7 9.02×108 39.1% (noUS) approx.1.5h 2mol%Acetanilide 43 40 561 7.32×10−7 1.88×1010 56.2% (US100%P) 2mol%Acetanilide 15.5◦C 105 54 7.01×10−7 1.02×109 55.3% (noUS) 2mol%Metacetamol& Acetanilide 34.4 37.3 346 1.19×10−7 1.51×1010 42.2% (US100%power) Aftermaintaining 2mol%Metacetamol& at15◦Cfor 87–90 48 9.61×10−7 1.14×109 32.0% Acetanilide(noUS) approx.2.5h 1mol%Metacetamol& 1mol%Acetanilide 44 87 61 7.19×10−7 1.38×109 40.6% (50%USpower) 3.3.1. CrystallisationTemperature Thenucleationtemperaturemeasuredwithandwithouttheuseofultrasoundforcrystallisation ofparacetamolinthepresenceofmetacetamoland/oracetanilideisshowninTable3. Eventhough nucleation is a stochastic process and some scatter may be anticipated among the measured data the experimental results clearly show that ultrasound has a significant effect on the nucleation process. Forexample,inthecaseofparacetamolcrystallisationinthepresenceof2%metacetamol, the ultrasound treated sample started to nucleate at around 36 ◦C, and was in the final stages of crystallisationbythetimethesuspensionhadbeencooledto15◦C.Bycontrastthesamplenottreated withultrasoundonlystartedtonucleateafterholdingat15◦Cforapproximately1.5h. Thisisbelieved tobeduetotheslownucleationandcrystalgrowthkineticsinthepresenceofimpurities. Ultrasound canpromotenucleationandgeneratesubstantialnumbersofsecondarynucleifromexistingparent

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Introduction. Crystallisation is the principal purification technique in the pharmaceutical, fine chemical, paint, pigments and agrochemical sector. It allows the .. Agilent High Performance Liquid Chromatography 6130 dual source model (Agilent, Santa Clara, CA, .. efficient crystallisation process
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crystals Article The Effect of Ultrasound on the Crystallisation of Paracetamol in the Presence of Structurally Similar Impurities ThaiT.H.Nguyen1 ID,AzeemKhan1,LaylaM.Bruce1 ID,ClarissaForbes1,2,3, RichardL.O’Leary2andChrisJ.Price1,3,* ID 1 DepartmentofChemical&ProcessEngineering,UniversityofStrathclyde,GlasgowG11XQ,UK; [email protected](T.T.H.N.);[email protected](A.K.);[email protected](L.M.B.); [email protected](C.F.) 2 TheCentreforUltrasonicEngineering,DepartmentofElectronic&ElectricalEngineering, UniversityofStrathclyde,GlasgowG11XW,UK;[email protected] 3 EPSRCCentreforContinuousManufacturingandCrystallisation,UniversityofStrathclyde, GlasgowG11RD,UK * Correspondence:[email protected] AcademicEditor:JudyLee Received:17August2017;Accepted:26September2017;Published:30September2017 Abstract: Sono-crystallisationhasbeenusedtoenhancecrystallineproductqualityparticularlyin termsofpurity,particlesizeandsizedistribution.Inthiswork,theeffectofimpuritiesandultrasound on crystallisation processes (nucleation temperature, yield) and crystal properties (crystal size distributiondeterminedbyFocusedBeamReflectanceMeasurement(FBRM),crystalhabit,filtration rate and impurity content in the crystal product by Liquid Chromatography-Mass Spectroscopy (LC-MS))wereinvestigatedinbulksuspensioncrystallisationexperimentswithandwithoutthe useofultrasound. Theresultsdemonstratethatultrasonicinterventionhasasignificanteffecton both crystallisation and product crystal properties. It increases the nucleation rate resulting in smallerparticlesandanarrowerParticleSizeDistribution(PSD),theyieldhasbeenshowntobe increaseashastheproductpurity. Theeffectofultrasoundistoreducethelevelacetanilideimpurity incorporated during growth from a 2 mol% solution of the selected impurity from 0.85 mol% to 0.35mol%andlikewiseultrasoundreducestheuptakeofmetacetamolfrom1.88mol%to1.52mol%. Keywords: suspension crystallisation; impurities; crystal size distribution; filtration rate; optical microscopy;imageanalysis;crystalmorphology;purification;HPLC;ultrasoundintensity 1. Introduction Crystallisationistheprincipalpurificationtechniqueinthepharmaceutical,finechemical,paint, pigmentsandagrochemicalsector. Itallowsthedesiredproducttobeobtainedinapurestateleaving unwantedorhazardousimpuritiesinsolutionwheretheycanberemovedeffectivelybyfiltration and washing. During crystallisation, molecules of the product assemble together to form crystals witharegular3Dpackingarrangementknownasacrystallattice. Purificationoccursbymolecular recognitionatthesolution-latticeinterface. Themismatchbetweensomeimpuritymoleculesandthe crystallatticeissosignificantthattheimpuritymoleculecannotbeincorporatedinthelatticeandis rejected. However,ifthemolecularmismatchissmallenough,theimpuritymoleculecanbecome incorporatedintothecrystallattice. Iftheportionoftheimpuritymoleculeprojectingoutfromthe crystalsurfaceisdifferentfromtheadjacentmoleculesinthesurfacelayerofthecrystalthisislikely todisruptandretardsubsequentgrowthatthatgrowthsiteandadjacentsitesonthatcrystalface. Crystals2017,7,294;doi:10.3390/cryst7100294 www.mdpi.com/journal/crystals Crystals2017,7,294 2of24 Increasingthecrystallisationdrivingforce,i.e.,increasingsupersaturationlevel,reducesselectivity allowingeasierincorporationoftheimpurityintothecrystallatticeandsubsequentovergrowth.Inone oftheauthor’sindustrialexperience,typicalfeedstreamstoindustrialcrystallisationcontainseveral mole%ofimpuritiessointeractionsbetweenimpuritymoleculesandthegrowingcrystalsurfaceare veryfrequentandcanhaveundesirableconsequences. Impuritypoisoningofgrowingcrystalfaces increases processing time and slows the approach to equilibrium. In some instances, a significant amountofproducthastobeleftinsolutionandlostinthewastestreaminorderfortheprocesstobe runwithaplausiblebatchduration. Sometimestheproductissoimpurethatithastobere-crystallised tomeettherequiredspecification. Mostimpuritiesthatarereadilyincorporatedintothegrowingcrystallatticeandactascrystal growth inhibitors are close analogues of the active pharmaceutical ingredient and are produced inadvertentlyasby-productsordegradantsduringthesyntheticprocess. Aswellasretardingcrystal growththeyalsomodifycrystalhabit. Asaconsequence,otherattributesoftheisolatedcrystalssuch asbulkdensityandpowderflowaremodifiedandcaninfluenceboththesubsequentformulation processanddrugproductperformance. Severalrouteshavebeenidentified[1]bywhichimpurities becomeentrappedinfinalcrystallineproduct: (i)Depositiononcrystalsurfacesduetotheincomplete removalofimpuremotherliquorduringfiltrationandwashing;(ii)incorporationwithinthecrystal latticebymolecularrecognition/substitutionor(iii)entrapmentofmultipleimpuritymoleculeswithin inclusionsorbetweenindividualcrystallitesinagglomerates. Theimpactofspecificimpuritieson crystallisationprocessesdependson;thestructureoftheimpurity,itsconcentration,thecrystallisation solvent, the supersaturation and the temperature of the crystallising solution. The presence of impurities during the crystallisation process can significantly modify the kinetics of nucleation, the growth rate of specific crystal faces, crystal morphology (habit) and the polymorphic phase crystallized. Theseundesiredeffectscancausecostlydelaysduringtheresearchanddevelopment processwithinthepharmaceuticalindustry.Therearemanycasestudiesofimpurityeffectsreportedin thecrystallisationliterature[2–5].Theeffectofincreasingamountsoftheimpurityp-acetoxyacetanilide on paracetamol nucleation is to increase the metastable zone width and lengthen the induction time[3,6,7]. Ithasbeenreportedthatthisduetoitsabilitytodisrupttheformationandgrowthofthe criticalnucleus[3,8]. Impuritieshavebeenreportedbothtosuppressandoccasionallytoaccelerate crystalgrowthprocesses[9]. N-phosphonomethylphosphoricacid(PMG)crystallisationisreported tobeaffectedbytheimpurities,iminobismethylenephosphonicacidandaminomethylphosphoric acidbyselectiveabsorptionontothe(100)faceinhibitingthegrowthofthisface;whiletheimpurity N-phosphonomethyliminodiaceticacid(PIDA)doesnotchangecrystalhabitnoticeably[10]. Also, animpurityhasbeenreportedtoaffectthesolution-mediatedphasetransformationofthemetastable AformtothestableBformofanactivepharmaceuticalingredient[11]. Thepresenceofimpurities iswidelyreportedtoinfluencecrystalgrowthandcrystalmorphology[9,12–15]. Thisisthecasefor aminoacidsonthehabitofglycinecrystals[16],orureacrystallisationinthepresenceofbiuret[15]. Thechangeofcrystalhabitisduetoadifferenceintheextentofadsorptionandmagnitudeofbinding energiesondifferentcrystalfaces[16]. Forthisreason,identification,quantificationandreductionof impuritiesintheearlystagesofsyntheticprocessdevelopmentcanavoidproblemsincrystallisation development,enhanceproductperformanceandreducedevelopmenttime[17]. Ultrasound(US)hasbeenusedinthechemicalandfoodindustriestoenhancecrystallineproduct quality in terms of particle size, size distribution and impurity and is termed sono-crystallisation. Ultrasound has been widely reported to influence the primary nucleation process accelerating nucleation kinetics, this is typically expressed in terms of reducing the induction time and MSZW [18–33]. Ultrasound can also increase the rate of secondary nucleation, this is manifested as a reduction on the product crystal size distribution [20,22,24,31,32,34–43]. Ultrasound can also influence crystal growth [20,25,26,36,40,44–46] although the effect on crystal growth is not as dramatic as on nucleation and arises largely from enhanced mass transfer [46] and can influence crystal morphology. Other reported outcomes of ultrasonic intervention include influencing; Crystals2017,7,294 3of24 which polymorph nucleates [23,47,48], crystal structure [30], crystal properties [49] and reaction crystallisation[45]. Severalproposedmechanismsoftheeffectofultrasoundoncrystallisationhave beenpublished.Theseincludetheformationoflocalhotspotswhicharisefromthelargeenergyrelease onthecollapseofcavitationbubblescreatinghighlylocalisedregionsofextremelyhightemperature and pressure [50,51], or due to rapid cooling which follows; shockwaves released from cavitation bubbles[52,53],promotingmasstransferandcollisionsbetweencrystalsandadjacentsurfaces[54]. These effects of ultrasound on crystallisation have been demonstrated on pharmaceuticals and commoditychemicalsincluding;lactose[35,39,42,55],alpha-dextrosemonohydrate[20],glycine[48], p-aminobenzoic acid [47], adipic acid [28], benzoic acid [31], acetylsalicylic acid [27], protein [19] variousfoodproducts[30,56,57]andinthecrystallisationofinorganicmaterialssuchaspotassium sulphate[26],potassiumdihydrogenphosphate[32]andcalcite[34]. Ultrasoundhasalsobeenutilized incontinuouscrystallisation[28,58–60]. Whilesomeauthorsmentionthatultrasoundcanimprove crystal purity [54]; there is very limited data on the effect of ultrasound on the purity of the final crystallineproduct. Thisworkfocusesontheuseofultrasoundinsuspensioncrystallisationprocesses to improve product purity, yield and crystal size distribution. The objective is to develop a bulk suspension sonocrystallisation process at lab scale which exploits ultrasound to improve product purity, yield and crystal habit. The research hypothesis is that through active intervention in the molecularprocessesoccurringatgrowingsurfacesitmaybepossibletoremoveimpuritymolecules fromthesurfacesandreducetheentrapmentofimpuritiesinsideagglomeratesformedduringgrowth. Thesemeasurementsaimtoincreaseunderstandingofhowultrasonicinterventionsaffectproduct puritybothdirectlythroughinfluencingimpurityincorporationduringgrowthandindirectlythrough influencingnucleationkinetics,crystalsizedistributionandagglomeration,whichallinfluencethe purityoffinalproductsbymodifyingtheextenttowhichimpuritiesareremovedduringfiltration andwashing. Paracetamol(Acetaminophen)hasbeenusedasamodelcompoundforthisstudybecauseits crystallisationbehaviouriswellcharacterised[2–5]andmultiplestructurallyrelatedimpuritiesare readilyavailable. Threepolymorphsofparacetamolhavebeenreported[61–63]butsofaronlyforms IandIIhavebeenobtainedassinglecrystalswhichhaveallowedthecrystalstructuretobesolved. PolymorphI(monoclinic,P21/n)isthethermodynamicallystableformatroomtemperature,thiscan bepreparedaslargesinglecrystalsfromsolutionsinvarioussolvents. PolymorphII(orthorhombic, Pcab) is metastable at ambient conditions. Crystals of paracetamol form I exhibit three dominant crystal habit faces; {100}, {001} and {110}. Individual paracetamol crystals exhibit different crystal habits,forexamplesignificantchangesofthegrowthrateandresultantmorphologyofparacetamol singlecrystalsareobservedinpure[64]andimpuresystems[4]. 2. MaterialsandMethodology 2.1. Materials Paracetamol (BioXtra grade, purity ≥ 99.0%, Lot number 637515L263) was obtained from Sigma-Aldrich(St. Louis,MO,USA).TheimpuritiesinvestigatedwereAcetanilide99.0%Lotnumber STBD0193VandMetacetamol97.0%LotnumberMKBX4643VbothalsoobtainedfromSigma-Aldrich, all three samples were analysed on receipt to confirm the reported assay. The basis for selecting acetanilideisthatitisstructurallysimilartoparacetamolbutlacksthehydroxylgroupandsowhile it may be incorporated into the crystal lattice it is deficient in a hydrogen bonding opportunity. Metacetamol was selected as a positional isomer which is also likely to be incorporated into the crystallattice;however,themisplacedhydroxylgroupislikelytodisruptthelocalhydrogenbonding arrangement. Importantlybotharemoresolublethanparacetamolin3-methyl-1-butanol,theselected solventensuringlittleriskofthemcrystallizingindependentlyduringtheexperiments. The crystallisation solvent 3-methyl-1-butanol (isoamyl alcohol) was selected because the solubility relationship with temperature for paracetamol is appropriately steep over the chosen Crystals2017,7,294 4of24 temperature range and the product crystals tend not to form agglomerates. 3-methyl-1-butanol wasobtainedfromSigma-Aldrich98%,n-heptane99%fromAlfaAesar(WardHill,MA,USA)usedfor filtercakewashingfollowingfiltration. HPLCgrademethanolandwaterusedfortheanalysiswere purchasedfromSigma-Aldrich. 2.2. EquipmentApparatus 2.2.1. SolubilityMeasurements GravimetricMethod In order to evaluate the effect of impurities on the crystallisation of paracetamol it was first necessarytomeasuretheextenttowhichtheimpuritiesaffectthesolubilityofparacetamolinthe crystallisationsolvent. SolubilitymeasurementswereperformedbyequilibrationusingaStuartSI60D Incubator(Stuart,Staffordshire,UK).AgitationoftheequilibratingsampleswasprovidedbyaThermo scientific submersible telesystem 15.20 magnetic stirrer plate (Thermo Fisher Scientific, Waltham, MA,USA).ThetemperaturewasrecordedusinganOmegaHH800SWtemperaturesensor(Omega, Manchester, UK).SamplesweretakenusinganEppendorfpipetteweighedonanA&DGRseries balance(A&DInstrumentsLimited,Manchester,UK)andevaporatedtodrynessinaMemmertGmbH vacuumovenV0200(MemmertGmbH+Co. KG,Schwabach,Germany)at55◦C. DetectionoftheDissolutionTemperatureMethodUsingCrystalline-TechnobisCrystallisationSystems Solubility measurements of acetanilide and metacetamol were also conducted in a Technobis Crystalline system, a multi-reactor crystallisation platform which has eight independent Peltier heater-coolers able to maintain temperatures from −15 ◦C to 150 ◦C. Each 8 mL (34 × 10 mm) crystallizerisequippedwithathree-blademarineimpellerwithoverheadstirring.Eachvesselposition isequippedwithaturbiditysensorandacameraallowingturbidityandimagestoberecordedand synchronisedwiththetemperaturetimeprofile. 2.2.2. Sono-CrystallisationStudies Aschematicdiagramoftheexperimentalequipmentusedtoevaluatetheeffectofultrasoundon crystalpurityisshowninFigure1. Thesystemcomprisedtwocellcultureflasks,doublesidearm, Celstir® 125mLplacedontoasubmersibleTelesystem15.20stirrerfromThermoScientific(Waltham, MA,USA)immersedinaXUB25ultrasonicbathfromGrantInstruments(Cambridge,UK)operatingat 35±3kHz. ThetemperatureofthewaterintheultrasonicbathandhencethesolutionsintheCelstir® flaskswascontrolledusinganImmersionCompactThermostat(ICC)fromIKA(StaufenimBreisgau, Germany)whichwasconnectedtoaHaileaHC-150Achiller(GuangDong,China). Additionalcooling capacity was provided by a stainless-steel dip coil running around the base of the ultrasonic bath andconnectedtoaLauderLCK1913,ECORE420Gthermocirculator(LaudaBrinkmann,NJ,USA). ThetemperatureofsolutionswasmonitoredusingaprecisePPL-GMH-3750thermometerandPt100 probe(±0.03◦C)(GHMMesstechnikGmbHStandortGreisinger,Regenstauf,Germany). Thepoint ofnucleationwasdeterminedbyvisualobservation,initiallyafewparticleswereobservedandthe solution gradually became cloudy. On completion of the crystallisation (~3–3.5 h after nucleation processoccurs)theproductcrystalsizedistributionwasmeasuredinsitubyFocusedBeamReflectance (FBRM)(MettlerToledo,Greifensee,Switzerland). TheproductsuspensionwasfilteredusingaVac Master10system(BiotageLtd.,Uppsala,Sweden)whichhadbeenmodifiedtoaccommodate50mL graduatedcylinderswhichallowedthefiltrationratetobemeasured,filtrationtobehaltedatdryland, andthemotherliquorandindividualwashliquorstobesegregatedforsubsequentassay.Thefiltration drivingforcewasmonitoredandcontrolledusingaBüchiV800vacuumcontroller(BüchiUKLtd., Oldham,UK). Crystals2017,7,294 5of24 Crystals 2017, 7, 294 5 of 24 Figure 1. (a) Schematic diagram and (b) Annotated photograph showing the experiment setup for Figure1. (a)Schematicdiagramand(b)Annotatedphotographshowingtheexperimentsetupfor suspension cooling crystallisation of paracetamol in the presence of impurities using an ultrasonic suspensioncoboatlhin. gcrystallisationofparacetamolinthepresenceofimpuritiesusinganultrasonicbath. 2.3. Experimental Method Chemicalanalysisofproductcrystals,motherliquorsandwashliquorswasperformedusingan AgilentHigh2P.3e.1r. fSoorlumbialintyc eLiquidChromatography6130dualsourcemodel(Agilent,SantaClara,CA, USA)providedwithathermostatedautosampler,athermostatedcolumncompartmentandasingle Gravimetric Method wavelengthultraviolet(UV)detectoranda2.7µmPoroshell120EC-C18Column: 4.6×75mmto Solubility measurements were performed by equilibration using a Stuart SI60D Incubator determinetheopcerraytsedta olvlienr ethpe rtoemdpuecrattuprue rriatnyg.e 25 to 50 °C. The sample size employed to prepare saturated solutions to determine solubility was 15 mL. The effect of impurities on solubility was determined by 2.3. ExperimenditsaslolMvinegt hao dknown target amount of metacetamol and/or acetanilide in the solvent prior to the addition of paracetamol. Individual vials were prepared with specific impurity loadings and then equilibrated with an excess of paracetamol. The vials were placed onto a Thermo scientific 2.3.1. Solubility submersible telesystem 15.20 magnetic stirrer plate and agitated at 190 rpm. The temperature was kept within ±0.2 °C of the desired temperature which was recorded with an Omega precise GravimetricMethod thermocouple. After equilibration for 24 h, the excess solid paracetamol was allowed to settle for 1 h without agitation. A 2 mL sample of the clear saturated solution was withdrawn using an Eppendorf SolubilitymeasurementswereperformedbyequilibrationusingaStuartSI60DIncubatoroperated pipette taking great care not to disturb the settled solids. The samples were then transferred into a overthetemplaeberlaletdu raendr awnegiegh2ed5 tvoia5l. 0T◦hCe .sTamhpeles avmialp cloenstaiizneinge mthpe losaytuerdatetdo psorleuptioanr ewsaas tuwreaigtheedd solutionsto determinesoilmumbeildiitaytewly. aTshi1s 5sammpLl.inTg hperoecefsfse cwtaso freipmeapteud rfiotri eeascho neqsuoililburbatieldit vyiawl aansd dtheet searmmpilense wderbey dissolving placed in a fume hood and allowed to evaporate to dryness for 24 h, after evaporation the samples, a known target amount of metacetamol and/or acetanilide in the solvent prior to the addition of were then transferred to a vacuum oven and allowed to dry for a further 48 h at 55 °C. The dry residue paracetamol. Individualvialswerepreparedwithspecificimpurityloadingsandthenequilibrated withanexcessofparacetamol. ThevialswereplacedontoaThermoscientificsubmersibletelesystem 15.20magneticstirrerplateandagitatedat190rpm. Thetemperaturewaskeptwithin±0.2◦Cofthe desiredtemperaturewhichwasrecordedwithanOmegaprecisethermocouple. Afterequilibrationfor 24h,theexcesssolidparacetamolwasallowedtosettlefor1hwithoutagitation. A2mLsampleofthe clearsaturatedsolutionwaswithdrawnusinganEppendorfpipettetakinggreatcarenottodisturb thesettledsolids. Thesampleswerethentransferredintoalabelledandweighedvial. Thesample vialcontainingthesaturatedsolutionwasweighedimmediately. Thissamplingprocesswasrepeated foreachequilibratedvialandthesampleswereplacedinafumehoodandallowedtoevaporateto drynessfor24h,afterevaporationthesamples,werethentransferredtoavacuumovenandallowed todryforafurther48hat55◦C.Thedryresiduemass,wasdeterminedandthesolubility,expressed inmgofsolute/gofsolvent,wascalculatedwithsubtractionoftheknownamountofimpurityinthe Crystals2017,7,294 6of24 drysamplesbasedonthepresumptionthattheimpurityremainedevenlydistributedthroughoutthe Crystals 2017, 7, 294 6 of 24 liquidphase. mass, was determined and the solubility, expressed in mg of solute/g of solvent, was calculated with DissolutionTemperatureDetectionMethod subtraction of the known amount of impurity in the dry samples based on the presumption that the Aimspeurriietsy orefmsuaisnpeedn esvioennlsy odfisktrniobuwtendc tohnrocuenghtroautti othneo lifqmuiedt apcheatsaem. ol(50–130mg/g)andacetanilide (80–200mg/g)in3-methyl-1-butanolwerepreparedin8mLvials. Thevialswereheatedfrom5◦Cto 70◦CDaitsshoeluattiinong Traemtep0e.1ra◦tuCr/e mDiente.cTtihoen tMemetphoedra tureofdissolutionwasdeterminedatthepointatwhich alltheparAti cselersiews oefr esucsopmenpslieotnesl yofd kisnsoowlvne cdo.nBceynmtraatkioinn gofm meeatsauceretammeonl t(s50a–c1r3o0s smagr/ga)n agnedo afcceotamnpiliodsei tions theso(8lu0–b2i0li0t ymcgu/gr)v ienw 3-amsedtheytel-r1m-biunteadnoal nwderteh eprseoplaurbedil iitny 8a mtsLp veicailfis.c Ttheem vpiaelrsa wtuerree shewaittehdi fnrotmhi s5 r°aCn tgoe can 70 °C at heating rate 0.1 °C/min. The temperature of dissolution was determined at the point at which beinterpolated. all the particles were completely dissolved. By making measurements across a range of compositions 2.3.2.thUel tsroalusobniliitcyI cnutrevnes iwtyasM deetaesrumrienmede nantsd the solubility at specific temperatures within this range can be interpolated. ThesonomechanicalactivityfromtheXUB25ultrasonicbathwascharacterisedbymeasurement of aco2.u3.s2t.i cUlitnrtaesnonsiicty Inutesninsigtya MNeaHsu4r0e0m0ePnVts DF needle hydrophone (Precision Acoustics Ltd., Dorset, UK).TheexperimentalarrangementwasasshowninFigure1exceptthelidoftheCelstirvesselwas The sonomechanical activity from the XUB25 ultrasonic bath was characterised by measurement replaocfe dacwouitshtica ipntleungsimtya unsuinfagc atu NreHd40fr0o0m PVPDVFC nteheadtlea lhloydwreodphtohneen (ePerdecliesihoynd Arocopuhsotincse Ltotdb.,e Dpoorsseitti,o ned 25 mUmKf)r. oTmhe tehxpeebriamseenotafl tahreraCngeelmsteirntv wesasse als, sahliogwnne din wFiigtuhret h1e excceenpttr tahlea lixdi sofo tfheth Ceelssatimr vee.ssIenl worads er to makerempleaacseud rwemithe na tpolufga mcoaunsutfiaccitnutreedn sfirtoymw PiVthCi nthtahte alCloewlsetdir tvhee snseeeld,lteh heytdimroephdoonme atoin bew paovseitfioornmed from theN2H5 m40m00 frhoymd trhoep bhaosne eofw thaes Creelcsotirrd veedsswel,i tahligannedA wgiiltehn tthTe eccehntnroall oagxiise osfI tnhfien snamiVei.s Iino norXde2r0 t2o4 m-Aakdei gital measurement of acoustic intensity within the Celstir vessel, the time domain waveform from the oscilloscope(AgilentTechnologies,SouthQueensferry,UK).Atimingtriggerforthemeasurement NH4000 hydrophone was recorded with an Agilent Technologies InfinniVision X2024-A digital wasprovidedviaasubmersiblepiezoelectrictransducer,sensitiveattheoperatingfrequencyofthe oscilloscope (Agilent Technologies, South Queensferry, UK). A timing trigger for the measurement XUB25bath,andpositionedonthetopsurfaceofthestirrerplate. was provided via a submersible piezoelectric transducer, sensitive at the operating frequency of the Priortostartingthemeasurements,theNH4000hydrophonewaswettedandsoakedfor1hour XUB25 bath, and positioned on the top surface of the stirrer plate. indeionisedwater. AswasdescribedinSection2.3.3,thecrystallisationwasundertakenusingorganic Prior to starting the measurements, the NH4000 hydrophone was wetted and soaked for 1 hour solveinnt dwehioicnhiseisd inwcaotemr.p Aatsi bwleasw ditehsctrhibeePdV iDn FSehcytidorno p2.h3.o3n, ethteip c.rIynstoarlldiseartitoon pwroatse cutntdheerthakyednr oupshinogn etip durinogrgtahneicm seoalsvuenret mwehnictho fist hiencaocmoupasttiibclien wteinthsi ttyhei nPtVhDeFc rhyystdarlolpishaotinoen tmip.e dIniu omrd,ethr etoh ypdrorotepcth othnee was placehdyidnrsoipdheonane t8ipm dmuridngia tmhee mteeralsautreexmreunbt boef rthseh aecaotuhsfiticll eindtewnsiitthy dine tihoen icsreydstawlliastaetrio.nT mheedCiuelmst, itrhve essel usedhfoyrdrsoupshpoennes iwonasc prylascteadll iisnastiidoen aenx p8 emrimm edniatmswetears lfialtleexd ruwbibthera snheaalitqhu foiltleodf wthiethc dryesiotanliisseadt iwonatseor.l vent; The Celstir vessel used for suspension crystallisation experiments was filled with an aliquot of the thehydrophone,completewithprotectivesheath,wasimmersedintothecrystallisationmediumas crystalisation solvent; the hydrophone, complete with protective sheath, was immersed into the showninFigure2. Measurementsofacousticintensitywerethenundertakenwiththecrystallisation crystallisation medium as shown in Figure 2. Measurements of acoustic intensity were then vesselplacedinsidetheXUB25bath,itwaslocatedaroundthedefinedpositionsonthestirrerplateat undertaken with the crystallisation vessel placed inside the XUB25 bath, it was located around the thebottomoftheultrasonicbath—allmeasurementswererecordedat30◦C.Thepeakinstantaneous defined positions on the stirrer plate at the bottom of the ultrasonic bath—all measurements were acousticintensityoftherecordedwaveformwasdeterminedatboth50%and100%powersettingon recorded at 30 °C. The peak instantaneous acoustic intensity of the recorded waveform was theXdUeBte2r5mbinaetdh .at both 50% and 100% power setting on the XUB25 bath. Figure 2. Photograph of the hydrophone arrangement within the Celstir vessel set-up for ultrasonic Figure2.PhotographofthehydrophonearrangementwithintheCelstirvesselset-upforultrasonic intensity measurement. intensitymeasurement. Crystals2017,7,294 7of24 2.3.3. Sono-Crystallisation A 150 mL suspension containing 12.65 g of paracetamol and 1% or 2% mol of metacetamol and/oracetanilidein115g3-methyl-1-butanolwaspreparedincellcultureflasks,Celstir®125mL. Theparacetamolsuspensionin3-methyl-1-butanolwiththepresenceofimpurities,wasimmersedand sonicatedintheultrasonicbath,XUB25,operatingat35±3kHzandwascontinuouslystirredata rateof~150rpmusingasubmersibleTelesystem15.20. Thesolutionwasheatedto65◦Candheldat 65◦Cfor15mintoensurecompletedissolutionwhichwasverifiedbyvisualinspectionbeforeslow coolingto15◦Cover2h. Duringthecoolingcrystallisationprocess,thenucleationtemperatureofthe solutionswasrecorded. Attheendofthecrystallisation(3hafternucleation)andimmediatelyprior toisolation,thecrystalsizedistributionwasmeasuredinsituusinganFBRMtodeterminethemean chordlengthdistribution. Thentheproductcrystalswereseparatedfromthemotherliquorsusing themodifiedVacMaster10systematpressuredrivingforceof200mbarusinga70mLIsolutefilter tubewithapolyethylenefilterwithanominalporesizeof10µm(BiotageLtd.,Uppsala,Sweden). Thetimerequiredtocollectfiltratevolumesof5mL,10mL,15mLetc. wererecorded. Thefiltration was halted at “dry land” the point where the filter cake surface is first exposed above the mother liquors. Themassofthesolventwetcakewasmeasured. Fromthefiltrationdata,thefiltrationrate andfiltercakeresistancewereobtainedusingDarcy’sequation[65]. dt µαC µR = V+ m (1) dV ∆PA2 A∆P where: tistime(s); V isvolume(m3); αiscakeresistance(m/kg); µisthemotherliquorviscosity (kg/s.m);∆Pispressuredifference(Pa);Cisconcentrationofsolids(kg/m3);Aisareaofcake(m2); R isresistanceoffiltermedium(m−1). m Inthiswork,filtrationwascarriedoutatconstantpressuredifference,∆P=200mbar. Integration Darcy’sequationgives: t µαC µR = V+ m (2) V 2∆PA2 A∆P Plottingt/VversusVwillallowthecakeresistanceαtobedetermined. Theratiooftheconcentrationofimpurityintheproductcrystalstotheconcentrationofimpurity relativetoparacetamolinthemotherliquorswasalsodeterminedbydissolutionofproductcrystals andHPLCAnalysis. 2.3.4. ImpurityAnalysisUsingHPLC TheseparationofanalyteswasachievedusinganAgilentPoroshellcolumnoperatedat40◦C with an isocratic elution of 1 mL/min, the mobile phase composition was 80% water and 20% methanol. Thedetectionwavelengthwas243nm,whichrepresentsthemaximumabsorbanceforboth paracetamolandmetacetamol[66]whilestillremainingclosetothelambdamaxforacetanilideat 242nm[67]. Thematerialcorrespondingtoeachpeakinthechromatogramwasidentifiedusingmass spectroscopy. Theanalyticalsampleusedtodeterminethepurityoftheproductcrystalswasprepared byweighing14mgofdryproductcrystalsintoa100mLvolumetricflaskanddissolvingthemina 5%methanol/95%watermixturetoprepareasolutionwithaconcentrationwhichwaswithinthe concentrationrangeusedtocalibratetheinstrument. Motherliquorsweresimilarlydilutedbymassto ensureappropriatecompositionforassay. 3. Results 3.1. Solubility Thesolubilitycurvesofparacetmol,metacetamolandacetanilidein3-methyl-1-butanolprepared usingtheisothermalequilibrationandgravimetricanalysisandpolythermaldissolutiontemperature detection method are shown in Figure 3. These data are summarised in Table 1. Full details of Crystals2017,7,294 8of24 Crystals 2017, 7, 294 8 of 24 the gravimetric studies and dissolution temperature detection are given in Section S1 within the ESI†dmetaaitlesr oiaf ltsh.e gravimetric studies and dissolution temperature detection are given in Section S1 within tTheh eESsIo†l umbaitleitryiaolsf. paracetamol,metacetamolandacetanilideincreasewithincreasingtemperature. ParacetamThoel issotlhuebilleiatys tsoof lupbalreacinet3am-moel,t hmyle-t1a-cbeutatamnool laanndd aacecetatanniilliiddee isinthcreeamseo stwsiothlu binlecraenadsinegx hibits the stetrmopnegreastutrde.e pPearnadceetnacmyolo nis ttehme pleearsat tusorleub(Flei ginu r3e-m3)e.thEyxl-a1-mbuintainnogl tahned daacteatapnirleidsee niste tdhei nmFoisgt ure 3, soluble and exhibits the strongest dependency on temperature (Figure 3). Examining the data therewasadiscrepancyinsolubilityofmetacetamolobtainedbyisothermalequilibrationfollowedby presented in Figure 3, there was a discrepancy in solubility of metacetamol obtained by isothermal gravimetricanalysisandbyobservingthedissolutiontemperatureduringheatingusingtheTechnobis equilibration followed by gravimetric analysis and by observing the dissolution temperature during Crystalline. Determining the dissolution temperature using the Crystalline involves identifying a heating using the Technobis Crystalline. Determining the dissolution temperature using the clearpointatwhichdissolutionispresumedtohaveoccurred. Theclearpointwasdeterminedusing Crystalline involves identifying a clear point at which dissolution is presumed to have occurred. The bothtransmissivitymeasurementandexaminingimagesfromthecrystallinecamera. Thedissolution clear point was determined using both transmissivity measurement and examining images from the kinetcircysstdaellpineen dcaomnertah.e Tshize edaisnsdolushtiaopn ekoinfetthices cdreypsetanlds odnis tshoel vsiinzeg aanndd sthhaepier aobf itlhitey ctroysitmalps eddisesothlveinpga ssage ofligahntd( tthraeinr sambiilsitsyiv tiot yim)opredtoe tbhee cplaesasralgyer oefs olilgvhetd (tirnanasnmiimssiavgitey()c oarm toe rbae bclaesaerdly mreesaoslvuerde mine annt )i.mAaglteh ough them(ceaamsuerrae mbaesnedtw maesapsuerrefmoremnte)d. Aalttahomuogdh etshteh meaetaisnugrermateenot fw0a.1s ◦pCer/fomrmine,dth aet pao mssoidbeilsitt yheoaftoinvge rrsahteo oting thedoifs 0s.o1l °uCti/monint,e tmhep peorsastiubirleityre omf oavineresdh.oMotientga ctheet mdiosslohluatsioanv teemryptehraintunree eredmlea-ilnikede. cMryetsatcaeltmmoolr hpahso logy; a very thin needle-like crystal morphology; the crystals appear to persist some while after they could thecrystalsappeartopersistsomewhileaftertheycouldhavedissolvedinanisothermalexperiment. have dissolved in an isothermal experiment. As a result complete dissolution is detected at slightly Asaresultcompletedissolutionisdetectedatslightlyhighertemperaturethanseeninthegravimetric higher temperature than seen in the gravimetric method. Interestingly, there is no similar discrepancy method. Interestingly,thereisnosimilardiscrepancyinthedatacollectedusingthetwomethods in the data collected using the two methods for acetanilide, this is believed to be due to the higher foracetanilide,thisisbelievedtobeduetothehighersolubilityofacetanilideandthemorerapid solubility of acetanilide and the more rapid dissolution which may be linked to the thin plate-like dissolutionwhichmaybelinkedtothethinplate-likecrystalhabit. crystal habit. 300 250 Paracetamol (Gravimetric) ) g g/ m200 Metacetamol n ( (Gravimetric) o ti150 Metacetamol (Crystalline) a r t n e Acetanilide (Gravimetric) c100 n o C Acetanilide (Crystalline) 50 0 0 10 20 30 40 50 60 Temperature (°C) FiguFriegu3.reS o3.l uSobliulibtiylitoyf opfa praarcaecteatmamool,l,m meettaacceettaammool laanndd acaecteatnainlidileid ine i3n-m3e-mthyelt-h1y-blu-1ta-bnuolt aonbotalinoebdt abiyn edby isothiseormthearlmeqaul ileiqburialtibiorantifoonll ofwolelodwbeydg rbayv imgraevtriimceatnriacl yasnisalaynsdis baynodb sbeyrv ionbgsetrhveindgi sstohleu tdioisnsotelumtiponer ature duritnegmhpeearattiunrge udsuirninggt hheeaTtiencgh unsoibnigs tCher yTsetcahlnlionbei.s Crystalline. Table 1. Molecular weights, melting points, enthalpy of fusion and measured solubilities of Table 1. Molecular weights, melting points, enthalpy of fusion and measured solubilities of paracetamol, metacetamol and acetanilide determined using the gravimetric method. paracetamol,metacetamolandacetanilidedeterminedusingthegravimetricmethod. Measured Solubility in Compounds Molecular Weight (g/mol) Melting Point (K) ΔHfusion (kJ mol-1) 3-meMtheyals-1u-rbeudtSanoolul b(miligty/gi)n ComPaproaucentdasmol MolecularW1e5i1g.1h6t (g/mol) M44e3l.t6in [g68P];o 4in42t.(9K [)69] ∆2H7.f1u s[i6o8n](; k3J0.m72o l[-619)] 2255543 °.-◦8CmC ethy4l70-41 4°.-3Cb0 u ◦tCano51l52(4°m.C35g 5/g◦)C Metacetamol 151.16 420 [70,71] 26.0 [71]; 28.8 [70] 81.4 116.7 162.6 ParaAcceetatamnoillide 15113.156.17 443.6[6388]7;.454 [26.99][ 69] 27.1[6280].;3300 [.6792][ 69] 16524..88 241.784 .3 - 124.3 Metacetamol 151.16 420[70,71] 26.0[71];28.8[70] 81.4 116.7 162.6 Acetanilide 135.17 387.5[69] 20.30[69] 162.8 241.8 - The solubility of a crystalline organic material typically depends on the lattice structure (polymorph), melting point, molecular weight and solvent choice. The measured solubility of pTahraecestoamluobli alintdy moeftaacectarmysotla allrien reelaotrigvealnyi scimmilaatre irni acolmtypparicisaolnly wdithe paecentdansiloidne, tthhies ilsa ctotincseistsetnrut cture (poly morph), melting point, molecular weight and solvent choice. The measured solubility of paracetamolandmetacetamolarerelativelysimilarincomparisonwithacetanilide,thisisconsistent Crystals2017,7,294 9of24 withtheirrelationshipaspositionalisomerscontainingthesamefunctionalgroups. Theparacetamol crystalstructureisdominatedbyhydrogen-bondedmolecularchainspackedina‘herringbone’pattern. Similarly,Cmryesttalas c20e1t7a, 7m, 29o4l crystalsareboundtogetherbyanetworkofhydrogenbondin9g ofi 2n4t eractions. Acetanilidehoweverhasnohydroxylgroupinthepara-positionsolacksaprotondonor. Inaddition, with their relationship as positional isomers containing the same functional groups. The paracetamol the melting point and the enthalpy of fusion decrease in the order Paracetamol > Metacetamol > crystal structure is dominated by hydrogen-bonded molecular chains packed in a ‘herring bone’ Acetanilidpeat(tseerne. TSiambillearl1y), .mFeotarceatcaemtoaln cirlyidstealst haere cbroyusntda ltosgtreuthcetru brye ais nseutwcohrkt hoaf thmydorolegecnu lbeosndairneg boundby weakerforicnetesratchtaionnsi.n Apceatraanicleidtea mhoowledveure hatso nloa hckydorofxtyhl egrhoyupd rino txhyel pgarrao-upopsirteiodnu scoi lnacgkst ha eprooptopno drotnuonr.i tytoform In addition, the melting point and the enthalpy of fusion decrease in the order Paracetamol > ahydrogenbondingnetwork. Acetanilidehasasubstantiallylowerheatoffusionandalowermelting Metacetamol > Acetanilide (see Table 1). For acetanilide the crystal structure is such that molecules pointthanparacetamolandmetacetamol. Therelativesolubilityispresumedtoaffecttheimpurity are bound by weaker forces than in paracetamol due to lack of the hydroxyl group reducing the segregatioonppoofrtthuneitfiyn tao lfcorrmys ata hllyidnreogperno bdouncdti.ng network. Acetanilide has a substantially lower heat of The dfuastiaonp arneds ean tloewderi nmFelitginugr epo4init ntdhainc aptearatcheatatmtohle anpdr emseetnacceetaomfo1l. –T4h%e roeflattihvee ssoelulebciltietyd isi mpurities doesnotspigrensiufimceadn ttol yaffaefcfte tchte tihmepusroitlyu sbeiglrietygaotifonp oafr tahcee ftinaaml coryl.stAaltlin2e5 p◦rCoduacntd. 40◦C,itwasshownthatthe The data presented in Figure 4 indicate that the presence of 1–4% of the selected impurities does solubilityissimilarorincreasesslightlywiththepresenceoftheselectedimpurities. At55◦C,thedata not significantly affect the solubility of paracetamol. At 25 °C and 40 °C, it was shown that the showsincrsoelausbeilditys cisa stitmerilaarn odr itnhceretarseesn dsligishtlleys wsipthr othneo purnesceendce. oIft tchaen sebleectceodn imclpuudreitdiest. hAatt 5t5h °eCe, fthfeec tof1–4% metacetamdoatla/ sahcoewtas ninilcirdeaeseodn sctahteters oanludb thilei ttyrenodf pisa lersasc pertoanmouonlciesd.m Ito cdane sbte. concluded that the effect of 1–4% metacetamol/acetanilide on the solubility of paracetamol is modest. Figure 4. Solubility of paracetamol in 3-methyl-1-butanol with the presence of impurities Figure4.Solubilityofparacetamolin3-methyl-1-butanolwiththepresenceofimpurities(metacetamol (metacetamol and acetanilide) obtained by equilibration and gravimetric assay. andacetanilide)obtainedbyequilibrationandgravimetricassay. 3.2. Ultrasonic Intensity Measurements 3.2. UltrasonicTIhnet eunltsriatsyouMndea isnuternemsiteyn mtseasurements reveal that the local ultrasonic field is highly chaotic and intensities range from 0.12 to 0.25 mW/cm2 at 50% ultrasonic power and from 0.9 to 1.68 mW/cm2 Theultrasoundintensitymeasurementsrevealthatthelocalultrasonicfieldishighlychaoticand at 100% power (see Table 2). It is clear from this data that the % ultrasound power is not a linear intensitiesdreasncrgipetofrr.o Cmry0st.a1l2listaotio0n.2 e5xmpeWrim/ecnmts 2waetre5 0co%nduulcttreads oatn picospitoiownse r1 aanndd 2fr oanmd 0th.9e tuoltr1a.s6o8unmd W/cm2at 100%poweinrte(nsesietyT aapbplelie2d) .dIutriisngc lethaersefr oexmpetrhimisendtas tcaatnh baet tchhear%actuerlitsreads oasu; nzderpo o(0w merWis/cnmo2)t laowlin, e50a%r descriptor. ultrasound power (0.19 ± 0.06 mW/cm2) and high, 100% ultrasound power (1.45 ± 0.21 mW/cm2). Crystallisationexperimentswereconductedatpositions1and2andtheultrasoundintensityapplied during these experiments can be characterised as; zero (0 mW/cm2) low, 50% ultrasound power Table 2. The ultrasonic intensity was measured at four positions within the ultrasonic bath. (0.19±0.06mW/cm2)andhigh,100%ultrasoundpower(1.45±0.21mW/cm2). Ultrasonic Intensity (mW/cm2) Positions on the Stirrer plate at the Bottom of the Ultrasonic Bath 50% Ultrasonic Power 100% Ultrasonic Power Table2.Theultrasonicinte1 nsitywasmeasuredatfourpo0s.i1t3i ±o 0n.0s2 withintheu1l.2t5r a± s0o.1n3 icbath. 2 0.25 ± 0.03 1.68 ± 0.25 3 0.24 ± 0.02 1.32 ± 0.09 4 0.12 ±U 0l.t0r4a sonicIntensity0.9(m ± W0.0/7c m2) PositionsontheStirrerplateattAhveeBraogteto vmaluoefs theUltrasonicBath 50%U0l.t1r9a ±so 0n.0i7c Power 110.209% ± 0U.3l2t rasonicPower 1 0.13±0.02 1.25±0.13 2 0.25±0.03 1.68±0.25 3 0.24±0.02 1.32±0.09 4 0.12±0.04 0.9±0.07 Averagevalues 0.19±0.07 1.29±0.32 Crystals2017,7,294 10of24 3.3. Sonocrystallisation The data comprise 11 suspension crystallisation experiments designed using the Design of Experiments software MODDE. (Umetrics Modde, Version 11, MKS Instruments, Umea, Sweden) to facilitate multivariate analysis. A full factorial (2 level) method was used to create a data set that was then analyzed using multiple linear regression (MLR) methods to measure effects of the three independent variables on the experimental responses. The parameters investigated were; theconcentrationsofthetwoimpuritieswheretheparameterrangewasselectedas0–2mol%and ultrasonicpowerwheretheparameterrangewas0%to100%powersettingsontheultrasonicbath. Whentheultrasonicpowerwasmeasuredthecenterpoint(50%ultrasoundpower)theintensitywas foundtobe0.19±0.06mW/cm2andat100%ultrasoundpowertheintensitywas1.45±0.21mW/cm2. Theresponsesanalyzedwerenucleationtemperature,particlesize,filtrationrate,productyieldand thepercentageofimpuritiesintheproductcrystals. Theeffectofthepercentageofimpuritiespresentinsolutionatthestartofcrystallisationand ultrasonicpoweron;nucleationtemperature,crystalsizedistribution,filtrationrateandprocessyield atadefinedcrystallisationendpointaresummarisedinTable3. Table3. Summaryofcrystallisationtemperature,crystalsizedistribution,filtrationtime(for50mL suspensionsolution),filtrationrate,cakeresistanceandprocessyieldasafunctionofthepercentageof impuritiesandultrasonicpower. Experiments Tcrys(◦C) PSLDenMgethan(µCmho)rd FTiilmtraeti(os)n RFaitletr(amtio3/ns) Cake(mRe/ksigs)tance Yield Pureparacetamol 41.3 47–55 209 1.90×10−7 7.03×1011 57.7% (100%powerUS) Pureparacetamol 36.0 85–100 95 4.29×10−7 2.62×109 54.3% (noUS) 2mol%Metacetamol 36.4 47 361 1.07×10−7 1.52×1010 45.5% (100%powerUS) Aftermaintaining 2mol%Metacetamol at15◦Cfor 100–109 45 1.06×10−7 9.02×108 39.1% (noUS) approx.1.5h 2mol%Acetanilide 43 40 561 7.32×10−7 1.88×1010 56.2% (US100%P) 2mol%Acetanilide 15.5◦C 105 54 7.01×10−7 1.02×109 55.3% (noUS) 2mol%Metacetamol& Acetanilide 34.4 37.3 346 1.19×10−7 1.51×1010 42.2% (US100%power) Aftermaintaining 2mol%Metacetamol& at15◦Cfor 87–90 48 9.61×10−7 1.14×109 32.0% Acetanilide(noUS) approx.2.5h 1mol%Metacetamol& 1mol%Acetanilide 44 87 61 7.19×10−7 1.38×109 40.6% (50%USpower) 3.3.1. CrystallisationTemperature Thenucleationtemperaturemeasuredwithandwithouttheuseofultrasoundforcrystallisation ofparacetamolinthepresenceofmetacetamoland/oracetanilideisshowninTable3. Eventhough nucleation is a stochastic process and some scatter may be anticipated among the measured data the experimental results clearly show that ultrasound has a significant effect on the nucleation process. Forexample,inthecaseofparacetamolcrystallisationinthepresenceof2%metacetamol, the ultrasound treated sample started to nucleate at around 36 ◦C, and was in the final stages of crystallisationbythetimethesuspensionhadbeencooledto15◦C.Bycontrastthesamplenottreated withultrasoundonlystartedtonucleateafterholdingat15◦Cforapproximately1.5h. Thisisbelieved tobeduetotheslownucleationandcrystalgrowthkineticsinthepresenceofimpurities. Ultrasound canpromotenucleationandgeneratesubstantialnumbersofsecondarynucleifromexistingparent

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Introduction. Crystallisation is the principal purification technique in the pharmaceutical, fine chemical, paint, pigments and agrochemical sector. It allows the .. Agilent High Performance Liquid Chromatography 6130 dual source model (Agilent, Santa Clara, CA, .. efficient crystallisation process
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