15 crystallization

UNZA Pharmacy Training Lecture notes

2. 6/21/2020 2
CRYTALLIZATION

3. Crystallization
Crystallizationisaseparationandpurificationtechnique
employedtoproduceawidevarietyofmaterials.
Crystallizationistheprocessbywhichmoleculesoratoms
arrangethemselvesintodefinitegeometricalpatternscalled
crystals.
Duringcrystallization,phasechangetakesplaceinwhicha
crystallineproductisobtainedfromasolution.
Importance of crystallization
1. Purification.
2. Improvement of flowability.
3. Improvement of stability.
4. Enhancement of filtration and washing.
5. Decrease of caking.
6. Improvement of appearance.

4. Crystallizationfromsolution
Consistsof3steps:
a.Inductionofsupersaturation.
b.Nucleation.
c.Crystalgrowth.
A] Methods of induction of super saturation:
1. Cooling:
Suitableforsubstanceswhosesolubilityincreaseswith
temperature.
ItiscommonwithinorganicsaltssuchasKNO
3andNaNO
3.
2.Solventevaporation:
Suitableforsubstanceswhosesolubilityisindependentof
temperature.
ItiscommonwithsaltssuchasNaClandcalciumacetate.

5. 3.Adiabaticevaporation:
Suitableforthermolabilesubstances.
Itinvolvesmaintaininglowpressureinachamber
containingsolutionwhichwillbegintoevaporateto
balancelostpressure.
4. Addition of a third substance:
a.Ithasahigheraffinitytothesolvent,whichwill
resultin↓solubilityofsoluteinsolventsaltingout.
b.Itformsaprecipitatebyreactingwiththesolute
c.ItchangesthepHofthesolution,resultinginthe
precipitationofthesolute.

6. B] Nucleation
Mier's Theory:
1.AsolutionwithtemperatureandconcentrationAis
saturatedby:a.coolingtotemperatureB
b.increasingitsconcentrationtoCbyevaporation.
Uponfurthercoolingorevaporation,super- saturationoccurs.
2.Inthemetastableregion(BB'orCC),thereisno
spontaneousnucleation.
Crystallizationrequirestheadditionofexternalnuclei.
3.Uponfurthercoolingorevaporation, themetastable
regionisexceededandspontaneousnucleationoccurs.

7. C] Crystal Growth
Therateofcrystalgrowthinasolutiondependson:
1.Concentrationgradientfortransferofsolutefrombulkof
liquidtowardsthecrystalface.
2.Temperaturegradientfordepositionofheatof
crystallizationatcrystalface.
* Heat of crystallization:
Istheheatevolvedorabsorbedwhen1moleofasubstancecrystallizes.
3.Relativevelocity(rotationspeed)betweensolidandliquid.

8. Crystal Size
1.FineCrystalsareproducedby:
Rapidcoolingandfrequentagitationahigh
nucleationrateandslowrateofcrystalgrowth.
Theobtainedcrystalsarecohesive,formacakeand
aredifficulttowash.
Thepurityisgenerallylessthanmediumorlargesize
crystals
2.MediumCrystalsareproducedby:
Slowcoolingwithoutmechanicalagitation.

9. 3.VeryLargeCrystalsareproducedby:
(i)allowinglargevolumeofsolutiontoevaporate
spontaneouslyor
(ii)slowcontrolledcoolingofthesolutioninthe
reactionvessel.
Crystalgrowthoccursmoreslowlyand
subsequentfiltrationandwashingresultsinthe
formationofperfectlypurecrystals.
Forlargecrystalstogrow,thesolutionshould
beperfectlyclearbyfiltrationandkeptinadust-
freeenvironment.
Theformationoflargecrystalsmaybe
facilitatedbyseeding.

10. Factors affecting crystallization
process
1.Temperature
↑temperature↑or↓solubilityofthesolute.
KCl04(potassiumchlorate)possessesalargepositivetemperature
coefficientofsolubility(↑temperature↑solubility).
Itcrystallizesbycoolingofasaturatedsolution.
NaClpossessesaverysmalltemperaturecoefficientofsolubility.
Crystallizationbycoolingisnoteffective.Crystallizationbysolventevaporation.
Sodiumhydrogenphosphateandferroussulphateshowchangesinthe
stableformofthematerialwithtemperature.
CrystallizationofFeSO4<50°Cresultsintheformationof(FeSO4.7H2O)
AthighertemperatureyieldFeSO4.4H2OoranhydrousFeSO4.

11. 2.PresenceofImpurities:
Adsorptionofimpuritiesonthesurfaceofthenucleolusor
crystalsmay:
a.retardrateofnucleationandcrystalgrowth
(0.1%HClpreventsthecrystalgrowthofNaClcrystals).
b.resultincrystalshapemodification
(e.g.crystallizationofNaClinpresenceofureaformoctahedral
insteadofcubiccrystals)
3.NucleiFormationVersusCrystalGrowth:
Growthrateistheincreaseinsizeperunittime.
Nucleationrateisthenumberofnewcrystalsproducedper
unittime.
Atlowsuper-saturation, growthpredominates.
Athighersuper-saturation, nucleationpredominates.

12. 4. Effect of Agitation:
Initially,itincreasescrystalgrowthrateby:
1.↑heattransferrateby↓thermalresistanceoftheboundary
layer.
2.↓thicknessanddiffusionalresistanceoftheboundary
layer.

Atcertainpoint, nomoreincreaseincrystalgrowthrate
occurs.
Motherliquor
Theliquidremainingafteracropofcrystalsisobtained,
(generallysubjectedtofurtherconcentrationtoformcrystals).
*Theprocessisrepeateduntilrecoveryofallofthedissolved
substances.
*Cropsofcrystalsobtainedbyconcentrationofthemother
liquorarelesspurethanthe1stcropandrequirere-
crystallization.

13. A] Cooling Crystallizers
1. Oslo cooler crystallizer
Supersaturationisproducedin
onepartofthecrystallizerandis
releasedinanother.
Thehotconcentratedsolutionis
fedintothecooler,wheresuper
saturationtothemetastable
regionoccursbutwithout
crystallization.
Apumpcirculatesthesolution
fromthecoolertothetank.
Thesupersaturatedsolution
passesthroughthecontrolpipeto
thebottomofthecrystallizer
containingabedofseeds(actas
nuclei)wherecrystallizationand
crystalgrowthoccurs.

14. Large crystalsare collected from the bottom of the crystallizer
by Hydraulic classification.
Small crystalsare formed at a higher level of solution and are
removed by the cyclone separator.
Themotherliquorre-entersthecrystallizerwiththehot
incomingfeedandtheoperationisrepeated.
Advantages of Oslo cooler crystallizer
1. Smaller crystals can be separated from large ones.
2. No precipitation takes place in the cooler
3. Can be operated in batch & continuous modes.
4. High capacity.
5. Used to crystallize salts with a +ve temperature coefficient,
e. g. NaNO3, NaClO3, KCl03 and NH4Cl
Process Control Parameters:
1. Feed rate.
2. Feed temperature.
3. Heat removal in the cooler.

15. 2. Howard Crystallizer
Itisaverticalconicaldevice
throughwhichthesolution
flowsinanupwarddirection.
Coolingisusedtoachieve
super- saturationatwhich
stagenucleationoccurs.
Nucleigrowastheymove
upwarduntiltheirsizeisjust
enoughtoovercomegravity.
Atthispoint,thecrystals
settlewithauniformsize.
Thecrystalsizeiscontrolled
byfeedvelocity.

16. Oslo Evaporative Crystallizer
Thesolutionisfedand
heatedbytheheater,followed
byflashingthesolutioninthe
flashingheadtolosepartofits
solventasvaporandbecome
supersaturated.
Thesupersaturatedsolution
fallsdownacentralpipeand
upthroughascreentothebed
ofcrystalsthatissuspendedin
thecrystallizationchamber.
B] Evaporative Crystallizers

17. Thesolutiongetsincontactwiththe
suspendedcrystalsforcrystallizationand
crystalgrowthtooccur.
Largecrystalsaredischargedfromthebottom
Finecrystalsrecirculatewiththefeedsolution.
Thismethodisrapidandproducessmalluniform
crystals.
Itcanbeusedformaterialswithzeroornegative
temperaturecoefficient.

18. C] Vacuum Crystallizers
Theyachievesupersaturationbyadiabatic
evaporationandcooling.
Ahotconcentratedsolutionentersachamber
(keptatalowpressure),thesolutionbeginsto
evaporatetobalancelostpressure.
Thelatentheatofevaporationwillbetaken
fromthesolutionitself,whichinturnbecomes
coldandsupersaturatedwithoutexternalheat
transfer.

19. Oslo vacuum crystallizer
Used forthermolabile
materials.
Hassimilardesigntooslo
evaporativecrystallizer,
butwithoutaheater.Advantages:
a.Absenceofheatedhead
makeitoflowcost.
b.Absenceofcooling
medium preventsthe
surfacecorrosion.

20. Separation of a Mixture by
Extraction: Crystallization

21. Objectives
Separationofamixturecontainingan
acidicandaneutralcompoundsby
extraction.
Purificationofthesolidcomponentby
crystallization.
IdentifythosecomponentsfromitsIR
spectrumanditsmeltingpoint.

22. Terms
Separation
Extraction
Crystallization

23. Separation
Whyweneedtoseparatemixture??
Toisolateorconcentratecomponents
fromamixture.
Toseparateacomponentsfromother
speciesthatwouldinterfereinthe
analysis

24. Methods of Separation
Extraction
Crystallization
Distillation
Chromatography

25. Extraction
Extraction: Transferofasolutefromone
phasetoanother.

26. Types of Extraction
Canusemostanycombinationof
phases(solid,liquid,gas,supercritical
fluid).
Solid–Liquid
-Usefulfortheisolationand
purificationofnaturallyoccurring
sources.

27. Extraction
Makingcoffeeisanexampleforextraction.

28. Extraction
Liquid–Liquid
-Morecommonmethod
-Dependonsolubilitypropertiesof
components.
Like dissolves like
-Soideally,theextractingsolvent
shouldbesimilartothesolute.

29. Extraction
Wewillusetwo
immiscibleliquids.
-Typicallyaqueous/
organicsolventcombos

30. Extraction
Organicsolventslessdensethanwater.
-Diethylether,Toluene,Hexane
Organicsolventsmoredensethan
water.
-Dichloromethane,Chloroformand
Carbontetrachloride.

31. Qualities of the Solvent
Immisciblewithothersolvent.
Itshouldreadilydissolvethecompound
tobeextracted.
Itshoulddissolvelittleornoneofthe
unwantedcompounds/impurities.
Easilyseparatedfromthecompound.
Shouldnotundergoanyreactionwiththe
compounds.

32. Extraction

33. Extraction
Equilibriumconstantforthispartitioning
isK(partitioncoefficientordistribution
coefficient)
K=
[S]
2
[S]
1

34. Extraction
ChemicallyInertExtraction.
ChemicallyActiveExtraction.

35. Chemically Active Extraction
Areagentthatreactschemicallywiththe
substancetobeextracted.
Solubilitypropertychangesafterthe
reaction.

36. Chemically Active Extraction
COOH
COONa
Soluble in Diethyl ether
& Insoluble in Water
10 % NaOH
Soluble in Water & Stay in aqueous layer
10 % NaOH
No Reaction
& Stay in ether
layer

37. Chemically Active Extraction
NO
2
CH
2
NH
2
CH
2
NH
3
+
Soluble in Diethyl ether
& Insoluble in Water
10 % HCl
Soluble in Water & Stay in aqueous layer
10 % HCl
No Reaction
& Stay in ether
layer

38. Procedure for Today’s Lab
Getyourunknownmixture.
Transferallyourunknownintoa100mL
beakerandfindthemassofyour
unknown.
Add30mLofdiethylether,stirslowlyto
dissolvethemixture.
Add15mLmoreofdiethyletherand
rinsethebeaker.

39. Procedure for Today’s Lab
Add15mLof5%sodiumbicarbonateto
theethersolution.
Swirltheseparatoryfunnelfirstand
shakegently.
Separatethetwolayers.
Repeatthesestepstwotimesusing
fresh5%sodiumbicarbonatesolution.
Poolalltheaqueouslayersi.e.sodium
bicarbonatesolution

40. Recovery of Acidic Compound
Coolalltheaqueousextractsforabout5
minutesinanice–waterbath.
Add3mLofconcentratedhydrochloric
acid.
Testtheacidityofthissolutionwithblue
litmuspaper(TURNRED).
Ifitisnotacidicenough; add1mLof
acidmore.

41. Recovery of Neutral Compound
Placeasmallpieceofcottoninadry
glassfunnel.
KeepafreshanddryErlenmeyerFlask
underthefunnel.
Add5g.ofanhydroussodiumsulfate
overthecottonplugandtransferallthe
etherlayercarefullythroughtheneck.

42. Recovery of Neutral Compound
Rinsetheseparatoryfunnelwith5mLof
etherpourintodryingagent.
Addfewboilingchipsandkeepona
steambath.
Corktheflasktightlyoncealltheether
hasgone.

43. Recrystallization
It’s a technique to purify the solid organic
compounds.
1. Slow evaporation
2. Slow cooling
3. Liquid diffusion
4. Use of seed crystal

44. Recrystallization
Compoundtobepurified:
1.Moderateorhighsolubilityinhotsolvent
2.Lowincoldsolvent
Impurities:
1.
Insolubleinhotsolventorhighsolublein
coldsolvent.
Easilyremovedaftercrystallization.
Shouldnotreactwithsubstancebeing
purified.

46. Procedure for Recrystallization
Dissolvealltheacidiccompoundin
minimumamountofhotsolvent.
Filterthesolutionwhenitishot.
Slowlycoolthesolutiontoroom
temperature; thenkeeponicebath.
Filterthecrystals,washitwithminimum
amountofcoldsolvent.
Allowtodryonitsown.

47. Characterization
NeutralCompound
1.Findtheamountofneutral
compound yourecoveredfrom
themixture.
2.ObtainitsIRspectrum.
AcidicCompound
1.Calculatethe%ofrecovery.
2.Finditsmeltingpoint.

48. Changes
UseBlueLitmusinsteadofCongo
Red.

49. Notes
Donotforgettoaddtheboilingchips
whenyouevaporatediethylether.
Venttheseparatoryfunnelveryoftento
relievethedevelopedpressure.

50. Caution
NO FLAMES IN LAB TODAY

51. Any Questions or Additions

52. THANK YOU

53. Definethefollowingterms:
[Crystallization,Nucleation, etc]
Respondtothefollowingquestions:
Giveadetailedaccountof………………
Explainindetailstheprocessof…………..
Describeindetailswithexamplesthe…………
Withexamples,illustratethepharmaceuticalapplicationsof……………

54. Groupworkdiscussionalquestions:
Explainindetailstheprocessof………
Describewithexamplesindetailsthe…………..
Withexamples,illustratethepharmaceuticalapplicationsof…….