Åke C. Rasmuson Chemical Engineering and Technology KTH - Royal Institute of Technology SE - 100 44...
Transcript of Åke C. Rasmuson Chemical Engineering and Technology KTH - Royal Institute of Technology SE - 100 44...
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Åke C. Rasmuson
Chemical Engineering and TechnologyKTH - Royal Institute of Technology
SE - 100 44 Stockholm, [email protected]
Molecules, Aggregation, Nucleation and
Crystallization, april 2007
Crystallization of organic fine chemicals and pharmaceuticals
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Outline
Introduction Fundamentals Crystal shape and purity Polymorphism Control of particle size Reaction crystallization
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Properties of product crystals
compound polymorph purity size and size distribution crystal shape agglomeration
downstream properties end-use properties
Overall performance
Specific physical properties
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Ammonium sulphate
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Sodium chloride
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Sugar
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Citric acid monohydrate
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Pharmaceuticals and fine chemicals are more difficult to crystallize than common
bulk chemicals!
solvates and salts different polymorphs larger molecules flexible molecules impurities – tailor-made-additive-like not specialized equipment not specialized agitation
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Outline
Introduction Fundamentals Crystal shape and purity Polymorphism Control of particle size Reaction crystallization
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Fundamentals
• Solubility• Generation of supersaturation• Crystal nucleation• Crystal growth
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Temperature
Co
nce
ntr
atio
n
Solubilitycurve
supersaturated
undersaturated
Solubility
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So
lub
ilit
y [
mo
l S
A/m
ol
tota
l]
Temperature [oC]
0
100
200
300
400
500
600
5 10 15 20 25 30 35 40 45 50 55
MeOH
ACN
Hac
Acetone
EtAc
H2O
So
lub
ilit
y [
mo
l S
A/m
ol
tota
l]
Temperature [oC]
0
100
200
300
400
500
600
5 10 15 20 25 30 35 40 45 50 55
MeOH
ACN
Hac
Acetone
EtAc
H2O
Solubility of Salizylic acid
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Temperature
Co
nce
ntr
atio
n
AB
C
Solubilitycurve
supersaturated
undersaturated
CoolingEvaporationDrowning-outReaction
cooling
evaporation
Generation of supersaturation
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Temperature
Co
nce
ntr
atio
n
Solubility
undersaturated
metastable
supersaturated
Metastability
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Temperature
Co
nce
ntr
atio
n
Solubility
undersaturated
metastable
supersaturated
Primary nucleation
Primarynucleation
supersaturation
nu
cle
atio
n r
ate
Primary nucleation
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Clustering and nucleation
Nucleation depends on:
• supersaturation• temperature• the solvent• impurities• additives
• large molecules• flexible molecules• branched molecules
....can be more difficult to nucleate
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Thermodynamic barrier for nucleation
surface term
volume term
G = GS + GV = 4r2 + 4/3 r3Gv
kT
GKB crpp exp1
22
323
)ln(27
4
SkTk
vkG
v
smacr
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The interfacial energy [J/m2]
The molecules at the surface possess additional energy by an amount that is equal to the missing contributions to its bonding always 0 ;
slp,T
sl A
G
Interfacial energy = increase in free energy as a result of formation of 1
unit of surface
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Interfacial energy
Contact angle
coslvsvsl vs. ST 23 ln/1indln t
The solid-liquid interfacial energy is difficult to determine experimentally
eqeq x
xT
23 ln/1
2
4
6
8
0E+00 2E-06 4E-06 6E-06
ln tind
(35-65)(30-70)(25-75)(20-80)
wt.% (acetone-water)
Induction time
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Solubility of paracetamol in acetone-water at 30 °C
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Crystal growth
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Crystal growth
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Crystal growth depends on:• supersaturation• temperature• the solvent• impurities• additives
Crystals of ........
• large molecules• flexible molecules• branched molecules
....can be more difficult to grow. Impurities in ppm concentration can have a dramatic effect
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Outline
Introduction Fundamentals Crystal shape (habit) and purity Polymorphism Control of particle size Conclusions
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Crystal shape
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Crystal shape – e.g. ibuprofen
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Paracetamol – various faces
The unit cell
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Paracetamol {110}
Swedish Research Council for Engineering Science
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Paracetamol {011}
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Tailor-made additives
e.g. Influence of benzoic acid on benzamide crystals
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a) solution adhering to the surface
b) incorporation into the lattice
c) macroscopic cavities inside the crystal
d) “adsorbed” in lattice channels and cavities
Purity
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Outline
Introduction Fundamentals Crystal shape and purity Polymorphism Control of particle size Reaction crystallization
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Polymorphs
diamond
graphite
same chemical compound - different crystal structures
different physicalproperties, e.g.:densityhygroscopicitymelting pointsolubilitystabilitydissolution ratesurface propertieshardnesscompactibilitytensile strength
shelf lifebioavailabilityreliable processingpatent protection
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Polymorphs
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Polymorphs - Chocolate
Form V
Form VI
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Polymorphs of potassium para-amino benzoic acid
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Nucleation of Polymorphs
TkG
JJ critΔexp0 2
23
2
23
STkF
)(FG mSLmSL
crit lnΔ
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Polymorphism
monotropyenantiotropy
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Outline
Introduction Fundamentals Crystal shape and purity Polymorphism Control of particle size Reaction crystallization
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Particle size and morphology
Agglomerate properties: Texture Internal structure Strength Degree of agglomeration
Crystal size ”not a unique
value”
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Crystal size – the number controls the size
Equal mass
Hence operate to control the number generation
27 particles d=1 1 particle d= 3filtration 9 times faster
d
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Temperature
Co
nce
ntr
atio
n
Solubilitycurve
supersaturated
undersaturated
cooling
Generation of supersaturation
Primarynucleation
Secondary nucleation
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Batch cooling crystallization
time
nucleation rate supersaturation
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Outline
Introduction Fundamentals Crystal shape and purity Polymorphism Control of particle size Reaction crystallization
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Reaction crystallization
• Reactant solutions are mixed• Often solubility very low• Supersaturation often very high where reactants mix
*/ ccS
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Crystal size – the number controls the size
Equal mass
Hence operate to control the number generation
27 particles d=1 1 particle d= 3filtration 9 times faster
d
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• reactant concentrations• feed flow rate - feeding time• type of agitator• agitation rate • feed point position• feed pipe diameter• feed pipe shape
NaBe
HCl
Low soluble compound
255*
c
cS
Semi-batch crystallization of benzoic acid
stoichiometric0,002 kg/kg*c
Experimental variables
HBeNaClHClNaBe
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(Åslund and Rasmuson, 1992)
Semibatch precipitation
Influence of reactant concentrations
Benzoic acid
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Semibatch precipitationInfluence of feeding time Benzoic acid
(Åslund and Rasmuson, 1992)
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(Åslund and Rasmuson, 1992)
Semibatch precipitation
Influence of agitation rate
Benzoic acid
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(Ståhl, Åslund and Rasmuson)
T-mixer precipitationBenzoic acid