Post on 18-Dec-2015
Åke C. Rasmuson
Chemical Engineering and TechnologyKTH - Royal Institute of Technology
SE - 100 44 Stockholm, Swedenrasmuson@ket.kth.se
Molecules, Aggregation, Nucleation and
Crystallization, april 2007
Crystallization of organic fine chemicals and pharmaceuticals
Outline
Introduction Fundamentals Crystal shape and purity Polymorphism Control of particle size Reaction crystallization
Properties of product crystals
compound polymorph purity size and size distribution crystal shape agglomeration
downstream properties end-use properties
Overall performance
Specific physical properties
Ammonium sulphate
Sodium chloride
Sugar
Citric acid monohydrate
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
Outline
Introduction Fundamentals Crystal shape and purity Polymorphism Control of particle size Reaction crystallization
Fundamentals
• Solubility• Generation of supersaturation• Crystal nucleation• Crystal growth
Temperature
Co
nce
ntr
atio
n
Solubilitycurve
supersaturated
undersaturated
Solubility
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
Temperature
Co
nce
ntr
atio
n
AB
C
Solubilitycurve
supersaturated
undersaturated
CoolingEvaporationDrowning-outReaction
cooling
evaporation
Generation of supersaturation
Temperature
Co
nce
ntr
atio
n
Solubility
undersaturated
metastable
supersaturated
Metastability
Temperature
Co
nce
ntr
atio
n
Solubility
undersaturated
metastable
supersaturated
Primary nucleation
Primarynucleation
supersaturation
nu
cle
atio
n r
ate
Primary nucleation
Clustering and nucleation
Nucleation depends on:
• supersaturation• temperature• the solvent• impurities• additives
• large molecules• flexible molecules• branched molecules
....can be more difficult to nucleate
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
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
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
Solubility of paracetamol in acetone-water at 30 °C
Crystal growth
Crystal growth
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
Outline
Introduction Fundamentals Crystal shape (habit) and purity Polymorphism Control of particle size Conclusions
Crystal shape
Crystal shape – e.g. ibuprofen
Paracetamol – various faces
The unit cell
Paracetamol {110}
Swedish Research Council for Engineering Science
Paracetamol {011}
Tailor-made additives
e.g. Influence of benzoic acid on benzamide crystals
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
Outline
Introduction Fundamentals Crystal shape and purity Polymorphism Control of particle size Reaction crystallization
Polymorphs
diamond
graphite
same chemical compound - different crystal structures
different physicalproperties, e.g.:densityhygroscopicitymelting pointsolubilitystabilitydissolution ratesurface propertieshardnesscompactibilitytensile strength
shelf lifebioavailabilityreliable processingpatent protection
Polymorphs
Polymorphs - Chocolate
Form V
Form VI
Polymorphs of potassium para-amino benzoic acid
Nucleation of Polymorphs
TkG
JJ critΔexp0 2
23
2
23
STkF
)(FG mSLmSL
crit lnΔ
Polymorphism
monotropyenantiotropy
Outline
Introduction Fundamentals Crystal shape and purity Polymorphism Control of particle size Reaction crystallization
Particle size and morphology
Agglomerate properties: Texture Internal structure Strength Degree of agglomeration
Crystal size ”not a unique
value”
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
Temperature
Co
nce
ntr
atio
n
Solubilitycurve
supersaturated
undersaturated
cooling
Generation of supersaturation
Primarynucleation
Secondary nucleation
Batch cooling crystallization
time
nucleation rate supersaturation
Outline
Introduction Fundamentals Crystal shape and purity Polymorphism Control of particle size Reaction crystallization
Reaction crystallization
• Reactant solutions are mixed• Often solubility very low• Supersaturation often very high where reactants mix
*/ ccS
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
• 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
(Åslund and Rasmuson, 1992)
Semibatch precipitation
Influence of reactant concentrations
Benzoic acid
Semibatch precipitationInfluence of feeding time Benzoic acid
(Åslund and Rasmuson, 1992)
(Åslund and Rasmuson, 1992)
Semibatch precipitation
Influence of agitation rate
Benzoic acid
(Ståhl, Åslund and Rasmuson)
T-mixer precipitationBenzoic acid