Åke C. Rasmuson Chemical Engineering and Technology KTH - Royal Institute of Technology SE - 100 44...

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

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

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


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 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


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


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


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



Semibatch precipitation

Influence of agitation rate

Benzoic acid

(Ståhl, Åslund and Rasmuson)

T-mixer precipitationBenzoic acid

Åke C. Rasmuson Chemical Engineering and Technology KTH - Royal Institute of Technology SE - 100 44...

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