1. Crystallization of organic fine chemicals and pharmaceuticals
Molecules, Aggregation, Nucleation and Crystallization, april 2007
Crystallization of organic fine chemicals and pharmaceuticals
Åke C. Rasmuson
Chemical Engineering and Technology
KTH - Royal Institute of Technology
SE Stockholm, Sweden

2. Outline Introduction Fundamentals Crystal shape and purity
Polymorphism
Control of particle size
Reaction crystallization

3. Properties of product crystals
Specific physical properties
compound
polymorph
purity
size and size distribution
crystal shape
agglomeration
Overall performance
downstream properties
end-use properties

4. Ammonium sulphate
Rasmuson, Å, Fin- och specialkemikalieteknik kurskompendium, 1998.

5. Sodium chloride
Rasmuson, Å, Fin- och specialkemikalieteknik kurskompendium, 1998.

6. Sugar
Rasmuson, Å, Fin- och specialkemikalieteknik kurskompendium, 1998.

7. Citric acid monohydrate
Rasmuson, Å, Fin- och specialkemikalieteknik kurskompendium, 1998.

8. 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

9. Outline Introduction Fundamentals Crystal shape and purity
Polymorphism
Control of particle size
Reaction crystallization

10. Fundamentals Solubility Generation of supersaturation
Crystal nucleation
Crystal growth

11. Solubility Concentration Solubility curve Temperature supersaturated
undersaturated
Temperature

12. Solubility of Salizylic acid

13. Generation of supersaturation
Cooling
Evaporation
Drowning-out
Reaction
Concentration C
supersaturated
evaporation B A
cooling
Solubility
curve
undersaturated
Temperature

14. Metastability Concentration Solubility Temperature supersaturated
metastable
undersaturated
Temperature

15. Primary nucleation Concentration Solubility Temperature
supersaturation
nucleation rate
Primary nucleation
supersaturated
Concentration
Primary
nucleation
Solubility
metastable
undersaturated
Temperature

16. Clustering and nucleation
Nucleation depends on:
supersaturation
temperature
the solvent
impurities
additives
large molecules
flexible molecules
branched molecules
....can be more difficult to nucleate

17. Thermodynamic barrier for nucleation
surface term
volume term
Myerson, A.S., Solutions and solution properties, In Handbook of Industrial Crystallization, Chapter 1, Myerson, A.S. (Ed.), Butterworth-Heinemann, Maryland, 1993, 18; Mullin, J.W., Crystallization, 3rd Ed., Butterworth-Heinemann, Great Britain, 1993, 174.
The free energy change of homogeneous nucleation for a sphere
A nucleus smaller than critical size is unstable and will dissolve. A nucleus is assumed to reach the critical size because of local energy fluctuations in the solution.
The overall excess free energy between a small solid particle of solute and the solute in solution is equal to the sum of the surface excess free energy, i.e. the excess free energy between the surface of the particle and the bulk of the particle, and the volume excess free energy, i.e. the excess free energy between a very large particle and the solute in solution.
DGv is the free energy change of the transformation per unit volume
g is the interfacial tension
DG = DGS + DGV = 4pr2g + 4/3 pr3DGv

18. The interfacial energy
[J/m2]
Interfacial energy = increase in free energy as a result of formation of 1 unit of surface
The molecules at the surface possess additional energy by an amount that is equal to the missing contributions to its bonding

19. Interfacial energy
The solid-liquid interfacial energy is difficult to determine experimentally
Induction time
Contact angle
vs.

20. Solubility of paracetamol in acetone-water at 30 °C

21. Crystal growth

22. Crystal growth

23. 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

24. Outline Introduction Fundamentals Crystal shape (habit) and purity
Polymorphism
Control of particle size
Conclusions

25. Randolph, A. D. , and Larson, M. A
Randolph, A.D., and Larson, M.A., Theory of particulate processes, 2nd ed., Academic Press, USA, 1988, 10.

26. Crystal shape

27. Crystal shape – e.g. ibuprofen
Bunyan, J.M.E., Shankland, N., and Sheen, D.B., Solvent effects on the morphology of ibuprofen, AIChE Symp. Ser., 87 (1991), No. 284, 44‑57.

28. Paracetamol – various faces
The unit cell

29. Swedish Research Council for Engineering Science
Paracetamol {110}
Swedish Research Council for Engineering Science

30. Paracetamol {011}

31. Tailor-made additives
e.g. Influence of benzoic acid on benzamide crystals
Mullin, J.W., Crystallization, 3rd Ed., Butterworth-Heinemann, Great Britain, 1993, 253.
After substituting a benzoic acid molecule to the lattice of a benzamide molecule the hydrogen bonding is no longer possible. The growth along this direction is thus hindered.

32. Purity solution adhering to the surface incorporation into the lattice
c) macroscopic cavities inside the crystal
d) “adsorbed” in lattice channels and cavities
Rasmuson, Å, Fin- och specialkemikalieteknik kurskompendium, 1998.

33. Outline Introduction Fundamentals Crystal shape and purity
Polymorphism
Control of particle size
Reaction crystallization

34. Polymorphs same chemical compound - different crystal structures
shelf life
bioavailability
reliable processing
patent protection
different physical
properties, e.g.:
density
hygroscopicity
melting point
solubility
stability
dissolution rate
surface properties
hardness
compactibility
tensile strength
graphite
diamond

35. Polymorphs

36. Polymorphs - Chocolate
Form V
Form VI

37. Polymorphs of potassium para-amino benzoic acid
Rasmuson, Å, Fin- och specialkemikalieteknik kurskompendium, 1998.

38. Nucleation of Polymorphs

39. Polymorphism
monotropy
enantiotropy

40. Outline Introduction Fundamentals Crystal shape and purity
Polymorphism
Control of particle size
Reaction crystallization

41. Particle size and morphology
Crystal size
”not a unique value”
Agglomerate properties:
Texture
Internal structure
Strength
Degree of agglomeration

43. Crystal size – the number controls the size
Equal mass d
27 particles d=1
1 particle d= 3
filtration 9 times faster
Hence operate to control the number generation

44. Generation of supersaturation
Secondary
nucleation
Concentration
Primary
nucleation
supersaturated
cooling
Solubility
curve
undersaturated
Temperature

45. Batch cooling crystallization
nucleation rate supersaturation
time

46. Outline Introduction Fundamentals Crystal shape and purity
Polymorphism
Control of particle size
Reaction crystallization

47. Reaction crystallization
Reactant solutions are mixed
Often solubility very low
Supersaturation often very
high where reactants mix

48. Crystal size – the number controls the size
Equal mass d
27 particles d=1
1 particle d= 3
filtration 9 times faster
Hence operate to control the number generation

49. » c * 25 5 * - » = c S Semi-batch crystallization of benzoic acid HCl
Low soluble compound
stoichiometric c *
0,002 kg/kg
NaBe
HCl 25 5 * - = c S
Experimental variables
reactant concentrations
feed flow rate - feeding time
type of agitator
agitation rate
feed point position
feed pipe diameter
feed pipe shape

50. Semibatch precipitation
Influence of reactant concentrations
Benzoic acid
(Åslund and Rasmuson, 1992)

51. Semibatch precipitation
Influence of feeding time
Benzoic acid
(Åslund and Rasmuson, 1992)

52. Semibatch precipitation
Influence of agitation rate
Benzoic acid
(Åslund and Rasmuson, 1992)

53. T-mixer precipitation
Benzoic acid
(Ståhl, Åslund and Rasmuson)