Åke C. Rasmuson

1. 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 - 100 44 Stockholm, Sweden rasmuson@ket.kth.se

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

5. Sodium chloride

6. Sugar

7. Citric acid monohydrate

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 supersaturated Solubility curve 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 supersaturated Concentration Solubility metastable undersaturated Temperature

15. Primary nucleation nucleation rate supersaturation 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. surface term volume term Thermodynamic barrier for nucleation DG=DGS+DGV=4pr2g+4/3pr3DGv

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

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

26. Crystal shape

27. Crystal shape – e.g. ibuprofen

28. Paracetamol – various faces The unit cell

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

30. Paracetamol {011}

31. Tailor-made additives e.g. Influence of benzoic acid on benzamide crystals

32. Purity • solution adhering to the surface • incorporation into the lattice • c) macroscopic cavities inside the crystal • d) “adsorbed” in lattice channels and cavities

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

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. HCl c = » - S 5 25 c * NaBe Semi-batch crystallization of benzoic acid Low soluble compound stoichiometric » c * 0,002 kg/kg 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)