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Introduction

Scale-up effects in the rates of solution mediated polymorphic transformations: the role of mass transfer and secondary nucleation Elena S Ferrari, Roger J Davey Department of Chemical Engineering. Introduction .

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Introduction

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  1. Scale-up effects in the rates of solution mediated polymorphic transformations: the role of mass transfer and secondary nucleation Elena S Ferrari, Roger J Davey Department of Chemical Engineering

  2. Introduction • It would be of great significance if the rate of crystallisation and polymorphic transformation could be predicted from laboratory data (scale-up problems) • systems chosen: glycine dihydroxybenzoic acid (DHB) L-glutamic acid

  3. Small scale 50 & 100mL jacketed vessel waterbath for temperature control magnetic stirrer PTFE magnetic stirring bar Scale-up 500, 1000 & 2000mL jacketed vessel waterbath for temperature control Heidolph RZR-2000 stirrer motor glass stirring paddle or Rushton turbine 125; 150 & 250rpm Transformation: metastablestable Analysed by microscopy, UV/Vis, IR, Raman & XRD

  4. Glycine    Grows at pH<3 & pH>9 Metastable form  single crystal

  5. Glycine1:    Experimental conditions temperature: T=35°C solvent: water/ethanol (%) 20:80 v:v 9:91v:v supersaturation: s=3.1; 3.8 & 4.0 scales: 50 & 1000mL source: Sigma-Aldrich UK (99%) 1 E.S. Ferrari, R.J. Davey et al.; Crystal Growth & Design 3 (2003), 53-60

  6. b (001) at ~18o a (100) at ~19o PXRD 50mL scale (20:80) No g (110) at 25.5o

  7. Results

  8. DHB Form 1 Form 2 Metastable form from toluene Stable form from chloroform & low s

  9. DHB2: Form 1Form 2 • Experimental conditions • temperature: T=25; 30 & 35°C • solvent: toluene • chloroform • supersaturation: s=0.9; 1.25 & 1.6 • scales: 100; 500 & 2000mL • source: Sigma-Aldrich UK (99%) 2 R.J. Davey, N. Blagden, S. Righini et al: Journal Physical Chemistry B 106 (2002), 1954-1959

  10. 100mL scale (toluene) T=25oC s=0.9 s=1.25 s=1.6 Crystallisation Form1 Transformation: Form1 to Form2 Crystallisation Form 2

  11. Results (100mL)

  12. Results scale-up (in toluene) 100mL scale longest transformation time: ~200min

  13. Surface nucleation of: Form 2 on Form 1 Optical microscope SEM

  14. L-glutamic acid   metastable form stable form from low s & T<25oC from high s & T>45oC

  15. Glutamic acid:ab • Experimental conditions • temperature: T=45°C • solvent: water • concentration: 48g/l • scales: 50 & 1000mL • source: Ajinomoto Japan (99%)

  16. Results

  17. Sliding cell Microscope cell Role of secondary nucleation (metastable form; mechanical attrition & crystal damage) Crystals obtained were filtered, washed with cold water and dried

  18. Experimental conditions Solubility data for glutamic acid in water (Kitamura 1989) a s3 b s2 s1 T3 Solubility (g/l) T2 T1

  19. Results

  20. Microscope cell: 15g/L; 35oC t=0h t=6h a t=24h b

  21. Surface nucleation of:b on a crystal b Optical microscope SEM

  22. Raman spectra Single crystal (a) Crystal b (b)

  23. Summary • Induction time: small scale <5min • scale-up >15-20min • Mixing method: overhead stirrer increased time • Mixing speed: higher speed reduced time • Temperature: higher T reduced time • Supersaturation: higher s lower time • Crystal yield: increased byincreasing s

  24. Summary • Solvent: template effect on DHB; no effect on glycine • Seeding: positive effect on DHB and glutamic acid (metastable seed); no effect for glycine • Crystal damage & defects: of metastable form can induce growth of stable polymorph HOW?

  25. Glutamic acid {11-1} a {101} b

  26. b [101] b b axis {101} b {11-1} a

  27. Conclusions • Impact of seed crystals with cell walls & stirrer causes formation of secondary nuclei • These grow or dissolve according to s; at high s number of nuclei surviving is greater (collision breeding theory) • Surface damage and defects favour crystallisation; polymorph obtained controlled by s • In small scale the convective mass transfer is enhanced; also mechanical attrition and crystal damage are more likely. • Transformation is facilitated because number of secondary nuclei increased.

  28. Acknowledgements • Sebastien Righini (Rhodia Lyon) • Members of the CCI research group at UMIST • EPSRC for funding

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