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. Transformation: metastable  stable 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 Analysed by microscopy, UV/Vis, IR, Raman & XRD

4. Glycine     single crystal Metastable form Grows at pH 9

5. Glycine 1 :    Experimental conditions temperature: T=35°C solvent: water/ethanol (%) 20:80 v:v 9:91v:v supersaturation:  =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. PXRD 50mL scale (20:80)  (001) at ~18 o  (100) at ~19 o No  (110) at 25.5 o

7. Water/ethanol (%)50mL (min)Avg (min)1000mLAvg 20:80 (  =3.1) 30 40 34 90min 95min 120min 102min 9:91 (  =3.8) 180 200 210 19710h 24ht> 10h 9:91 (  =4.0) 90 150 140 127 Results

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

9. DHB 2 : Form 1  Form 2 Experimental conditions temperature: T=25; 30 & 35°C solvent: toluene chloroform supersaturation:  =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)  =0.9  =1.25  =1.6 T=25 o C Crystallisation Form1 Transformation: Form1 to Form2 Crystallisation Form 2

11. Results (100mL) T ( o C)Solvent  Time (min) 25Toluene 0.9 1.25 1.6 220 140 90 25 30 35 Toluene0.9 175 143 126 25 30 35 Chloroform0.9 42 13 6

12. Results scale-up (in toluene) T ( o C)  Speed (rpm)Time 251.6NoNo transformation after 96h 251.6magn23h 251.6125No transformation after 96h 251.625040h 100mL scale longest transformation time: ~200min

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

14.  metastable form from low  & T<25 o Cfrom high  & T>45 o C stable form L-glutamic acid

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

16. Results Scale (mL)Time (min)Average (min) 50 5 8 10 8 1000 160 200 220 190

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

18. Experimental conditions   Solubility data for glutamic acid in water (Kitamura 1989) T1 T2 T3    Solubility (g/l)

19. Results T ( o C)Conc. (g/L)No seedSliding exp. Microscope exp. 35 15 17.5 20 -  (24h)  +  (24h)  (2h);  +  (6h)  diss.,  grow  grow,  grow 45 22 25 27  (24h)  +  (4h)  clusters (5h)  clusters (3h)  (2h);  +  (4h)  diss.,  grow  grow,  grow  grow,  grow (6h)  diss.,  grow (24h) 55 32 36 40  (3h)  +  (2h)  clusters (2h)  clusters +  (2h)  +  (30min);  +  (2h)  diss.,  grow  grow,  grow (6h)  diss.,  grow (24h)

20. Microscope cell: 15g/L; 35 o C t=0ht=6h t=24h  

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

22. Raman spectra Single crystal (  ) Crystal 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   lower time Crystal yield: increased by increasing 

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. {11-1}  {101}  Glutamic acid

26. {11-1}  {101}   b axis  [101]

27. Conclusions Impact of seed crystals with cell walls & stirrer causes formation of secondary nuclei These grow or dissolve according to  ; at high  number of nuclei surviving is greater (collision breeding theory) Surface damage and defects favour crystallisation; polymorph obtained controlled by  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.

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