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

M M CM o l e c u l a r M a t e r i a l s C e n t r e

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

Transformation: metastablestable 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

GlycineNH3+

O

O

single crystal

Metastable form

Grows at pH<3 & pH>9

Glycine1:

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

PXRD 50mL scale (20:80) (001) at ~18o

(100) at ~19o

No (110) at 25.5o

Water/ethanol (%) 50mL (min) Avg (min) 1000mL Avg

20:80 (=3.1)

303040

3490min95min

120min102min

9:91 (=3.8)

180200210

197 10h <t> 24h t> 10h

9:91 (=4.0)

90150140

127

Results

C 2C 1

O

HC 3OO 2

O 1

H 1

H 2

1

2

DHB

Form 1 Form 2

Metastable form from toluene

Stable form from chloroform & low

DHB2: Form 1Form 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

100mL scale (toluene)

=0.9

=1.25

=1.6

T=25oC

Crystallisation Form1

Transformation: Form1 to Form2

Crystallisation Form 2

Results (100mL)

T (oC) Solvent Time

(min)

25 Toluene

0.9

1.25

1.6

220

140

90

25

30

35

Toluene 0.9

175

143

126

25

30

35

Chloroform 0.9

42

13

6

Results scale-up (in toluene)

T (oC) Speed (rpm) Time

25 1.6 No No transformation after 96h

25 1.6 magn 23h

25 1.6 125 No transformation after 96h

25 1.6 250 40h

100mL scale longest transformation time: ~200min

Optical microscope

Surface nucleation of: Form 2 on Form 1

SEM

OH

O

O

O

NH3+

metastable form from low & T<25oC from high & T>45oC

stable form

L-glutamic acid

Glutamic acid:

Experimental conditions

• temperature: T=45°C

• solvent: water

• concentration: 48g/l

• scales: 50 & 1000mL

• source: Ajinomoto Japan (99%)

Results

Scale (mL) Time (min) Average (min)

50 5810

8

1000160200220

190

Role of secondary nucleation

• Sliding cell

• Microscope cell

Crystals obtained were filtered, washed with cold water and dried

(metastable form; mechanical attrition & crystal damage)

Experimental conditions

0

10

20

30

40

50

60

70

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70

temperature (oC)

Solubility data for glutamic acid in water (Kitamura 1989)

T1 T2

T3

Sol

ub

ilit

y (g

/l)

Results

T (oC) Conc. (g/L) No seed Sliding exp. Microscope exp.

35

15 17.5

20

- -

(24h)

(24h) + (24h)

(2h); + (6h)

diss., grow grow, grow grow, grow

45

22 25 27

(24h) (24h)

+ (4h)

clusters (5h) clusters (3h)

(2h); + (4h)

diss., grow grow, grow

grow, grow (6h) diss., grow (24h)

55

32 36 40

(3h) (3h)

+ (2h)

clusters (2h) clusters + (2h)+ (30min);

+ (2h)

diss., grow diss., grow

grow, grow (6h) diss., grow (24h)

Microscope cell: 15g/L; 35oC

t=0h t=6h

t=24h

Surface nucleation of: on

crystal b

SEM Optical microscope

Raman spectra

0

50

100

150

200

250

0 500 1000 1500 2000 2500 3000 3500 4000

wavenumber (cm-1)

Inte

nsity

(a.

u.)

Single crystal () Crystal b ()

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

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?

{11-1}

{101}

Glutamic acid

{11-1}

{101} b axis

[101]

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.

Acknowledgements

• Sebastien Righini (Rhodia Lyon)

• Members of the CCI research group at UMIST

• EPSRC for funding