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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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slide1

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
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 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

Transformation: metastablestable

Analysed by microscopy, UV/Vis, IR, Raman & XRD

glycine
Glycine

Grows at pH<3 & pH>9

Metastable form

 single crystal

glycine 1

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

slide6

b (001) at ~18o

a (100) at ~19o

PXRD 50mL scale (20:80)

No g (110) at 25.5o

slide8

DHB

Form 1

Form 2

Metastable form from toluene

Stable form

from chloroform & low s

dhb 2 form 1 form 2
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

slide10

100mL scale (toluene)

T=25oC

s=0.9

s=1.25

s=1.6

Crystallisation Form1

Transformation: Form1 to Form2

Crystallisation Form 2

results scale up in toluene
Results scale-up (in toluene)

100mL scale longest transformation time: ~200min

slide14

L-glutamic acid



metastable form

stable form

from low s & T<25oC

from high s & T>45oC

glutamic acid a b
Glutamic acid:ab
  • Experimental conditions
  • temperature: T=45°C
  • solvent: water
  • concentration: 48g/l
  • scales: 50 & 1000mL
  • source: Ajinomoto Japan (99%)
role of secondary nucleation
Sliding cell

Microscope cell

Role of secondary nucleation

(metastable form; mechanical attrition & crystal damage)

Crystals obtained were filtered, washed with cold water and dried

experimental conditions
Experimental conditions

Solubility data for glutamic acid in water (Kitamura 1989)

a

s3

b

s2

s1

T3

Solubility (g/l)

T2

T1

surface nucleation of b on a
Surface nucleation of:b on a

crystal b

Optical microscope

SEM

raman spectra
Raman spectra

Single crystal (a)

Crystal b (b)

summary
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
summary24
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?

slide25

Glutamic acid

{11-1} a

{101} b

slide26

b [101]

b b axis

{101} b

{11-1} a

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