Towards Crystallization Using a Strong Electric Field

Towards Crystallization Using

by Norbert RadacsiDelft University of Technology

Co-authors: A.E.D.M. van der Heijden, J. H. ter Horst

a Strong Electric Field

Norbert Radacsi - Towards Crystallization Using a Strong Electric Field

Electric field effects?

• 5.6✕ 105 V m-1

• Cooling crystallization

• 1,4-dioxane (non-polar, D = 0.45 Debye)

1


Model compounds

• Isonicotinamide (polar molecule, D = 3.56 Debye)

• Niflumic acid (polar molecule, D = 2.43 Debye)

• 4-hydroxybenzoic acid (polar molecule, D = 2.8 Debye)

2


Theory

3

Solution

Suspension

Induced Convection

2.5 kV 7 kV 5 kV 4 kV

Principle Action Phenomenon Leading to

Growth rate change

Change of Polymorph

Product quality control

Particle Separation Techniques

Crystal Nucleation

Understanding

In situ Product Removal

Techniques

Organic Compound &

Solvent

Electric Field


Orientation of molecules by electric field

A. Ziabicky, L. Jarecki, Macromol. Symp. 1996, 104, 65 – 87.

- Orientation can change the fraction of collisions successful attachment of molecules to the nucleus

τ max = pE max

Isonicotinamide:7.28 ✕ 10-24 Nm

4


Electric field effect on nucleation work and rate

cε=3ε0εm(εc-εm)vo/2(εc+εm)

W*= 16πvo2γ3/3(Δµ+cεE2)2

D. Kashiev, Nucleation: Basic Theory with Applications, Butterworth-Heinemann, Oxford, 2000.

Js = zf*C0 exp [-B/( kTlnS+cεE2)2]

5


Electric field effect on nucleation work and rate

cε=3ε0εm(εc-εm)vo/2(εc+εm)

D. Kashiev, Nucleation: Basic Theory with Applications, Butterworth-Heinemann, Oxford, 2000.

εc > εm

εc < εm

εc = εm

W* decreased

W* increasedW* unchanged

6

Norbert Radacsi - Towards Crystallization Using a Strong Electric Field 7

Experimental setup #1

Text

Raman Spectroscope

Raman Probe

Crystalline

Camera System

DC Power Supply

Crystalline Particle Viewer with Raman Spectroscope

Sample in the vial

E ≦ 5.6 x 105 V/m


Experiment temperature profile

Time (min)

Solution becomes clear

Electric field turned ON

Constant T, S, E

5 oC/m

in

8

ResultsVisualization


Visualization - crystals

Crystals grew on the

Hammadi, Z.; Astier, J.P.; Morin, R.; Veesler, S., Crystal Growth & Design, 2009, 9, 3346 – 3347.

9

anodecathode

Changing the polarity

NIF A4-HB A

INA

in situ product removal!


Visualization - Induction time probability measurement

• Isonicotinamide

• Preliminary induction time probability shows increase in +DC mode

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

0 10 20 30 40 50 60 70 80

P(t)

t [min]

With E

Without E

10


• Crystal growth rate in the presence of the E field: 126 µm/min• Crystal growth rate in the absence of the E field: 8.3 µm/min

Visualization - Crystal Growth Rate - Isonicotinamide

With E Without E

15 x

Real time:20 min

11


Summary - Crystal growth rate

• Growth rate of isonicotinamide & 4 hydroxybenzoic acid increased!

12


• Isonicotinamide • 4 Hydroxybenzoic acid

0 kV1 kV2 kV3 kV4 kV5 kV6 kV7 kV8 kV

Visualization - Suspension

13

Polymorph control


Polymorph control of isonicotinamide

• 6 polymorphs (form II is the stable form)

form II form I, III, IV, V

14

• Polymorphism of niflumic acid and 4-hydroxybenzoic acid is not influenced by the used electric field


Cooling crystallization experiments• By recrystallizing isonicotinamide in 1,4-dioxane:

form I

Head-to-tail

no E

15


Crystal structure - Raman spectroscopy

16

Cathode

Norbert Radacsi - Towards Crystallization Using a Strong Electric Field 17

Experimental setup #2Parallel plate setup

Anode

+-

E ≦ 5.6 x 105 V/m

Natural cooling!


Current measurement

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0 1 2 3 4 5 6 7 8 9 10

Cur

rent

[µA

]

Potential difference [kV]

18

Potential difference [kV]

Cur

rent

[µA

] 10 mA


Crystal structure - X-ray Powder Diffraction

Table - XRPD

Without electric field With electric field

Polymorph Form I Form II

19

Electrochemical reactions


Redox reactions?

20

• No bubble formation

• Solution NMR showed the original compound

• ICP - copper content in solutions:

• Isonicotinamide: 0.0 ppm

• Niflumic acid: 0.93 ppm

• 4-hydroxybenzoic acid: 0.24 ppm

0.08 ppm

Summary

Without E With +E

Crystal location

In situ product removal

Crystal growth

rate

8.3 µm/min

126 µm/min

Increased

Induction time p=1

10 min 72 min Decreased(?)

Polymorph form I form II Changed

Explanation?


Electromigration

+

+-

+-

+-

+-Electromigration is the transport of molecules towards an electrode caused by the electric field

An

ode

22


Increased local supersaturation ratio

23

15 = K(SE −1)2

K(S0 −1)2

SE = 5.06 (2.5x higher)

R = K(S-1)2

R = K(S −1)2


Recrystallizing isonicotinamide at different concentrations

24

Conclusions

• Electric fields affect crystallization

• Control of crystallization (localized growth, induction time, polymorphism)

• Increased local supersaturation - electromigration

Thank you for your attention!


⎟⎟⎠

⎞⎜⎜⎝

⎛−=

STkcv

CfzJ 233

3320

274

0 lnexp**

γξ

Interfacial energy

Concentration of nucleation sites

Supersaturation

Activity factor

Classical Nucleation Rate Expression

Attachment frequency

2explnBJ ASS

⎛ ⎞= −⎜ ⎟⎝ ⎠

D. Kashiev, Nucleation: Basic Theory with Applications,

Butterworth-Heinemann, Oxford, 2000.


[ppm] 9.0 8.5 8.0 7.5

[rel

] 0

5

1

0 1

5

8.71

868.

7051

8.23

32

7.76

757.

7525

7.71

18

2.00

00

0.97

15

2.99

43

isonicotineamide

Radacsi 1 1 D: nmrsu

Answer:Solution NMR


Crystal structure - DSC

60 70 80 90 100 110 120 130 140 150 160 170 180 Temperature [°C]

20 mW

ManufacturerRecrystallized in the absence of the electric field

Science

Towards Crystallization Using a Strong Electric Field