CGOM

Crystallization Kineticsin Polymorphic Organic Compounds有机物多晶型现象的结晶动力学研究

Ir. Shanfeng JIANGPromotor: Prof. dr. ir. P.J. Jansens;copromotor: Dr. ir. J.H. ter Horst

Process & Energy Department,Delft University of Technology

2nd Nov. 2009

What is polymorphism?什么是多晶型现象？

• Polymorphs are crystalline solids which are chemically identicalbut have different crystal structures à different physicochemicalproperties such as stability, solubility, density, dissolution rate,bioavailability, and morphology.

o-aminobenzoic acidL-HistidineIntroduction Study on o-ABA Nucleation rate method Conclusions

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Form I Form II

Form III

Why control over polymorphism?为什么要控制多晶型现象？

• Polymorphism plays an important role in industries e.g.pharmaceutical, chemical, food, dye and pigment.

ØFoodCocoa butter in chocolate has 6polymorphs. Different melting point, tastechanged. Form V (33.8°C) is the mostdesired form for chocolate products.

ØMedicineRitonavir treats HIV in 1996. After twoyears on the market, sudden occurrenceof a more stable polymorph with muchlower solubility à withdrawal.

Introduction Study on o-ABA Nucleation rate method Conclusions3/16

Concomitant polymorphism伴随多晶型现象

o-aminobenzoic acid@ initial SI = 1.6xv,w = 0.5 (25oC)Real duration:16.5 minutes

100mm

Form II

Form I

Form INot desirable inindustry

Introduction Study on o-ABA Nucleation rate method Conclusions4/16

Heat

Solution

Polymorphic crystallization多晶型的结晶行为

10 20 30 40 50

Conc.

Temp [oC]

supersaturated

undersaturated

S

Product QualityCrystal sizedistribution

Polymorphic fractionMorphology

Purity

primarynucleation

primarynucleation

crystal growth

crystal growth

Polymorphtransformation

Metastablestable

Introduction Study on o-ABA Nucleation rate method Conclusions5/16

Studies on o-aminobenzoic acid (o-ABA)关于邻氨基苯甲酸的研究

o-ABA

ØApplication: perfumes, dyes,pigments, & pharmaceuticals

ØThree polymorphic forms:form I, II, & III

CO2

H

NH2

Quantitativeanalysis

Solubility

Anti-solventCrystallization

CoolingCrystallization

Solid-statetransformation

Solvent-mediatedtransformation

Crystallizationkinetics

Transformationbehaviors

Thermodynamicdata

Factors that affectpolymorphsformation

Controlpolymorphism

Introduction Study on o-ABA Nucleation rate method Conclusions6/16

Raman shift [cm-1]

1530 1550 1570 1590 1610 1630 1650

I

II

III

Intensity[-]

0

0.2

0.4

0.6

0.8

1

0 0.2 0.4 0.6 0.8 1

Actual fraction [-]

Predictedfraction[-]

Form I/III

Form I/II

Form II/III

Quantitative analysis: Raman spectra定量分析：拉曼光谱

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Characteristic Raman spectrum peaks Calibration line

Introduction Study on o-ABA Nucleation rate method Conclusions7/16

Form I à III at 90°C in solid state晶体型 I à III 在 90°C 固态下的转换

0 min

1

2

330 min

Form I

Form III

Step 1: fast surface transformation

95.5 hr1.5 hr

1

23

Step 2: slow vapor-mediated transformation

Transformation completed inabout 20 days in oven at 90°C

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transparent opaque

Form IIà III at 90°C in solid state晶体型IIà III 在 90°C 固态下的转换

Needle-like crystals: form II

Plate-like crystal: form III

Smooth surface ofform II after 20 days inoven

Slow vapor-mediated transformation

Two polymorphs of the samecompound can have totallydifferent solid-statetransformation behaviors.

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Form IIIà I at 25°C in solution晶体型III à I 在 25°C 溶液中的转换

100mm

0

0.2

0.4

0.6

0.8

1

0 200 400

XI[-]

25 oC 35 oC 42 oC

Time [min]

IIIàI

Transformation among thepolymorphs of o-ABA in solution canoccur at lower temperature andproceed faster than in solid state.

Introduction Study on o-ABA Nucleation rate method Conclusions10/16

Proposed phase diagram建议的状态图表

III

I

II

>60

o C <50 oC

> 50oC

>50 oC

<50

o C

III

I

II

>60

o C <50 oC

> 50oC

>50 oC

<50

o C

Temperature~50oC ~60oC

Form II

Form I

Form III

Solubility

Temperature~50oC ~60oC

Form II

Form I

Form III

Solubility

A diagram summarizing thetransformation in solution among threepolymorphs of o-ABA

Proposed phase diagram in terms oftemperature for three forms of o-ABA

Introduction Study on o-ABA Nucleation rate method Conclusions11/16

40

45

50

55

60

65

70

Temp.[oC]

Time0

0.2

0.4

0.6

0.8

1

0 200 400 600 800 1000 1200 1400

XI[-]

Time [min]

100 mm

Form II Form III

Form I II à I45 oC

I à III53 oC

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Control over polymorph formation控制多晶型晶体的形成

Introduction Study on o-ABA Nucleation rate method Conclusions12/16

40

45

50

55

60

65

70

Temp.[oC]

Time0

0.2

0.4

0.6

0.8

1

0 200 400 600 800 1000 1200 1400

XI[-]

Time [min]

100 mm

Form II Form III

Form I II à I45 oC

I à III53 oC

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Control over polymorph formation控制多晶型晶体的形成

Introduction Study on o-ABA Nucleation rate method Conclusions12/16

Form I Form II Form III

Nucleation晶核形成

…… …

nucleus n*

Ø The arrangement of molecules is settled at the stage of nucleation à crucialin the polymorphism control strategy.

Nucleation Crystal growth

Random process

Introduction Study on o-ABA Nucleation rate method Conclusions13/16

New method to determine nucleation rates测定晶核形成速率的新方法

The large variation of induction timereflects the statistical nature of nucleationà determine the nucleation rate J.

( ) 01 exp ( )gP t JV t té ù= - - -ë û0

2000

4000

6000

8000

10000

12000

1 11 21 31 41 51

Experiment number [-]

t [s]

10 20 30 40 500

2000

4000

6000

8000

10000

12000

1 11 21 31 41 51

Experiment number [-]

t [s]

10 20 30 40 50

012345678

0 2 4 61/ln2S [-]

ln(J/S)[-]

m-ABA L-Histidine

012345678

0 2 4 61/ln2S [-]

ln(J/S)[-]

m-ABA L-Histidine

0

0.25

0.5

0.75

1

0 5000 10000 15000

t [s]

P (t )[-]

m-ABA

S=1.83

S=2.15

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L-His

Conclusions结论

• Crystallization kinetics were studied to improve the understanding ofpolymorphic crystallization behavior.

• Using the improved fundamental understanding, control over thepolymorphism for the selected organic compounds was established àhelpful to control over the other organic or inorganic compounds.

• A novel experimental method to determine nucleation rates in solution wasdeveloped à useful for both scientists to validate nucleation theories andfor engineers to measure the nucleation rates.

• A molecular simulation was also performed to study nucleation kinetics in a2D polymorphic system.

Introduction Study on o-ABA Nucleation rate method Conclusions15/16

Acknowledgements感谢

• Promoter: Prof. dr. ir. P.J. JansensCo-promoter: Dr. ir. J.H. ter Horst

• Financially supported by NWO and SenterNovem

• All my colleagues in P&E, TU Delft

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