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Page 1: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

Constructing Cocrystal Phase Diagrams

Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium

25th September 2018

Brings to you the webinar on...

Page 2: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

Your Speaker

Leads the Physical Chemistry research group at UCL in Belgium. Hisgroup is focused on Crystallization and Crystal Engineering of organicmulti-component compounds.

Prof. Dr. Tom Leyssens

The audience is muted and send the questions to [email protected]

This webinar will last 45 minutes

This webinar is being recorded and will be made available.

Page 3: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

TECHNOBIS CRYSTALLIZATION SYSTEMS Privately owned company 65 employees Located in Alkmaar, The Netherlands Leader in 3 major markets: Pharma, Agro

and Fine Chemicals

Portfolio 3 products for: crystallization,

process optimization, formulationrelated research

Page 4: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

Products

Discover• Early stage salt, polymorph screening• Single crystal growth

Screen• Solubility, MSZW• Phase diagrams• Selecting solvents• Polymorphs, Salt and Co-crystals

screening

Optimize• Form control• Habit control• Particle size• Process optimization• Formulation

Working volume:0.5 – 1 ml

16 reactors

Working volume:2.5 – 5 ml8 reactors

Working volume:0.06 – 0.1 ml32 reactors

Page 5: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

Constructing and using Cocrystal Phase Diagrams in the context of dissolution studies

Technobis, 25-Sept-2018

Tom Leyssens

Page 6: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

6

Page 7: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

7

Personal Expertise!2.5y, Automation Team Leader UCB Pharma (2007-2009)

Process optimization (Crystallization process)

Polymorphism issues, optimization, purity, crystalform, PSD, …

Page 8: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

8

Personal Expertise!Crystallization from a lab-scale in a controlled and

robust manner to industrial plant!!

Process control but from a macroscopic point of view(thermodynamics and kinetics / nucleation and crystal growth)

Page 9: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

UCL Professor in Physical chemistry (2009-…)

Research group in Crystallization and Crystal Engineering of organic multi-component compounds

9

Personal Expertise!

E. Grothe, … Cryst. Growth Des. 2016, 3237.

Hydrogen bonds

Piracetam: mandelic acid

Page 10: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

10

??Citric acid

Mandelic acid

Caffeine

Isonicotinamide

??

My group!

Page 11: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

Constructing cocrystal phase diagrams

11

Phase Diagr.CrystallizationDissolution

Page 12: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

1. Constructing cocrystal Phase Diagrams

12

Thermodynamics = where do you want to end up (end-situation needsto be stable and easy to handle)./ Phase diagrams

Kinetics = road to get there (different possibilities: will impact particlesize distribution, purity, … quality of the end product).

Phase Diagr.CrystallizationDissolution

Page 13: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

13

Like a solubility curve, look for the right conditions.

Variables: Compound A Compound B Solvent temperature

Reduce variables !!! Phase Diagr.

CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 14: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

14

Like a solubility curve, look for the right conditions.

Variables: Compound A Compound B Solvent temperature

Reduce variables !!! Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Variables: Conc. A Conc. B

Page 15: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

15

Solution thermodynamics (Phase Diagram)

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

ABs A + BKsp

Ksp=[A][B]

[A]=Ksp[B]

Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 16: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

16

congruent

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 17: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

17

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

BUT …. Life is not alwaysthat easy!

Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 18: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

18

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 19: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

19

xA

xB

L+A

L+B

xB*(T)

L+AB

L+AB+B

L+AB+A

incongruent

xA*(T)

Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 20: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

20

Like a solubility curve, look for the right conditions.

Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 21: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

Ter Horst, J.H..; Deij, M.A.; Cains, P.W. Cryst. Growth Des. 2009, 9, 1531–1537. Gagnière, E.; Mangin, D.; Puel, F.; Rivoire, A.; Garcia, E.; Klein, J.P. J. Cryst. Growth 2009, 311, 2689–2695.

C M

S

21

Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 22: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

22

Congruent system= easier to handle/sell.

Incongruent Incongruentcongruent

Skewedness depends on the relative solubilities. (try to use similarsolubilitities)

A system can behave congruently in one solvent and incongruently in another

Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 23: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

23

Make ternary phase diagrams.

X X X X X X X X X

Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 24: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

24

Make ternary phase diagrams.

X X X X X X X X X

Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 25: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

25

Make ternary phase diagrams.

X X X X X X X X X

Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 26: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

26

CaCl2

Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 27: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

27

Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 28: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

28

Phase Diagr.CrystallizationDissolution

1. Constructing cocrystal Phase Diagrams

Page 29: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

Solution Co-crystallization

29

Phase Diagr. Crystallization

Dissolution

Page 30: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

2. Cocrystallization from solution

30

Thermodynamics = where do you want to end up (end-situation needsto be stable and easy to handle)./ Phase diagrams

Kinetics = road to get there (different possibilities: will impact particlesize distribution, purity, … quality of the end product).

Phase Diagr. Crystallization

Dissolution

Page 31: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

31

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Page 32: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

32

Thermodynamics = where do you want to end up (end-situation needsto be stable and easy to handle).

Kinetics = road to get there.

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Page 33: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

33Thermodynamic regions, can be cut in kinetic regions.

xA

xB

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Page 34: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

34Thermodynamic regions, can be cut in kinetic regions.

xA

xB

L+B

xB*(T)

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Page 35: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

35Thermodynamic regions, can be cut in kinetic regions.

xA

xB

L+B

xB*(T)

L+A

xA*(T)

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Page 36: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

36Thermodynamic regions, can be cut in kinetic regions.

xA

xB

L+B

xB*(T)

L+A

xA*(T)

L+AB

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Page 37: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

37Thermodynamic regions, can be cut in kinetic regions.

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Page 38: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

38

1A = B

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

1B = B / B or AB

3A = AB3B = AB / A or AB 3D = AB / A or B or AB

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Page 39: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

39

congruent

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by evaporation

Page 40: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

40

congruent

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by evaporation

Page 41: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

41

congruent

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by evaporation

Page 42: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

42

congruent

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by evaporation

Page 43: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

43

congruent

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by evaporation

Page 44: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

44

congruent

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by evaporation

Page 45: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

45

congruent

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by evaporation

Page 46: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

46

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

incongruent

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by evaporation

Page 47: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

47

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

incongruent

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by evaporation

Page 48: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

48

xA

xB

L+A

L+B

xB*(T)

L+AB

L+AB+B

L+AB+A

incongruent

xA*(T)

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by evaporation

Page 49: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

49

xA

xB

L+A

L+B

xB*(T)

L+AB

L+AB+B

L+AB+A

incongruent

xA*(T)

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by evaporation

Page 50: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

50

xA

xB

L+A

L+B

xB*(T)

L+AB

L+AB+B

L+AB+A

incongruent

xA*(T)

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by evaporation

Page 51: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

51

xA

xB

L+A

L+B

xB*(T)

L+AB

L+AB+B

L+AB+A

incongruent

Start with equimolarmixture only if congruent ; Seeding is alwaysrecommended! (situation can occur where A or B

spontaneously crystallize out (meta-stable)!! Yield can be extracted from curve.

xA*(T)

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by evaporation

Page 52: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

52

congruent

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by cooling

Page 53: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

53

congruent

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by cooling

Page 54: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

54

congruent

xA

xB

L+A

L+B

xB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by cooling

Page 55: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

55

congruent

xA

xB

L+A

L+BxB*(T)

xA*(T)

L+AB

L+AB+B

L+AB+A

If congruent : cooling is straigthforward Seeding remains recommended.

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Cocrystallization by cooling

Page 56: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

56

Thermodynamics = where do you want to end up (end-situation needsto be stable and easy to handle).

Kinetics = road to get there (different possibilities: will impact particlesize distribution, purity, … quality of the end product).

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Page 57: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

57

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

Case 1 : crystallization of stable co-crystal

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Spontaneous cocrystallization from supersaturated solution

Page 58: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

58

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Case 1 : crystallization of stable co-crystal

Spontaneous cocrystallization from supersaturated solution

Page 59: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

59

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Case 1 : crystallization of stable co-crystal

Spontaneous cocrystallization from supersaturated solution

Page 60: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

60

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Case 1 : crystallization of stable co-crystal

Spontaneous cocrystallization from supersaturated solution

Page 61: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

61

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Case 1 : crystallization of stable co-crystal

Spontaneous cocrystallization from supersaturated solution

Page 62: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

62

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Case 1 : crystallization of stable co-crystal

Spontaneous cocrystallization from supersaturated solution

Page 63: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

63

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

Case 2 : crystallization of meta-stable forms

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Spontaneous cocrystallization from supersaturated solution

Page 64: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

64

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

Case 2 : crystallization of meta-stable forms

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Spontaneous cocrystallization from supersaturated solution

Page 65: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to

65

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

Case 2 : crystallization of meta-stable forms

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Spontaneous cocrystallization from supersaturated solution

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66

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

Case 2 : crystallization of meta-stable forms

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Spontaneous cocrystallization from supersaturated solution

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67

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

Case 2 : crystallization of meta-stable forms

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Spontaneous cocrystallization from supersaturated solution

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68

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

Case 2 : crystallization of meta-stable forms

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Spontaneous cocrystallization from supersaturated solution

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69

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

Case 2 : crystallization of meta-stable forms

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Spontaneous cocrystallization from supersaturated solution

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70

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

Case 2 : crystallization of meta-stable forms

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Spontaneous cocrystallization from supersaturated solution

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71

xA

xB

xB*(T)

xA*(T)

1A1B 2A

2B

3A 3B

3C3D

5A

5B

4A

4B

Case 2 : crystallization of meta-stable forms

Final outcome (yield/nature) is thermodynamic.

2. Cocrystallization from solution

Phase Diagr. Crystallization

Dissolution

Spontaneous cocrystallization from supersaturated solution

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Dissolution behavior of cocrystals

72

Phase Diagr.Crystallization

Dissolution

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73

Multi-Component CrystalsSynthesis, Concepts, FunctionEd. by Tiekink, Edward / Zukerman-Schpector, Julio

Phase Diagr.Crystallization

Dissolution

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74

85% of drugs are commercialized as ORAL drugs

40% among them exhibit lowwater-solubility

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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75

Pharmacokinetic study for bioavailability

Dosage high enough? Time span long enough? Eliminated or not ? …

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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76

MODEL = DISSOLUTION CURVE

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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77

Solid state impacts behavior

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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78

Understand the dissolution using cocrystal phase diagrams.

Variables: Compound A Compound B Solvent Temperature

Reduce variables !!!

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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79

Understand the dissolution using cocrystal phase diagrams.

Variables: Compound A Compound B Solvent

Reduce variables !!!

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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80

A only

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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81V

A only

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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82V V

A only

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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83V V V

A only

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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84V V V V

A only

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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85

AB cocrystal

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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86

AB cocrystal

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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87

AB cocrystal

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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88

AB cocrystal

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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89

xA(AB)*

AB cocrystal

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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90

Congruent system = co-crystallization is usefull if the rate of dissolution can be

improved. does this always imply a lower API solubility??

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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91

Congruent system = co-crystallization can also be used to improve the solubility.This occurs when compound B impacts the solubility of compound A!!

phenazopyridine:phthalimide, carbamazepine:nicotinamide, acyclovir:fumaric acid, Genistein:Caffeine, ezetimibe:methylparaben, Adefovir:p-hydroxybenzoic acid

*T. Leyssens, J. Ter Horst in Multi-component Crystals: Synthesis, Concepts, Function'. - Solution Co-crystallization and its applications. P205-236.

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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92

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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93

InCongruent system

DISSOLUTION = KINETIC !!!!!

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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94

A only

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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95V

A only

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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96V V

A only

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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97V V V

A only

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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98

AB cocrystal

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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99

AB cocrystal

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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100

AB cocrystal

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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101

xA(AB)*

Rapid Co-crystal dissolution

AB cocrystal

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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102

AB cocrystal

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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103

AB cocrystal

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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104

V

V

Slow crystal growth of A

Quercetine:proline, Danazol-Vaniline, Myricetin-proline, Megestrol acetate:saccharin, and dexlansoprazole:isonicotinamide.

AB cocrystal

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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105

Myrcetine Proline Isonicotinamidedexlansoprazole

*T. Leyssens, J. Ter Horst in Multi-component Crystals: Synthesis, Concepts, Function'. - Solution Co-crystallization and its applications. P205-236.

Phase Diagr.Crystallization

Dissolution

3. Dissolution profiles of cocrystals

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Thank you for your attention!

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