Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof....
Transcript of Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof....
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Constructing Cocrystal Phase Diagrams
Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium
25th September 2018
Brings to you the webinar on...
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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.
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TECHNOBIS CRYSTALLIZATION SYSTEMS Privately owned company 65 employees Located in Alkmaar, The Netherlands Leader in 3 major markets: Pharma, Agro
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Portfolio 3 products for: crystallization,
process optimization, formulationrelated research
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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
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Constructing and using Cocrystal Phase Diagrams in the context of dissolution studies
Technobis, 25-Sept-2018
Tom Leyssens
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Personal Expertise!2.5y, Automation Team Leader UCB Pharma (2007-2009)
Process optimization (Crystallization process)
Polymorphism issues, optimization, purity, crystalform, PSD, …
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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)
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UCL Professor in Physical chemistry (2009-…)
Research group in Crystallization and Crystal Engineering of organic multi-component compounds
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Personal Expertise!
E. Grothe, … Cryst. Growth Des. 2016, 3237.
Hydrogen bonds
Piracetam: mandelic acid
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…
??Citric acid
Mandelic acid
Caffeine
Isonicotinamide
??
My group!
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Constructing cocrystal phase diagrams
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Phase Diagr.CrystallizationDissolution
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1. Constructing cocrystal Phase Diagrams
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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
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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
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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
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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
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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
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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
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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
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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
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Like a solubility curve, look for the right conditions.
Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
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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
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Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
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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
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Make ternary phase diagrams.
X X X X X X X X X
Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
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Make ternary phase diagrams.
X X X X X X X X X
Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
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Make ternary phase diagrams.
X X X X X X X X X
Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
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CaCl2
Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
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Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
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Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
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Solution Co-crystallization
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Phase Diagr. Crystallization
Dissolution
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2. Cocrystallization from solution
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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
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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
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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
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33Thermodynamic regions, can be cut in kinetic regions.
xA
xB
2. Cocrystallization from solution
Phase Diagr. Crystallization
Dissolution
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34Thermodynamic regions, can be cut in kinetic regions.
xA
xB
L+B
xB*(T)
2. Cocrystallization from solution
Phase Diagr. Crystallization
Dissolution
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/50.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/51.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/52.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/53.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/54.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/55.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/56.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/57.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/58.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/59.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/60.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/61.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/62.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/63.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/64.jpg)
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](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/65.jpg)
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
![Page 66: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/66.jpg)
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
![Page 67: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/67.jpg)
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
![Page 68: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/68.jpg)
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
![Page 69: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/69.jpg)
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
![Page 70: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/70.jpg)
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
![Page 71: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/71.jpg)
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
![Page 72: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/72.jpg)
Dissolution behavior of cocrystals
72
Phase Diagr.Crystallization
Dissolution
![Page 73: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/73.jpg)
73
Multi-Component CrystalsSynthesis, Concepts, FunctionEd. by Tiekink, Edward / Zukerman-Schpector, Julio
Phase Diagr.Crystallization
Dissolution
![Page 74: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/74.jpg)
74
85% of drugs are commercialized as ORAL drugs
40% among them exhibit lowwater-solubility
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 75: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/75.jpg)
75
Pharmacokinetic study for bioavailability
Dosage high enough? Time span long enough? Eliminated or not ? …
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 76: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/76.jpg)
76
MODEL = DISSOLUTION CURVE
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 77: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/77.jpg)
77
Solid state impacts behavior
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 78: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/78.jpg)
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
![Page 79: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/79.jpg)
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
![Page 80: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/80.jpg)
80
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 81: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/81.jpg)
81V
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 82: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/82.jpg)
82V V
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 83: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/83.jpg)
83V V V
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 84: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/84.jpg)
84V V V V
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 85: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/85.jpg)
85
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 86: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/86.jpg)
86
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 87: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/87.jpg)
87
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 88: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/88.jpg)
88
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 89: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/89.jpg)
89
xA(AB)*
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 90: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/90.jpg)
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
![Page 91: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/91.jpg)
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
![Page 92: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/92.jpg)
92
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 93: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/93.jpg)
93
InCongruent system
DISSOLUTION = KINETIC !!!!!
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 94: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/94.jpg)
94
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 95: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/95.jpg)
95V
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
![Page 96: Constructing Cocrystal Phase Diagrams...Constructing Cocrystal Phase Diagrams Presented by: Prof. Dr. Tom Leyssens Catholic University Leuven, Belgium 25 th September 2018 Brings to](https://reader033.fdocuments.us/reader033/viewer/2022052519/5f1fc797c6a2805187751e5e/html5/thumbnails/96.jpg)
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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