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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...
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 info@crystallizationsystems.com
This webinar will last 45 minutes
This webinar is being recorded and will be made available.
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
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
Constructing and using Cocrystal Phase Diagrams in the context of dissolution studies
Technobis, 25-Sept-2018
Tom Leyssens
6
7
Personal Expertise!2.5y, Automation Team Leader UCB Pharma (2007-2009)
Process optimization (Crystallization process)
Polymorphism issues, optimization, purity, crystalform, PSD, …
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)
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
10
…
??Citric acid
Mandelic acid
Caffeine
Isonicotinamide
??
My group!
Constructing cocrystal phase diagrams
11
Phase Diagr.CrystallizationDissolution
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
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
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
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
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
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
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
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
20
Like a solubility curve, look for the right conditions.
Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
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
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
23
Make ternary phase diagrams.
X X X X X X X X X
Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
24
Make ternary phase diagrams.
X X X X X X X X X
Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
25
Make ternary phase diagrams.
X X X X X X X X X
Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
26
CaCl2
Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
27
Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
28
Phase Diagr.CrystallizationDissolution
1. Constructing cocrystal Phase Diagrams
Solution Co-crystallization
29
Phase Diagr. Crystallization
Dissolution
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
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
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
33Thermodynamic regions, can be cut in kinetic regions.
xA
xB
2. Cocrystallization from solution
Phase Diagr. Crystallization
Dissolution
34Thermodynamic regions, can be cut in kinetic regions.
xA
xB
L+B
xB*(T)
2. Cocrystallization from solution
Phase Diagr. Crystallization
Dissolution
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Dissolution behavior of cocrystals
72
Phase Diagr.Crystallization
Dissolution
73
Multi-Component CrystalsSynthesis, Concepts, FunctionEd. by Tiekink, Edward / Zukerman-Schpector, Julio
Phase Diagr.Crystallization
Dissolution
74
85% of drugs are commercialized as ORAL drugs
40% among them exhibit lowwater-solubility
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
75
Pharmacokinetic study for bioavailability
Dosage high enough? Time span long enough? Eliminated or not ? …
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
76
MODEL = DISSOLUTION CURVE
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
77
Solid state impacts behavior
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
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
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
80
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
81V
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
82V V
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
83V V V
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
84V V V V
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
85
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
86
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
87
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
88
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
89
xA(AB)*
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
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
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
92
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
93
InCongruent system
DISSOLUTION = KINETIC !!!!!
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
94
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
95V
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
96V V
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
97V V V
A only
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
98
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
99
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
100
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
101
xA(AB)*
Rapid Co-crystal dissolution
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
102
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
103
AB cocrystal
Phase Diagr.Crystallization
Dissolution
3. Dissolution profiles of cocrystals
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
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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