Particle Formation by Crystallization
Particle Formation by Crystallization
Herman J.M. Kramer Intensified Reaction & Separation Systems Process & Energy Delft University of Technology
Leeghwaterstraat 39 2628 CB Delft The Netherlands [email protected]
Acknowledgement JoopProcess ter &Horst Energy – Intensified I use some Reaction of his & Separation slides Systems Crystallization
A. Crystallization: Phenomena, Process & Product Properties Introduction Crystallization Crystals as Product: Crystal purity, Crystal Size Distribution, Crystal shape and crystal solid form Crystallization kinetics Nucleation, Crystal Growth, Attrition Crystallization process thermodynamics process design equipment
B. Advanced crystallization topics Polymorphism Chiral crystallization
2 JMBC Particle Technology Course: Crystallization Literature
Basic references • Industrial Crystallization, fundamentals and application, A. Lewis, M.S. Seckler, H.J.M. Kramer and G.M van Rosmalen, Cambrridge University press, will appear in 2015 • Handbook of Industrial Crystallization, A.S Myerson, 2002, Butterworth- Heinemann • Crystallization, J.W. Mullin, 2001,Butterworth & Heinemann • Crystallization, H.J.M. Kramer, G.M. van Rosmalen, In: Encyclopedia of Separation Science, Ed. I.D. Wilson, 2000, Vol. 1, page 64-84.
3 JMBC Particle Technology Course: Crystallization Crystallization
A separation unit operation Crystalline product 99.99% pure Synthesis Crystallization of API Filtration Solution containing impurities and dissolved V High selectivity synthesis V Mild conditions product V Low energy demand V Particular product V Slow process
4 JMBC Particle Technology Course: Crystallization The Crystalline Product
Table salt • Crystal purity >99.9% • Crystal size distribution f(L)
L [ µm] • Crystal shape: cubic • Crystal form: anhydrate
5 JMBC Particle Technology Course: Crystallization Other properties of crystal products
Type of polymorph • Shape • Color • Solubility • Stability
Chirality • Bio activity
5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile JACS 122 (2000) 585
6 JMBC Particle Technology Course: Crystallization Crystal shape: cubic Molecular structure: the crystal unit cell
Adipic acid Aspartame Monoclinic (P21/c) Tetragonal (P41) a≠b≠c, α=β=90°≠γ a=b ≠c, α=β=γ=90°
7 JMBC Particle Technology Course: Crystallization Crystallization occurs at molecular level
step
terrace Incorporation of single molecules into the crystal lattice kink
Arrangement of millions of molecules into crystal lattice Interaction at surface with solvent and impurities
8 JMBC Particle Technology Course: Crystallization Product • Purity • Size distribution Fundamentals • Shape (molecular • Crystal form Equipment interactions) design
Crystallization
Phenomena Process • Nucleation • Creation of supersaturation • Growth • Crystallization method • Attrition Process • Batch ⇔ continuous • Agglomeration design
9 JMBC Particle Technology Course: Crystallization MgSO4 Crystallisation plant
10 JMBC Particle Technology Course: Crystallization Product ˜ phenomena
Impurity effect on product quality
11 JMBC Particle Technology Course: Crystallization Product ˜ process
Stimulate agglomeration during process to enhance filterability
Gypsum - CaSO4.2H2O
12 JMBC Particle Technology Course: Crystallization Process ˜ phenomena
• Primary nucleation or vapor seeding • Primary nucleation and growth • Secondary nucleation • Growth • Agglomeration
13
JMBC Particle Technology Course: Crystallization What is a crystal?
A crystal is a solid in which its building units (molecules, atoms, ions) are packed in regularly ordered, repeated patterns extending in all 3 dimensions
14 JMBC Particle Technology Course: Crystallization Crystal unit cell
Adipic acid Aspartame Monoclinic (P21/c) Tetragonal (P41) a≠b≠c, α=β=90°≠γ a=b ≠c, α=β=γ=90°
15 JMBC Particle Technology Course: Crystallization Crystallization is a molecular level process the growth mechanism
A directed spontaneous self-assembly of a 3-dimensional array of atoms, molecules or ions.
step
terrace
kink
16 JMBC Particle Technology Course: Crystallization Crystallization is a molecular level process
Crystallization is highly selective One step crystallizations can result in 99.9% pure products
17 JMBC Particle Technology Course: Crystallization Pro’s & Con’s of Crystallization
• Highly selective • Slurry handling • Energy efficient • Solid/liquid separation • Mild conditions • Complex control • No auxiliary phase • Fundamental knowledge • Solid particulate • Product specific designs product • Slow process
99.9-100% pure
18 JMBC Particle Technology Course: Crystallization Crystallization as a molecular affinity separation
• A directed spontaneous self-assembly of a 3- dimensional array of atoms, molecules or ions • Crystallization is more than a separation technique: integration of separation and product formation • Product quality aspects • Purity, CSD, shape, crystal form • Crystallization requires sold/liquid separation steps
19 JMBC Particle Technology Course: Crystallization Main product quality characteristics
5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile JACS 122 (2000) 585
20 JMBC Particle Technology Course: Crystallization Product • Purity • Size distribution Fundamentals • Shape (molecular • Crystal form Equipment interactions) design
Crystallization
Phenomena Process • Nucleation • Creation of supersaturation • Growth • Crystallization method • Attrition Process • Batch ⇔ continuous • Agglomeration design
21 JMBC Particle Technology Course: Crystallization Main product quality characteristics Product quality
Crystal form Crystal size distribution Crystal shape Purity
Polymorphs Filterability Filterability Impurity content Solvates Packing density Packing density Inclusions Salts Caking Caking Agglomeration Color Surface area Surface area Polymorphs Solubility … Morphology … Dissolution behavior Agglomeration Bioavailability … Stability ..
Customer demands
22 JMBC Particle Technology Course: Crystallization Crystal form
23 JMBC Particle Technology Course: Crystallization Crystal form A- H+ API Co-former Solvent Acid
A- A- A- H+ H+ H+ stable polymorph A- A- A- H+ H+ H+
Structure change
A- A- A- H+ H+ H+ Metastable
polymorph
H H H
+ + +
A A A
- - -
Free base Co-crystal Solvate Salt
24 Composition change JMBC Particle Technology Course: Crystallization Crystal form: Hydrates and solvates
Gypsum (CaSO 4.2H 2O) Anhydrite (CaSO 4)
25 JMBC Particle Technology Course: Crystallization Crystal form: Polymorphism
L-Glutamic acid
α-form β-form
26 JMBC Particle Technology Course: Crystallization Crystal form: Polymorphism
CaCO3 - Calcite (lozenges) and vaterite (spheres)
27 JMBC Particle Technology Course: Crystallization Crystal form: Polymorphism
6 polymorphs!
5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile JACS 122 (2000) 585
28 JMBC Particle Technology Course: Crystallization Crystal Size Distribution
29 JMBC Particle Technology Course: Crystallization Crystal size versus particle size
A A C
B C B Sólido regular Sólido irregular
Particle size is a broader term
30 JMBC Particle Technology Course: Crystallization Particle size definitions
name definition
length maximal length
sieve diameter width of the minimum square aperture through which the particle will pass volume diameter diameter of a sphere having the same volume as the crystal surface diameter diameter of a sphere having the same surface area as the crystal projected area diameter of a sphere having the same projected area diameter as the crystal viewed from a fixed direction • Each method for size measurement captures a specific feature of particle size • Do not compare sizes measured by distinct methods !
31 JMBC Particle Technology Course: Crystallization Particle size: Sieving
Aperture
32 JMBC Particle Technology Course: Crystallization Size range Mass Particle size distributions [µm] Mass density distribution [g] 0 - 40 0.1 48.0% 0.5 40 - 100 2.9 100 - 200 19.2 0.4 200 - 400 48.0
Mass 0.3 400 - 600 19.2 fraction 600 - 1000 9.6 19.2% 19.2% [-] 0.2 1000 - 2000 1.0
9.6% 0.1 2.9% 0.1% 1.0% 0 0 40 100 200 400 6001000 2000 Size rangeL m [ µm]
33 JMBC Particle Technology Course: Crystallization Crystal Shape
34 JMBC Particle Technology Course: Crystallization Crystal shape
35 JMBC Particle Technology Course: Crystallization Crystal shape Crystal shape
Crystal structure crystal form (equilibrium shape)
nucleation Phenomena growth agglomeration
supersaturation Process impurities solvent temperature
36 JMBC Particle Technology Course: Crystallization Crystal morphology
• Morphology is determined by the slowest growing faces
fast
slow
37 JMBC Particle Technology Course: Crystallization Crystal shape: supersaturation effect
Lysozyme
38 JMBC Particle Technology Course: Crystallization Crystal shape
Thermal roughening
Temperature (S=1) Kinetic roughening
Supersaturation (constant T)
39 JMBC Particle Technology Course: Crystallization Crystal shape: solvent effect RDX crystal morphology from different solvents
Solvent can have a distinct effect on the crystal shape
40 JMBC Particle Technology Course: Crystallization Crystal shape: impurity effect NaCl crystals
4- grown in the presence of Fe(CN) 6 Table salt
41 JMBC Particle Technology Course: Crystallization Crystal shape: crystallizer
NaCl from a fluid bed crystallizer NaCl from an Oslo crystallizer
NaCl grown in a rotating flow NaCl grown under high supersation
42 JMBC Particle Technology Course: Crystallization Crystal Purity
43 JMBC Particle Technology Course: Crystallization Product purity • Impurity incorporation in crystal lattice • Inclusion of mother liquor • due to impurity and growth • due to attrition / secondary nucleation • Impure product due to agglomeration • Adhering mother liquor
44 JMBC Particle Technology Course: Crystallization Crystallization phenomena
• Nucleation (formation of a new crystalline phase) • Primary nucleation • Secondary nucleation • Crystal growth (mass deposition on existing crystals ) • Mass transfer • Integration of solute molecules in crystal lattice • Agglomeration • Collision • Cementation • Rupture
45 JMBC Particle Technology Course: Crystallization Phase Behavior (binary systems)
Eutectic system, constant P Lever-rule:
LZ Suspension density = LC
Solid A + solid B
46 JMBC Particle Technology Course: Crystallization crystallization kinetics
n Homogeneous Nucleation (HON) spherical cluster Primary in solution Nucleation n Heterogeneous substrate cap-shaped cluster Nucleation (HEN) on a substrate Primary nucleation is the process of random generation of nanoscopically small formations of a new phase that have the ability for irreversible growth to macroscopically large sizes.
47 JMBC Particle Technology Course: Crystallization Primary nucleation
Nucleation model of Szilard: nucleation is a series of bimolecular “reactions” between molecules (monomers) and clusters.
fn−1 fn 1 2 3 … n* −−−1 n* n* +1 … gn gn+1
… …
fn – attachment frequency of monomers to n-sized cluster gn – detachment frequency of monomers to n-sized cluster
48 JMBC Particle Technology Course: Crystallization Nucleation work for HON
∆Gs Free For spherical particles: energy W(n) 16 π v 2 γ 3 W * = 2 2 2 0 W* 3k T ln S n* γ Interfacial energy W(n) and ∆GV supersaturation ratio S
π2 γ 3 = −W* = − 16v 0 J Aexp Aexp 3 3 2 Cluster size kT 3k T ln S n
49 JMBC Particle Technology Course: Crystallization Homogeneous and heterogeneous nucleation There are always heterogeneous particles (dust particles, impurities, …) present in solutions
Homogeneous AHON > AHEN Heterogeneous A = 10 30 -10 35 A = 10 15 -10 25 HON γγγ> γγγ HEN γ ef γ Ψγ ef = with 0<Ψ<1 At high S At lower S Homogeneous nucleation Heterogeneous nucleation dominant dominant
50 JMBC Particle Technology Course: Crystallization Primary nucleation rate 1.0E+18
The number of crystals created 1.0E+15 HEN per unit of volume and time A=10 20 1.0E+12 J Ψ=0.7 [#/m 3s] J in units [m-3s-1] 1.0E+09 HON 1.0E+06 Arrhenius type reaction A=10 30 with energy barrier W * 1.0E+03 1 10 100 1000 10000 100000 1000000 SupersaturationS ratio S
W* 16vπ2 γ 3 J= Aexp − = Aexp − kT 3k3 T 3 ln 2 S Highly non-linear behavior towards S and γ
51 JMBC Particle Technology Course: Crystallization Secondary nucleation Attrition
• Takes place in the presence of larger crystals (parent crystals) • Stages: • generation of attrition fragments • removal of fragments from parent crystal • survival and growth of the fragments
52 JMBC Particle Technology Course: Crystallization Secondary nucleation rate: power law
= i h j = 1 σ bk j B0 kN GL N M T or B0 k NPMsp T
-3 -1 B0 = Secondary nucleation rate [# m s ] σ b GL = Crystal growth rate (m/s), G L = k g N = Impeller rotational speed [rpm]
MT = Total mass of crystals per unit volume σ = relative supersaturation σ (-) 3 Psp = specific power input P sp ~ N k and k 1 are constants related to crystallizer geometry (impeller N N type, number of blades, scale of operation)
1 < b < 3; 0.6 < k < 0.7; j = 1 or 2
53 JMBC Particle Technology Course: Crystallization Nucleation & growth in a batch process Unpredictable start of nucleation Uncontrollable 50%
40%
30% Metastable zone limit
c c [w%] 20% Solubility 10%
0% 0 20 40 60 80 100 120 Temperature
JMBC Particle Technology Course: Crystallization Crystal growth: Smooth or rough surface Smooth or layer growth • growth units attach to kinks sites in the steps • steps propagate along the crystal surface and form growth layers • two step sources generate steps: • Birth and Spread growth mechanism • Spiral growth mechanism
Rough growth • growth units attach anywhere to the rough crystal surface • Rough growth mechanism
The growth units are incorporated in an existing crystal lattice 55 JMBC Particle Technology Course: Crystallization Dutch painter Escher Polymorphism
Fish form I Fish form II
56 JMBC Particle Technology Course: Crystallization Crystal form A- H+ API Co-former Solvent Acid
A- A- A- H+ H+ H+ stable polymorph A- A- A- H+ H+ H+
Structure change
A- A- A- H+ H+ H+ Metastable
polymorph
H H H
+ + +
A A A
- - -
Free base Co-crystal Solvate Salt
57 Composition change JMBC Particle Technology Course: Crystallization Polymorphism: product quality
The ability of a chemical compound to crystallize into different crystalline compounds
58 JMBC Particle Technology Course: Crystallization Polymorphism
• The number of forms known for a given compound is proportional to the time and money spent in research on that compound (McCrone, 1965) • Currently not true anymore – although now and then a new polymorph pops up • Succesfull research strategies have been developed to search for polymorphs
Record: 17 polymorphs J.A. Pesti, R.A. Chorvat, G.F. Huhn, Chem. Innovations 2002, Oct. 28
59 JMBC Particle Technology Course: Crystallization Polymorphism: L-histidine
α-form β-form Orthorhombic monoclinic (P21 21 21) (P21) a≠b≠c, α=β=γ=90° a≠b≠c, α=β=90°≠γ
60 JMBC Particle Technology Course: Crystallization Polymorphism: Ritonavir
• The HIV-1 and HIV-2 protease inhibitor Ritonavir
• In 1996 Ritonavir was introduced on the market
• In 1998 a new, more stable form appeared • The new polymorph had a 4 times lower solubility • This affected the bioavailability of the pharmaceutical • The company Abbott withdrew Ritonavir from the market
• 1 year of research effort enabled the production of the old less stable polymorph again.
• Costs : 100 of millions of dollars
61 JMBC Particle Technology Course: Crystallization Thermodynamic stability: solubility
monotropic enantiotropic c* c*
Tt Temperature Temperature
The transition temperature is independent from the solvent
62 JMBC Particle Technology Course: Crystallization Kinetics in cooling crystallization II
I c* c
Tt Temperature Thermodynamics: Above Tt I is obtained, below Tt II is obtained, but …
63 JMBC Particle Technology Course: Crystallization Kinetics in cooling crystallization Metastable zone widths II
I Adjustable by c* changing solvent c
Tt Temperature
64 JMBC Particle Technology Course: Crystallization Kinetics in cooling crystallization II
I c* c
Tt Temperature
65 JMBC Particle Technology Course: Crystallization Kinetics in cooling crystallisation
II
I
Concentration + seeds
T Temperature transform
66 JMBC Particle Technology Course: Crystallization Solvent mediated polymorph transformation: L- glutamic acid Supersaturation Supersaturation
Nucleation Nucleation & & crystal growth crystal growth
Solvent Unstable mediated Stable Polymorph α polymorph Polymorph β transformation
67 JMBC Particle Technology Course: Crystallization Solvent mediated polymorph transformation: L- glutamic acid & Raman spectroscopy α-form β-form
0.800 ααα-form fraction 0.750 in crystalline phase
0.700 0% 0.650 31% Raman can detect Relative 0.600 intensity 0.550 polymorphic fraction in 0.500 crystal phase of 68% 0.450 suspension
0.400 97% 0.350
0.300 600 650 700 750 800 850 Raman Shift [cm -1]
68 JMBC Particle Technology Course: Crystallization Control & optimization of polymorph crystallization
100
80 25ºC 60 α-form fraction 50ºC 45ºC 40ºC [wt%] 40
20 I II
0 -10 2 4 6 8 10 Time [hr] Large effect of temperature on transformation process
69 JMBC Particle Technology Course: Crystallization Kinetics in cooling crystallization Metastable zone widths II High possibility of concomitant I polymorphism c* c
Tt Temperature
70 JMBC Particle Technology Course: Crystallization Concomitant polymorphism
Calcite and vaterite
(CaCO3) 1,1-dicyano-4-(4-dimethylaminophenyl)-1,3-butadiene
71 JMBC Particle Technology Course: Crystallization Kinetics in cooling crystallization: oiling out
100% solute-rich and solute-poor phase with equal chemical potential
c* c liquid-liquid I phase split
0 Temperature crystallization usually starts in the solute rich phase
Roger Davey, Chem. Comm. 2003 72 JMBC Particle Technology Course: Crystallization Anti-solvent crystallization
• Why? • Thermally instable API • Removal from remaining solution after cooling crystallization Ascorbic acid from EtOH/CO 2 • Solubility is variable • Be aware of local conditions • Many process configurations • Wide variety of particle size distributions and polymorphs
Acetaminophen from EtOH/CO 2
73 JMBC Particle Technology Course: Crystallization Kinetics in antisolvent crystallization AS → Solubility Solubility S
°Slow addition °mild conditions 0 w% antisolvent → 100 AS °less chance for unwanted polymorph
74 JMBC Particle Technology Course: Crystallization Kinetics in antisolvent crystallization S → Solubility Solubility AS
°Extreme supersaturations 0 w% antisolvent → 100 AS °Concomitant polymorphism
75 JMBC Particle Technology Course: Crystallization Polymorphism: Ritonavir
• The HIV-1 and HIV-2 protease inhibitor Ritonavir
• In 1996 Ritonavir was introduced on the market
• In 1998 a new, more stable form appeared • The new polymorph had a 4 times lower solubility • This affected the bioavailability of the pharmaceutical • The company Abbott withdrew Ritonavir from the market
• 1 year of research effort enabled the production of the old less stable polymorph again.
• Costs : 100 of millions of dollars
76 JMBC Particle Technology Course: Crystallization Kinetics in antisolvent crystallization
How to obtain the metastable form I of Ritonavir?
1. Crystallize form I a. suspension form I seeds in anti-solvent b. fed-batch addition of solution to anti-solvent
2. Inhibition of transition I => II Choice of solvent mixture inhibits transition Ethyl-acetate/Heptane 2:1 >90% polymorph II Ethyl-acetate/Heptane 1:2 mostly polymorph I
77 JMBC Particle Technology Course: Crystallization Conclusions
• Polymorphism is the ability of a chemical compound to form different crystalline lattices • polymorphs differ in their physical properties and is therefore an important issue in pharmaceutical industry • The crystallization of polymorphs is a process of nucleation and growth of both polymorphs and the possible solvent mediated transition from a metastable form to a more stable form. • Crystallization of polymorphs is a balance between thermodynamics and kinetics
78 JMBC Particle Technology Course: Crystallization References
• Joel Bernstein, Polymorphism in molecular crystals, Clarendon Press, Oxford, 2002 • T. Threlfall, Crystallisation of Polymorphs: Thermodynamic Insight into the Role of Solvent, Organic Process Research Development 4 (2000) 384-390 • J. Bernstein, J. Dunitz, Disappearing polymorphs, Acc. Chem. Res. 28 (1995) 193-200. • S. Gracin, Å.C. Rasmuson, Polymorphism and crystallization of p- aminobenzoic acid, Crystal growth design 4(5) (2004) 1013-1023. • J. Bauer et al., Ritonavir: An extraordinary example of conformational polymorphism, Pharmaceutical research 18 (6) (2001) 859-866. • T. Ono, J.H. ter Horst, P.J. Jansens, Quantitative Measurement of the Polymorphic Transformation of L-Glutamic Acid Using In-Situ Raman Spectroscopy, Crystal Growth Design 4(3) (2004) 465-469. • C.S. Towler, R.J. Davey, R.W. Lancaster, C.J. Price, Impact of molecular speciation on crystal nucleation in polymorphic systems: the conundrum of glycine and molecular “self poisioning”, J. Am. Chem. Soc. 126 (2004) 13347-13353.
79 JMBC Particle Technology Course: Crystallization Chiral separation
Herman J.M. Kramer Intensified Reaction & Separation Systems Process & Energy Delft University of Technology
Leeghwaterstraat 39 2628 CB Delft The Netherlands [email protected]
80
Process & Energy – Intensified Reaction & Separation Systems Chirality
“I call any geometrical figure, or group of points, chiral, and say it has chirality, if its image in a plane mirror, ideally realised, cannot be brought to coincide with itself.”
Lord Kelvin. Baltimore Lectures on Molecular Dynamics and the Wave Theory of Light, 1904.
81 JMBC Particle Technology Course: Crystallization Enantiomers
Enantiomers are stereoisomer pairs in a mirror-image relationship.
Enantiomer pairs possess identical physical properties, but their biological activitiesand effects can be markedly different.
82 JMBC Particle Technology Course: Crystallization Amino acids L-leucine D-leucine L-phenylalanine D-phenylalanine L-tyrosine D-tyrosine L-tryptophan D-tryptophan All taste bitter. All taste sweet.
Aspartames
NH2 NH2 H H HOOC N L COOCH3 HOOC N D COOCH3
O CH2Ph O CH2Ph sweet bitter
83 JMBC Particle Technology Course: Crystallization Thalidomide
In the 1960s, thalidomide was administered as a mixture of two enantiomeric forms:-
O O
H H N N
O O O N O O N O H H R-thalidomide S-thalidomide mild sedative Causesteratogen birth defects
84 JMBC Particle Technology Course: Crystallization Chiral compounds
Racemic compound enantiopure compound
+ +
Escher 85 JMBC Particle Technology Course: Crystallization Crystallization from a racemic mixture
Racemic compound
conglomerate
Escher 86 JMBC Particle Technology Course: Crystallization Crystallization from a racemic mixture
• Racemic crystals (92%). • Enantiomer pairs incorporated stoichiometrically into the unit cell. • Resolvable only by chemical intervention. • Conglomerates (8%). • Mechanical mixtures of homochiral crystals of the two enantiomer forms. • Resolvable physically by crystallization methods. • Pseudoracemates (very few). • Crystallize as solid solutions. • Require chemical intervention for resolution.
87 JMBC Particle Technology Course: Crystallization Solubility 1/T
c Ln x
T
If the solubility is low, the saturation temperature is high
JMBC Particle Technology Course: Crystallization Clear & Cloud Point Measurements Clear point, 100% transmission Transmission
T Ts=42.2°C Ts=42.3°C
JMBC Particle Technology Course: Crystallization Clear Point & Solubility
Thermodynamic Solubility point
JMBC Particle Technology Course: Crystallization Chiral compounds Co-crystal Binary phase diagram
Conglomerate Racemic compound Solid solution
The phaseL diagram reflectsL the kind of solid Lstate
T S+L R+L RS+L S+L R+L RS R+S S+RS R+RS SR S R S R yR yR yR
JMBC Particle Technology Course: Crystallization Chiral Compounds: Asparagine in Water Ternary phase diagram screening
30 80 a x=25 x=25 b x=15 x=15 25 70 20
T 15 s 60 x s [°C] [mmol/mol] 10 50 5
0 40 0 5 10 15 20 25 30 0 0.25 0.5 0.75 1
x R [mmol/mol] y R [-] Conglomerate
JMBC Particle Technology Course: Crystallization Chiral Compounds: Ibuprofen in Hexane Ternary phase diagram screening
200 60 x =175 c d
50 150 40 x s [mmol/mol] T 100 s 30 [°C]
20 50 10
0 0 0 50 100 150 200 0 0.25 0.5 0.75 1 y [-] x R [mmol/mol] R Racemic compound
JMBC Particle Technology Course: Crystallization Chiral Compounds: Atenolol in Ethanol Ternary phase diagram screening
30 60 e x=25x=25 x=25x =25 f x=10x=10 x=10x =10 50
20 40
x T s s 30 [mmol/mol] [°C]
10 20
10
0 0 0 10 20 30 0 0.25 0.5 0.75 1
x R [mmol/mol] y R [-] Solid solution
JMBC Particle Technology Course: Crystallization Chiral Compounds Ternary phase diagram screening
Racemic Compound, Conglomerate or Solid Solution?
• Saturation temperature measurements can be used to identify the kind of solid state of a chiral pharmaceutical at solution crystallization conditions • The ternary phase diagram is obtained as a bonus
S. Sukanya, J.H. ter Horst, Racemic Compound, Conglomerate, or Solid Solution: Phase Diagram Screening of Chiral Compounds, Crystal Growth Design10 (4) (2010) 1808-1812.
JMBC Particle Technology Course: Crystallization Phase diagram
(S) (S)
S' S'
s(+) + l s(-) + l s(+) + l s(R) + l s(-) + l
s(+) + s(R) + l s(-) + s(R) + l s(+) + s(-) + l
(+) (-) (+) (-) Racemic crystals Conglomerate S. Srisanga, J.H. ter Horst, Crystal growth design, 2010
96 JMBC Particle Technology Course: Crystallization Resolution of Conglomerates - Methods available
1. Preferential crystallization
2. Crystallization of diastereomers
3. The grinding method: Combining a racemization reaction with suspension grinding
97 JMBC Particle Technology Course: Crystallization 1. Preferential crystallization - principle Solvent
Grow S Dissolve S Dissolve R Grow R
Grow S & R Dissolve S Nucleate & Grow R
S Seed fraction R
98 JMBC Particle Technology Course: Crystallization 1. Preferential crystallization - principle Solvent Add seeds with excess S:
Only R crystals dissolve
S Seed fraction R
99 JMBC Particle Technology Course: Crystallization 1. Preferential crystallization - principle Solvent Grow S crystals,
Remove S crystals
S R
100 JMBC Particle Technology Course: Crystallization 1. Preferential crystallization - principle Solvent Add seeds with excess R:
Only S crystals dissolve
S R
101 JMBC Particle Technology Course: Crystallization 1. Preferential crystallization - principle Solvent Grow R crystals,
Remove R crystals
S R
102 JMBC Particle Technology Course: Crystallization 1. Preferential crystallization - principle Solvent Take care in avoiding Crystallization of the Other enaniomer: Difficult!
S R
103 JMBC Particle Technology Course: Crystallization 2. Resolution of racemic crystal systems.
A single-enantiomer resolving agent can be used to form a pair of products in a diastereomeric relationship.
Example: racemic acid (±)-A-H+ and resolving base (+)-B: (±)-A-H+ + (+)-B → [(+)-A-.(+)-BH +] + [ (-)-A-.(+)-BH +] ‘p’-salt ‘n’-salt
Compounds in diastereomeric relationships often exhibit significantly different physical properties, unlike enantiomer pairs. Selectionof resolving agent is a trial-and-error exercise.
104 JMBC Particle Technology Course: Crystallization 2. Resolution of racemic crystal systems. Model system
CH3 R + - NH3 OOC
R = CH3, C2H5, OH
105 JMBC Particle Technology Course: Crystallization 2. Resolution of racemic crystal systems
1 Solubilities – R = CH 3
R-form
0.5
S-form Solubility mol/L
0 0 20 40 60
Temperature C
106 JMBC Particle Technology Course: Crystallization 2. Resolution of racemic crystal systems
1 Solubilities – R = OH
S-form
0.5 Solubility mol/L R-form
0 0 20 40 60 Temperature C
107 JMBC Particle Technology Course: Crystallization 3. The grinding method Combining a racemization reaction and suspension grinding
conglomerate Enantiopure
W.L. Noorduin et al., J. Am. Chem. Soc. 130 (2008) 1158. 108 JMBC Particle Technology Course: Crystallization Chiral separation
• A conglomerate system can be separated using preferential crystallization
• A racemic compound can be separated by finding a suited resolving agent forming diastereomeric salts • This pair of products can have distinct physical properties such as solubilities exploitable for chiral separation through crystallization
• The newly proposed grinding method combines a racemization reaction and grinding
109 JMBC Particle Technology Course: Crystallization