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
H.J.M.Kramer@tudelft.nl

Acknowledgement
Process & Energy – Intensified Reaction & Separation 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
modelling optimization and control

B. Advanced crystallization topics

Polymorphism
Chiral crystallization
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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, 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.

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
 High selectivity synthesis
 Mild conditions product
 Low energy demand
 Particular product
 Slow process
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JMBC Particle Technology Course: Crystallization

Pro’s & Con’s of Crystallization
• High distribution coefficient KA of compound to be crystallized
• Low distribution coefficient KS of solvent and impurities
• High selectivity α
• Pure product in one process step xAcr 1
KA   (very large)
xA * xA *

xScr 0
KS   (very small)
xS * xS *
Ki
a= (very large)
KS

99.9-100% pure

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:
• Growth rate ~ 10-8-10-7 m/s

99.9-100% pure

JMBC Particle Technology Course: Crystallization

Crystallization is more than a separation
technique

• Separation
• Table salt, soda, sugar
• Purification
• Pharmaceuticals, caprolactam, parrafin, proteins
• Concentration
• Beverages, waste water
• Particulate Product Formation
• nano-scale (creams, magnetic tapes, catalysts, zeolites)
• micro-scale (inhalers)
• macro-scale (silicon wafers)
• Pharmaceutical crystal form: organic salt, polymorphism, co-
crystals
• Analysis
• Proteins

integration of separation and crystalline product formation

JMBC Particle Technology Course: Crystallization

Relevance of Crystallization
• About 70% of all products are solids
• After distillation the most important separation technology
• The most frequently used separation technology

• Food - Sugar, cacao butter, iced beer, sweeteners

• Pharmaceuticals - Aspirin, inhalers, antibiotics, enzymes, insuline
• Salt & derivatives - Table salt, soda
• Fine-chemicals - Pigments
• Petrochemicals - Starting material for polymers
• Electronics - Silicon wafers
• Agriculture - Fertilizer
• Waste treatment - Freeze-concentration, metal-recovery

JMBC Particle Technology Course: Crystallization

The Crystalline Product
Table salt
• Crystal purity >99.9%
• Crystal size distribution

f(L)

L [m]
• Crystal shape: cubic
• Crystal stucture
• Solvates
• Polymorphs
• Chiral crystals

JMBC Particle Technology Course: Crystallization

Crystallization occurs at molecular level
step

Incorporation of terrace
single molecules into
the crystal lattice
kink

Arrangement of
millions of molecules
into crystal lattice
Interaction at surface
with solvent and
impurities

Crystallization is highly selective 10

One step
JMBC Particle crystallizations
Technology can result in 99.9% pure products
Course: Crystallization
Molecular structure: the crystal unit cell

Adipic acid Aspartame

Monoclinic (P21/c) Tetragonal (P41)
abc, ==90° a=bc, ===90°

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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

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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
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JMBC Particle Technology Course: Crystallization

MgSO4
Crystallisation
plant

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JMBC Particle Technology Course: Crystallization

Product  phenomena

Impurity effect on product quality

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JMBC Particle Technology Course: Crystallization

Product is dependent on process conditions

Stimulate agglomeration during process to enhance filterability

Gypsum - CaSO4.2H2O
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JMBC Particle Technology Course: Crystallization

 Crystallization Process
Principle phenomena

• Primary nucleation
• Secondary nucleation
• Attrition /breakage
• Growth
• Agglomeration

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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

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JMBC Particle Technology Course: Crystallization

Solid Forms in Pharmaceutical Industry
Some bestselling small molecule drugs in 2009
Brand Company API Sales # solid
Name [billions $] phases
Lipitor Pfizer Atorvastatin 12.5 41
Calcium
Diovan Novartis Valsartan 6.0 10
Nexium AstraZeneca Esomeprazole 5.0 4
magnesium

1998 Product withdrawal of Norvir (ritonavir). Dissolution failure of oral capsules as a

result of the appearance of a thermodynamically more stable form.
2008 Recall of Neupro (transdermal rotigotine) patches. Crystallization of a new
polymorph that resembled snowflake-like crystals.
2010 Recall of the popular blood thinner Coumadin (warfarin sodium 2-propanol
solvate). Variation in the 2-propanol levels, which affect the crystallinity of
warfarin sodium.

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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

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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
Surface area Surface area Polymorphs
Color … Morphology …
Solubility Agglomeration
Dissolution behavior …
Bioavailability
Stability
..

Customer demands
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JMBC Particle Technology Course: Crystallization

 Crystal form

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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

23
Composition change
JMBC Particle Technology Course: Crystallization
Crystal form: Hydrates and solvates

Gypsum (CaSO4.2H2O) Anhydrite (CaSO4)

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JMBC Particle Technology Course: Crystallization

Crystal form: Polymorphism
L-Glutamic acid

-form -form

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JMBC Particle Technology Course: Crystallization

Crystal form: Polymorphism

CaCO3 - Calcite (lozenges) and vaterite (spheres)

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JMBC Particle Technology Course: Crystallization

 Crystal Size Distribution

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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

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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 !

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JMBC Particle Technology Course: Crystallization

Particle size: Sieving

Aperture
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JMBC Particle Technology Course: Crystallization

 Size range Mass
Particle size distributions [m] [g]
Mass density distribution
0 - 40 0.1
48.0%
40 - 100 2.9
0.5

100 - 200 19.2

0.4
200 - 400 48.0
Mass 0.3 400 - 600 19.2
fraction 600 - 1000 9.6
[-] 0.2 19.2% 19.2%
1000 - 2000 1.0

9.6%
0.1
2.9%
0.1% 1.0%
0
0 40 100 200 400 600 1000 2000

Size range
L m
[m]
<L>=362m
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JMBC Particle Technology Course: Crystallization

 Crystal Shape

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JMBC Particle Technology Course: Crystallization

Crystal shape

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JMBC Particle Technology Course: Crystallization

 Crystal shape
Crystal shape

Crystal structure crystal form (equilibrium shape)

nucleation
Phenomena growth
agglomeration

supersaturation
Process impurities
solvent
temperature
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JMBC Particle Technology Course: Crystallization

Crystal morphology

• Morphology is determined by the slowest growing

faces

fast

slow

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JMBC Particle Technology Course: Crystallization

Crystal shape: supersaturation effect

Lysozyme

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JMBC Particle Technology Course: Crystallization

 Crystal shape

Thermal
roughening

Temperature (S=1)
Kinetic roughening

Supersaturation (constant T)
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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

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JMBC Particle Technology Course: Crystallization

Crystal shape: impurity effect
NaCl crystals

grown in the presence of Fe(CN)4-6

Table salt

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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

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JMBC Particle Technology Course: Crystallization

 Crystal Purity

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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

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JMBC Particle Technology Course: Crystallization

Crystallization kinetics

• Solubility, supersaturation and phase diagrams

• 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
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JMBC Particle Technology Course: Crystallization

Solubility, supersaturation and Phase diagrams
Lever-rule:
Eutectic system, constant P LZ
Suspension density 
LC

Solubility ideal system:

Enthalpy of dissolution of B
 H  1 1  
x*  exp      
 R  T Tm  

Solid A + solid B Mole fraction

of B Melting temperature
Of pure B

Be careful solubility not dependent on the

properties of the solvent. Not realistic!!! 44

JMBC Particle Technology Course: Crystallization! However the temperature dependence is.
Solubility, supersaturation and Phase diagrams
Lever-rule:
Eutectic system, constant P LZ
Suspension density 
LC

Definition supersaturation
   L  S
S  Seq   Leq   L *kT ln aeq
Solid A + solid B L  L *  kT ln a
a
  kT ln
aeq
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JMBC Particle Technology Course: Crystallization

 Supersaturation a
  kT ln
aeq

a x c c  ceq
ln  ln  ln   
aeq xeq ceq ceq

Ideal system Dilute 1<C/Ceq<1.1 Relative

dilute system system supersaturation
low supersaturation

Methods to generate supersaturation

• See handbooks
• Important for the design of the crystallization process

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JMBC Particle Technology Course: Crystallization

 How to measure solubility?

Temperature
control

Stirrer
Suspension
• Establish an equilibrium in a stirred suspension at a given T,P
between the solid and liquid phase
• Filter solution of crystals to isolate liquid
• Analyse the liquid phase to measure concentration at given T,P by
evaporating the solvent or by analytical techniques

JMBC Particle Technology Course: Crystallization

Alternative technique
Measure saturation temperature

Light X Light

Suspension Clear solution

(Low T) (high T)

Clear point:
The temperature at which a suspension becomes a clear solution
during heating with a certain rate
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JMBC Particle Technology Course: Crystallization

 Clear & Cloud Point Measurements
Clear point, 100% transmission

Transmission
T
Ts=42.2°C
Ts=42.3°C

1440 min = 1 day

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JMBC Particle Technology Course: Crystallization

Crystallization kinetics

Primary nucleation

ORP Pbca

 = 46.1°
 = 39.4°
… …

O
N
O
ROY
50

H

JMBC Particle Technology Course: Crystallization

S
 Crystallization kinetics
n
Homogeneous
Nucleation (HON) spherical cluster
Primary in solution

Nucleation n
substrate
Heterogeneous
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.
• Primary nucleation is primarily driven by the level of
supersaturation and conditions that facilitate the
formation of a surface 51

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

ORP Pbca

 = 46.1°
 = 39.4°
… …

O
N
fn – attachment frequency of monomers to n-sized cluster

O
gn – detachment frequency of monomers to n-sized cluster

ROY

H

52

S
JMBC Particle Technology Course: Crystallization

m
R

C
 Nucleation work for HON
1. Creation of volume, ΔGV
2. Creation of surface, ΔGS
3. To form a cluster with n molecules, ΔGs
W (n) = ΔGV + ΔGS Free
energy
W(n)
16 v  2 3
W* 
3k 2T 2 ln 2 S 0 n*
W*

Interfacial energy  W(n)

and ΔGV
supersaturation ratio S
Cluster size n
 W*  16 v 2  3  0
J  A exp     A exp   3 3 2 
 kT   3k T ln S  53

JMBC Particle Technology Course: Crystallization

 Homogeneous and heterogeneous nucleation
Heterogeneous particles (dust particles, impurities, …) are always present
These particles affect the  while also A is strongly different

Homogeneous AHON > AHEN Heterogeneous

AHON = 1030-1035  > ef AHEN = 1015-1025
 ef = 
with 0<<1
At high S At lower S
Homogeneous nucleation Heterogeneous nucleation
dominant dominant
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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=1020
J
1.0E+12
=0.7
[#/m3s]
J in units [m-3s-1] 1.0E+09

HON
A=1030
1.0E+06
Arrhenius type reaction
with energy barrier W * 1.0E+03
1 10 100 1000 10000 100000 1000000

Supersaturation
S
ratio S

 W*  16 v 2  3 
J  A exp     A exp   3 3 2 
 kT   3k T ln S 
Highly non-linear behavior towards S and 
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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
• Is affected by hydrodynamics, design of equipment and the
supersaturation and particle properties
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JMBC Particle Technology Course: Crystallization

Secondary nucleation rate: power law
k
B0  k N G N M i
L
h
T
j
or B0  k σ P sp M Tj
1
N
b

B0 = Secondary nucleation rate [# m-3 s-1]

GL = Crystal growth rate (m/s), GL = kg  b
N = Impeller rotational speed [rpm]
MT = Total mass of crystals per unit volume
 = relative supersaturation  (-)
Psp = specific power input Psp ~ N3

kN and kN1 are constants related to crystallizer geometry (impeller

type, number of blades, scale of operation)

1 < b < 3; 0.6 < k < 0.7; j = 1 or 2

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JMBC Particle Technology Course: Crystallization

 Nucleation & growth in a batch process
Unpredictable
start of nucleation Uncontrollable
50%

40%

30% Metastable zone limit

c [w%]

20%
Solubility
10%

0%
0 20 40 60 80 100 120
Temperature

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JMBC Particle Technology Course: Crystallization

Crystallization Characteristics
Clear point - Upon heating there is a temperature that a
suspension turns into a clear solution
Cloud point - Upon cooling a solution there is a temperature that
crystals will be detected
Metastable Zone Width - The difference between the saturation
temperature (Clear point) and cloud point is the

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JMBC Particle Technology Course: Crystallization

 Isonicotinamide in Ethanol: Metastable zone
width
60 100

55 90

50
80

45
70
Clear point

Transmissivity (%)
40
Temperature (oC)

60
35

Temperature
50
30
MSZW Cloud point
Transmission
[°C] 25
40
of light
30
[%]
20

20
15

10 10

5 0
6:00 7:12 8:24 9:36 10:48 12:00
Time (hour)

Why is there a difference between clear and cloud point?

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JMBC Particle Technology Course: Crystallization

 Intermezzo
Non-Photochemical

Light Source

Photochemical
Effect

Non-
Photochemical
Effect

NPLIN: Used to study the fundamental of primary nucleation 61

Facilitate primary nucleation at mild (low supersaturaton) conditions
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

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JMBC Particle Technology Course: Crystallization

 Dutch painter Escher
Polymorphism

Fish form I Fish form II

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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

64
Composition change
JMBC Particle Technology Course: Crystallization
Polymorphism: product quality

The ability of a chemical compound to crystallize into

different crystalline compounds

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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

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JMBC Particle Technology Course: Crystallization

 Polymorphism: L-histidine

-form -form
Orthorhombic monoclinic
(P21 21 21) (P21)
abc, ===90° abc, ==90°

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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

68

JMBC Particle Technology Course: Crystallization

 Thermodynamic stability: solubility

monotropic enantiotropic
c* c*

Tt
Temperature Temperature

The transition temperature is independent from the solvent

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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 …
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JMBC Particle Technology Course: Crystallization

Kinetics in cooling crystallization
Metastable zone widths
II

I
Adjustable by
c* changing solvent
c

Tt Temperature

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JMBC Particle Technology Course: Crystallization

Kinetics in cooling crystallization
II

I
c*
c

Tt Temperature

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JMBC Particle Technology Course: Crystallization

Kinetics in cooling crystallisation
II

Concentration I

+ seeds

T Temperature
Ttransform
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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  polymorph Polymorph 
transformation
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JMBC Particle Technology Course: Crystallization

 Solvent mediated polymorph transformation: L-
glutamic acid & Raman spectroscopy
-form -form

-form fraction
0.800

0.750
in crystalline phase
0.700
0%
0.650

31% Raman can detect

Relative 0.600

intensity0.550
polymorphic fraction in
0.500
68%
crystal phase of
0.450 suspension
97%
0.400

0.350

0.300

600 650 700 750 800 850

Raman Shift [cm-1]

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JMBC Particle Technology Course: Crystallization

 Control & optimization of polymorph
crystallization
100

80
25ºC
60
-form fraction
[wt%] 50ºC 45ºC 40ºC
40

20 I II

0
-1 0 2 4 6 8 10
Time [hr]

Large effect of temperature on transformation process

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JMBC Particle Technology Course: Crystallization

Kinetics in cooling crystallization
Metastable zone widths
II
High possibility of
concomitant
I
polymorphism
c*
c

Tt Temperature

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JMBC Particle Technology Course: Crystallization

Concomitant polymorphism

Calcite and vaterite

(CaCO3)
1,1-dicyano-4-(4-dimethylaminophenyl)-1,3-butadiene

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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 79

JMBC Particle Technology Course: Crystallization

Anti-solvent crystallization

• Why?
• Thermally instable API
• Removal from remaining
solution after cooling
crystallization Ascorbic acid from EtOH/CO2
• Solubility is variable
• Be aware of local conditions
• Many process configurations
• Wide variety of particle size
distributions and polymorphs
Acetaminophen from EtOH/CO2

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JMBC Particle Technology Course: Crystallization

 Kinetics in antisolvent crystallization
AS
Solubility →

S
 Slow addition
 mild conditions
0 w% antisolvent → 100 AS
 less chance for
unwanted polymorph
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JMBC Particle Technology Course: Crystallization

 Kinetics in antisolvent crystallization
S
Solubility →

AS

 Extreme supersaturations
0 w% antisolvent → 100 AS  Concomitant polymorphism

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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

83

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

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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

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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.

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 Chiral separation

87

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.

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Enantiomers

Enantiomers are stereoisomer pairs in a mirror-image relationship.

Enantiomer pairs possess identical physical

properties, but their biological activities and
effects can be markedly different.

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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
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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 teratogen
Causes birth defects
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JMBC Particle Technology Course: Crystallization

Chiral compounds

Racemic compound enantiopure compound

+ +

Escher 92

JMBC Particle Technology Course: Crystallization

Crystallization from a racemic mixture

Racemic compound

conglomerate
Escher 93

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.

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JMBC Particle Technology Course: Crystallization

 Solubility
1/T

c Lnx

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 phase
L diagram reflects
L the kind of solid Lstate

T
S+L R+L RS+L
S+L R+L
RS
R+S S+RS R+RS

S yR R S yR R S yR R

JMBC Particle Technology Course: Crystallization

 Chiral Compounds: Asparagine in Water
Ternary phase diagram screening

30 80
x=25 a b
x=25
x=15 x=15
25
70
20

Ts
15 60
xs [°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
xs
[mmol/mol]
Ts
100 30
[°C]

20
50
10

0 0
0 50 100 150 200 0 0.25 0.5 0.75 1
x R [mmol/mol] y R [-]

Racemic compound

JMBC Particle Technology Course: Crystallization

Chiral Compounds: Atenolol in Ethanol
Ternary phase diagram screening

30 60
x=25 e x=25
x =25 f
x=25
x=10
x=10 x =10
x=10
50

20 40

xs Ts
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 Design 10(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
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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

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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
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JMBC Particle Technology Course: Crystallization

1. Preferential crystallization - principle
Solvent
Add seeds
with excess S:

Only R crystals dissolve

S Seed fraction R
106

JMBC Particle Technology Course: Crystallization

1. Preferential crystallization - principle
Solvent
Grow S crystals,

Remove S crystals

S R
107

JMBC Particle Technology Course: Crystallization

1. Preferential crystallization - principle
Solvent
Add seeds
with excess R:

Only S crystals dissolve

S R
108

JMBC Particle Technology Course: Crystallization

1. Preferential crystallization - principle
Solvent
Grow R crystals,

Remove R crystals

S R
109

JMBC Particle Technology Course: Crystallization

1. Preferential crystallization - principle
Solvent
Take care in avoiding
Crystallization of the
Other enaniomer:
Difficult!

S R
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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.
Selection of resolving agent is a trial-and-error exercise.

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JMBC Particle Technology Course: Crystallization

2. Resolution of racemic crystal systems.
Model system

CH3 R
+ -
NH3 OOC

R = CH3, C2H5, OH

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JMBC Particle Technology Course: Crystallization

2. Resolution of racemic crystal systems
1
Solubility mol/L Solubilities – R = CH3

R-form

0.5
S-form

0
0 20 40 60
Temperature C

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JMBC Particle Technology Course: Crystallization

2. Resolution of racemic crystal systems

Solubility mol/L 1 Solubilities – R = OH

S-form

0.5

R-form

0
0 20 40 60
Temperature C

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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. 115

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

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JMBC Particle Technology Course: Crystallization