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Small Molecule

Crystallization

Jessica K. Liang

Department of Chemical Engineering

Illinois Institute of Technology

ACS Summer School July 2003 Chicago IL

Overview

Basic Crystal Science

Crystallization Process

Our Research Projects

Lab Tour

New York

What is a Crystal?

Crystal

Amorphous

London

Ø Solid with short and long range order
with atoms or molecules in a fixed lattice
arrangement

Definition of Crystal

Ø The distinction between a crystal and
an amorphous solid is that between
order and disorder over large distances

Ø Internal structure of crystals
accessible by x-ray diffraction analysis

Crystal Structure

Unit cell parameters: a, b, c,

Space Groups

Ø 230 space groups

Ø For organic
molecules, statistics
shows that

95%

of all

compounds crystallize
out in these

space

groups

• P21/c monoclinic
• P21 monoclinic
• P21/m monoclinic
• P2/c monoclinic
• C2/c monoclinic
• C2/m monoclinic
• Cc monoclinic
• C2 monoclinic
• P-1 triclinic

• P1 triclinic
• P212121 orthorhombic
• Pbca orthorhombic
• Pnma orthorhombic

• Pna21 orthorhombic

• Pbcn orthorhombic
• Pca21 orthorhombic
• P21212 orthorhombic

X-Ray Diffraction

Structure Determination

Need good quality single crystal

Send to Crystallographer.

Ø They determine lattice type, parameters i.e. a, b, c,

atom positions and space group

Ø Space groups relate crystal symmetry on an atomic

scale to possible arrangement of atom which possess
that symmetry.

Ø Given systems and space group you can calculate all

possible arrangement of atoms which meet this
symmetry.

Types of Crystals

Ø Ionic –

Charged ions held in place on

lattice by electrostatic forces (NaCl)

Ø Covalent –

Atoms connected by

framework of covalent bonds (Diamond)

Ø Molecular Crystals –

Usually organic,

composed of discrete molecules held
together by weak attractive forces (Urea)

Ø Metallic Crystals –

Ordered arrays of

identical cations (Copper)

Morphology and Habit

Crystal morphology is defined as the general
appearance of crystals described by the
Miller indices of the faces that show and give
the crystals their characteristic shape

Crystal habit means the general shape of a
crystal as given by the relative length of the
various major axes.

Both morphology and habit depend on growth
conditions and can vary under different
process conditions.

Crystal Size Distribution

Ø CSD: the most widely applied quality
test of a crystalline product

Ø Many industrial processes demand a
narrow range of particle size as this
results in good filtering, drying and free-
flow ability

Polymorphism

The phenomenon of a
chemical species having
more than one possible
crystal form

e.g. Carbon

(graphite: top and pencil and
diamond: bottom) whilst
remaining chemically identical

Different forms maybe
significantly different in terms
of both their structures and
physical & chemical
properties

Reference: Yu, L.; Stephenson, G. A.; Mitchell, C. A.; Bunnell, C. A.; Snorek, S. V.; Bowyer, J. J.; Borchardt, T. B.; Stowell, J. G;
Byrn, S. R.

J. Am. Chem. Soc

. 2000, 122, 585

5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile

“ROY”

6 Polymorph

Forms

McCrone’s Law

‘Every compound has different
polymorphic forms, and that, in
general,the number of forms known for a
given compound is proportional to the
time and money spent in research on that
compound.’

McCrone, W.C.

Polymorphism in Physics and Chemistry of the Organic Solid

State

, Ed. by Fox D, Labes MM, Weissberger A1965, Vol. II,

pp. 726-767

, Wiley

Interscience New York.

Types of Polymorphism

Packing Polymorphism

Ø Packing and bonding arrangement of the structure in its
different forms are significantly different

Conformational Polymorphism

Ø The existence of different conformers of the same
molecule in different polymorphic modifications
Ø Low energy difference between various conformations

Pseudopolymorphism

Ø A new structure of a compound that is hydrated or
solvated

Packing Polymorphism

Glycine

(C2H5NO2)

Albrecht G and Corey RB

J. Am. Chem. Soc

1931

, 61, 1037.

Y. Iitaka,

Proc. Jap. Acad

1954

; Vol. 30,109-112

Hexagonal

Monoclinic

Conformational

Polymorphism

Koch MH,

Acta Cryst

B29,

1973

, 379.

Azibi M et al.,

J. Pharm Sci

., 72,

1983

, 232.

Spiperone
(

C23H26FN3O2

)

Polymorphic Properties

Packing Properties

Molar volume, density, refractive index, conductivity, hygroscopicity

Thermodynamic Properties

Melting and sublimation temperature, structural energy, Enthalpy,

Heat capacity, Entropy, Free energy and chemical potential,
Thermodynamic activity, Vapor pressure, Solubility

Kinetic Properties

Dissolution rates, rates of solid state reactions, stability

Spectroscopic Properties
Surface Properties

Surface free energy, interfacial tension, morphology

Mechanical Properties

Hardness, tensile strength, compactability, handling, flow

Bioavailability

Characterization Methods

Crystallography: X-Ray Diffraction

Single Crystal X-Ray Diffraction

X-Ray Powder Diffraction

Morphology: Microscopy

Polarizing Optical Microscopy

Thermal Microscopy

Phase Transitions: Thermal Methods of Analysis

Thermogravimetry

Differential Thermal Analysis

Differential Scanning Calorimetry

Molecular Motion: Vibrational Spectroscopy

Infrared Absorption Spectroscopy

Raman Spectroscopy

Chemical Environment: Nuclear Magnetic Resonance
Spectrometry

On-lined

Monotropic System

One form is metastable
relative to the other at all
temperatures below the
melting point

Polymorphs are not
interconvertible

Solubility of the stable form is
always lower than the
metastable form

Monotropic System

β−

form

α−

form

L-glutamic acid C5H9NO4

Enantiotropic System

Polymorphic form dependent
upon the temperature and
pressure of the system

Reversible transition point
where relative
thermodynamic stabilities
change

Transition point below
melting point for any of the
solid phase

L-Phenylalanine

Monohydrat

e stable

Anhydrate

stable

Ø Metastable
form may exist
for a long time;

Ø Presence of
the stable form
results in
solvent
mediated phase
transformation

Crystallization

Formation of a crystalline phase
from a parent phase, e.g. solution

One of the oldest and most
important unit operations, e.g.
extracting salt crystals from sea
water

Over

90%

of all pharmaceutical

products contain drug substances
in crystalline form

Crystallization Process

Final Product

Liquid

Mixture

Nucleation:

Birth of Solid

Phase

Crystal

Growth

Generation of

Supersaturatio

Driving force

Solid Form

(Polymorph,Hydrate

)

Ratio of Rate of
Nucleation to Growth
Controls Final Product
Size Distribution

Crystal Habit,
Crystal Purity

Definition of Supersaturation

C* : equilibrium concentration for a given temperature
C : solution concentration; T*: saturated temperature;
Tcry: Crystallization temperature

Supercooling

Generation of

Supersaturation

Mode

Supersaturation

generation method

Cooling

Reduction in temperature

Evaporation

Lost of solvent

Dilution

Adding anti-solvent

Reaction

Generation of solute

Vacuum

Cooling, flashing

evaporation

Ø Supersaturated zone:

Spontaneous nucleation is
expected

Ø Metastable zone:

Spontaneous nucleation is
impossible

Ø Stable zone:

Nucleation

is impossible

Metastable Zone

Solubility & Supersolubility

Diagram

Metastable Zone Width

Ø MSZW is a

nucleation kinetic-limited

parameter that is highly dependent on process
conditions

Ø Many factors may influence the value of
MSZW, e.g.

rate of cooling, agitation, the

presence of foreign particles and impurities

Ø Metastable zone width (MSZW) is a

critical

parameter

in the crystallisation process as it

reveals the nucleation behaviour of the system

Effects of Cooling Rate & Agitation

Ø MSZW decreases as stirrer

speed increases

Ø MSZW widens at N>400rpm

Ø MSZW widens as cooling

rate rises

Cooling crystallization of aqueous
L-glutamic acid solutions

200

250

300

400

500

0.2°C/min
0.5°C/min

0.3°C/min

Nucleation

Homogeneous:

Spontaneous

Heterogeneous:

Induced by the

presence of foreign

particles

Primary

Nucleation:

Nucleation in crystal

free system

Secondary

Nucleation:

Induced by the presence

of crystals

Homogenous Nucleation

radius of cluster

vm:

specific volume of solute

molecules

SB:

supersaturation of the solution

solid-liquid interfacial tension

Gibbs Free
Energy Change

Heterogeneous Nucleation

Ø Heterogeneous nucleation: caused
by dust, dirt, rough spots on walls, etc
Ø In industrial processes,
homogeneous nucleation is

rare

Ø Nucleation is usually heterogeneous
and/or secondary

Heterogeneous Nucleation

Ø Lower energy barrier

Energy Ratio

Contact
angle

Empirical Nucleation Model

J :Nucleation rate
kn:Nucleation rate constant
m:Nucleation order

C*:equilibrium concentration at

nucleation temperature

C:solution concentration

Secondary Nucleation

Stirring rate

Suspension

density

Ø Nucleation caused by interaction of existing crystals with
vessel, impeller or by collisions

Ø The main source of nuclei in many industrial applications

Ø Empirical model: B secondary nucleation rate

Secondary Nucleation

Supersaturation

Stirrer speed

Secondary Nucleation of Potassium Chloride

Secondary Nucleation

Ø Higher secondary
nucleation rate using
steel impeller

Ø Secondary
nucleation rate
increases as agitator
speed rises

Crystal Growth

(1)Transport
from bulk to
boundary layer

(2)Diffusion
to crystal
surface

(3) Absorb

onto

surface and

partial

desolvation

(4)Diffusion to energetically

favorable sites

(4*)

Diffusion

away

(5)

Integration

at a kink

and total

desolvatio

Molecule Incorporation

Single molecule incorporation on flat areas of a
crystal face is not energetically favorable

Molecule is bonded both to a
step face as well as to the
surface

Most energetically
favorable: three
sides of molecular
cube are bonded
( kink site)

Surface Structure of a Growing Crystal

Ø Where do the steps come from?

Ø What is the rate control factor in
determining the crystal growth rate?

Crystal Growth Theories

BCF (Burton Cabrera Frank) Theory

Ø Dislocations in the crystal are the source of
new steps

(dislocations are a certain type of

irregularity in the structure of the crystal
lattice)

Ø Screw dislocation provides a way for the
steps to grow continuously

Spiral Growth from a Screw

Dislocation

Empirical Growth Model

Mass
Deposition Rate

: Growth order is generally between 0 and 2.5, most commonly equal to 1;

kG:

Overall rate constant,depends on temperature, crystal size, hydrodynamics

and presence of impurities;

AT: Total surface area of the crystals
m: Mass of the crystals; L : Mean crystal size;

: volume and area shape factors;

: Crystal density

Overall Linear
Growth Rate

“Designer”

Particles

Particle Engineering

Bioavailability (solubility)
Chemical and physical stability

Physicochemical

Chemical purity

Crystal Habit

Crystal Structure

(Polymorphism/

hydrate/imperfe-

ction)

Thermodynamic

properties

Physicotechnical

Mechanical properties

(compressibility)

packing & flowability

Particulate Properties

Crystal size, shape &

surface

Seeding Technology

Objectives:

Ø Design the crystallization process
to achieve a certain final product
size using seeds
Ø By seeding the preferable
polymorph form, obtain desired
crystal morphology and polymorph
or pseudo-polymorph

Approach

MultiMax

reactor

system

4x50

ml scale

Temperature
Stirring rate
Dosing rate

PXRD

Polymorphic

form

Lasentec

FBRM In-situ

particle sizing

BET

Particle

surface area

Model

Population

balance

equation

Crystal
growth

Nucleation

Super-

saturation

balance

Solubility

Seed properties:

size, shape,

mass, surface

area

Nucleation and

crystal growth

kinetic parameters

Population Balance
Model

Simulated final

crystal size

distribution & yield

Measured final

crystal size

distribution

Verification

Optimization
& design

What do we do?

Ø Crystallization process development and
optimization

Ø Nonphotochemical laser-induced nucleation
of small molecules and proteins

Ø Template-directed nucleation and growth of
molecular crystals

Ø Electrodynamic levitation of single solution
droplet to study the activity of supersaturated
small molecule and protein solutions