Crystallization:

Concepts, Development
& Manufacturing
Strategies

Agenda
Crystallization in the Pharmaceutical
Industry
Crystallization kinetics
Crystallization development
Particle size engineering
Analytical tools Lasentec
Practical examples

Crystallization in the Pharma

Industry

Most of the Active Product Ingredients (APIs)

and the intermediate products form stable
crystalline compounds at room temperature.
Crystallization is an efficient process to isolate
these compounds with high productivity and
high purity.

Crystallization in the Pharma

Industry (contd)

Batch Crystallization Process

Formation of solid particles within a homogeneous phase by modifying the

solubility of the component of interest
Vf

Vi
Ti
Ci
S

k
i

Tf
C fj

j 1..N

k 1..M
Solutes

S kf

k 1..M

The change in solubility is accomplished by:

Solutes and
Solvents
j 1..N

decreasing the temperature of the solution (cooldown Xon)

Changing composition of solvent by adding a solvent in which the compound is
insoluble (antisovent crystallization)

In some cases crystallization is not achieved by a change in solubility reactive

crystallization

Crystallization Objectives

Isolate substrate

PSD, Crystal habit

Solvent Selection, PSD
Solubility, T

Purify Substrate

Filtration
Drying
Yield

Impurity Rejection
Solvent removal
Washing Properties

Relative Solubility
PSD
Cake porosity

Downstream Manufacturability

Flow Properties of product

PSD
Filtration (specific cake resistance)
PSD, habit, agglomeration
Drying rate/LOD
PSD, habit, solvate
Physical Attributes PSD, Polymorph

Crystallization Kinetics:
Supersaturation

Concentration

TIME

Spontaneous
Nucleation
Curve
e
M

t
s
ta

le
b
a

on
i
g
e
R

C A C A S A
Equilibrium
Solubility

Undersaturated
Solution
Temperature

Crystallization Kinetics: Nucleation

Two common types of nucleation mechanisms

Primary nucleation:

Homegeneous: occurs at the onset of crystallization, when the

concentration of the solvent exceeds the metastable region.
Heterogeneous:occurs when solid particles of foreign substances
cause an increase in the rate of nucleation.

Secondary nucleation: is caused by contacts between a

crystal and another surface, and occurs within the
metastable region (difficult to scale up)

Crystallization Kinetics: Growth

Typically follows an initial stage of either

homogeneous or heterogeneous nucleation, unless a
"seed" crystal, purposely added to start the growth,
was already present.
Addition of solute to faces of crystal
For controlled growth operate crystallization under
low supersaturation levels
Growth & nucleation are competing processes!

Crystallization development

Requirement to isolate as many solid forms as

possible in order to select the form with best
attribute for further development (screening of
polymorphs)
Develop best crystallization procedure with
means available at hand to enable scale-up for
New Drug Toxicology and other campaigns.

Crystallization development (contd)

Determine solubility of the substance in

common solvents

Where: VGS: very good solvent, GS: good solvent, AS:

acceptable solvent, B: bad solvent, Scc: Solvent for cooling
crystallization, AS: anti-solvent.

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Crystallization development (contd)

Crystallization method development

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Crystallization- Engineering
Particle size distribution:

Particle size reduction

Greater surface area

Faster dissolution
Better bioavailability
Better compactibility

Particle size increase

Faster filtration/drying
Better handling
Better flowability

Crystal shape:
- Influence the flowability of the resulting powder.

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Crystallization/Particle Engineering

Particle Size Enhancement:

Cubic Crystallization

Strategic Seeding

Thermal methods

Target Property Improvements

Flowability

Filtration

Bulk density

Drying rate

Linear cooling

Thermal cycle
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Crystallization/Particle Engineering

Particle Size Reduction

Wet Milling
Ultrasounds

High-shear Polymorph Transformation

Dry milling

Wet milling

Target Property Improvements

Dissolution rate

Exposure, bioavailability

PSD
Compactability/ Compressibility

Dry milling
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Particle size reduction

Why not just mill all the APIs?

Usually undesired in manufacturing

Safety issues related to dust explosion potential
Issues of physical stability of crystals--potential loss of
crystallinity due to stresses applied to crystals
Wide particle size distribution, more fines
Possibility of reduced yield
Noise
Another unit operation
Productivity, equipment/facility issues
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Particle size increase

Salt crystallization at low supersaturation by cubic
addition of sulfuric acid into the solution with seeds
Cubic addition: addition at a variable rate, slow at first
and gradually faster towards the end as the surface area
for growth increases
Increased filtration rate and wash efficiency

From linear crystallization

From cubic crystallization

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Particle shape modification

To improve flowability, bulk density, and handling

To increase filtration rate
Needles to bricks or plates to cubes

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Shape modification - Example

Particle engineering of
"needles into bricks using
series of sonication and
temperature cycling

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100 um

Spherical agglomeration

Uniform agglomerates sized 20-100m

consisting of smaller primary crystals
Excellent flowability and handling
Compactibility needs to be tested

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Spherical Agglomeration

Can be triggered by temperature

45C

back to 53C

56C <1h

cooled to 20C
and aged

56C 1h

cooled to 48C

56C 8h

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53-56C >1d

Spherical Agglomeration
Can also be triggered by by-product or
a 3rd solvent (e.g. Toluene)
Not necessarily spherical in shape

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Crystallization Analytical Tools InProcess PSD by Lasentec FBRM

Particle size
Particle size distribution
Crystallization kinetics

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Lasentec FBRM applications

Practical case 1: low flowability

2007 campaign: 30% batches did not meet flow

specifications
2008 campaign: modifications done into crystallization
protocol17% batches did not meet flow spec
2009 campaign:modifications done into crystallization
protocolAll the batches met the flow specifications
2010: Same crystallization protocol as per 200825%
batches did not meet flow specifications
2011: investigation on-going
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Practical case 1: low flowability (contd)

Compound A Crystallisation is pH and temperature

controlled.
Crystallisation sequence starts when pH is lowered
below pH6
Controlled HCl charge rates for pH <6.0 are used to
control saturation, nucleation and crystal growth
Crystal growth is achieved by a combination of
controlled HCl charge rates, specific pH ranges &
seeding coupled with short hold periods at constant
temperature for optimal, controlled crystal growth.
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Practical case 1: low flowability (contd)

Multiple changes done over years based on

Lasentec data analysis and pH and
Temperature trends comparison.

Good flowability

Bad flowability

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Practical case 1: low flowability (contd)

Typical Lasentec data for good and bad

batches
Poor flowability
< 6 g/s
Good flowability

Number of
fines

> 6 g/s

#/sec between
1 and 21 m

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Practical case 1: low flowability (contd)

Lasentec data at nucleation point

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Practical case 1: low flowability (contd)

Lasentec data post nucleation, bad flow, high
number of fines

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Practical case 1: low flowability (contd)

Lasentec data post nucleation, bad flow, high
number of fines

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Practical case 2: Slow filtrations

Seed Type

Flux (L/m2h)

No seeds

1200

Unmilled

1560

Thermal Ramp option

2230

Jet-milled

4160

Wet-milled

3480

unseeded
32 hr isolation

wet-milled seeds
11 hr isolation
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Q&A

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