Crystallization:
Concepts, Development &
Manufacturing Strategies
1
Agenda
Crystallization in the Pharmaceutical
Industry
Crystallization kinetics
Crystallization development
Particle size engineering
Analytical tools – Lasentec
Practical examples
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2
Crystallization in the Pharma
Industry
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Most of the Active Product Ingredients (API’s)
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.
3
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:

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j
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
4
Crystallization Objectives

Isolate substrate
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PSD, Crystal habit
Solvent Selection, PSD
Solubility, T
Purify Substrate
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Filtration
Drying
Yield
Impurity Rejection
Solvent removal
Washing Properties
Relative Solubility
PSD
Cake porosity
Downstream Manufacturability
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Flow Properties of product
Filtration (specific cake resistance)
Drying rate/LOD
Physical Attributes
PSD
PSD, habit, agglomeration
PSD, habit, solvate
PSD, Polymorph
5
Crystallization Kinetics:
Supersaturation
Concentration
TIME
“Spontaneous”
Nucleation
Curve
CA  CA  S A
Equilibrium
Solubility
Undersaturated
Solution
Temperature
6
Crystallization Kinetics: Nucleation
Two common types of nucleation mechanisms

Primary nucleation:
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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)
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Crystallization Kinetics: Growth

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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!
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Crystallization development

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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.
9
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
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Greater surface area
Faster dissolution
Better bioavailability
Better compactibility

Particle size increase
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Faster filtration/drying
Better handling
Better flowability
• Crystal shape:
- Influence the flowability of the resulting powder.
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Crystallization/Particle Engineering

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Particle Size Enhancement:
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Cubic Crystallization

Strategic Seeding
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Thermal methods
Target Property Improvements

Flowability

Filtration

Bulk density
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Drying rate
Linear cooling
Thermal cycle
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Crystallization/Particle Engineering

Particle Size Reduction
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Wet Milling
Ultrasounds
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High-shear Polymorph Transformation

Dry milling
Wet milling
Target Property Improvements

Dissolution rate
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Exposure, bioavailability

PSD
Compactability/ Compressibility

Dry milling
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Particle size reduction
Why not just mill all the API’s?
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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
15
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
16
Particle shape modification
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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
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Uniform agglomerates sized 20-100mm
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
45°C
back to 53°C
56°C <1h
cooled to 20°C
and aged
56°C 1h
cooled to 48°C
56°C 8h
20
53-56°C >1d
Spherical Agglomeration
• Can also be triggered by by-product or
a 3rd solvent (e.g. Toluene)
• Not necessarily spherical in shape
21
Crystallization Analytical Tools —InProcess PSD by Lasentec FBRM
• Particle size
• Particle size distribution
• Crystallization kinetics
22
Lasentec FBRM applications

Practical case 1: low flowability
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2007 campaign: 30% batches did not meet flow
specifications
2008 campaign: modifications done into crystallization
protocol→17% batches did not meet flow spec
2009 campaign:modifications done into crystallization
protocol→All the batches met the flow specifications
2010: Same crystallization protocol as per 2008→25%
batches did not meet flow specifications
2011: investigation on-going
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Practical case 1: low flowability (contd)
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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.
Batch 6D15259 (#4)
Batch 6D15514 (#1)
pH
pH
Temperature
4
3.95
Nucleation - Exotherm
pH
3.9
Temperature
42
4
42
41
3.9
41
40
3.8
40
Nucleation Exotherm
3.85
39
3.7
3.6
38
39
3.8
38
3.75
37
3.5
37
3.7
36
3.4
3.65
35
3.3
36
Nucleation - pH drift
pH fall across nucleation - crystal growth affected / stunted.
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3.6
34
3.2
34
3.55
33
3.1
33
3.5
32
3
21:36:00
T °C
pH
T °C
Nucleation - pH climb
16:19:12
16:48:00
17:16:48
17:45:36
18:14:24
Time
Good flowability
18:43:12
19:12:00
19:40:48
20:09:36
22:04:48
22:33:36
23:02:24
23:31:12
00:00:00
00:28:48
00:57:36
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01:26:24
Time (21/04/2006)
Bad flowability
25
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 μm
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Practical case 1: low flowability (contd)
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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
29
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
31