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Best Practices forCrystallization Development
Benjamin Smith, Mettler-Toledo AutoChem, Inc.
A Review of Modern Techniques
Crystallization and precipitation are
critical processing steps in chemical
development. They can serve as
purification and separation steps, and
have implications on the yield, purityand particle size distribution. Even
though crystallization has advanced
significantly over the past decade, many
chemists have such short deadlines that
they must base everyday decisions on past
experience rather than understanding
the crystals in situ. Due to the complexity
of crystallization, a process may be
developed simply by crashing solids out
of solution and transferring a non-robust
process with inconsistencies in the yield,purity and particle size distribution.
Today every crystallization and precipita-
tion step has an opportunity for improved
understanding and quality. Chemists
use established inline Process Analytical
Technology (PAT) techniques to under-stand what is changing during the process
and gain knowledge to ensure the desired
size, shape and form is isolated. In the
past, understanding crystallization pro-
cesses was considered time consuming,
and reserved for specialized groups, who
focused on the most important process
steps. Today new generations of intuitive
process analytical tools provide a rapid
understanding of changes (nucleation,
growth, oiling out, agglomeration andsupersaturation) from within the crystal-
lizer. These tools make it easy to gain
high quality information, accelerate un-
derstanding, and establish knowledge for
crystallization development and transfer.
This paper demonstrates the methodol-ogy chemists use to identify operating
parameters such as temperature, solvent
addition rates and seeding to improve
crystallization, batch repeatability, and
crystal size and shape distribution.1 By
accelerating process understanding,
more robust crystallization processes
are developed with higher yield and
higher purity. Examples include a 10%
yield improvement2, elimination of a
costly process impurity17
, and increasedmonthly throughput by 20%4.
New Technologies forCrystallization Development
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Contents
A Crystallization Workstation:
Optimized Space for Process Understanding 3
Integrated Experiment Platform 3
Establishing Solubility and Metastable Zone Width to
Accelerate Crystallization Development 4
Immediately Understand What is Changing,
and Establish Direction for the Next Experiment 4
Quickly Understand Agglomeration and
Oiling Out Conditions to Improve Purity 5
Accelerate Development by Understanding
Changes to Nucleation and Secondary Nucleation 6
Optimize Seeding and Mixing Conditions to
Produce Fine or Coarse Crystals 7
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Counts/se
c
Peak
Height(A.U.)
C
Relative Time
Ref. counts/sec No Wt
Paracetamol 1517
Ref Tr
14000
12000
10000
8000
6000
4000
2000
0.30
0.28
0.26
0.24
0.22
0.20
0.18 0
02:00:00 04:00:00 06:00:00 08:00:00 10:00:00
60
55
50
45
40
35
30
25
20
Total Counts
Tr
1517cm-1 Peak Area
Common questions during crystallization development are easily
answered with intuitive process monitoring tools by tracking changes
from within the crystallization vessel:
Did the solids crash out?
Did a solvent oil out?
When did the crystals begin to agglomerate?
Is it easily transferred to our manufacturing facilityor Contract Manufacturing Organization (CMO)?
Did I seed at the right temperature?
Will the product have the purity and yield we require?
Is the process consistent batch to batch?
What will be the filtration rate?
What is the solubility?
Integrated Experiment Platform
By providing a crystallization development platform for rapid
laboratory data acquisition, EasyMax and OptiMax syn-
thesis workstations, combined with a standardized software
interface, simplify and accelerate process optimization. Seamless
data acquisition and control within a single software suite allows
crystal size and shape, solubility, and supersaturation to be
quickly interpreted and understood. Synchronized data from
inline process analytical technologies along with temperature,
mixing, pH, and anti-solvent addition enables users to quicklyconvert data to information and make insightful decisions about
the next experiment to perform.
Everyday development chemists must quickly identify the correct
input and process parameters and understand crystal transfor-
mations to ensure product quality and process performance. A
crystallization workstation with inline process analytical tools
enables users to quickly establish direction in everyday crystal-
lization and precipitation processes.
A Crystallization Workstation:
Optimize Space for Process Understanding
During crystallization development, chemists often produce
crystals rapidly without time for a full Design of Experiment
(DoE). There is very little time for thorough process optimiza-
tion, yet it is a perfect time to screen design parameters and
determine the solubility, solvent, and temperature profile. It
is an ideal point to establish a direction which avoids future
disturbances such as impurities, undesired polymorph forms, or
particle size and shape distributions that are difficult to process
downstream. When disturbances like these occur they require
costly re-designs which can be prevented if caught earlier in
crystallization development.
Traditional round bottom or jacketed laboratory reactor vessels
provide a manually controlled temperature and mixing environ-
ment. They are time consuming to set up, not repeatable, and
are challenging to configure with in-process analytical tools.
Established small volume crystallization workstations (such as
EasyMax or OptiMax) provide a platform where chemists
quickly and efficiently carry out experiments day and night with
tight control over temperature, mixing, dosing, and pH control.
These vessels are easy to use, highly repeatable, and quickly
integrate with process analytical tools.
Figure 1. Synchronized data from process
analytical technologies
What is EasyMax?
Designed to replace the jacketed lab reactor,
EasyMax and OptiMax are fast and easy to
set up. They capture experimental data to deliver
an enhanced understanding of the process, allow-
ing users to optimize crystallization design with
precise control over critical process variables such
as temperature, mixing conditions, and anti-solven
addition rates.
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Establishing Solubility and Metastable Zone Width to
Accelerate Crystallization Development
When a crystallization workstation is integrated with in situ mid-IR (such as
ReactIR), it provides a hardware and software solution for rapid and highly sensitivemeasurements of the solute concentration and solubility curve, without interference
from the suspended crystals. Knowledge of the solubility curve sets the direction for all
future crystallization development and enables chemists to maximize yield, purity, and
the particle size distribution.
Early crystallization development also requires fundamental knowledge of the real-time
solution concentration relative to the equilibrium solubility. The kinetic l imit between
the nucleation point and the solubility curve is the metastable zone width (MSZW). The
MSZW is essential to successful crystallization development and provides the funda-
mentals for knowledge transfer during the later stages of development. A crystallization
workstation coupled with an inline particle characterization tool (such as FBRM)provides a real-time integrated measurement of the nucleation and growth associated
with the mid-IR measurement of real-time solute concentration.
Powerful yet simple software tools synchronize the operating conditions (temperature,
pH, mixing rate, and solvent dosing) from the crystallization workstation with data
from all process analytical technologies to provide informative reports which show the
impact of the variables on the process.
Immediately Understand what is Changing,and Establish Direction for the Next Experiment
While developing a crystallization, in situ measurement techniques allow users to
quickly identify the size and shape of crystals, particles, or oil droplets. Inline particle
vision and measurement techniques are especially insightful by offering an eye into a
vessel or pipeline at elevated temperatures and concentration where supersaturation is
high and offline sampling is impossible. For example in Figure 4, inline images (cap-
tured with PVM technology) provide immediate understanding of crystal morphology
dynamics without the need for sampling. Users can quickly understand the temperature
and solvent conditions at the exact point of transition, and with this information, PVM
users make immediate, real-time decisions regarding the next experiment and the
direction of development.
Figure 2. Solubility curve and MSZW (Metastable
Zone Width)
Barrett, M. et al, Chemical Engineering Research
and Design6
Figure 3. PVM images showing changes in crys-
tal morphology
Concentration
Metastable
Solubility
Temperature
t = 1:04:01
t = 1:16:15
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What is PVM?
PVM (Particle Vision and Measurement) is a prob
based vision tool which enables users to study and
immediately understand crystallization with inline
high resolution digital images capturing crystals as
they naturally exist in-process, eliminating the nee
for offline sampling. With PVM, users observe rea
time movies which simply replay the crystallization
process. When implementing PVM in a crystal-
lization workstation virtually no data analysis is
necessary since the images themselves explain th
particle size and shape changes, and are synchro-
nized with process temperature, mixing, solvent
addition.
In everyday crystallization development, PVM
enables users to immediately visualize the cr ystall
zation, understand what is changing, and establish
direction for the next experiment.
Quickly Understand Processing Conditions to Improve Purity
Crystal purity is a common concern and rapid agglomeration may trap impurities within
the crystal structure. Consequently, avoiding agglomeration is frequently preferred.
Inline PVM images quickly reveal the process parameters affecting crystal shape and
the extent of agglomeration. By providing clear insight into the crystal morphology
and agglomeration kinetics, PVM enables users to quickly identify correct seeding,
temperature, and supersaturation parameters. This ensures the development of a robust
crystallization process by avoiding agglomeration and ensuring the desired form and
purity.7
Any chemist or engineer involved with crystallization development for some period of
time will experience unexpected events such as phase separation (oiling out), which is
often a source of impurities. Oiling out is usually impossible to see by eye and representa-
tive sampling is typically unobtainable at elevated temperature and supersaturation.
Inline tools offer insight, which is impossible with traditional techniques. Many case
studies have highlighted the ability to use PVM to identify oiling out and to quickly
investigate the root cause of unexpected events7,8,9. In a single experiment, PVM provides
information which would have taken excessive time and effort to detect using traditional
analytical techniques. PVM is used to reduce process development time by months to
ensure projects are on time and meet purity requirements.
Figure 4. Inline PVM images
tracking two batches of an
identical organic crystal
molecule with and without
agglomeration
Figure 5. Inline PVM images
help identify conditions which
caused the immiscible phase
(drop) formation during a fast
precipitation process.
100m100m
100m 100m
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Accelerate Development by Understanding Changes
to the Particle Size and Particle Count
Tracking and quantifying inline changes to crystal dimension and count provides a
rapid understanding of the particle systems response to changing process parameters.For example, probe based particle measurement provides a fast understanding of crystal
growth and nucleation rates while determining seeding, temperature, and solvent
parameters11.
By understanding how the particle system responds to changing process parameters,
FBRM users quickly establish conditions to ensure crystal product meets quality
requirements and process performance, repeatability, and stability goals.12, 13, 14, 15
What is FBRM?
FBRM (Focused Beam Reflectance Measurement)
measures a fingerprint distribution of the particle
system that is sensitive to changes in dimension,shape and count. Real-time measurements track
the rate and degree of change to particles and par-
ticle structures as they naturally exist in the proces
eliminating the need for offline sampling11.
Figure 6. (left)FBRM measures bimodal distribution; (right) Inline
PVM image confirmation
Figure 7. Inline FBRM measurements track the growth of
the seed and subsequent nucleation of fine crystals during
cooling.10
80000
0
20000
40000
60000
60
70
0
10
20
30
40
50
0 1:00 1:1500:30 00:4500:15
Counts
(no.weight)
Te
mp(C)
Relative Time
TemperatureG400 3/sec 0-20m
100m
100m
1000
200
400
600
800
00 10010 1000
Counts(no.weight)
Chord Length (m)
300m
175m
100m
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Optimizing Conditions to Produce Fine or Coarse Crystals
During crystallization, a typical goal is to maximize yield while improving filtration
rates and avoiding downstream bottlenecks17, 18, 19. FBRM technology provides immedi-
ate process understanding by presenting which process conditions produces fine-small
particles and which produce large-coarse particles.20
For example, FBRM
enables users to understand the effect of antisolvent addition ratesand mixing rates by tracking the number of fine particles (in the range of 1-5m) over
time and providing immediate indication of nucleation, growth rates, and endpoints.
Inline particle characterization allows researchers to modify addition velocity condi-
tions and increase mixing rates to minimize undesirable nucleation and eliminate
filtration bottlenecks during laboratory development and scale-up. By improving the
mixing conditions, yield losses caused by excessive fines in the filter, centrifuges, and
dryers (dust) are eliminated.
Figure 8. FBRM tracks the nucle-
ation kinetics when seed crystals ar
added at varying temperatures and
supersaturation.16
Figure 9. FBRM tracks the reduction in fines
resulting in improved mixing rates
00:03 00:06 00:09 00:12 00:100:00
0
500
1000
1500
2000
2500
C
ounts(1-5mr
ange)
Time (hr:min)
Nucle
ationR
ate
Reduction in Fine
with Improved Mix
Nucleation Events3.2mm Pipe
1.6mm Pipe
0.78mm Pipe
0.3 mm Pipe
Counts/sec(1-10m)
Time
19C
Seeding Temp
27C
33C
0.25g
Seed
Added
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Understanding Crystallization Development
METTLER TOLEDO is the world leader in expanding the role of process ana-
lytical technologies for more effective and efficient development of everyday
crystallization processes. Crystallization is a critical process for the purifica-
tion and isolation of chemical compounds in the manufacture of many fine
chemical and pharmaceutical products. The results of the crystallization step
have far reaching impacts on overall process efficiency and final product
quality. It is also a difficult process to understand without inline tools which
provide immediate insight from within crystallization workstations. Chemists
have many opportunities to apply inline process analytical measurements
with integrated crystallization workstations to immediately understand the
crystallization and make rapid decisions regarding the direction of development
and future process viability. Chemists use these tools to reduce development
time, minimize disturbances in later phases of development, and ensure a
crystal product is produced that meets necessary specifications for crystal size
and shape distributions.
Our process analytical instrumentation includes technologies for
in-process crystal population measurement of crystal count and
dimensions (FBRM), in-process crystal imaging (PVM), and
in situ supersaturation monitoring (ReactIR). FBRM, PVM,
and ReactIR technologies are available for 30ml to 2000ml
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manufacturing scale, and continuous flow pipelines.
Our Crystallization Workstation Vessels (including EasyMax,
Optimax, and RC1e) provide an integrated hardware platform
with state of the art control of critical process variables includ-
ing mixing rate, cooling rate and anti-solvent addition rate.
Our iC software suite ties it all together with an integrated software
package that provides precise control of the laboratory reactor
with synchronized data from in situ analytics for understanding
the crystallization.
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Benjamin Smit
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