Best Practices for
Crystallization Development
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, purity
and 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.
New Technologies for
Crystallization Development
Benjamin Smith, Mettler-Toledo AutoChem, Inc.
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 and
supersaturation) 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 increased
monthly throughput by 20%4.
 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

2
 Common questions during crystallization development are easily
answered with intuitive process monitoring tools by tracking changes
from within the crystallization vessel:
A Crystallization Workstation:
Optimize Space for Process Understanding
“Did the solids crash out?”
During crystallization development, chemists often produce
crystals rapidly without time for a full Design of Experiment “Did a solvent oil out?”
(DoE). There is very little time for thorough process optimiza- “When did the crystals begin to agglomerate?”
tion, yet it is a perfect time to screen design parameters and
“Is it easily transferred to our manufacturing facility
determine the solubility, solvent, and temperature profile. It
or Contract Manufacturing Organization (CMO)?”
is an ideal point to establish a direction which avoids future
disturbances such as impurities, undesired polymorph forms, or “Did I seed at the right temperature?”
particle size and shape distributions that are difficult to process “Will the product have the purity and yield we require?”
downstream. When disturbances like these occur they require
“Is the process consistent batch to batch?”
costly re-designs which can be prevented if caught earlier in
crystallization development. “What will be the filtration rate?”
“What is the solubility?”
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.
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-
Integrated Experiment Platform ing users to optimize crystallization design with
precise control over critical process variables such
By providing a crystallization development platform for rapid as temperature, mixing conditions, and anti-solvent
laboratory data acquisition, EasyMax™ and OptiMax™ syn- addition rates.
thesis workstations, combined with a standardized software
interface, simplify and accelerate process optimization. Seamless
60
data acquisition and control within a single software suite allows 14000 1517cm-1 Peak Area
0.30
crystal size and shape, solubility, and supersaturation to be 55
12000
quickly interpreted and understood. Synchronized data from 50 0.28 Tr
inline process analytical technologies along with temperature,
Peak Height (A.U.)

10000
45
mixing, pH, and anti-solvent addition enables users to quickly
Counts/sec

0.26
Ref. counts/sec No Wt
8000
convert data to information and make insightful decisions about
°C

40 Paracetamol 1517
Ref Tr
0.24
the next experiment to perform. 6000
35
0.22
4000
Everyday development chemists must quickly identify the correct 30
Total Counts
input and process parameters and understand crystal transfor- 25
0.20 2000
mations to ensure product quality and process performance. A
20 0.18 0
crystallization workstation with inline process analytical tools 02:00:00 04:00:00 06:00:00 08:00:00 10:00:00
enables users to quickly establish direction in everyday crystal- Relative Time
lization and precipitation processes.
Figure 1. Synchronized data from process
analytical technologies

3
 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 sensitive

Concentration
measurements of the solute concentration and solubility curve, without interference
from the suspended crystals. Knowledge of the solubility curve sets the direction for all Metastable
future crystallization development and enables chemists to maximize yield, purity, and
the particle size distribution. Solubility

Early crystallization development also requires fundamental knowledge of the real-time

solution concentration relative to the equilibrium solubility. The kinetic limit between Temperature

the nucleation point and the solubility curve is the metastable zone width (MSZW). The Figure 2. Solubility curve and MSZW (Metastable
MSZW is essential to successful crystallization development and provides the funda- Zone Width)
mentals for knowledge transfer during the later stages of development. A crystallization
Barrett, M. et al, Chemical Engineering Research
workstation coupled with an inline particle characterization tool (such as FBRM®) and Design6
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.
t = 1:16:15

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 t = 1:04:01
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 3. PVM® images showing changes in crys-

tal morphology

4
 Figure 4. Inline PVM® images
tracking two batches of an
identical organic crystal
molecule with and without
agglomeration

100µm 100µm

Figure 5. Inline PVM® images

help identify conditions which
caused the immiscible phase
(drop) formation during a fast
precipitation process.

100µm 100µm

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.
What is PVM®?
PVM® (Particle Vision and Measurement) is a probe
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 need
for offline sampling. With PVM®, users observe real
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 the
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 crystalli-
zation, understand what is changing, and establish
direction for the next experiment.

5
 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 system’s 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®?
1000 FBRM® (Focused Beam Reflectance Measurement)
300µm measures a fingerprint distribution of the particle
800
system that is sensitive to changes in dimension,
shape and count. Real-time measurements track
Counts (no. weight)

the rate and degree of change to particles and par-

600 175µm ticle structures as they naturally exist in the process
– eliminating the need for offline sampling11.
400
100µm

200

0
0 10 100 1000
Chord Length (µm)

Figure 6. (left) FBRM® measures bimodal distribution; (right) Inline

PVM® image confirmation

70

80000
60
Temperature 100µm
Counts (no. weight)

60000 G400 3/sec 0-20µm 50

Temp (°C)

40
40000
30

20000 20

10
0

0
0 00:15 00:30 00:45 1:00 1:15
Relative Time

100µm
Figure 7. Inline FBRM® measurements track the growth of
the seed and subsequent nucleation of fine crystals during
cooling.10

6
 Figure 8. FBRM® tracks the nucle-
ation kinetics when seed crystals are
added at varying temperatures and
supersaturation.16
Counts/sec (1-10µm)

0.25g
Seed
Added

Seeding Temp
19°C
27°C
33°C

Time

Optimizing Conditions to Produce Fine or Coarse Crystals 2500 3.2mm Pipe

1.6mm Pipe
Nucleation Events

During crystallization, a typical goal is to maximize yield while improving filtration 0.78mm Pipe
0.3 mm Pipe
2000
rates and avoiding downstream bottlenecks17, 18, 19. FBRM® technology provides immedi-
ate process understanding by presenting which process conditions produces fine-small Counts (1-5µm range)
1500
particles and which produce large-coarse particles.20
1000

Rate
For example, FBRM® enables users to understand the effect of antisolvent addition rates
ation
and mixing rates by tracking the number of fine particles (in the range of 1-5µm) over 500
Nucle

Reduction in Fines
time and providing immediate indication of nucleation, growth rates, and endpoints. with Improved Mixing

Inline particle characterization allows researchers to modify addition velocity condi- 0

00:00 00:03 00:06 00:09 00:12 00:15
tions and increase mixing rates to minimize undesirable nucleation and eliminate Time (hr:min)
filtration bottlenecks during laboratory development and scale-up. By improving the
mixing conditions, yield losses caused by excessive fines in the filter, centrifuges, and Figure 9. FBRM® tracks the reduction in fines
dryers (dust) are eliminated. resulting in improved mixing rates

7
 ®
M
PV

™
IR
act
Re

METTLER TOLEDO: World Leaders in Technology for

®

Understanding Crystallization Development FB

RM
METTLER TOLEDO is the world leader in expanding the role of process ana-
lytical technologies for more effective and efficient development of everyday
iC
crystallization processes. Crystallization is a critical process for the purifica- Software
tion and isolation of chemical compounds in the manufacture of many fine ALR

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 Our People
provide immediate insight from within crystallization workstations. Chemists METTLER TOLEDO has a global net-
have many opportunities to apply inline process analytical measurements work of Technology and Application
with integrated crystallization workstations to immediately understand the Consultants with extensive research
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crystallization and make rapid decisions regarding the direction of development
organic chemistry, chemical develop-
and future process viability. Chemists use these tools to reduce development
ment and scale-up.
time, minimize disturbances in later phases of development, and ensure a
crystal product is produced that meets necessary specifications for crystal size Email: autochem@mt.com
and shape distributions. Phone: 410-910-8500

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References
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Internet: http://www.mt.com/crystallization

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