Crystallization Development Best Practices
Crystallization Development Best Practices
Crystallization Development Best Practices
Crystallization Development
A Review of Modern Techniques
Crystallization and precipitation are Today every crystallization and precipita- high quality information, accelerate un-
critical processing steps in chemical tion step has an opportunity for improved derstanding, and establish knowledge for
development. They can serve as understanding and quality. Chemists crystallization development and transfer.
purification and separation steps, and use established inline Process Analytical
have implications on the yield, purity Technology (PAT) techniques to under- This paper demonstrates the methodol-
and particle size distribution. Even stand what is changing during the process ogy chemists use to identify operating
though crystallization has advanced and gain knowledge to ensure the desired parameters such as temperature, solvent
significantly over the past decade, many size, shape and form is isolated. In the addition rates and seeding to improve
chemists have such short deadlines that past, understanding crystallization pro- crystallization, batch repeatability, and
they must base everyday decisions on past cesses was considered time consuming, crystal size and shape distribution.1 By
experience rather than understanding and reserved for specialized groups, who accelerating process understanding,
the crystals in situ. Due to the complexity focused on the most important process more robust crystallization processes
of crystallization, a process may be steps. Today new generations of intuitive are developed with higher yield and
developed simply by crashing solids out process analytical tools provide a rapid higher purity. Examples include a 10%
of solution and transferring a non-robust understanding of changes (nucleation, yield improvement2, elimination of a
process with inconsistencies in the yield, growth, oiling out, agglomeration and costly process impurity17, and increased
purity and particle size distribution. supersaturation) from within the crystal- monthly throughput by 20%4.
lizer. These tools make it easy to gain
Contents
A Crystallization Workstation:
Optimized Space for Process Understanding 3
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
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
4
Figure 4. Inline PVM® images
tracking two batches of an
identical organic crystal
molecule with and without
agglomeration
100µm 100µm
100µm 100µm
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.
200
0
0 10 100 1000
Chord Length (µm)
70
80000
60
Temperature 100µm
Counts (no. weight)
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
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
7
®
M
PV
™
IR
act
Re
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8
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