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How In Situ Vision Simplifies

Crystallization and Precipitation


A Review of Modern Technologies

Understand Crystallization
Processes Faster than any
other Method
Des OGrady PhD and Eric Dycus, Mettler-Toledo AutoChem, Inc.

Acquiring process understanding vision and microscopy tools to visualize acquired. In addition, these techniques
enables scientists to make evidence- crystallization as it happens in the only offer information at a limited
based decisions, anticipate scale-up reactor or pipeline. Scientists directly number of time points and cannot
issues and ultimately bring the observe key mechanisms such as crystal provide the same mechanistic view
highest possible quality product growth, secondary nucleation, seed of the crystallization as a continuous
to market - as quickly as possible. aggregation and oiling out, meaning sequence of images taken throughout
For crystallization processes such previously unobtainable information the process.
fundamental understanding is can now be acquired simply and
especially important because this systematically. In this white paper examples from
single unit operation controls product GlaxoSmithKline (GSK), Merck, Sintef,
yield, purity, polymorphic form, and Although traditional offline analytical and University College Dublin (UCD)
particle size distribution, and directly techniques, such as light microscopy, are presented that demonstrate how
influences the efficiency of downstream are commonly applied to observe in situ microscopy offers a unique and
operations such as filtration, drying crystals at certain points in time powerful perspective to scientists and
and formulation. In order to achieve these techniques require sampling engineers engaged in the development
in-depth crystallization process and preparation and the resulting of crystallization processes.
understanding scientists are now temperature (or pressure) change often
applying a new generation of in situ reduces confidence in the information
Contents

Introduction 2

Identifying the Root Cause of a Poor Crystal Product 3

- Visualizing Delicate Crystal Structures 4

Capturing Transient and Elusive Crystallization Mechanisms 5

- Polymorphic Transitions 5

- Phase Separation 7

Producing the Desired Crystal Size and Shape Distribution 8

- Visualizing the Influence of Cooling Rate 8

Conclusion 9

Appendix A: Particle Vision and Measurement 11

Introduction
Since the development of the first microscope over 400 years ago, humans have been
able to visualize tiny things with ever increasing clarity and resolution. Today a
magnified image remains one of the most intuitive and powerful analytical methods
available to scientists seeking to understand complex systems at the micron scale. For
scientists studying crystallization and precipitation, the light microscope represents
a simple way to develop in-depth process understanding in a short space of time
and has become a standard method in laboratories and production facilities across
many industries.

Microscope technology has made many great advances over the years with the
development of breakthrough techniques such as scanning electron microscopy
(SEM) and atomic force microscopy (AFM). Another type of microscope technology,
which represents a clear leap forward, are probe based technologies which remove
the need for sampling and sample preparation while eliminating the time-delay Meet PVM
associated with offline analysis. PVM (Particle Vision and Measurement) is a probe
based vision tool for studying and immediately
In situ microscopy offers the ability to collect thousands of high resolution images understanding crystallization. With inline high
resolution digital images capturing crystals as they
over the course of a particulate process without the need for scientists to attend to,
naturally exist in-process, PVM eliminates the need
or sample from, the system. These images, taken at fixed time intervals or at critical for offline sampling. When implementing PVM in a
junctures, can be sequenced to create a video which comprehensively describes the crystallization workstation virtually no data analysis
particulate process from start to finish. Not only is key information about the particle is necessary since the images themselves explain
the particle size and shape changes, and are syn-
size, shape and structure conveyed but dynamic mechanisms such as growth, nucle- chronized with process temperature, mixing and
ation, agglomeration breakage and shape change can be visualized and quantified solvent addition.
with little ambiguity. This capability enables a group of scientists to fundamentally
In everyday crystallization development, PVM
agree on the key crystallization mechanisms at play and come to a consensus on the enables the immediate visualization of the process,
best path forward for improvement and optimization. understanding of what is changing, and establish-
ing direction for the next experiment.

2
Identifying the Root Cause of a
Poor Crystal Product
The formation of crystal product with a wide or bimodal par- tseed
ticle size distribution can be concerning for many reasons. Seed Crystals
The combination of fine and coarse crystals can cause poor Observed
formulation behavior, bottlenecks during filtration and drying,
and can indicate a poorly controlled process; either in terms
of friability during isolation or via an uncontrolled secondary
nucleation event during the crystallization itself.
100 m

Such was the case during the development of a crystalline


product, used as a food additive, where a bimodal particle
size distribution caused poor filtration performance. In situ
microscopy was implemented to monitor the entire crystal-
lization process with the hope of identifying the root cause
of the final particle size problem. In Figure 1 four images (of t s e e d + 2 min
Dendritic
hundreds acquired) illustrate the key mechanisms that led to
Growth
an undesirable final product1.

Over the course of this 30 minute experiment a number of


observations were made that allowed definitive conclusions to
be drawn about process mechanisms:
-- Seed crystals exhibit a wide variety of sizes and shapes
indicating a possible lack of consistency in the seed
generation process
-- Crystals do not grow in the classically understood way
and instead dendritic growth occurs with small
needles growing orthogonally from the seed crystal
t s e e d + 10 min
-- These dendrites break from the seed crystal and Dendritic Growth
drive an aggressive secondary nucleation mechanism Continues,
-- The final picture, after 25 minutes, shows a bimodal Secondary
Nucleation Occurs
crystal distribution with dendritic structures persisting

This unambiguous vision-based understanding of the crys-


tallization revealed the root cause of a challenging problem
in the space of a single experiment; dry milling of the seed
led to defect formation on the crystal surface and orthogonal
dendritic growth during the process.

t s e e d + 30 min
Poorly Filtering
Material

Figure 1. In situ images, captured via Particle


Vision and Measurement (PVM) technology, track
dendritic growth and breakage of d-mannitol
crystals during the first 25 minutes of the process

3
Visualizing Delicate Crystal Structures
Dendritic crystal growth is a common crystallization mechanism but is rarely
observed offline under a light microscope. This is due to the delicate nature of
the dendrites and the destructive action of sampling in most cases. In Figure 2 in
situ and offline microscope images are compared at the end of two crystallization
processes2. Under one set of process conditions (Figure 2A) roughly identical images
are captured indicating sampling has had little effect on the crystal size or shape and
that the sample taken was representative. Under the second set of process conditions
(Figure 2B) dramatic differences in the size, shape and structure of the crystals are
observed. The sampling protocol and slide preparation in this case has destroyed the
delicate dendritic structures that the second set of process conditions yielded. Such an
erroneous offline result could seriously undermine scientists efforts to optimize this
crystallization process since the presence of fine crystals at the end of an experiment
is typically linked to excessive nucleation rates and a high level of supersaturation.
However, the in situ images clearly show that the formation of delicate dendritic
structures is actually the mechanism of interest here and a different strategy is needed
to further optimize the process.

In Situ PVM images Offline Microscope Images

Process A: Representative
Sampling

100 m

Process B: Non-representative
Sample

100 m

Figure 2. In situ PVM images compared with


offline microscope images captured at the same
point during Processes A and B

4
Capturing Transient and Elusive
Crystallization Mechanisms
Identifying and characterizing dendritic growth during crystallization can be
extremely valuable, however there are two other crystallization mechanisms that
are even more difficult to capture using offline methods and are perhaps even
more important to understand. Polymorphism and phase separation (oiling out)
commonly occur during crystallization process development and failure to identify
and understand these phenomena can lead to extended development times, difficult
scale-up procedures, purity concerns, and ultimately poor performance in produc-
tion. Both of these phenomena are difficult to characterize using offline techniques
since changes in temperature and shear can upset the delicate kinetic equilibria that
only exist under certain transient conditions in the process itself.

Polymorphic Transitions
In Figure 3, a sample of in situ images captured during the development of a
pharmaceutical API at Merck & Co. show how the unexpected appearance of a
polymorph was captured3. Throughout the process the images exhibited the expected
crystal shape and size (thin needles) but at a specific temperature a large prismatic
crystal appeared. XRPD (Xray Powder Diffraction Analysis) and DSC (Differential
Scanning Calorimetry) were used to confirm the presence of a previously unknown
polymorph something which had gone undetected on offline microscope slides
and via in situ Raman spectroscopy due to the low concentration of the new form.
In situ imaging proved to be the most sensitive technique for tracking the formation
and disappearance of the metastable polymorph and was chosen to help understand
the set of process conditions under which the polymorph would turnover completely
and consistently.

100 m 100 m 100 m

Figure 3. In situ PVM images enabled Merck to


detect the formation of an unexpected polymorph
and identify the process conditions under which it
formed

5
100 m 100 m 100 m

Figure 4. Inline PVM images track polymorph


transition and change in shape/habit over time
In some cases when a polymorph has been identified early in development the
transition from a metastable form to the most stable form during the process itself is
desired; in order to ensure a high quality product and an efficient process. In Figure
4 such an example is illustrated where scientists from GSK used in situ microscopy to
monitor the polymorphic transition as part of a standard process4. Here the metastable
form (long thin needles) slowly dissolved as the stable form (blocks) crystallized. A
solvent mediated transition was confirmed and the process conditions under which
this would occur reliably were developed.

When it is understood that a system exhibits polymorphism, it can be very useful to


determine solubility curves for each crystal form to facilitate effective crystalliza-
tion design. In Figure 5 the polymorphic transformation of P-aminobenzoic acid is
visualized using in situ microscopy5. When combined with other in situ technologies
the phase diagram was developed allowing solubility curves for this challenging
enantiotropic system to be aquired (Figure 6). It should be noted that the solubility
information is collected at or below -10 C which would be virtually impossible if
sampling had been required.

2 min 15 min

240
Form Solubility
Form Solubility
220

200

100 m 100 m 180


Solubility

160
20 min 30 min
140

120

100

80
-10 10 30 50
100 m 100 m
Temperature (C)

Figure 5. (left) Enantiotropic Transformation of


P-aminobenzoic Acid Polymorphs captured via in
situ images (PVM technology); form = needles,
form = platelets

Figure 6. (right) Solubility of and forms of


P-aminobenzoic Acid

6
Phase Separation
The second elusive kinetic event that is important to understand
during crystallization development is phase separation (or oil-
ing out). Phase separation typically occurs when a crystalliza- 50 mins
tion process moves into a region of the phase diagram where a Formation of
liquid-liquid split is favored over the more typical liquid-solid Oil Phase Upon
split. This usually occurs at high levels of supersaturation Heating
and can indicate a poorly controlled and potentially difficult
process. In situ microscopy is particularly powerful for studying
phase separation behavior because sampling inevitably results
in the crystallization of solid particles from the liquid phase
100 m
meaning the mechanism is rarely observed offline. In Figure
7 a classic example of liquid-liquid phase separation is shown
with droplets appearing, coalescing and then breaking apart
before a rapid crystallization event consumes the droplets and
forms solid particles6.

In this example the size of the liquid droplets prior to crystal- 4 hr


lization directly influenced the final crystal size and impurity Coalescence of
Oil Droplets
profile. By utilizing the process understanding provided by
the in situ images a control strategy was developed to avoid
conditions which caused the phase separation, and ensure a
consistent purity and crystal size distribution.
100 m

4 hr 10 min
Dispersion of
Oil Phase into
Solution

100 m

4 hr 30 min
Crystallization

100 m

Figure 7. In situ microscopy (PVM) at four stages


of the crystallization process

7
Producing the Desired Crystal
Size and Shape Distribution
Visualizing the Influence of Cooling Rate
In most cases, especially during a final isolation step, the final crystal size distribution
is the most important crystal product attribute. In situ imaging can guide efforts
to produce crystals of the desired size and shape by providing immediate feedback
when experiment conditions are changed. In Figure 8 in situ images are shown (and
compared with offline SEM images) for three different crystallization processes,
conducted using different cooling rates7. Adjusting the cooling rate directly influences
the prevailing level of supersaturation and the nucleation and growth kinetics of the
process. In situ images provide strong evidence that cooling rate greatly influences
the crystallization kinetics and the final crystal size distribution.

PVM images SEM images

a. Fast Cooling Rate

150 m 150 m

b. Slow Cool Down

150 m 150 m

c. Controlled Fast Cooling

150 m 150 m

Figure 8. In situ PVM images and


corresponding SEM images of final benzoic
acid particle morphology and dimension
obtained from different cooling rates

8
Often the crystal shape distribution is
just as important as the size distribution
especially in cases where certain crystal
shapes can cause processing issues.
This is a common problem across the
chemical, petroleum, and pharmaceuti-
cal industries. For example, flat crystals
can quickly block filters as layer upon
layer of crystals build up on the centri-
150 m 150 m
fuge or filter cloth. In this example from
Sintef and NTNU, the precipitation of
Piperazine as part of a CO2 sequestra- Figure 9a. In situ images of crystals in a 61.5 %
tion process resulted in various crystal piperazine solution at 1 min (left) and 4 min (right)

morphologies that caused fouling and


blocking of process equipment. These
processes are prone to reduce sequestra-
tion rates so it was critical to understand
how processing conditions influenced
the crystal shape. In Figure 9 the effect
of increasing Piperazine concentration
on the morphology of crystals is shown
and the presence of an anhydrous form
(long needle) was also identified8.
150 m 150 m

Figure 9b. In situ images of crystals in a 34.5 %


piperazine solution at 1 min (left) and 4 min (right)

Conclusion
In this white paper it has been demonstrated how in situ microscopy offers a faster
alternative to traditional offline visualization methods. While no single technique
offers a complete solution for successful crystallization development in situ imaging
tools have many of the attributes needed to become standard tools for successful
crystallization development. The automated and unattended nature of the tech-
nique means time is not wasted sampling and analyzing offline. In addition, the
opportunity to acquire powerful visual information overnight or at non-ambient
temperatures and elevated supersaturation is now a reality. Avoiding unnecessary
sampling also improves safety and limits the potential for erroneous results and
wasted development time. Ultimately in situ microscopy offers scientists the ability to
collect previously unattainable data and convert it quickly into unambiguous process
understanding. This process understanding becomes a platform for the successful
and timely development of the optimum crystallization process.

9
Appendix A:
Particle Vision and Measurement (PVM)
Vision for understanding and optimization PVM is a real-time probe
based vision tool which provides instant critical insight into crystal,
particle, and droplet systems. PVM enables chemists and engineers
to detect and understand process changes that could take months to
discover with traditional offline microscopy techniques.

www.mt.com/PVM

CCD Camera

Objective Lens

Illumination Lens Particle System

Sapphire Window

How does PVM work?


PVM uses a high resolution
CCD camera and internal illumination
source to obtain high quality images
even in dark and concentrated suspen-
sions or emulsions. With no calibration
needed and easy data interpretation,
PVM quickly provides critical knowledge
of crystal, particle, and droplet behavior.

200 m

Left: PVM inline image;


Right: Offline microscope

10
References
1. METTLER TOLEDO industrial collaboration
2. OSullivan, B. The Use of In situ Analytics for Crystallization Process Development,
Ph.D. Thesis, University College Dublin, 2005
3. Fernandez, P. Online Monitoring of Crystallization of a Polymorphic Compound Using
FBRM-PVM -Raman, Merck, FBRM Users Conference 2002
4. Gillian, J. et al. An Approach to Fit-for-Purpose Crystallization Design Utilizing www.mt.com/psc
Lasentec FBRM and PVM, GSK, International Process Development Conference,
Annapolis, 2008
5. Hao et al, Org. Process Res. Dev., 2012, 16 (1), pp 3541
6. Duffy et al. In Situ Monitoring, Control and Optimization of a Liquid-Liquid Phase
Separation Crystallization, Chemical Engineering Science., 2012, 77, pp 112121
7. Barrett et al. Supersaturation Tracking for the Development, Optimization and Control Our People
of Crystallization Processes, Chem. Eng. Res. Des., 2010, 88 (8), pp 1108-1119
METTLER TOLEDO has a global
8. Kim et al. Study of the Solid-Liquid Solubility in the Piperazine-H2O-CO2 System network of Technology and Application
Using FBRM and PVM, Energy Procedia., 2012, 23, pp 7281
Consultants with extensive research
and industry experience supporting
inline particle characterization
applications.

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