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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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Our People

METTLER TOLEDO has a global net-

work of Technology and Application

Consultants with extensive research

and industry experience supporting

organic chemistry, chemical develop-

ment and scale-up.

Email: [email protected]

Phone: 410-910-8500

Website

We are online at the

METTLER TOLEDO website

(www.mt.com/crystallization),

where you can find additional detailed

information on our products and appli-

cations including an extensive list of

upcoming and on-demand webinars.

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Scale-up is our Blog highlighting the

latest publications and providing expert

commentary from our own internal

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Customer Community

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Social Media

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neering and scale-up.

ALR

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iC

Software

METTLER TOLEDO: World Leaders in Technology for

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

laboratory development, 2-100 liter kilolab or 100-50,000 liter

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.
http://www.mt.com/autochemhttp://www.mt.com/autochemhttp://www.mt.com/autochemhttp://www.mt.com/autochemhttp://www.mt.com/autochemhttp://www.mt.com/autochemhttp://www.mt.com/autochemhttp://www.mt.com/autochemhttp://blog.autochem.mt.com/http://blog.autochem.mt.com/http://blog.autochem.mt.com/http://blog.autochem.mt.com/http://blog.autochem.mt.com/http://blog.autochem.mt.com/http://blog.autochem.mt.com/https://community.autochem.mt.com/index.php?q=user/838/edithttps://community.autochem.mt.com/index.php?q=user/838/edithttps://community.autochem.mt.com/index.php?q=user/838/edithttps://community.autochem.mt.com/index.php?q=user/838/edithttps://community.autochem.mt.com/index.php?q=user/838/edithttps://community.autochem.mt.com/index.php?q=user/838/edithttps://community.autochem.mt.com/index.php?q=user/838/edithttps://community.autochem.mt.com/index.php?q=user/838/edithttp://www.facebook.com/pages/METTLER-TOLEDO-AutoChem-Chemical-Synthesis-Engineering-and-PAT/108259144525http://twitter.com/MettlerToledoAChttp://www.facebook.com/pages/METTLER-TOLEDO-AutoChem-Chemical-Synthesis-Engineering-and-PAT/108259144525http://twitter.com/MettlerToledoAChttps://community.autochem.mt.com/index.php?q=user/838/edithttp://blog.autochem.mt.com/http://www.mt.com/autochemhttp://twitter.com/MettlerToledoAChttp://www.facebook.com/pages/METTLER-TOLEDO-AutoChem-Chemical-Synthesis-Engineering-and-PAT/108259144525https://community.autochem.mt.com/index.php?q=user/838/edithttps://community.autochem.mt.com/index.php?q=user/838/edithttps://community.autochem.mt.com/index.php?q=user/838/edithttps://community.autochem.mt.com/index.php?q=user/838/edithttps://community.autochem.mt.com/index.php?q=user/838/edithttps://community.autochem.mt.com/index.php?q=user/838/edithttps://community.autochem.mt.com/index.php?q=user/838/edithttps://community.autochem.mt.com/index.php?q=user/838/edithttp://blog.autochem.mt.com/http://blog.autochem.mt.com/http://blog.autochem.mt.com/http://blog.autochem.mt.com/http://blog.autochem.mt.com/http://blog.autochem.mt.com/http://blog.autochem.mt.com/http://www.mt.com/autochemhttp://www.mt.com/autochemhttp://www.mt.com/autochemhttp://www.mt.com/autochemhttp://www.mt.com/autochemhttp://www.mt.com/autochemhttp://www.mt.com/autochemhttp://www.mt.com/autochem


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

Subject to technical changes

08/2011 Mettler-Toledo AutoChem, Inc.

7075 Samuel Morse Drive

Columbia, MD 21046 USA

Telephone +1 410 910 8500

Fax +1 410 910 8600

Email [email protected]

www.mt.com/crystallizatio

Benjamin Smit

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http://madd.polytech-lille.net/Download/EPIC09/Airiau.pdf

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3. Scott et al, Organic Process Research & Development 9, (6): 890-893, 2005.

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4. K. Wood-Kaczmar, The Applications of FBRM to Resolve Batch Processing Problems in Drug

Manufacture, A Case History, Proceedings of 2001 Lasentec User Conference, Barcelona, 2001.

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