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Best Practices for Crystallization Development

A Review of Modern Techniques

New Technologies for Crystallization Development

Benjamin Smith, Mettler-Toledo AutoChem, Inc. 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. Today every crystallization and precipitation step has an opportunity for improved understanding and quality. Chemists use established inline Process Analytical Technology (PAT) techniques to understand what is changing during the process and gain knowledge to ensure the desired size, shape and form is isolated. In the past, understanding crystallization processes 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 crystallizer. These tools make it easy to gain high quality information, accelerate understanding, and establish knowledge for crystallization development and transfer. This paper demonstrates the methodology 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.

A Crystallization Workstation: Optimized Space for Process Understanding

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 Quickly Understand Agglomeration and Oiling Out Conditions to Improve Purity Accelerate Development by Understanding Changes to Nucleation and Secondary Nucleation Optimize Seeding and Mixing Conditions to Produce Fine or Coarse Crystals 4 5 6 7

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 optimization, 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 environment. 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.

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 facility or 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?

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, allowing users to optimize crystallization design with precise control over critical process variables such as temperature, mixing conditions, and anti-solvent addition rates.

Peak Height (A.U.)

0.26 0.24 0.22 0.20 0.18


Integrated Experiment Platform By providing a crystallization development platform for rapid laboratory data acquisition, EasyMax and OptiMax synthesis 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 quickly convert 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 transformations to ensure product quality and process performance. A crystallization workstation with inline process analytical tools enables users to quickly establish direction in everyday crystallization and precipitation processes.

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Ref. counts/sec No Wt Paracetamol 1517 Ref Tr

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Figure 1. Synchronized data from process analytical technologies

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 measurements 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 limit 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 fundamentals 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.





Figure 2. Solubility curve and MSZW (Metastable Zone Width) Barrett, M. et al, Chemical Engineering Research and Design6

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 (captured 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.

t = 1:04:01

Figure 3. PVM images showing changes in crystal morphology

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.



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 representative 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 crystallization workstation virtually no data analysis is necessary since the images themselves explain the particle size and shape changes, and are synchronized with process temperature, mixing, solvent addition. In everyday crystallization development, PVM enables users to immediately visualize the crystallization, understand what is changing, and establish direction for the next experiment.

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?
300m 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 particle structures as they naturally exist in the process eliminating the need for offline sampling11.

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Figure 6. (left) FBRM measures bimodal distribution; (right) Inline PVM image confirmation

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Temperature G400 3/sec 0-20m

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

Temp (C)

Figure 8. FBRM tracks the nucleation kinetics when seed crystals are added at varying temperatures and supersaturation.16

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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 immediate 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 rates and 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 conditions 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.

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Reduction in Fines with Improved Mixing 00:06 00:09 Time (hr:min) 00:12 00:15


Figure 9. FBRM tracks the reduction in fines resulting in improved mixing rates





METTLER TOLEDO: World Leaders in Technology for Understanding Crystallization Development METTLER TOLEDO is the world leader in expanding the role of process analytical technologies for more effective and efficient development of everyday crystallization processes. Crystallization is a critical process for the purification 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 including 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.




iC Software

Our People METTLER TOLEDO has a global network of Technology and Application Consultants with extensive research and industry experience supporting organic chemistry, chemical development and scale-up. Email: autochem@mt.com 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 applications including an extensive list of upcoming and on-demand webinars. Blog Chemical Research, Development and Scale-up is our Blog highlighting the latest publications and providing expert commentary from our own internal experts and from academic and industry professionals. Customer Community Our Customer Community Site provides owners and users of our technologies with free access to archived citation lists, application reports, case studies, and extensive training materials including immediate access to all of our on-demand webinars. Social Media Get real-time updates through Facebook and Twitter on the latest developments in chemical synthesis, chemical engineering and scale-up.

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Benjamin Smith Ben_Smith@mt.com


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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 autochem@mt.com