Optimization and Scale-up of Batch Crystallization - METTLER TOLEDO

Optimization and Scale-up of Batch Crystallization

Generate Supersaturation and Determine Final Crystal Product

A well-designed batch crystallization process is one that can be scaled successfully to production scale - giving the desired crystal size distribution, yield, form and purity.

Maintaining adequate control of the crystallizer temperature (or solvent composition) is the most basic prerequisite to successful optimization of batch crystallization. Synthesis Workstations in combination with FBRM and PVM crystal monitoring ensure a clear understanding of how changes in fundamental process variables directly impact the crystal product. More advanced process development, involving seeding and particle engineering, will only be successful if we are capable of controlling these underlying critical crystallization process parameters.

A more advanced design of an optimized crystallization process goes even further, requiring understanding of the process map (solubility and Metastable Zone Width Determination) and control of the driving force (supersaturation) of the crystallization. 

Optimization and Scale-up of Batch Crystallization
Optimization and Scale-up of Batch Crystallization

Applications

Optimization of Crystal Properties and Process Performance

Scientist recrystallize high value chemical compounds to obtain a crystal product with desired physical properties at optimal process efficiency. Seven steps are required to design the ideal recrystallization process from choosing the right solvent to obtaining a dry crystal product. This recrystallization guide explains step-by-step the procedure of developing a recrystallization process. It explains what information is required at each stage of recrystallization and outlines how to control critical process parameter

Solubility and Metastable Zone Width (mzw) Determination
The Building Blocks of Crystallization

Solubility curves are commonly used to illustrate the relationship between solubility, temperature, and solvent type. By plotting temperature vs. solubility, scientists can create the framework needed to develop the desired crystallization process. Once an appropriate solvent is chosen, the solubility curve becomes a critical tool for the development of an effective crystallization process.

Crystal Nucleation and Growth
The Driving Force For Crystal Nucleation and Growth

Scientists and engineers gain control of crystallization processes by carefully adjusting the level of supersaturation during the process. Supersaturation is the driving force for crystallization nucleation and growth and will ultimately dictate the final crystal size distribution.

Measure Crystal Size Distribution
Improve Crystallization with Inline Particle Size, Shape, and Count Measurement

In-process probe-based technologies are applied to track particle size and shape changes at full concentration with no dilution or extraction necessary. By tracking the rate and degree of change to particles and crystals in real time, the correct process parameters for crystallization performance can be optimized.

Crystallization Seeding Protocol
Design and Optimize Seeding Protocol for Improved Batch Consistency

Seeding is one of the most critical steps in optimizing crystallization behavior. When designing a seeding strategy, parameters such as: seed size, seed loading (mass), and seed addition temperature must be considered. These parameters are generally optimized based on process kinetics and the desired final particle properties, and must remain consistent during scale-up and technology transfer.

Particle Engineering and Wet Milling
Control Particle Size With High Shear Wet Milling

Milling of dry powders can cause significant yield losses and can generate dust, creating health and safety hazards. In response to this, wet milling produces particles with a specifically designed size distribution. It is now common to employ high shear wet milling to break large primary crystals and agglomerates into fine particles.

Anti-Solvent Addition on Supersaturation
How Solvent Addition Can Control Crystal Size and Count

In an antisolvent crystallization, the solvent addition rate, addition location and mixing impact local supersaturation in a vessel or pipeline. Scientists and engineers modify crystal size and count by adjusting antisolvent addition protocol and the level of supersaturation.

Temperature Effects Crystallization Size and Shape
Supersaturation Control Optimizes Crystal Size and Shape

Crystallization kinetics are characterized in terms of two dominant processes, nucleation kinetics and growth kinetics, occurring during crystallization from solution. Nucleation kinetics describe the rate of formation of a stable nuclei. Growth kinetics define the rate at which a stable nuclei grows to a macroscopic crystal. Advanced techniques offer temperature control to modify supersaturation and crystal size and shape.

Temperature Effects Crystallization Size and Shape
Scaling-Up Agitation, Dosing, and Crystallization

Changing the scale or mixing conditions in a crystallizer can directly impact the kinetics of the crystallization process and the final crystal size. Heat and mass transfer effects are important to consider for cooling and antisolvent systems respectively, where temperature or concentration gradients can produce inhomogeneity in the prevailing level of supersaturation.

Chemical Process Development & Scale-Up
Design Robust and Sustainable Chemical Processes For Faster Transfer To Pilot Plant and Production

Design Robust and Sustainable Chemical Processes For Faster Transfer To Pilot Plant and Production

Chemical Reaction Kinetics Studies
Study Chemical Reaction Rates and Measure Kinetics Inline

In situ chemical reaction kinetics studies provide an improved understanding of reaction mechanism and pathway by providing concentration dependences of reacting components in real-time. Continuous data over the course of a reaction allows for the calculation of rate laws with fewer experiments due to the comprehensive nature of the data.  Reaction Progression Kinetics Analysis (RPKA) uses in situ data under synthetically relevant concentrations and captures information throughout the whole experiment ensuring that the complete reaction behavior can be accurately described.

Polymorphism Identification and Control
Understand Polymorphism and the Impact of Process Parameters

Polymorphism is a common phenomenon with many crystalline solids in the pharmaceutical and fine chemical industry. Scientists deliberately crystallize a desired polymorph to improve isolation properties, help overcome downstream process challenges, increase bioavailability or to prevent patent conflicts. Identifying polymorphic and morphological transformations in-situ and in real time eliminates unexpected process upset, out of specification product and costly reprocessing of material.

Scientist recrystallize high value chemical compounds to obtain a crystal product with desired physical properties at optimal process efficiency. Seven steps are required to design the ideal recrystallization process from choosing the right solvent to obtaining a dry crystal product. This recrystallization guide explains step-by-step the procedure of developing a recrystallization process. It explains what information is required at each stage of recrystallization and outlines how to control critical process parameter

Solubility and Metastable Zone Width (mzw) Determination

Solubility curves are commonly used to illustrate the relationship between solubility, temperature, and solvent type. By plotting temperature vs. solubility, scientists can create the framework needed to develop the desired crystallization process. Once an appropriate solvent is chosen, the solubility curve becomes a critical tool for the development of an effective crystallization process.

Crystal Nucleation and Growth

Scientists and engineers gain control of crystallization processes by carefully adjusting the level of supersaturation during the process. Supersaturation is the driving force for crystallization nucleation and growth and will ultimately dictate the final crystal size distribution.

Measure Crystal Size Distribution

In-process probe-based technologies are applied to track particle size and shape changes at full concentration with no dilution or extraction necessary. By tracking the rate and degree of change to particles and crystals in real time, the correct process parameters for crystallization performance can be optimized.

Crystallization Seeding Protocol

Seeding is one of the most critical steps in optimizing crystallization behavior. When designing a seeding strategy, parameters such as: seed size, seed loading (mass), and seed addition temperature must be considered. These parameters are generally optimized based on process kinetics and the desired final particle properties, and must remain consistent during scale-up and technology transfer.

Particle Engineering and Wet Milling

Milling of dry powders can cause significant yield losses and can generate dust, creating health and safety hazards. In response to this, wet milling produces particles with a specifically designed size distribution. It is now common to employ high shear wet milling to break large primary crystals and agglomerates into fine particles.

Anti-Solvent Addition on Supersaturation

In an antisolvent crystallization, the solvent addition rate, addition location and mixing impact local supersaturation in a vessel or pipeline. Scientists and engineers modify crystal size and count by adjusting antisolvent addition protocol and the level of supersaturation.

Temperature Effects Crystallization Size and Shape

Crystallization kinetics are characterized in terms of two dominant processes, nucleation kinetics and growth kinetics, occurring during crystallization from solution. Nucleation kinetics describe the rate of formation of a stable nuclei. Growth kinetics define the rate at which a stable nuclei grows to a macroscopic crystal. Advanced techniques offer temperature control to modify supersaturation and crystal size and shape.

Temperature Effects Crystallization Size and Shape

Changing the scale or mixing conditions in a crystallizer can directly impact the kinetics of the crystallization process and the final crystal size. Heat and mass transfer effects are important to consider for cooling and antisolvent systems respectively, where temperature or concentration gradients can produce inhomogeneity in the prevailing level of supersaturation.

Chemical Process Development & Scale-Up

Design Robust and Sustainable Chemical Processes For Faster Transfer To Pilot Plant and Production

Chemical Reaction Kinetics Studies

In situ chemical reaction kinetics studies provide an improved understanding of reaction mechanism and pathway by providing concentration dependences of reacting components in real-time. Continuous data over the course of a reaction allows for the calculation of rate laws with fewer experiments due to the comprehensive nature of the data.  Reaction Progression Kinetics Analysis (RPKA) uses in situ data under synthetically relevant concentrations and captures information throughout the whole experiment ensuring that the complete reaction behavior can be accurately described.

Polymorphism Identification and Control

Polymorphism is a common phenomenon with many crystalline solids in the pharmaceutical and fine chemical industry. Scientists deliberately crystallize a desired polymorph to improve isolation properties, help overcome downstream process challenges, increase bioavailability or to prevent patent conflicts. Identifying polymorphic and morphological transformations in-situ and in real time eliminates unexpected process upset, out of specification product and costly reprocessing of material.

Publications

Related Products

Tools For Supersaturation and Determining Final Crystal Product

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