Supersaturation in Crystallization
The Driving Force
Scientists gain control of crystallization processes by carefully controlling the prevailing level of supersaturation during the process. When a saturated solution is cooled, the system enters a metastable region where the solution becomes supersaturated, in other words, more of the solute is in solution that the solubility curve predicts. As cooling continues, a certain temperature will be reached where crystal nucleation will occur, the metastable limit.
Once the metastable limit is reached and crystallization starts, supersaturation is consumed and eventually the liquid phase concentration will reach equilibrium at the solubility curve.
Why is Supersaturation Important?
Because supersaturation is the driving force for crystal nucleation and growth and will ultimately dictate the final crystal size distribution, it is critical to understand the concept of supersaturation.
Nucleation is the birth of new crystal nuclei – either spontaneously from solution (primary nucleation) or in the presence of existing crystals (secondary nucleation). Crystal growth is the increase in size (or more accurately “characteristic length”) of crystals as solute is deposited from solution. The relationship between supersaturation, nucleation, and growth is defined by a well-known set of (somewhat simplified) equations first outlined by Nyvlt (Journal of Crystal Growth, Volumes 3–4, 1968, Pages 377-383)
Crystal Nucleation and Growth
For organic crystallization systems, the value of the growth order (g) is typically between 1 and 2 and the value of the nucleation order (b) is typically between 5 and 10. When we plot these equations for a theoretical organic crystallization process the importance of supersaturation becomes clear. At low supersaturation, crystals can grow faster than they nucleate, resulting in a larger crystal size distribution. However, at higher supersaturation, crystal nucleation dominates crystal growth, ultimately resulting in smaller crystals. In the figure to the right, relating supersaturation to nucleation, growth, and crystal size clearly illustrate how controlling supersaturation is vitally important when it comes to creating crystals of the desired size and distribution.
Modern techniques such as ReactIR, outlined here by Barett et al (Chemical Engineering Research and Design, Volume 88, Issue 8, August 2010, Pages 1108-1119) allow solubility traces to be developed quickly and easily, and the prevailing level of supersaturation to be monitored continuously throughout a crystallization experiment. Faster cooling rates result in nucleation at lower temperatures and the highest level of supersaturation throughout the process. A very slow cool down results in a higher nucleation temperature and low supersaturation throughout the process. A one-hour cubic cool down (slow at first and fast at the end) has a medium level of supersaturation throughout. The influence of varying supersaturation on crystal size and shape distribution can be clearly observed by comparing ParticleView (a probe based real-time microscope) images for each experiment. Higher supersaturation results in the smallest crystals – since nucleation will be favored over growth.
Case Studies on Monitoring and Control
Using experimental data, much has been accomplished in supersaturation monitoring and the estimate of crystallization kinetics. The approach has been extended to allow model-based control of crystallization processes.
Technologies to Monitor, Optimize, and Control
Crystallization unit operations offer the unique opportunity to target and control an optimized crystal size and shape distribution. Doing so can dramatically reduce filtration and drying times, avoid storage, transport, and shelf life issues, and ensure a consistent and repeatable process at a lower cost.
How to Monitor & Control Supersaturation
This poster describes the use of a calibration-free method where the temperature during cooling crystallization is controlled automatically in a water/IPA solvent in order to maintain a constant level of supersaturation.
Optimizing Crystallization with Supersaturation Control
A method is presented which facilitates the calibration free use of in situ ATR-FTIR spectra for the production and control of qualitative supersaturation trajectories.
Guide to Effective Process Development
This white paper series covers basic and advanced strategies to optimize crystal size and shape distribution.
Applications
Applications For The Driving Force For Crystal Nucleation and Growth
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
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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 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.
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.
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.
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.
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.
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.
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.
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.
Design Robust and Sustainable Chemical Processes For Faster Transfer To Pilot Plant and Production
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 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
Publications For The Driving Force For Crystal Nucleation and Growth
White Papers
Dynamic mechanisms key to understanding crystallization processes can now be observed with in situ microscopy. A white paper explains how leading chem...
The quality of a crystallization process greatly influences the quality of the final product. Our new white paper introduces you to the fundamentals o...
This white paper discusses strategies to optimize crystal size distribution during process development and manufacturing.
Industrial crystallization is an important separation and purification step in the chemical industry. A white paper shows how inline particle technol...
Seeding is a key step in optimizing a crystallization process, ensuring a consistent filtration rate, yield, polymorphic form and particle size distri...
Real-time monitoring of crystallization is shown to provide benefits leading to improved methods for process development, optimization and scale-up. T...
This white paper demonstrates the methodology chemists use to optimize critical crystallization parameters such as: Temperature profile Addition rates...
This white paper introduces some of the most common particle size analysis approaches and how they can be deployed for the effective delivery of high...
Webinars
This webinar describes an investigation into the characterization, design and operation of continuous crystallization. Robust crystallization process...
Crystal engineering is applied when the crystal size distribution is too large to meet downstream specifications. By designing the crystallization to...
The quantitative use of in situ ATR-FTIR for real time supersaturation assessment has been extremely well defined within the literature. However, thes...
The webinar focuses on a semi-quantitative method for the optimization and scale-up of hydrodynamically limited anti-solvent crystallization process....
This webinar introduces case studies and highlights best practices used to overcome crystallization and precipitation challenges. The focus will be on...
Application Notes
Ensure fast and efficient scale-up by optimizing crystallization early in development. Target particle size specifications to speed up downstream proc...
Improve purity by ensuring total polymorphic form conversion. Enhance process robustness by monitoring crystallization processes in real time. Charact...
Citations
Crystallization and precipitation citation list and publications
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