
Common Ways to Reduce Solubility
Crystallization is achieved by reducing the solubility of the product in a saturated starting solution by:
- Cooling
- Adding Anti-Solvent
- Evaporation
- Some Combination of the Above Methods
Another common method used to induce crystallization is via a chemical reaction where two or more reactants are mixed to form a solid product insoluble in the reaction mixture; a common example of this would be the reaction of an acid and a base to form a salt.
The method chosen to crystallize product can vary depending on a number of factors. For example, protein crystals are temperature-sensitive ruling out cooling and evaporation and leaving anti-solvent addition as the most common crystallization method. For many crystallization processes, cooling can be advantageous as it is reversible; the saturated solution can be reheated in the event of a non-optimal operation.

The Importance of Solubility Curves
Solubility curves (figure at right) are commonly used to illustrate the relationship between solubility, temperature, and solvent type. By plotting temperature vs. solubility, scientists create the framework needed to develop the desired crystallization process. Here, the solubility of the given material in Solvent A is high – meaning more material can be crystallized per unit mass of solvent. Solvent C has a low solubility at all temperatures, indicating it could be a useful anti-solvent for this material.
Once an appropriate solvent is chosen, the solubility curve becomes a critical tool for the development of an effective crystallization process. With this information, the starting concentration and temperature or anti-solvent ratio can be chosen, the theoretical yield can be calculated and the first important decisions regarding how the crystallization will be developed can be made.

How To Measure Solubility
A probe-based instrument that tracks the rate and degree of change to particle size and count as particles exist in process, ParticleTrack, can be used to measure the solubility curve and MSZW (Metastable Zone Width) by accurately identifying the point of dissolution (point on the solubility curve) and point of nucleation (point on the MSZW) at various solute concentrations.
In a study by Barrett and Glennon (Trans ICHemE, vol. 80, 2002, pp. 799-805), an unsaturated solution is cooled at a slow, fixed rate until the point of nucleation is measured by ParticleTrack (Lasentec FBRM) indicating a point on the MSZW. Next, the solution is heated slowly until the point of dissolution is measured indicating a point on the solubility curve. Solvent is then added to the system to reduce the concentration and the process is repeated. In this way, the solubility curve and MSZW can be measured rapidly over a wide range of temperatures.
In this figure, the solubility curve and metastable zone width(s) for potassium aluminum sulphate is shown. While the solubility curve is thermodynamically fixed for a given solvent-solute system the MSZW is a kinetic boundary and can change depending on process parameters such as cooling rate, agitation, or scale. Characterizing the MSZW under a range of process conditions can help scientists understand how a crystallization process may behave at different scales - or in the event of a process upset. Variability in the MSZW under different conditions may indicate that the system may not behave consistently in terms of nucleation point and kinetics. Such a result may justify investigating the possibility of seeding the process in order to fix the nucleation point for every experiment or batch.

Case Studies on Solubility and MSZW
Dynamic approaches to solubility determination, such as this one, are sometimes limited in their accuracy since a fast heating rate means the exact point of dissolution can be overestimated. Static methods, such as gravimetric analysis may offer more accuracy – but are more time-consuming and cumbersome to implement. Many techniques can be used to measure solubility curves and recent research aimed at predicting solubility in different solvents is showing promise.

Technologies For Solubility and and MSZW
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.

Crystallization Best Practices
This continuing review of crystallization literature is distilled into a summary that provides guidelines for understanding and optimizing the challenging unit operations of crystallization and precipitation.

Guide to Effective Process Development
This white paper series covers basic and advanced strategies to optimize crystal size and shape distribution.

Use Image Analysis to Optimize Crystallization
Discover how image-based process trending can reduce crystallization cycle time and improve quality while maintaining a similar crystal size and shape.
Applications
Building Blocks of Crystallization Applications
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.
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.