
Guide to Crystallization Development

Controlling Addition Rates
With In Situ Supersaturation Profiling
Supersaturation is generated by reducing the solubility of the product in solution, typically by cooling or adding an antisolvent. The rate at which a solution is cooled or antisolvent is added directly influences the level of supersaturation.
In this example, undersaturated solutions of benzoic acid in ethanol-water mixtures are prepared and water is added at a fixed rate of 0.1 g/s and 0.2 g/s respectively, at a fixed temperature of 25 °C. The liquid concentration is measured in real time with in situ FTIR spectroscopy. In the figure to the right, the solubility curve for benzoic acid in ethanol-water mixtures with desupersaturation profiles for each experiment are displayed. The desupersaturation profile shows that the solution begins in the undersaturated region. As water is added, the process moves past the solubility curve into the supersaturated region. The liquid concentration decreases upon crystal nucleation and stays close to the solubility curve. At the end of the antisolvent addition period, the liquid concentration drops to the solubility curve. When antisolvent is added at the faster rate, the supersaturation level is higher throughout the process - due to a buildup that cannot be relieved fast enough through crystal growth and nucleation.

Optimize Process Parameters
To Control Supersaturation and Size
In this experiment, changing process parameters and supersaturation influence both crystal size and shape. Images captured with PVM technology (ParticleView) at the end of each experiment illustrate this point (shown on the right). The slow addition rate yields large, well-formed elongated plates, while the fast addition rate yields fine needles that readily agglomerate. This result shows that by changing supersaturation in a crystallization system, it is possible to modify crystal size, shape, and the degree of agglomeration. This also demonstrates the importance of understanding and controlling the prevailing level of supersaturation.
This simple example illustrates a critical principle:
- To make large crystals, generate supersaturation slowly
- To make small crystals, generate supersaturation quickly

Challenges with Supersaturation
Purity and Scale-up
Controlling antisolvent addition rates to control crystal size is well understood and established in sound scientific principles. However, effective and evidence-based crystallization process development and improvement is more nuanced. For example, generating supersaturation at a fast rate can lead to the generation of unwanted impurities in the form of transient oil phases (a), or unwanted polymorphic forms (b). Similarly, in an effort to generate large crystals, cycle time cannot always be sacrificed, meaning extremely slow cooling or antisolvent addition rates are not possible.

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.
Technologies to Monitor, Optimize, and Control
Crystallization unit operations offer the unique opportunity to target and control and optimized crystal size and shape distribution to:
- Reduce Filtration and Drying Times
- Avoid Storage, Transport and Shelf Life Issues
- Ensure a Consistent and Repeatable Process at Lower Costs
Applications
Applications For Antisolvent Addition on Supersaturation
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.
Liquid/Liquid phase separation or oiling out is an often difficult to detect particle mechanism that can occur during crystallization processes. Quick generation of supersaturation and/or high impurity levels can kinetically hinder nucleation and delay crystal formation. Oiling out occurs when the system is driven to a point in the phase diagram where a Liquid/Liquid phase split is possible and causes the formation of a product-rich oil phase in the solvent matrix. Processes that oil out often show high impurity profiles and slow isolation performance. Oiling out can also cause residue on crystallization equipment that is difficult to clean – especially at larger scales.
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.
Chemical Process Development and Scale-Up guides the development of a commercially important molecule from synthesis in the lab to large scale manufacture of a quality product.
Chemical reaction kinetics, also known as reaction kinetics, reflect rates of chemical reactions and provide a better understanding of their dependencies on reaction variables. Reaction kinetic studies provide enhanced insight into reaction mechanisms. Learn how to obtain data rich information for more complete reaction kinetic information.
Polymorphism chemistry is a common phenomenon with many crystalline solids in the pharmaceutical and fine chemical industries. 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.
Liquid/Liquid phase separation or oiling out is an often difficult to detect particle mechanism that can occur during crystallization processes. Quick generation of supersaturation and/or high impurity levels can kinetically hinder nucleation and delay crystal formation. Oiling out occurs when the system is driven to a point in the phase diagram where a Liquid/Liquid phase split is possible and causes the formation of a product-rich oil phase in the solvent matrix. Processes that oil out often show high impurity profiles and slow isolation performance. Oiling out can also cause residue on crystallization equipment that is difficult to clean – especially at larger scales.
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.
Chemical Process Development and Scale-Up guides the development of a commercially important molecule from synthesis in the lab to large scale manufacture of a quality product.
Chemical reaction kinetics, also known as reaction kinetics, reflect rates of chemical reactions and provide a better understanding of their dependencies on reaction variables. Reaction kinetic studies provide enhanced insight into reaction mechanisms. Learn how to obtain data rich information for more complete reaction kinetic information.
Polymorphism chemistry is a common phenomenon with many crystalline solids in the pharmaceutical and fine chemical industries. 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.