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Seeding is one of the most straightforward methods used to control supersaturation. During seeding, a small mass of crystals is added to a supersaturation in order to:
Choosing the correct seed loading (mass) and seed size can helop produce final crystal product of a specified size. If we consider a theoretical crystallization system where only growth occues and the crystals are spherical, it is possible to develop a simple model where the final crystal size can be predicted simply based on the starting seed size and loading (right). Consider the case where we seed a crystallization with 1% seed. In this case, 1% is simply the ration of seed mass to the final anticipated product mass. Since the seed and final product have identical density, it is simple to convert mass ratio to volume ration. Then, the next logical step is to convert volume ratio to diameter ratio.
While this simple model is useful for demonstrating how seed size and loading affect the final crystal size distribution, the assumptions are not commonly observed in real systems. Crystals are rarely spherical, meaning more complex models are needed to predict the size of needles. Crystallization processes are rarely, if ever, completely growth dominated. Some degree of nucleation and attrition almost always occurs in order to develop an effective seeded crystallization. As this example demonstrates, real-time microscopy offers a unique opportunity to better understand seeding events. In the images on the right, the seeding process is observed directly during an organic crystallization using real time microscopy. After seed crystals are added to the supersaturated solution (a), it becomes apparent that the surface nucleation on the seed crystals occurs (b). Over time, dendritic growth occurs with small crystal "branches" growing orthogonally from the seed crystal (c). After thirty minutes, a bimodal size and shape distribution is present, indicating that the final crystal product may filter and dry poorly (d).
Process knowledge can be easily obtained by visualizing seeding mechanisms during crystallization development.
The supersaturation level at which seed will be added is another critical variable to consider when designing a seeded crystallization process. In a cooling crystallization, this might be referred to as the “seeding temperature”, but it is actually the supersaturation level that is being considered. Seeding at high supersaturation levels may result in excessive secondary nucleation, rendering the seeding process itself redundant, unless the goal is a fine crystal size distribution. If crystal growth is desired, then seeding closer to the solubility curve, at lower supersaturation, may be a wise choice. This approach is shown in the graph to the right, where three crystallization processes are compared using ParticleTrack with FBRM technology at three different seeding temperatures. By comparing particle counts between 0 μm and 10 μm for each crystallization, it is possible to compare relative nucleation rates at different seeding temperatures. The lowest seeding temperature (highest supersaturation) results in the highest degree of nucleation and fine crystals at the end of the process.
When seeding, another important factor to consider is that during preparation and storage, seed crystals can stick together and form aggregates. Often, an isothermal hold after seeding is required to ensure that seed crystals are able to fully disperse, and the full surface area is available for crystallization to progress. Such an isothermal hold can also help seed crystals grow, increasing the surface area available for growth. In the example on the right, a ParticleTrack process trend that describes a crystallization process where it takes four hours for seeds to fully disperse. This example, along with the others provided above, indicate that careful characterization of the seeding process, in terms of a number of critical process variables, is vital to ensure consistency and product quality.
Although crystallization has improved over the years, the seeding step still presents challenges. This paper reviews how to design a seeding strategy and what parameters should be considered when implementing a seeing protocol.
Crystallization unit operations offer the unique opportunity to target and control an optimized crystal size and shape distribution to:
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 parameters.
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.
Vědci a inženýři mají úplnou kontrolu nad celým procesem krystalizace díky možnosti přesného stanovení úrovně přesycení v průběhu procesu. Přesycení je hnací silou při tvorbě jader a růstu během krystalizace a rozhoduje o výsledné distribuci velikosti krystalů.
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. Learn more.
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.
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.
Protein crystallization is the act and method of creating structured, ordered lattices for often-complex macromolecules.
Lactose crystallization is an industrial practice to separate lactose from whey solutions via controlled crystallization.
Chemical process development and scale-up guide the development of a commercially important molecule from synthesis in the laboratory to manufacturing in a plant.
Chemical reaction kinetics, also known as reaction kinetics, reflect rates of chemical reactions. Learn how reaction kinetic studies provide enhanced insight into reaction mechanisms.
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 parameters.
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.
Vědci a inženýři mají úplnou kontrolu nad celým procesem krystalizace díky možnosti přesného stanovení úrovně přesycení v průběhu procesu. Přesycení je hnací silou při tvorbě jader a růstu během krystalizace a rozhoduje o výsledné distribuci velikosti krystalů.
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. Learn more.
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.
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.
Protein crystallization is the act and method of creating structured, ordered lattices for often-complex macromolecules.
Lactose crystallization is an industrial practice to separate lactose from whey solutions via controlled crystallization.
Chemical process development and scale-up guide the development of a commercially important molecule from synthesis in the laboratory to manufacturing in a plant.
Chemical reaction kinetics, also known as reaction kinetics, reflect rates of chemical reactions. Learn how reaction kinetic studies provide enhanced insight into reaction mechanisms.
