Crystallization kinetics are characterized in terms of two dominant processes, nucleation kinetics and growth kinetics, occurring during crystallization from solution.
The governing equations of crystal growth and nucleation, also described in (J. Nývlt (1968) Kinetics of Nucleation in Solutions. Journal of Crystal Growth, 3 – 4, 377 – 383), show that the surface area of the crystal slurry plays an important role in determining crystal nucleation and growth kinetics. At the start of a crystallization process, the surface area of crystals present in the slurry is low – meaning nucleation can dominate over growth, regardless of other kinetic factors. As crystallization proceeds, the surface area increases and it is possible for growth kinetics to become more favorable. When a linear cooling rate is applied (as shown on the right) to a crystallization process, it is possible for supersaturation to build up initially when there is no surface area available for growth. This build up results in fast, and often, unpredictable crystallization kinetics – with nucleation often dominating.
A clever technique for enhancing growth is to cool very slowly at first, when surface area is limited (as shown on the right). This keeps supersaturation low and allows growth to dominate. After some time, when surface area has increased, the cooling rate can be increased, reducing batch time, while still favoring growth. This technique strikes the right balance between controlling supersaturation and excessive nucleation, while avoiding very long batch times (P. Barrett, B. Smith, J. Worlitschek, V. Bracken, B. O’Sullivan, and D. O’Grady 2005) A Review of the Use of Process Analytical Technology for the Understanding and Optimization of Production Batch Crystallization Processes. Organic Process Research & Development, 9(3), 348 – 355). One drawback from this approach is that implementing a non-linear cooling or anti-solvent addition profile in the plant can be difficult and adds complexity to a process. However, success can still be achieved by using a small number of linear ramps, which achieve a similar result.
The value of implementing non-linear cooling rates to keep supersaturation constant over the course of a process has been proven by implementing a control loop that adjusts process temperature in order to keep supersaturation constant. Such a result was described in V. Liotta and V. Sabesan (2004) Monitoring and Feedback Control of Supersaturation Using ATR-FTIR to Produce an Active Pharmaceutical Ingredient of a Desired Crystal Size. Organic Process Research & Development, 8(3), 488 – 494. Copyright (2004) American Chemical Society, where a control algorithm is used to perform a crystallization process at constant supersaturation (shown on the left). In this example, supersaturation is monitored using in situ FTIR monitoring and the resulting temperature profile is non-linear: slow at first, and fast towards the end.
This paper discusses common particle size analysis techniques and how they are used for the delivery of high-quality particles. Examples include the usage of offline particle size analyzers in combination with in-process particle characterization tools to optimize processes.
Crystallization unit operations offer the unique opportunity to target and control an optimized crystal size and shape distribution to:
Recrystallization is a technique used to purify solid compounds by dissolving them in a hot solvent and allowing the solution to cool. During this process, the compound forms pure crystals as the solvent cools, while impurities are excluded. The crystals are then collected, washed, and dried, resulting in a purified solid product. Recrystallization is an essential method for achieving high levels of purity in solid compounds.
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.
Supersaturation occurs when a solution contains more solute than should be possible thermodynamically, given the conditions of the system. Supersaturation is considered a major driver for crystallization.
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.
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.
Crystal polymorphism describes the ability of one chemical compound to crystallize in multiple unit cell configurations, which often show different physical properties.
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.
The MSMPR (Mixed Suspension Mixed Product Removal) crystallizer is a type of crystallizer used in industrial processes to produce high-purity crystals.
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. Batch crystallization optimization requires maintaining adequate control of the crystallizer temperature (or solvent composition).
Continuous crystallization is made possible by advances in process modeling and crystallizer design, which leverage the ability to control crystal size distribution in real time by directly monitoring the crystal population.
Recrystallization is a technique used to purify solid compounds by dissolving them in a hot solvent and allowing the solution to cool. During this process, the compound forms pure crystals as the solvent cools, while impurities are excluded. The crystals are then collected, washed, and dried, resulting in a purified solid product. Recrystallization is an essential method for achieving high levels of purity in solid compounds.
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.
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.
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.
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. Batch crystallization optimization requires maintaining adequate control of the crystallizer temperature (or solvent composition).
