Guide to Crystallization Development
Considering Process Scale
Influences of Mixing Conditions
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 anti-solvent systems respectively, where temperature or concentration gradients can produce inhomogeneity in the prevailing level of supersaturation. This often results in pockets of very high supersaturation close to the walls of the vessel for a cooling crystallization, or at the addition location for anti-solvent (and also reactive) crystallizations.
Comparing Mixing at Different Scales
Pockets of high supersaturation can cause very high nucleation and growth rates in certain regions of a large scale crystallizer, meaning the final crystal size distribution could vary dramatically from that achieved in a better-mixed environment in the lab during development. As seen in the graph to the right, a change from a 500 mL reactor to a 2 L reactor for the same crystallization process results in unexpected nucleation events characterized by ParticleTrack. Also, the number of fines generated throughout the batch is significantly higher.
Crystallization Repeatability
Varying Nucleation Kinetics
The effect of local supersaturation build-up on crystallization is shown here, where the repeatability of the nucleation point for an unseeded crystallization is shown for an anti-solvent crystallization system. For this process (right), when anti-solvent is added above the liquid surface and near the wall of the reactor, especially at higher addition rates, the nucleation point is extremely inconsistent, with wide error bars shown for these experiments that were conducted in triplicate (D. O’Grady, M. Barrett, E. Casey, and B. Glennon. (2007) The Effect of Mixing on the Metastable Zone Width and Nucleation Kinetics in the Anti-solvent Crystallization of Benzoic Acid. Chemical Engineering Research and Design, 85, 945 – 952). Additionally, when adding anti-solvent above surface and at the wall of the crystallizer, nucleation consistently occurs sooner, at lower anti-solvent concentrations. The reason for these two concerning results is that when anti-solvent is added close to the wall, the mixing conditions in the crystallizer make it difficult for the anti-solvent to be incorporated easily, and supersaturation builds up at the feed location.
Anti-Solvent Incorporation
The Effect on Crystallization Kinetics
The reason for this dramatic disparity in consistency is due to how anti-solvent is incorporated into the vessel. This video (left) show computational fluid dynamics (CFD) tracer experiments, for both addition locations shown above (center and wall). When anti-solvent is added above the surface and close to the wall, it is difficult to effectively incorporate the liquid into the bulk solution. When anti-solvent is added closer to the impeller, incorporation of the anti-solvent occurs immediately. For this crystallization system this difference in anti-solvent incorporation – and the associated difference in the homogeneity of supersaturation through the vessel – causes significant differences in the nucleation and consistency of the crystallization process .
Effect of Mixing on Breakage
Shear Rates
In addition to mass transfer effects, the shear rate in a crystallizer can have a physical impact on the crystals through breakage. Crystal breakage is a function of the solids concentration in the system as well as the shear rate. As scale and mixing conditions change - solids concentration and shear rate gradients may become important, meaning more or less breakage could occur as a crystallization process is scaled up. In this example (right), the chord length distributions acquired using FBRM technology (ParticleTrack) for a continuous crystallization process, are shown for three different agitation intensities (E. Kougoulos, A.G. Jones, and M.W. Wood-Kaczmar (2005) Estimation of Crystallization Kinetics for an Organic Fine Chemical Using a Modified Continuous Cooling Mixed Suspension Mixed Product Removal (MSMPR) Crystallizer, Journal of Crystal Growth, Volume 273, Issues 3 – 4, 3 January 2005, Pages 520 – 528). As agitation and the associated shear rate increase, the distributions shift to the left with an increase in fine crystal counts, indicating crystal breakage. This result is common. However, such behavior is difficult to predict as the volume changes, since agitation intensity is not a scalable parameter.
Particle Size Analysis for Process Optimization
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.
Technologies to Monitor, Optimize, and Control
Crystallization unit operations offer the unique opportunity to target and control an 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 Optimizing Crystal Size and Shape with Temperature Control
Optimization of Crystal Properties and Process Performance
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.
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 Crystallization
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
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.
Detect and Prevent Oiling Out (Liquid-Liquid Phase Separation)
Liquid-Liquid phase separation, or oiling out, is an often difficult to detect particle mechanism that can occur during crystallization processes.
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.
Understand Polymorphism and the Impact of Process Parameters
Crystal polymorphism describes the ability of one chemical compound to crystallize in multiple unit cell configurations, which often show different physical properties.
Create Structured, Ordered Lattices for Complex Macromolecules
Protein crystallization is the act and method of creating structured, ordered lattices for often-complex macromolecules.
Recover Lactose with High Yield and Scalable Process
Lactose crystallization is an industrial practice to separate lactose from whey solutions via controlled crystallization.
Improve Crystallization Experiments with Precise Control
The MSMPR (Mixed Suspension Mixed Product Removal) crystallizer is a type of crystallizer used in industrial processes to produce high-purity crystals.
Generate Supersaturation and Determine Final Crystal Product
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).
Real-Time Monitoring for Modeling and Control
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).
Publications
Publications on Crystallization Temperature Control
White Papers
Dynamic mechanisms key to understanding crystallization processes can now be observed with in-situ microscopy. A white paper explains how leading chem...
This white paper introduces you to the fundamentals of crystallization process development and provides guidance for the design of a high quality crys...
This white paper discusses strategies to optimize crystal size distribution during process development and manufacturing.
Optimization of the industrial crystallization process leads to increased yield and purity, reduced energy consumption and cost, and improved product...
Seeding is a key step in optimizing a crystallization process, ensuring a consistent filtration rate, yield, polymorphic form and particle size distri...
Scale-up of crystallization is notoriously complicated and companies are under pressure to develop scalable crystallization processes faster - at lowe...
This white paper demonstrates the methodology chemists use to optimize critical crystallization parameters such as temperature profile, addition rates...
Particle size analysis approaches are deployed for effective delivery of high quality particle products. Combining offline particle size analyzers wi...
Webinars
Eric Fang of Snapdragon discusses how continuous flow chemistry is applicable across the entire value chain. Early implementation of continuous flow...
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...
Citations
Crystallization and precipitation citation list and publications
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Technology For Crystallization Temperature Control
ReactIR
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Particle Size Analyzers
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Reaction Calorimeters
Reaction calorimeters measure the amount of energy released or absorbed by a chemical or physical reaction in chemical and pharmaceutical development.