Guide to Crystallization Development
Avoiding Sampling and Offline Analysis
Obtaining a Representative Sample
Offline analysis is commonly used to determine crystal distribution at the end of an experiment or during a production run. While such an approach is common, there are limitations to offline analysis which are relevant for crystals:
- Crystals are delicate and change with temperature – making representative sampling and analysis particularly difficult
- Many crystal systems are toxic and do not lend themselves well to sampling
- It is difficult to take enough offline samples to determine how a fast changing process, such as crystallization, behaves with respect to time.
- The time delay between sampling and offline analysis is often too long, especially in production, to make relevant decisions that can improve product quality
Why Crystal Size and Shape Are Important
Improve the Product and Process
This set of ParticleView images neatly illustrates the complex size, shape, and structure of various crystals. From large round “boulders” to beautifully delicate “dendrites”, crystal product is often varied, posing challenges to effective separation and downstream manipulation.
- The crystals in Image A will likely filter quickly and consistently. The larger boulders will leave plenty of space for the filtrate to pass through rapidly.
- Flat plates like these in Image B can be some of the most difficult to filter. Plates tend to stack on top of each other creating a layer of crystals that the filtrate cannot get through. This leads to long and potentially variable filtration times, depending on how the crystals are discharged from the crystallizer.
- Image C illustrates another case where filtration times can be long. Small crystals will plug the gaps left by the larger crystals making it difficult for the filtrate to pass through the bed of crystals. This is a common problem because many crystallization processes are designed with a fast cool or anti-solvent addition step at the end of the crystallization (to increase yield) that leads to excessive secondary nucleation. Additionally, in many cases the agitation is increased at the end of the batch to help with discharge and this leads to crystal breakage.
- Image D is more common than many would expect, at least in organic crystallization systems that are seeded. A structure such as this would be difficult to observe using an offline microscope as it will be crushed during sampling and preparation. However, ParticleView reveals a beautiful dendritic structure. A dendrite such as this often forms when crystallization is seeded with milled seed. Imperfections on the crystal surface lead to crystal growth from these areas and long crystal branches growing from a seed core. It is difficult to predict how something like this will filter, but it is likely to break apart resulting in variable filtration times.
Real-Time Microscopy
By studying crystals in real time, scientists can develop detailed and reliable process understanding on a routine basis. ParticleView V19 with PVM technology allows scientists to directly observe crystals and crystal structures in process without having to take a sample.
Crystallization mechanisms such as nucleation, growth, breakage, and shape changes can be observed under dynamic changing process conditions and the most suitable process parameters can be chosen with confidence. A simple image-based trend that indicates how crystal size, shape, and count complements high resolution real time images and allows important process events to be identified and investigated immediately.
In-Process Particle Characterization
ParticleTrack with FBRM technology tracks the rate and degree of change to crystals and crystal structures as they naturally exist in process. A precise measurement, sensitive to changing crystal size, shape, and count, is provided in real time under dynamic changing process conditions at full process concentrations. This technique is applied as a standard tool during crystallization development and is a powerful process monitoring instrument in production, where it is used to troubleshoot difficult processes and ensure batch-to-batch consistency.
Using ParticleTrack, scientists can:
- Study crystal count in individual size classes – to optimize fine and coarse ends of the crystal size distribution
- Identify the root cause of a poorly performing crystallization process
- Choose the correct process parameters for optimal crystallization performance using process-based evidence
- Monitor processes for repeatability and consistency
- Correlate in-process measurements to offline particle size analysis
- Model the influence of crystal size and count on product and process quality
Focused Beam Reflectance Measurement (FBRM)
Inline Particle Size, Count, and Shape
A ParticleTrack probe with FBRM technology is immersed into a flowing slurry or droplet system with no dilution necessary. A focused laser scans the surface of the probe window and tracks individual chord lengths - measurements of particle size, shape, and count. This real-time measurement is presented as a distribution and statistics (eg. mean, counts) are trended over time.
Technologies To Measure Crystal Size
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.
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.
Seeding a Crystallization Process
This white paper discusses best practices for designing a seeding strategy and what parameters should be considered when implementing a seeding protocol. Although crystallization understanding has improved over the last thirty years, the seeding step still presents challenges.
Applications
Particle Size, Shape, and Count Measurement To Improve Crystallization
Optimization of Crystal Properties and Process Performance
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
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 Crystal Nucleation and Growth
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.
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 Avoid 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. 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.
Control Particle Size With High Shear Wet Milling
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.
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.
Creating Safe, Efficient Processes from Lab to Plant
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.
Fundamental Understanding of Reactions Rates and Factors Affecting Them
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.
Understand Polymorphism and the Impact of Process Parameters
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.
Publications
Particle Size, Shape, and Count Measurement To Improve Crystallization
White Papers
By quickly identifying unnecessary hold times and determining how cooling rate influences crystal growth and nucleation, the cycle time for an interme...
Dynamic mechanisms key to understanding crystallization processes can now be observed with in situ microscopy. A white paper explains how leading chem...
The quality of a crystallization process greatly influences the quality of the final product. Our new white paper introduces you to the fundamentals o...
This white paper discusses strategies to optimize crystal size distribution during process development and manufacturing.
Industrial crystallization is an important separation and purification step in the chemical industry. A white paper shows how inline particle technol...
Seeding is a key step in optimizing a crystallization process, ensuring a consistent filtration rate, yield, polymorphic form and particle size distri...
Real-time monitoring of crystallization is shown to provide benefits leading to improved methods for process development, optimization and scale-up. T...
This white paper demonstrates the methodology chemists use to optimize critical crystallization parameters such as: Temperature profile Addition rates...
This white paper introduces some of the most common particle size analysis approaches and how they can be deployed for the effective delivery of high...
Webinars
This webinar describes an investigation into the characterization, design and operation of continuous crystallization. Robust crystallization process...
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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