Crystallization, or crystallisation, is the process of atoms or molecules arranging into a well-defined, rigid crystal lattice in order to minimize their energetic state. The smallest entity of crystal lattice is called a unit cell, which can accept atoms or molecules to grow a macroscopic crystal. During crystallization, atoms and molecules bind together with well-defined angles to form a characteristic crystal shape with smooth surfaces and facets. Although crystallization can occur in nature, crystallization also has a broad industrial application as a separation and purification step in the pharmaceutical and chemical industries.
What Is Crystallization?
The choice of operating conditions during a crystallization process directly influences important product attributes such as crystal size, crystal shape and purity. By understanding the crystallization process and choosing the right process parameters, it is possible to repeatedly produce crystals of the correct size, shape, and purity while minimizing downstream processing issues, such as long filtration times or inadequate drying.
Why is Crystallization Important?
Crystallization touches every aspect of our lives from the foods we eat and the medicines we take, to the fuels we use to power our communities. The majority of agrochemical and pharmaceutical products go through many crystallization steps during their development and manufacture. Key food ingredients, such as lactose and lysine, are manufactured using crystallization and the unwanted crystallization of gas hydrates in deep sea pipelines is a major safety concern for the petrochemical industry.
Key Crystallization Definitions
Crystallization
Crystallization is a process whereby solid crystals are formed from another phase, typically a liquid solution or melt.
Crystal
Crystal is a solid particle in which the constituent molecules, atoms, or ions are arranged in some fixed and rigid, repeating three-dimensional pattern or lattice.
Precipitation
Precipitation is another word for crystallization but is most often used when crystallization occurs very quickly through a chemical reaction.
Solubility
Solubility is a measure of the amount of solute that can be dissolved in a given solvent at a given temperature
Saturated Solution
At a given temperature, there is a maximum amount of solute that can be dissolved in the solvent. At this point the solution is saturated. The quantity of solute dissolved at this point is the solubility.
Supersaturation
Supersaturation is the difference between the actual solute concentration and the equilibrium solute concentration at a given temperature.
Types of Crystallization
Crystallization occurs when the solubility of a solute in solution is reduced by some means. Common methods to reduce solubility include:
a. Cooling
b. Antisolvent Addition
c. Evaporation
d. Reaction (Precipitation)
The choice of crystallization method depends on the equipment available for crystallization, the objectives of the crystallization process and the solubility and stability of the solute in the chosen solvent.
Common Crystallization Challenges
Crystallization proceeds through a series of interdependent mechanisms that are each uniquely influenced by the choice of process parameters:
- Nucleation
- Growth
- Oiling Out
- Agglomeration
- Breakage
- Polymorphism Chemistry
These mechanisms, which are often hidden form scientists, play a dominant role in defining the outcome of a crystallization process.
Crystallization Steps
- Choose an appropriate solvent. Common considerations included how much solute can be dissolved (solubility) and how practical the solvent is to handle (safety)
- Dissolve the product in the solvent by increasing the temperature until the last product molecule disappears. At this insoluble impurities may be filtered from the hot solution
- Reduce solubility via cooling, anti-solvent addition, evaporation or reaction. The solution will become supersaturated.
- Crystallize the product. As solubility is reduced a point is reached where crystals will nucleate and then grow. Highly pure product crystals should form and impurities should remain in solution.
- Allow the system to reach equilibrium after cooling (or another crystallization method stops).
- Filter and dry the purified product.
Crystallization Publications
Discover a selection of crystallization publications below:
The seminal study on the nucleation of crystals from solution
Jaroslav Nývlt, Kinetics of nucleation in solutions, Journal of Crystal Growth, Volumes 3–4, 1968.
Excellent study on how crystals grow form solution
Crystal Growth Kinetics, Material Science and Engineering, Volume 65, Issue 1, July 1984.
An excellent description of the reasons solute-solvent systems exhibit oiling out instead of crystallization
Kiesow et al., Experimental investigation of oiling out during crystallization process, Journal of Crystal Growth, Volume 310, Issue 18, 2008.
Detailed examination of why agglomeration occurs during crystallization
Brunsteiner et al., Toward a Molecular Understanding of Crystal Agglomeration, Crystal Growth & Design, 2005, 5 (1), pp 3–16.
A study of breakage mechanisms during crystallization
Fasoli & Conti, Crystal breakage in a mixed suspension crystallizer, Volume 8, Issue8, 1973, Pages 931-946.
A great overview of how to design effective crystallization processes in the high value chemicals industry
Paul et al., Organic Crystallization Processes, Powder Technology, Volume 150, Issue 2, 2005.
Techniques to ensure the correct polymorph is crystallized every time
Kitamura, Strategies for Control of Crystallization of Polymorphs, CrystEngComm, 2009,11, 949-964.
Common Crystallization Parameters & Transformations
While crystals have many important attributes the crystal size distribution probably has the greatest impact on the quality and effectiveness of the final product (and the process needed to deliver it). Crystal size and shape directly influence key steps downstream from the crystallizer, with filtration and drying performance being particularly susceptible to changes in these important attributes. Similarly, the final crystal size can also directly influence the quality of the final product. In a pharmaceutical compound, bioavailability and efficacy are often related to particle size with smaller particles often desired for their enhanced solubility and dissolution characteristics
Crystal size distribution can be optimized and controlled by carefully choosing the correct crystallization conditions and process parameters. Understanding how process parameters influence key transformations, such as nucleation, growth, and breakage, allow scientists to develop and manufacture crystals that will have the desired attributes and be efficient to bring to the market.
Case Study: Crystallization Cooling Rates
In this example, the cooling rate at the end of the batch induces secondary nucleation resulting in the formation of many fine particles - using particle size analyzers.
An increase in cooling rate generates supersaturation faster – which is consumed by nucleation rather than growth. Careful control of cooling rate is critical to ensure the desired crystal size distribution specification can be achieved.
The crystal size distribution of ice plays a vital role in the taste and consistency of ice cream, with crystals smaller than 50 μm being better than crystals larger than 100 μm. For agrochemicals, it is vital to ensure that particles are small enough to be sprayed without blocking nozzles while large enough not to drift into neighboring fields.
While it is often a challenge to control crystal size distribution across scales, an opportunity exists to understand crystallization processes to deliver an optimized size and shape distribution that will ensure a cost effective process with the highest possible quality.
Crystallization Equipment
Process Analytical Technology for Crystallization Engineering
A crystallization workstation allows scientists to obtain maximum scientific information from a single experiment in a centralized software suite. Process Analytical Technology (PAT) provides analytical information, including:
- Automated Reactors: EasyMax, OptiMax, RC1 reaction calorimeters and RX-10 provide 24/7 precise control and recording of process parameters, including the capture of crystallization enthalpies so that scientists can confidently identify Critical Process Parameters (CPPs)
- EasyViewer: A probe-based imaging tool with image analysis captures high-resolution images and calculate crystal, particle and droplet size distributions as they naturally exist in process
- ParticleTrack: Statistically, highly robust particle mechanism finger printing through particle size and count expedites successful scale-up from lab to fully ATEX rate plant scale
- ReactRaman: In-situ Raman spectroscopy provides molecular and structural information to help scientists understand complex polymorphic landscapes and select process parameter to always achieve the desired crystal form
- ReactIR: Real-time FTIR spectroscopy provides key information for concentration and supersaturation levels, metastable zone width, desupersaturation kinetics and crystallization endpoint so that crystallization processes can run repeatedly to a desired target endpoint everytime
- iC Software: Enables interoperability between all PAT tools so that all probes and reactors can communicate with each other and all analytical information (size, form, supersaturation, etc.) becomes a process control parameter
Automated Reactors
Precision Control of Critical Process Parameters
Process parameters like temperature, stirring and dosing rate have a direct impact on the product and process quality of particle systems. EasyMax, OptiMax, RC1 and RX-10 ensure precise control and recording of process conditions for true particle engineering.
- All process data is recorded whether you pre-program recipe steps like temperature or dosing ramps, or make adjustments during the process
- Information from Process Analytical Technology (PAT) tools, such as ReactIR, ReactRaman, EasyViewer and/or ParticleTrack, can be overlaid on process parameter trends for quick and easy understanding of particle mechanisms
- Precise execution allows chemists and engineers to run unattended processes with confidence
Particle Characterization
Measure Particles as they Naturally Exist in Process
Particle size, shape and concentration are critical pieces of information at every stage or scale during a crystallization process and hence make Critical Quality Attributes (CQA). Particle size analyzers quickly visualize and quantify particles and critical particle mechanisms for successful crystallization process development.
- Particle properties and particle mechanisms are recorded for review and analysis at all times, even if scientists cannot be in the lab
- Interoperability between Automated Reactors and ParticleTrack and EasyViewer enable scientists to set up Feedback Control Loops for particle size or count controlled cooling, or antisolvent dosing rates to minimize undesired particle populations, such as excessive fines
- The intuitive "Start Experiment Wizard" makes it easy for every scientists to quickly collect high-quality particle data
Molecular and Chemical Structure Analysis
Achieve the Target Endpoint – Every Time
Solution concentration, supersaturation and crystal form (polymorph) are often connected and largely determine the success of crystallization process development. ReactIR and ReactRaman systematically analyze solution and particle composition to achieve the desired process endpoint every time.
- Solution composition and particle unit cell configuration are systematically analyzed, recorded and visualized in real-time
- The combination of spectroscopic PAT tools, like ReactIR and ReactRaman, with Automated Reactors enable scientists to make supersaturation a control parameter; crystallization processes run at constant supersaturation levels to achieve more uniform particle size distributions
- Integrated One Click Analytics automatically finds and displays meaningful and easy-to-understand chemical and structural information for quick and evidence-based decision making
How to Design a Crystallization Process
The design of a crystallization process that will deliver pure crystals with an optimized yield and size, involves considering a number of important elements:
- Choose an appropriate solvent
- Screen for stability and unwanted polymorphs
- Determine growth and nucleation kinetics
- Define a seeding strategy
- Optimize cooling and anti-solvent profiles
- Understand the impact of mixing and scale
Applications
Application Guide to Crystallization Development and Scale-up
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
Crystallization and Precipitation Engineering Case Studies
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...
Citations
Crystallization and precipitation citation list and publications
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...
Presented by Prof. Zoltan Nagy of Purdue University, this talk provides an overview of recent advances of applications for in situ imaging and image a...
This presentation describes a strategy employed to design and develop robust, scalable crystallization processes that avoids Liquid-Liquid Phase Separ...
This presentation details how using data from in situ particle vision and measurement tools can be used to determine particle size and shape trends re...
During this webinar, two case studies are presented to illustrate the application of tools and strategies that were utilized to understand and manage...
This presentation details the development, understanding, and scale-up of an aseptic crystallization, which utilizes a novel wet milling during anti-s...
This presentation describes the case of crystals of an Active Pharmaceutical Ingredient (API) with high propensity to float in their mother liquors, d...
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