Crystallization and Precipitation

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.

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.

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.

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.

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.

1. Choose an appropriate solvent. Common considerations included how much solute can be dissolved (solubility) and how practical the solvent is to handle (safety)
2. Dissolve the product in the solvent by increasing the temperature until the last product molecule disappears. At this moment, insoluble impurities may be filtered from the hot solution
3. Reduce solubility via cooling, anti-solvent addition, evaporation or reaction. The solution will become supersaturated.
4. 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.
5. Allow the system to reach equilibrium after cooling (or another crystallization method stops).
6. Filter and dry the purified product.

Crystallization proceeds through a series of interdependent mechanisms that are each uniquely influenced by the choice of process parameters:

• Nucleation
• Growth
• Oiling Out in Crystallization
• Agglomeration
• Breakage
• Polymorphism Chemistry

These mechanisms, which are often hidden form scientists, play a dominant role in defining the outcome of a crystallization process.

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.

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.

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.

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

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 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

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

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