Crystallization and Precipitation

What Is Crystallization?

Crystallization 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 unit cell, which can add further atoms or molecules to grow a macroscopic crystal. During crystallization, the individual building blocks bind together under well-defined angles to form the characteristic crystal shape with smooth surfaces and facets.

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: A process whereby solid crystals are formed from another phase, typically a liquid solution or melt.

Crystal: Solid particles in which the constituent molecules, atoms, or ions are arranged in some fixed and rigid, repeating three-dimensional pattern or lattice

Precipitation: It is a little bit difficult to define the term precipitation. For some, it is simply a very fast, perhaps uncontrolled, crystallization process. For others it is crystal formation resulting from a chemical reaction.

Common Crystallization Parameters and 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 (monitored by ParticleTrack with FBRM technology) resulting in the formation of many fine particles - directly observed in real time using ParticleView with PVM technology.

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.

Consider 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. 

Antisolvent 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. 

Guide to Effective Process Development

This white paper series covers basic and advanced strategies to optimize crystal size and shape distribution.

Case Studies in Crystallization Improvement

Crystallization literature is filled with examples of how standard crystallization tools have been used to successfully improve both crystal product and process quality. Journals, whitepapers, and webinars from academia and industry help crystallization scientists develop and share new ideas.

Technologies to Monitor, Optimize & 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

Real-Time Microscopy

For Crystals, Droplets & Particles

This 7 minute presentation describes how to view particles in real time to acquire comprehensive process understanding.