AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Crystallization

 

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Crystallization is the (natural or artificial) process by which a solid forms, where the atoms or molecules are highly organized into a structure known as a crystal. Some of the ways by which crystals form are precipitating from a solutionfreezing, or more rarely depositiondirectly from a gas. Attributes of the resulting crystal depend largely on factors such as temperature, air pressure, and in the case of liquid crystals, time of fluid evaporation.

Crystallization occurs in two major steps. The first is nucleation, the appearance of a crystalline phase from either a supercooled liquid or a supersaturated solvent. The second step is known as crystal growth, which is the increase in the size of particles and leads to a crystal state. An important feature of this step is that loose particles form layers at the crystal’s surface lodge themselves into open inconsistencies such as pores, cracks, etc.

The majority of minerals and organic molecules crystallize easily, and the resulting crystals are generally of good quality, i.e. without visible defects. However, larger biochemical particles, like proteins, are often difficult to crystallize. The ease with which molecules will crystallize strongly depends on the intensity of either atomic forces (in the case of mineral substances), intermolecular forces (organic and biochemical substances) or intramolecular forces (biochemical substances).

Crystallization is also a chemical solid–liquid separation technique, in which mass transfer of a solute from the liquid solution to a pure solid crystalline phase occurs. In chemical engineering, crystallization occurs in a crystallizer. Crystallization is therefore related to precipitation, although the result is not amorphous or disordered, but a crystal.

The design of a successful crystallization process depends on choosing process parameters that will produce crystals of the required purity and yield, that can be isolated, filtered, and dried easily. Process parameters such as cooling rate, solvent composition, and agitation rate directly impact crystallization behavior. Scientists are tasked with understanding how these parameters will influence the outcome of the crystallization process. Often, process parameters for crystallization are chosen based on previous experience, and the outcome is determined by careful analysis of offline analytical data, such as particle size analysis, XRPD, or microscopy. This approach is common, but neglects to consider that crystallization occurs through a sequence of interdependent mechanisms which all contribute to the final outcome, and are each uniquely influenced by the choice of process parameters.

Crystal nucleation and growth, phase separation, breakage, agglomeration, and polymorph transformations can occur separately, but also simultaneously, and are influenced by process parameters in unique ways. This convolution of mechanisms can mask the true role process parameters play in determining the outcome of a crystallization process, and make crystallization process design a particular challenge for scientists. In the absence of mechanistic understanding for crystallization processes, scientists must often rely on trial-and-error to adjust process parameters and optimize yield, purity, and particle size. This can be a time-consuming task and is one that rarely delivers crystals that can be isolated, filtered, and dried in a facile manner.

In this series of articles, the most common crystallization mechanisms are described alongside strategies to optimize them. The complete guide to crystallization mechanisms can be downloaded here.

What is Nucleation?

Nucleation occurs when solute molecules assemble in a supersaturated solution and reach a critical size. Primary nucleation occurs when nuclei appear from a solution directly and secondary nucleation occurs when nulcei appear in the presence of solids. Nucleation is important to understand because the number and size of nuclei formed can have a dominant influence on the final outcome of the crystallization process. High nucleation rates can lead to excessive fines and a bimodal crystal population which can make product isolation, filtration, and further processing difficult.

Considerations for Control

The nucleation rate is dependent on the molecule being crystallized but can be manipulated by considering the solvent type, controlling the supersaturation level, and evaluating the role of impurities and mixing during crystallization design. Seeding is a common strategy deployed to control primary nucleation. Effective seeding can initiate nucleation at a consistent point, and by choosing the seed size and seed loading the nucleation rate can be controlled.

Secondary nucleation often occurs during a crystallization process when supersaturation increases above a critical limit. This can occur when cooling is too fast or when anti-solvent is added quickly in an effort to increase yield. Secondary nucleation is particularly critical to understand and control because it can suddenly appear during scale-up when process parameters are controlled with less precision compared to the lab

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.

Crystallization
Process-of-Crystallization-200px.png
Concepts
Crystallization · Crystal growth
Recrystallization · Seed crystal
Protocrystalline · Single crystal
Methods and technology
Boules
Bridgman–Stockbarger technique
Crystal bar process
Czochralski process
Epitaxy
Flux method
Fractional crystallization
Fractional freezing
Hydrothermal synthesis
Kyropoulos process
Laser-heated pedestal growth
Micro-pulling-down
Shaping processes in crystal growth
Skull crucible
Verneuil process
Zone melting
Fundamentals
Nucleation · Crystal
Crystal structure · Solid

Busting a myth about mechanochemical crystallization

Adding varying amounts of liquid yields multiple crystal forms
Chart and structures showing the different phases of caffeine and anthranilic acid cocrystals that are produced when different amounts of ethanol are added.
Credit: Cryst. Growth Des.

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Chart and structures showing the different phases of caffeine and anthranilic acid cocrystals that are produced when different amounts of ethanol are added.
Mechanochemical crystallization of caffeine and anthranilic acid yields polymorph I, polymorph II, or a mixture, depending on the amount of ethanol added.
Credit: Cryst. Growth Des.

Although it may seem counterintuitive to put a compound into a ball mill to turn it into a crystalline form, the approach nonetheless works—and adding varying amounts of liquid can determine the crystal form that results, reports a team led by Bill Jones of the University of Cambridge (Cryst. Growth Des.2016, DOI: 10.1021/acs.cgd.6b00682).

Compounds of interest for materials and pharmaceuticals applications often crystallize into different forms, called polymorphs. Because polymorphs can have varying stability, solubility, and other properties, forming a specific polymorph can be critically important.

Chemists have long thought that using one particular liquid when crystallizing compounds via mechanochemical milling always yields one particular polymorph. Seeking to test that dogma, Jones and coworkers crystallized 200 mg of a 1:1 equimolar mixture of caffeine and anthranilic acid using a ball mill, adding from 10 to 100 μL of 15 different liquids.

Four liquids—acetonitrile, nitromethane, ethylene glycol, and 1,6-hexanediol—formed one polymorph each, regardless of the amount of liquid. The rest of the liquids yielded different polymorphs or mixtures, depending on liquid volume: 10 to 20 μL of ethanol formed polymorph II, for example, whereas 40 to 60 μL formed polymorph I. Additionally, 10 μL of 1-hexanol, 1-octanol, or 1-dodecanol formed polymorph III, a polymorph previously only prepared by desolvation.

Similar effects could occur for single-component crystals, the authors say. The mechanism behind the phenomenon remains to be determined; the authors suggest that it could be a result of thermodynamic stabilization of nanoparticles, different growth mechanisms of the polymorphs, or changes in the free-energy difference between polymorphs caused by milling conditions.

See also

References

  1. Jump up^ Lin, Yibin (2008). “An Extensive Study of Protein Phase Diagram Modification:Increasing Macromolecular Crystallizability by Temperature Screening”. Crystal Growth & Design8 (12): 4277. doi:10.1021/cg800698p.
  2. Jump up^ Chayen, Blow (1992). “Microbatch crystallization under oil — a new technique allowing many small-volume crystallization trials”. Journal of Crystal Growth122 (1-4): 176-180. Bibcode:1992JCrGr.122..176Cdoi:10.1016/0022-0248(92)90241-A.
  3. Jump up^ Benvenuti, Mangani (2007). “Crystallization of soluble proteins in vapor diffusion for x-ray crystallography”. Nature Protocols2: 1663. doi:10.1038/nprot.2007.198.
  4. Jump up to:a b Tavare, N. S. (1995). Industrial Crystallization. Plenum Press, New York.
  5. Jump up to:a b McCabe & Smith (2000). Unit Operations of Chemical Engineering. McGraw-Hill, New York.
  6. Jump up^ “Crystallization”www.reciprocalnet.orgArchived from the original on 2016-11-27. Retrieved 2017-01-03.
  7. Jump up^ “Submerge Circulating Crystallizers – Thermal Kinetics Engineering, PLLC”Thermal Kinetics Engineering, PLLC. Retrieved 2017-01-03.
  8. Jump up^ “Draft Tube Baffle (DTB) Crystallizer – Swenson Technology”Swenson TechnologyArchived from the original on 2016-09-25. Retrieved 2017-01-03.

Further reading

  • A. Mersmann, Crystallization Technology Handbook (2001) CRC; 2nd ed. ISBN0-8247-0528-9
  • Tine Arkenbout-de Vroome, Melt Crystallization Technology (1995) CRC ISBN1-56676-181-6
  • “Small Molecule Crystallization” (PDF) at Illinois Institute of Technology website
  • Glynn P.D. and Reardon E.J. (1990) “Solid-solution aqueous-solution equilibria: thermodynamic theory and representation”. Amer. J. Sci. 290, 164–201.
  • Geankoplis, C.J. (2003) “Transport Processes and Separation Process Principles”. 4th Ed. Prentice-Hall Inc.
  • S.J. Jancic, P.A.M. Grootscholten: “Industrial Crystallization”, Textbook, Delft University Press and Reidel Publishing Company, Delft, The Netherlands, 1984.

External links

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.

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