Find out how to cope with impurities by using the Crystal16 and Crystalline instruments

  • Article
  • January 17, 2022

In 2021, Technobis Crystallization Systems products played an important role in research investigating the effect that impurities and additives have on crystal habit, polymorphism and process efficiency. The presence of impurities can have a significant effect on a crystallization process and end product quality. However, impurities can come in two forms, as either unwanted such as reaction byproducts, unreacted starting material or from human error. They can also be introduced as additives designed to controlling a crystallization process. Find out here more about how the Crystal16 and Crystalline instruments can help you to cope with impurities.

Within industrial crystallization, the purity of final products is of paramount importance. Failure to maintain high purity end product can result in reworking batches in order to meet regulation, wasting time and resources. Through a greater understanding of the effects impurities have on process and final products, it could be possible to design strategies that would mitigate the impacts impurities have, as well as design additives that give the desired crystal and process properties.

Urea is a common compound that is used in a wide range of industries, such as the manufacture of fertilizer, explosives and medicine. However, a common impurity that can alter the crystallization is biuret, a degradation impurity. Rizvi 1 et al studied this effect in more detail using the Crystal16 instrument by conducting polythermal crystallizations. They found that a 1% presence of the biuret impurity resulted in a larger metastable zone and hindered crystal growth. Work by Joop ter Horst 2 investigated the effect structural impurities have on process and product quality, using paracetamol as a model compound. Using both the Crystal16 and the Crystalline instruments for solubility and crystallization studies, they were able to demonstrate that the presence of metacetamol acts as a template to give the metastable Form 2 and acetanilide alters the morphology being incorporated into the crystal lattice. They were able to demonstrate that re-slurrying of the crystallization product improved the properties acting as an impurity purge. The purging of impurities during multiple synthesis step of a potential drug candidate was investigated by Santandrea 3 et al. Using the Crystal16 for solubility measurements, they were able optimize the synthesis process and design strategies for the control of impurities including the use of several salt formations at various process steps. The optimized process has since been demonstrated at a > 100 Kg scale with a higher yield.

Moreover, the use of additives in crystallization is a growing area of interest, as they offer a way of modifying crystal properties that might not be possible otherwise. An example of this is demonstrated by Eral 4 et al who use surfactants to selectively control the polymorphism of D-mannitol. Using the Crystalline instrument, seeded cooling crystallizations were conducted demonstrating that different mesoscopic phases of sodium dodecyl sulphate templated different β, α, and δ polymorphs of D-mannitol. A workflow describing how additives could be tailored and screened to optimizes a crystallization process was presented by Roberts 5 et al. Though investigating crystallographic data about the model compound α-para-aminobenzoic acid they identified synthons that were involved in the crystal bonding. From this, a series of additives were designed with these synthons and were screened using the Crystal16 instrument to determine the effect they have on the nucleation behaviour. It was found that the nucleation time was changed from instantaneous with no additives to progressive when additives were added. Subsequent calculations and modelling showed that the greater nucleation modulation was seen in additives with an increase in the effective interfacial tension, opening the possibility for further nucleation behaviour modification.


1. Aatika K. Rizvi, Kevin J. Roberts, and Toshiko Izumi, The Influence of Supersaturation and the Presence of Biuret on the Nucleation, Growth and Morphology of Urea Crystallised from Ethanolic Solutions, Isr. J. Chem. 2021, 61, 1 – 17,

2. Stephanie J. Urwin , Stephanie Yerdelen , Ian Houson  and Joop H. ter Horst, Impact of Impurities on Crystallization and Product Quality: A Case Study with Paracetamol, Crystals 2021, 11(11), 1344;

3. Ernesto Santandrea, Christine Waldraff, Gilles Gerber, Maël Moreau, and Pascal Beney, Development of the Late-Phase Manufacturing Process of ZPL389: Control of Process Impurities by Enhanced Process Knowledge, Org. Process Res. Dev. 2021, 25, 5, 1190–1205,

4. Frederico Marques Penha, Ashwin Gopalan, Jochem Christoffel Meijlink, Fatma Ibis, and Huseyin Burak Eral, Selective Crystallization of d-Mannitol Polymorphs Using Surfactant Self-Assembly, Cryst. Growth Des. 2021, 21, 7, 3928–3935,

5. Peter L. Kaskiewicz, Ian Rosbottom, Robert B. Hammond, Nicholas J. Warren, Colin Morton, Peter J. Dowding, Neil George, and Kevin J. Roberts, Understanding and Designing Tailor-Made Additives for Controlling Nucleation: Case Study of p-Aminobenzoic Acid Crystallizing from Ethanolic Solutions, Cryst. Growth Des. 2021, 21, 4, 1946–1958,