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Numerous studies on crystallization and especially on bio- and biomimetic mineralization have shown that the classical view on nucleation and growth of crystals may be too simplified. Non-classical concepts that include the formation of stable pre-nucleation clusters and amorphous intermediates appear to be key to a novel understanding of mineralization processes. The insights may be used in diverse fields ranging from materials chemistry and pharmacy to construction materials and medicine.


Crystallization is truly omnipresent. Many of the solid compounds that we handle everyday —at home or professionally as chemists— are crystalline, and re-crystallization is a standard laboratory procedure used for purification. There is a vast amount of industrial products and applications that are based on crystals, ranging from pigments, fillers and pharmaceuticals to construction materials like concrete and cement. Crystallization is also central to molecular biology, since structure determination of proteins in many cases relies on protein crystals. But there are unwanted aspects of crystallization as well, such as fouling and incrustration of industrial water circuits.

When it comes to the development of novel and advanced materials, finding inspiration in nature has proven to be a highly promising approach. For example, the perfomance of biologically formed crystalline minerals, so-called biominerals like bone, teeth or nacre, remains unmatched by man-made materials (1). In the biogenic examples, structure is elegantly matched to function, showing that organisms exhibit a high degree of control over crystallization.


Today, the mechanisms that underlie in vivo and in vitro crystallization control are not understood in detail. In order to mimic the designs that evolved in biominerals, or for the development of novel bottom-up approaches to advanced materials, though, a fundamental understanding of crystallization processes is required. Moreover, insight into the fundamentals of nucleation may help to inhibit unwanted crystallization in industrial heating and cooling circuits, in laundry machines or dishwashers. The common perception is that control over crystallization is achieved in vivo by a delicate interplay of bio(macro)molecules and organic matrices with the nascent minerals. It may be realized in a more simplified manner in vitro with the help of synthetic additives. Organic-inorganic interactions modulate crystallization and appear to be important throughout the different stages of crystallization (2, 3). It is evident that in crystallization control, the onset of precipitation from solution is the most fundamental step: nucleation.


Throughout crystallization processes, besides interactions of nucleating and growing minerals with biological or synthetic additives, also purely physical-chemical aspects are important. Observations in numerous crystallization and bio- and biomimetic mineralization studies strongly suggest that the classical physical-chemical view on nucleation (4) and crystallization, which is presented in textbooks, is too simplified. Recently, the concept of non-classical crystallization (5) has been expanded by the concept of prenucleation clusters (6). It has been shown that stable prenucleation clusters and not ions are the relevant species during nucleation of the biominerals calcium carbonate (mussel shells, exoskeletons of algae and chorals), calcium phosphate (bone, teeth) and calcium oxalate (kidney stones). These findings challenge classical nucleation theory, and may be key to answer topical questions like polymorph selection; it appears that distinct structures are encoded in prenucleation clusters in solution before precipitation occurs, giving rise to amorphous polymorphism (polyamorphism) in CaCO3 (7, 8).

What is known about prenucleation clusters?

Prenucleation clusters are chemical species (solutes) that form spontaneously in solution prior to the nucleation of a second phase (9). Their average size is around 2 nm in diameter, which may relate to approximately tens of ions in single clusters (6); however, a precise cluster size distribution remains yet unknown. Simulations of calcium carbonate solutions in combination with re-evaluations of experimental data suggest that prenucleation clusters are in fact highly dynamic, liquid-like, ionic polymers (10) (DOLLOP = dynamically ordered liquid-like oxyanion polymer). This structural form is the key to the thermodynamic stability of the clusters through strong hydration and a distinct entropic contribution associated to the high degree of conformational freedom (10). The transition of the polymeric calcium carbonate towards bulk-like structural forms requires a nucleation event, and it has been suggested that this event proceeds via liquid-liquid separation (11). The concept of polymeric calcium carbonates with a liquid-like character in solution provides a unifying framework that can explain the initial precipitation of liquid-like intermediate forms of calcium carbonate like the polymer induced liquid precursors (PILIP) (12).

Hence, prenucleation clusters can be conceived of as molecular precursors to a nanoscopic liquid-liquid separation, which is a mechanism of phase separation that may apply for the most common biominerals, including calcium carbonate and phosphate, iron (oxyhydr)oxides, silica, as well as amino acids (13).

The prenucleation cluster pathway (copyright: https://link.springer.com/referenceworkentry/10.1007%2F978-94-007-6178-0_380-2)

Our Research

The aim of our reserach is to understand the mechanisms of nucleation and crystallization. We believe that careful physical chemical analyses of nucleation and crystallization pathways are the clue to gain novel insights into the process that underlie crystallization as well as bio- and biomimetic mineralization. We utilize diverse techniques, from potential measurements and titration to electron microscopy, analytical ultracentrifugation and NMR. We aim to implement our insights into improved synthesis strategies of novel materials.

We perform fundamental research that is focused on, but not limited to:

  • Thermodynamics of prenucleation clusters and nucleation intermediates
  • Kinetics of nucleation and precipitation taking stable clusters into account
  • Structure of prenucleation clusters and intermediates
  • Proto-crystalline structures in amorphous intermediates and their crystallization (polyamorphism)
  • Mechanisms of additive-controlled nucleation and crystallization; towards target-oriented syntheses of advanced functional materials
  • Role of prenucleation clusters in living systems (biomineralization)
  • Principles of scale inhibition
  • Implementation of the prenucleation-cluster concept into nucleation theory
  • Application of non-classical nucleation & non-classical crystallization concepts to novel bottom-up approaches to advanced functional materials


1. H. Lowenstam, S. Weiner, On Biomineralization (Oxford University Press, New York, 1989)

2. D. Gebauer, A. Verch, H. G. Börner, H. Cölfen, Cryst. Growth Des. 9, 2398-2403 (2009)

3. D. Gebauer, H. Cölfen, A. Verch, M. Antonietti, Adv. Mater. 21, 435-439 (2009)

4. R. Becker, W. Döring, Ann. Phys. 24, 719-752 (1935)

5. H. Cölfen, M. Antonietti, Mesocrystals and Nonclassical Crystallization (John Wiley & Sons, Ltd., Chichester, 2008)

6. D. Gebauer, A. Völkel, H. Cölfen, Science 322, 1819-1822 (2008)

7. D. Gebauer et al., Angew. Chem. Int. Ed. 49, 8889-8891 (2010)

8. J. H. E. C. Cartwright, A. G. Checa, J. D. Gale, D. Gebauer, C. I. Sainz-Díaz, Angew. Chem. Int. Ed. 51, 11960 (2012)

9. D. Gebauer, H. Cölfen, Nano Today 6, 564-584 (2011)

10. R. Demichelis, P. Raiteri, J. D. Gale, D. Quigley, D. Gebauer, Nat. Commun. 2, 590 (2011)

11. A. F. Wallace et al., Science 341, 885 (2013)

12. L. B. Gower, Chem. Rev. 108, 4551 (2008)

13. D. Gebauer, M. Kellermeier, J. D. Gale, L. Bergström, H. Cölfen, Chem. Soc. Rev. 43, 2348 (2014)