Amorphous aggregates with a very wide size distribution play a central role in crystal nucleation

There is mounting evidence that crystal nucleation from supersaturated solution involves the formation and reorganization of prenucleation clusters, contradicting classical nucleation theory. Here, a range of amino acids and peptides is investigated using light scattering, mass spectrometry, and in situ terahertz Raman spectroscopy, showing that the presence of amorphous aggregates is a general phenomenon in supersaturated solutions. Significantly, these aggregates are found on a vast range of length scales from dimers to 30-mers to the nanometer and even micrometer scale, suggesting a continuous distribution throughout this range. Larger amorphous aggregates are sites of spontaneous crystal nucleation and act as intermediates for laser-induced crystal nucleation. These results are shown to be consistent with a nonclassical nucleation model in which barrierless (homogeneous) nucleation of amorphous aggregates is followed by the nucleation of crystals from solute-enriched aggregates. This provides a novel perspective on crystal nucleation.