In Situ Optical Spectroscopy to Investigate the Early Stage of Crystallization from Solution

Abstract The microscopic understanding of the early stage of crystallization remains a great challenge. The major difficulty in tackling this problem is the stochastic nature of crystallization, from which both experimental and theoretical approaches suffer. A traditional approach to studying crystal nucleation has been measuring the rate of nucleation and modeling the process using classical nucleation theory. Recently, there have been major breakthroughs in both experimental and theoretical approaches to advance understanding of crystal nucleation. The long-awaited moment of “seeing” the instant of crystal nucleation has been realized via microscopies such as in situ and cryo-transmission electron microscopy (TEM). Molecular dynamics (MD) simulations assisted by machine learning have been developed to access the molecular-level details of nucleation processes. Despite these advances, two major questions remain out of reach: what happens just before a crystal nucleus is formed, and when and how a certain polymorph is chosen. A technique that has been underused in probing the early stage of crystallization is optical spectroscopy. The advantages of optical spectroscopy that make it particularly suited for tackling this problem are its sensitivity to structural order and symmetry, its temporal resolution, and the relative ease of experiments and sample preparation. Thus, optical spectroscopy provides information that is complementary to the findings from microscopies and MD simulations. Collectively, we are at an exciting period in this field where we may finally understand the early stage of crystallization and rationally control polymorphism. This perspective highlights recent developments in in situ optical spectroscopy and opportunities awaiting us in the near future.