Nucleation.

Crystallization starts with nucleation and control of nucleation is crucial for the control of the number, size, perfection, polymorphism and other characteristics of crystalline materials. This is particularly true for crystallization in solution, which is an essential part of processes in the chemical and pharmaceutical industries and a major step in physiological and pathological phenomena. There have been significant recent advances in the understanding of the mechanism of nucleation of crystals in solution. The foremost of these are the two-step mechanism of nucleation and the notion of the solution-crystal spinodal. According to the two-step mechanism, the crystalline nucleus appears inside pre-existing metastable clusters of size several hundred nanometers, which consist of dense liquid and are suspended in the solution. While initially proposed for protein crystals, the applicability of this mechanism has been demonstrated for small molecule organic materials, colloids, polymers, and biominerals. This mechanism helps to explain several long-standing puzzles of crystal nucleation in solution: nucleation rates which are many orders of magnitude lower than theoretical predictions, the significance of the dense protein liquid, and others. At high supersaturations typical of most crystallizing systems, the generation of crystal embryos occurs in the spinodal regime, where the nucleation barrier is negligible. The solution-crystal spinodal helps to understand the role of heterogeneous substrates in nucleation and the selection of crystalline polymorphs. Importantly, these ideas provide powerful tools for control of the nucleation process by varying the solution thermodynamic parameters.