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Nucleation, or the formation of a crystalline phase from the liquid state, is probably the most important factor in controlling crystallization. The nucleation rate is the major determining factor in the number and size of crystals formed, their polymorphic form, and the ultimate distribution of crystalline solids. Crystallization cannot occur until the phase is supersaturated or subcooled. However, attaining the supersaturated or subcooled state is not necessarily sufficient to promote crystallization because a certain energy barrier exists to formation of nuclei.A nucleus is the smallest crystal that can exist in a solution at a certain temperature.The formation of a nucleus from the liquid phase, or the nucleation process, requires the molecules to organize into a crystal lattice. There is a free-energy barrier opposing this transition, but when nucleation does occur, there is a release of energy (latent heat of fusion) as the molecules assume the lower energy state in the crystal lattice. Based on these energy considerations, a free-energy maximum exists that must be overcome for nucleation to occur (24). At this maximum free energy, there is a critical size for a stable nucleus. Above this critical size, a stable nucleus is formed that continues to grow, whereas clusters smaller than the critical size can potentially disperse into the liquid state
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