Crystallization Kinetics of Tacrolimus Monohydrate in an Ethanol–Water System

Nucleation and growth during the crystallization process are crucial steps that determine the crystal structure, size, morphology, and purity. A thorough understanding of these mechanisms is essential for producing crystalline products with consistent properties. This study investigates the solubility of tacrolimus (FK506) in an ethanol–water system (1:1, v/v) and examines its crystallization kinetics using batch crystallization experiments. Initially, the solubility of FK506 was measured, and classical nucleation theory was employed to analyze the induction period to determine interfacial free energy (γ) and other nucleation parameters, including the critical nucleus radius (r*), critical free energy (∆G*), and the molecular count of the critical nucleus (i*). Crystallization kinetics under seeded conditions were also measured, and the parameters of the kinetic model were analyzed to understand the effects of process states such as temperature on the crystallization process. The results suggested that increasing temperature and supersaturation promotes nucleation. The surface entropy factor (f) indicates that the tacrolimus crystal growth mechanism is a two-dimensional nucleation growth. The growth process follows the particle size-independent growth law proposed by McCabe. The estimated kinetic parameters reveal the effects of supersaturation, temperature, and suspension density on the nucleation and growth rates.