Unveiling the conformational landscape of tizanidine and its effects on selective nucleation: Enabling controlled manipulation of polymorphs and solvates

Abstract

The intricate relationship between conformational diversity and polymorphic nucleation is evident, while the underlying mechanisms remain unclear. In this work, tizanidine (TZND) was selected as the model compound to investigate its selective nucleation behavior and the association between conformations and polymorphs. Crystallization experiments were conducted using TZND in seven solvents, resulting in two polymorphs and four solvates, five of which are reported for the first time. Quantum chemical calculations were employed to explore the conformational landscape of TZND. Furthermore, 2D nuclear Overhauser effect spectroscopy and molecular dynamics were utilized to analyze the predominant conformation and its evolution in different solvents with varying concentrations. The results revealed that the dominant conformation of TZND could nucleate directly in methanol and acetone, while a conformational transition occurred during nucleation in acetonitrile and dichloromethane. Additionally, proton transfer in DMSO, chloroform, and DMF resulted in the emergence of new conformational forms. Moreover, crystallographic analysis, spectroscopic studies and quantum chemical calculations were adopted to investigate the molecular mechanisms governing selective nucleation and the formation of polymorphs or solvates. The results indicated that the free energy and solute–solvent interaction energy at specific sites influence the dominant conformation and its evolution in the solution. Finally, the nucleation mechanisms of different polymorphs and solvates were proposed and discussed, illustrating an efficient and environmentally friendly regulation method through solvent switching.