Molecular conformational diversity plays a crucial role in both polymorphic nucleation and cocrystal formation during the cocrystallization process. However, the relationship between molecular conformation and cocrystallization polymorphism is not well-explored. Herein, the impact of molecular conformational landscapes on cocrystallization outcomes was investigated using tizanidine (TZND) as model compound. Four coformers, namely maleic acid (MA), salicylic acid (SA), p-hydroxybenzoic acid (pHBA), and heptanedioic acid (HDA), were employed and five salt forms were developed for the first time. Compared with TZND, all five salts showed significantly improved water solubility and dissolution rate. The cocrystallization behavior of TZND varied with each coformer: MA exhibited solvent-dependent polymorphism, while SA, pHBA, and HDA showed solvent-independent monomorphism. Crystal structure and conformational analyses revealed the conformational variation of TZND across different cocrystallization outcomes. Molecular dynamics simulations and quantum chemical calculations demonstrated that the interplay between solvent effects and coformer interactions determines the dominant conformations of TZND. The cocrystallization nucleation process was also examined, and the molecular mechanism that explains both polymorphism and monomorphism in the cocrystallization of TZND was proposed.
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