Interplay between Thermodynamics and Kinetics on Polymorphic Behavior of Vortioxetine Hydrobromide in Reactive Crystallization

Reactive crystallization (RC) of vortioxetine hydrobromide (VH) in four solvents was investigated in this work. In solvents with strong hydrogen bond acceptor capacity, the thermodynamics stable form B is preferred and the conversion rate from form A to form B increases. Meanwhile, supersaturation (S) is also an important factor affecting the polymorphic behavior. When supersaturation is high, the metastable form A is preferred, while the conversion rate also increases. Solubility data and nucleation rate were adopted to explain thermodynamic and kinetic reasons for solvent and supersaturation effects here. In addition, RC process in the four solvents at 313.15 K (SB ≈ 5.60) was detected by online attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy and offline power X-ray diffraction (PXRD). Results show that the effect of reaction kinetics on polymorph formation of VH can be ignored and nucleation and growth of form B is the controlling step of subsequent suspension polymorphic conversion process.