(200ad) Ternary Phase Diagram and Population Balace Model for Solvent-Mediated Phase Transformation of Lansoprazole

The combination of in situ techniques and mathematical simulations would be helpful for better understanding the crystallization process of pharmaceuticals which exhibit polymorphic phenomenon. In this work, two new polymorphs (monohydrate and ethanol solvate) of lansoprazole, with better flowability and higher solubility, were first discovered and fully characterized. The selected area electron diffraction (SAED) was also used to analysis the structure of different polymorphs. The ternary phase diagram of lansoprazole in binary solvent mixtures of ethanol and water at 15℃, 25℃ and 35℃ was established in order to determine the relative stability of the two polymorphs. Raman spectroscopy was used to in situ monitor the unseeded solvent-mediated transformation from monohydrate to ethanol solvate of lansoprazole. During transformation, the solution concentration was measured by UV spectroscopy. Furthermore, the population balance model （PBE） of the transformation process was built to describe the dissolution, nucleation and crystal growth process during transformation. This model was used to simulate the transformation process. By combining the experimental and simulation results, the rate-controlling step, the changing profiles of the size distribution and the solid compositions of both polymorphs were investigated and discussed. The valuable information of the process parameters which are difficult to determine by experiments are also obtained.