In this work, an ethanol solvate of argatroban was first discovered and fully characterized. The ternary phase diagrams for ethanol water argatroban at 35.0, 40.0, and 45.0 degrees C were established to determine the thermodynamic stability. In situ Raman and IR spectroscopy were applied for the analysis of the solution-mediated phase transformation of argatroban from monohydrate to ethanol solvate in ethanol water solvent. It is evident that the rate-controlling step is the growth of ethanol solvate at the initial stage and the dissolution of monohydrate at the later stage. To further understand and control the transformation process, the effects of solvent composition, temperature, and solid loading on the transformation behavior were investigated in detail. Furthermore, a kinetic model was established to get a more detailed insight into the temperature's role in this transformation process. This work can provide important instruction for optimum process control during the industrial production of argatroban.