Solution-MediatedPhase Transformation Processes ofAmorphous Iohexol: Mechanisms and Its Applications

Iohexol demonstrates a tendency to form particles in its amorphous state during the crystallization process. To obtain crystalline iohexol particles, the phase transformation of amorphous iohexol into a crystalline form was investigated. The dissolution behavior of iohexol in n-butanol was studied, revealing that amorphous iohexol undergoes transformation within a specific temperature range. Furthermore, the results indicated that the free energy difference facilitates this transformation, rendering it a spontaneous process. Using Focused Beam Reflectance Measurement (FBRM), it was confirmed that the transformation of iohexol follows a solution-mediated phase transformation (SMPT) mechanism that involves the dissolution of the amorphous form, followed by crystal nucleation and growth. Both offline and online analyses were conducted to ascertain that crystal nucleation is the rate-determining step in this process. The influences of the temperature, solid–liquid ratio, seed loading, stirring rate, and solvent on the SMPT process were systematically investigated. Several transformation kinetic models were employed to analyze the SMPT process of iohexol, with the chain mechanism model demonstrating the best performance. Moreover, the activation energy for the transformation was determined. This study enhances our understanding of the SMPT mechanism of iohexol and provides valuable insights for controlling the phase transformation from the amorphous to crystalline state.