Real Time PAT Monitoring of the Solvent-Mediated Transformation of Ciclesonide Acetone Solvate into Methanol or Cyclohexane Solvate

Due to structural differences, pseudopolymorphs of a given drug substance exhibit different physicochemical properties, which impacts drug dissolution, bioavailability, and efficacy. Therefore polymorphic transformation has been a vital aspect of pharmaceutical crystallization process engineering. In this work, three solvates of ciclesonide were characterized by Differential Scanning Calorimetry （DSC）, Thermogravimetry (TG), and X-ray Powder Diffraction (XRPD) analysis. The driving force of solvates transformation process was investigated via measuring solubility of ciclesonide solvates in different mixed solvent systems. To follow the crystallization process kinetics and understand the phase transformation mechanisms, , several Process Analytical Technology (PAT) techniques such as Fourier Transform Infrared Spectroscopy (FTIR), Raman Spectrum (RAMAN), Particle Video Microscope (PVM) and Focused Beam Reflectance Measurement (FBRM) were employed to monitor the phase transformation from acetone solvate into methanol or cyclohexane solvate in real time. In addition, the effects of temperature, solvent composition, and stirring rate on phase transformation process were discussed. Furthermore, it was demonstrated that real time PAT process monitoring can help to realize better process control and achieve desired crystal product quality attributes.