Utilization of Quality by Design, Kinetic Modeling, and Computational Fluid Dynamics for Process Optimization and Scale-Up

Under acidic conditions, 16-α hydroxy prednisolone (16-AHP) reacts with n-butyraldehyde through acetalization and epimer conversion to produce budesonide. To further understand the conversion of epimers, a kinetic study was conducted. Epimer A is converted to epimer B depending on the temperature and time following acetalization. Failure mode and effect analysis (FMEA), followed by the design of experiments, was used to identify and optimize the crucial process parameters. After purification and crystallization, the finished product was obtained. Maintaining the necessary epimer ratio and regulating the contaminants within the specifications were the biggest hurdles to the process. Even though all critical process parameters (CPPs) were under control and the mixing or velocity profile was accurately matched by computational fluid dynamics (CFD) simulation, it was a surprise when a few oxidation impurities formed at substantially higher levels during scale-up. To find the underlying causes, a thorough investigation was made. It was discovered that certain oxidation impurities were created during crystallization in the presence of dissolved oxygen, a metal reactor vessel, the temperature of the solution, and traces of hydrobromic acid (HBr). The process was successfully scaled-up with the desired quality after reoptimization and the establishment of an appropriate control approach for the CPPs.