Periodic steady-state flow crystallization of a pharmaceutical drug using MSMPR operation

In this paper a novel concept of periodic mixed suspension mixed product removal (PMSMPR) crystallization process is demonstrated. An integrated array of process analytical technologies (PAT), based on attenuated total reflectance ultra violet/visible spectroscopy (ATR-UV/vis), focused beam reflectance measurement (FBRM), particle vision microscopy (PVM) and Raman spectroscopy, and in-house developed crystallization process informatics system software (CryPRINS) were used to monitor the periodic steady-state flow crystallization of paracetamol (PCM). Periodic steady-state is a new concept defined as a state of a system that maintains itself despite transitory effects caused by periodic, but controlled disruptions (state of controlled operation). This work also illustrates the concept of “state of controlled operation” (SCO) instead of “steady-state operation” as a state that can characterize continuous (periodic) operation. The PMSMPR was configured as either a single- or two-stage unit and operated for up to 11 residence times without blockage or encrustation problems. The number of PMSMPR stages, seed characteristics (size, shape and distribution), and use of recycle stream were the main variables that influenced the periodic operation, significantly affecting the extent of secondary nucleation and growth. The results further illustrate the use of PAT and information system tools together to determine when the periodic operation reaches a state of controlled operation (periodic steady-state). These tools provided a better understanding of the variables and operating procedures influencing the periodic operation.