Quality by Statistical Control in Crystallization—Assessment of Mixing Conditions and Probability of Obtaining the Desired Particle Size

Abstract

Reactor hydrodynamics can play a significant role in antisolvent crystallizations. In this work, the impact of suspension height/clearance ratio (H/C) and power per volume (PV) on the particle size distribution (PSD) parameters Dv10, Dv50, and Dv90 of an active pharmaceutical ingredient (API) were evaluated. The API solution was added near the liquid surface of the antisolvent with a buret, at a rate of approximately 5 mL/min, between the impeller and the reactor’s wall. Statistical models were developed, and it was found that PSD parameters seem to be influenced by the H/C and PV. A relationship between the PSD parameters and the nucleation rate was also witnessed. Furthermore, different mathematical methodologies (indicator function and Monte Carlo simulations) were used to obtain a design space comprising the probability of success of having PSD parameters within specification. An operating region comprising the probability of success was estimated, which can aid in minimizing the risk of failure in antisolvent crystallization processes and consequently help reduce the financial losses caused by out-of-specification batches.

Membrane-Assisted Antisolvent Crystallization: Interfacial Mass-Transfer Simulation and Multistage Process Control

“…Antisolvent crystallization is an essential separation and purification technology in the manufacturing of fine chemicals , and pharmaceutical crystals. − By avoiding high-temperature operations, antisolvent crystallization is suitable for heat-sensitive materials with low energy consumption. − Also, the final product can be easily regulated by adjusting the operating parameters − and solution/antisolvent system. , While the traditional approach of antisolvent crystallization usually involves batch droplets and mixing of the antisolvent, this operation commonly induces a local high supersaturation degree and explosive nucleation, which easily result in broad crystal size distribution and undesired particle morphology. − The mixing rate and supersaturation distribution cannot meet the stable nucleation requirement of the scale-up operation . Thus, the accurate mass transfer and supersaturation control at the antisolvent–solvent mixing interface are the eternal concerns to hinder the exceeding local supersaturated concentration and explosive nucleation. − …”