Targeting Particle Size Specification in Pharmaceutical Crystallization: A Review on Recent Process Design and Development Strategies and Particle Size Measurements
Fan Liu, Sujay Bagi, Qinglin Su, Rajshree Chakrabarti, Rita C. Barral, Janaka C. Gamekkanda, Chuntian Hu, Salvatore Mascia
Abstract
Obtaining a particle size within the specifications for a pharmaceutical compound in an industrial crystallization can be a challenging task. The events affecting the final particle size of the product include nucleation, growth, breakage, and agglomeration, which are often convoluted. Secondary nucleation may significantly influence the particle size distribution. The strategies and techniques relevant to obtaining an in-spec particle size in crystallization are summarized and discussed from a perspective of process parameters. The effect of cooling profiles, seeding strategies, as well as mixing by agitation are reviewed, and an efficient and controlled crystallization process may be achieved using an optimized combination of these conditions. Multiple characterization methods for particle size and distribution are compared, and the discrepancies associated with the measurements are addressed.