Targeting Particle Size Specification in Pharmaceutical Crystallization: A Review on Recent Process Design and Development Strategies and Particle Size Measurements

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.

Microfluidic Crystallization for Screening of Spherical Particles of Pyraclostrobin

“…We investigated the interplay between the stirring rate and the crystallization process of pyraclostrobin. It is commonly believed that the stirring rate has a significant effect on crystal morphology . As clearly illustrated in Figure , we observed two different morphologies of spherical particles, namely, spherulites and spherical agglomerates.…”

“…It is commonly believed that the stirring rate has a significant effect on crystal morphology. 59 As clearly illustrated in Figure 8, we observed two different morphologies of spherical particles, namely, spherulites and spherical agglomerates. This phenomenon can be rationalized by the impact of elevated stirring rates, which facilitates the fragmentation of oil droplets into smaller dimensions, leading to an increase in the number of droplets and therefore promoting the emergence of additional nucleation sites.…”

Breakage-Facilitated Mixed-Suspension-Mixed-Product-Removal (MSMPR) Crystallization of Pharmaceutical Compounds

“…Continuous manufacturing has drawn increasing attention from both drug manufacturers and regulatory agencies for its advantages such as consistent product quality, high productivity, and small footprint. − However, the delivery of products meeting pharmaceutical quality specifications in highly sufficient manners can be very challenging in continuous processes. One of such challenges is crystallization, a separation process based on solubilized state to solid transition to produce crystals of desired physical, chemical, and biopharmaceutical properties. − In continuous mode, the targeted attributes at steady state are controlled through fixed operating conditions, which may lead to trade-off between the product attributes and process performance. − A successful development of continuous crystallization requires additional understanding toward crystallization kinetics to ensure a robust process operation and overall economical optimality. , …”