Seeding is used in crystallization processes to control supersaturation and hence the particle size distribution. Although most systems will nucleate spontaneously, seeding is generally a good practice. Seeding provides positive control of the crystallization process, improving process robustness especially when scaling up.

During crystallization studies of a pharmaceutical compound, we found significant morphological differences between material crystallized from seeded and unseeded processes. Crystals from seeded batches formed “rosette” structures (agglomerated with flake-like building blocks), while those from unseeded batches appeared to be primary particles (non-agglomerated) with significantly less surface area. The “rosette” crystals broke up readily in an agitated filter-dryer leadings to poor filtration. The cake heel consisted mostly of the fine, broken pieces of the rosette. Additional indication of the fragility of the rosette crystals came from dry powder particle size data collected at different dispersive pressures.

The solubility diagram and metastable zone width (MSZW) were established for this compound as part of a process robustness study. The final particle size was found to be relatively insensitive to variations in initial concentration and solvent composition at the point of seeding. Morphological differences and product particle size were determined mainly by the amount and size of the seed crystals. Large quantities of small seed crystals created small rosettes, while small quantities of large seed crystals produced large primary crystals. Our discussion is focused on the effectiveness of seeding, and on strategies that can be used to control the product surface area.