Prevention of Crystal Agglomeration: Mechanisms, Factors, and Impact of Additives

Abstract

Crystal agglomeration is a common phenomenon for most chemicals and pharmaceuticals. The formation of agglomerates usually lowers product purity and generates a broad particle size distribution. This review focuses on preventing agglomeration in solution crystallization, the storage of crystals, and pharmaceutical preparation processes. The agglomeration mechanisms in these stages are analyzed and the effects of operating parameters are summarized. Furthermore, effective control means related to the crystallization environment are elaborated, including solvents, ultrasound, and additives. Special attention is paid to the influence of additives in preventing the aggregation of both suspensions and dried powders. Besides additives used in solution crystallization, the roles of anti-caking agents, stabilizers of nanosuspensions, and excipients of solid dispersions are also discussed. The additive type and properties like hydrophilicity, hydrophobicity, ionic strength, viscosity, the steric hindrance effect, and intermolecular interactions between additives and crystals can greatly affect the degree of agglomeration.