Research progress on additives regulating drug crystal morphology

Crystal morphology significantly affects downstream processing and the solubility of pharmaceutical products. Therefore, controlling crystal morphology is of great importance in the pharmaceutical industry. In recent years, the use of additives to regulate drug crystal morphology has received widespread attention. Specific additives can influence crystal morphology by modulating crystal growth. Still, the underlying mechanisms through which additives control crystal morphology remain incompletely understood, and the application of additives for this purpose is still in the trial-and-error phase. This review discusses the mechanism of two types of additives-polymer (mainly pharmaceutical excipients) and small molecule (including surfactants and tailor-made additives)-on drug crystal morphology. These mechanisms include interfering with the attachment of solutes at the crystal-solution interface, altering the surface energy of crystals, and modifying solute-solvent interactions. By regulating the crystal growth process, these additives can effectively alter crystal morphology. This review also summarizes the application of these additives in solution crystallization, aiming to provide theoretical guidance for the use of additives in the modification of drug crystal morphology during crystallization processes.