Review of melt crystallization in the pharmaceutical field, towards crystal engineering and continuous process development

Abstract

Crystallization is a significant unit operation in the pharmaceutical industry, and much attention has been paid to solution crystallization in the few last decades. Melt crystallization offers several attractive features including no need for a solvent, and ability to achieve specific drug properties and process merits, e.g., high purity (>99.9%) and high energy and process efficiency. It has great application potential in the pharmaceutical industry and continuous crystallization process development. In this paper, we review the advances of melt crystallization in the pharmaceutical field towards crystal engineering and continuous process development. We systematically summarize the recent developments of melt crystallization in polymorphs screening, additive effects on polymorphisms, spherical-shaped crystal, and co-crystal formation, crystal growth from the melt, and high purity drug intermediates production. We also review the challenges and strategies during the continuous melt crystallization development, including designing methods and types of continuous melt crystallizers. Finally, the critical concerns and opportunities for further research and perspectives are proposed.