Unlocking the Potential of Co-Crystallization Technology: A Novel Strategy for Overcoming the Druggability Challenges of Natural Active Compounds

China is endowed with abundant natural product resources and a long history of clinical use experience, where active compounds are the marrow of these resources, known for their sheer quantity and high safety profiles in medical therapies. However, the applicability of these compounds in drug discovery is often limited by poor water solubility, low bioavailability, stability issues, and insufficient mechanical properties. Co-crystallization technology has proven to be capable of offering products with excellent pharmaceutical properties as well as creating and expanding intellectual property due to the diversity of ligands. This review systematically describes the progress in the development and application of cocrystallization to natural active compounds and explores its potential and limitations in improving the druggable properties of these compounds primarily from four perspectives: bioavailability, stability, mechanical properties, and taste masking. Furthermore, the relationship between the crystal structure of cocrystals and their resultant properties is analyzed in detail, along with the underlying mechanisms behind these changes. A comprehensive understanding of cocrystal engineering is believed to pave the way for the realization of more bioactive natural compounds into new drugs.