Pharmaceutical Cocrystals: A Review on Design, Preparation, Application and Challenges

Pharmaceutical cocrystals have emerged as a transformative approach in drug development, enhancing the physicochemical properties of active pharmaceutical ingredients (APIs) such as solubility, bioavailability, stability, and dissolution rate without altering their pharmacological characteristics. Defined as multicomponent crystalline solids composed of two or more neutral molecules in a stoichiometric ratio, cocrystals are formed through non-ionic interactions like hydrogen bonding and π-π stacking. This review explores the evolution, design, preparation, and applications of pharmaceutical cocrystals, highlighting their ability to improve drug performance, enable controlled release, and offer intellectual property opportunities. Various preparation methods, including solvent-based (e.g., solvent evaporation, cooling crystallization) and solid-based (e.g., grinding, liquid-assisted grinding) techniques, are discussed alongside design approaches like hydrogen bonding propensity and the supramolecular synthonic approach. The review also addresses challenges such as molecular compatibility, thermodynamic barriers, and regulatory considerations. With regulatory acceptance from agencies like the FDA and ongoing advancements in crystal engineering, pharmaceutical cocrystals hold significant promise for optimizing drug delivery and formulation, necessitating further research to fully realize their potential in commercial applications.