Crystal Engineering of Pharmaceutical Cocrystals: Emerging Strategies for Drug Solubility, Stability and Bioavailability Enhancement

Abstract

Pharmaceutical cocrystals have emerged as a promising crystal engineering strategy for improving the physicochemical and biopharmaceutical limitations of active pharmaceutical ingredients (APIs). In recent years, cocrystallization has gained significant attention in pharmaceutical research due to its ability to enhance solubility, dissolution rate, stability, permeability, bioavailability, and mechanical properties without altering the pharmacological activity of the drug molecule. This review comprehensively discusses the fundamental principles, classification, and preparation techniques of pharmaceutical cocrystals, including solvent evaporation, grinding, slurry conversion, hot melt extrusion, and supercritical fluid methods. The article further highlights the role of intermolecular interactions such as hydrogen bonding, π–π stacking, and van der Waals forces in cocrystal formation and stabilization. Various characterization techniques including Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), and nuclear magnetic resonance (NMR) are also summarized. Special emphasis is placed on the recent advancements of pharmaceutical cocrystals in improving therapeutic performance in oncology, antimicrobial therapy, and poorly water-soluble drugs. Additionally, regulatory perspectives, patent opportunities, industrial challenges, and future prospects associated with cocrystal-based formulations are critically analyzed. Overall, pharmaceutical cocrystals represent a versatile and innovative platform for modern drug development and offer substantial potential for enhancing drug efficacy, patient compliance, and formulation performance in advanced pharmaceutical applications.