A Review of Stoichiometrically Diverse Pharmaceutical Cocrystals: Preparation, Characterization, and Physicochemical Properties

Abstract Pharmaceutical cocrystals are constructed via non-covalent interactions between active pharmaceutical ingredients and coformers, enabling the improvement of solubility, stability, bioavailability, and processing suitability while preserving the structural integrity of drug molecules. Previous research on pharmaceutical cocrystals has predominantly focused on 1:1 stoichiometric systems; however, recent findings have revealed that stoichiometrically diverse cocrystals exhibit more diverse structural morphologies and greater flexibility in performance modulation. This review comprehensively summarizes the latest advances in synthesis strategies, characterization techniques, physicochemical properties, and application explorations of pharmaceutical cocrystals with different stoichiometric ratios. Stoichiometrically diverse cocrystals can be prepared by methods such as solution crystallization, mechanochemical synthesis, and vapor-induced phase transformation. Their crystal architecture, molecular arrangement, and physicochemical properties are strongly correlated with stoichiometry. Such cocrystals with stoichiometry departing from 1:1 offer significant advantages in solubility regulation, dissolution profile optimization, and bioactivity modulation, and some systems even enable reversible dynamic switching of stoichiometry. Furthermore, this review analyzes current challenges in the prediction of formation rules, stabilization of metastable phases, and scale-up production of stoichiometrically diverse pharmaceutical cocrystals, and outlines future development pathways, including machine learning-assisted design, multicomponent drug−drug cocrystals, and smart responsive cocrystals.