Background/Objectives: Pharmaceutical cocrystallization offers a promising strategy to enhance drug properties while preserving molecular integrity. Ezetimibe, a BCS Class II hypolipidemic agent, faces therapeutic limitations due to poor aqueous solubility. This study aimed to systematically evaluate cocrystallization of ezetimibe with organic acid (benzoic, tartaric, or succinic acid) at varying stoichiometric ratios (1:0.5–1:2) to optimize physicochemical properties and oral bioavailability. Methods: Cocrystals were prepared via solvent evaporation (SEV) and solvent/anti-solvent (SAS) methods. Structural characterization included Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder/single-crystal X-ray diffraction (PXRD/SCXRD). Physicochemical performance was assessed through saturation solubility, in vitro dissolution, and in vivo pharmacokinetics in male Sprague Dawley rats (n = 4/group). Results: Benzoic acid cocrystals (1:2 ratio, SEV) showed O−H⋯N hydrogen bonding (FTIR band shifts: 2928 → 3264 cm⁻¹) and novel crystalline phases (12.4°, 16.7°, and 24.9°). SCXRD confirmed monoclinic P2₁/n symmetry (a = 5.42 Å, b = 5.05 Å) for benzoic acid cocrystals. Ezetimibe/benzoic acid cocrystals (1:2) achieved 64-fold solubility enhancement and 2× faster dissolution vs. pure ezetimibe. Pharmacokinetics revealed 3× higher Cmax (18.38 ng/mL) and 4× greater AUC (40.36 h·ng/mL) for optimized cocrystals. Tartaric and succinic acid cocrystals showed moderate improvements, with melting points intermediate between parent compounds. Conclusions: Both stoichiometry and preparation method strongly determined cocrystal performance. Benzoic acid at a 1:2 ratio via SEV demonstrated superior solubility, dissolution, and bioavailability, addressing ezetimibe’s formulation challenges. These findings underscore the potential of rational cocrystal design to overcome solubility barriers in oral dosage development, particularly for hydrophobic therapeutics.

Pharmaceutical cocrystals represent a promising strategy to enhance drug properties while preserving molecular integrity. This study investigates cocrystallization of a poorly soluble drug with different organic acids (benzoic acid, tartaric acid, succinic acid) at various ratios using solvent evaporation and anti-solvent precipitation methods. The resulting cocrystals had a lower melting peak, with formation of O-H···N hydrogen bonds (band shifts 2928®3264 cm−¹ and C=O vibration alterations at 1726 cm−¹), and novel crystalline phases at 12.4°, 16.7°, and 24.9°. Further study revealed that cocrystals formed with benzoic acid (1:2 ratio) had a monoclinic lattice (space group P2₁/n) and achieved 64-fold solubility enhancement and 2-fold dissolution rate. The pharmacokinetic study in animals showed a 3-fold maximum plasma drug concentration and 4-fold improvement in systemic exposure (AUClast), with a delayed time to peak concentration (Tmax), confirming a sustained release. These findings demonstrate that organic acid as a coformer in appropriate stoichiometric ratio, incorporated to a poorly soluble drug using a suitable preparation method, can drastically improve the physicochemical properties and bioavailability. Amongst the evaluated coformers, benzoic acid cocrystals have a potential to overcome the solubility barrier and promote the effective oral dosage form.