Cocrystallization of Ezetimibe with Organic Acids at Different Stoichiometry to Improve Physicochemical Properties and Bioavailability

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.