Cocrystallization of Ezetimibe with Organic Acids: Stoichiometric Optimization for Improved Solubility and...

Area of Science:

• Pharmaceutical Science
• Drug Delivery
• Materials Science

Background:

• Ezetimibe, a hypolipidemic agent, exhibits poor aqueous solubility (BCS Class II), limiting its therapeutic efficacy.
• Pharmaceutical cocrystallization is a strategy to enhance drug properties while maintaining molecular integrity.
• Optimizing physicochemical properties and oral bioavailability of ezetimibe is crucial for improved drug delivery.

Purpose of the Study:

• To systematically evaluate the cocrystallization of ezetimibe with organic acids (benzoic, tartaric, succinic).
• To optimize physicochemical properties and oral bioavailability through varying stoichiometric ratios and preparation methods.
• To investigate the potential of rational cocrystal design for overcoming solubility barriers in hydrophobic therapeutics.

Main Methods:

• Cocrystal preparation using solvent evaporation (SEV) and solvent/anti-solvent (SAS) methods.
• Structural characterization via FTIR, DSC, PXRD, and SCXRD.
• Assessment of physicochemical performance including solubility, dissolution, and in vivo pharmacokinetics in rats.

Main Results:

• Benzoic acid cocrystals (1:2 ratio, SEV) demonstrated significant O-H⋯N hydrogen bonding and novel crystalline phases.
• Optimized ezetimibe/benzoic acid cocrystals exhibited a 64-fold increase in solubility and 2x faster dissolution.
• Pharmacokinetic studies showed a 3x higher Cmax and 4x greater AUC for the optimized cocrystals compared to pure ezetimibe.

Conclusions:

• Stoichiometry and preparation method critically influence cocrystal performance.
• Ezetimibe/benzoic acid cocrystals (1:2, SEV) offer superior solubility, dissolution, and bioavailability, addressing ezetimibe's formulation challenges.
• Rational cocrystal design is a viable approach to enhance the oral bioavailability of hydrophobic drugs.