Mechanism study on stability enhancement of adefovir dipivoxil by cocrystallization: Degradation kinetics and structure-stability correlation

The purpose of this study is to determine the mechanism by which cocrystallization can enhance the stability of adefovir dipivoxil (AD), a diester prodrug of adefovir with known chemical stability problem. Three multi-component crystals of AD with biologically safe coformers, including gallic acid cocrystal hydrate (1:1:1), salicylate salt (1:1), and maleate salt (1:1) were prepared and characterized by thermal analysis, infrared spectroscopy, powder and single crystal X-ray diffraction. DVS measurements and stability tests were applied to evaluate the stability. The new crystalline phases exhibit improved stability compared to pure drug in the order AD gallic acid cocrystal > AD maleate > AD salicylate > AD form I. Degradation kinetics and structure-stability correlation studies demonstrate that the stability enhancement mechanism by cocrystallization involves (1) inhibition of hydrolysis of AD by replacement of drug–drug homosynthons by stronger drug–coformer heterosynthons at adenine fragments; (2) suppression of dimerization of AD by separation of adenine fragments by inserting coformers in crystal lattices; (3) further reducing rates of hydrolysis by forming hydrogen bonds with hydrate water at phosphoryl fragments. This study has important implications for use of cocrystallization approach to some easily degradable drugs in pharmaceutical.

Adefovir dipivoxil (AD) was successfully cocrystallized with gallic acid, salicylic acid, and maleic acid and exhibits improved chemical stability in the order AD gallic acid cocrystal > AD maleate > AD salicylate > AD form I. Degradation kinetics and structure-stability correlation studies reveal the stability enhancement mechanism.Figure optionsDownload high-quality image (84 K)Download as PowerPoint slide