title: Mechanism study on stability enhancement of adefovir dipivoxil by cocrystallization: Degradation kinetics and structure-stability correlation.
abstract: 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.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
authors.forename: Rui-Zhen
authors.initials: RZ
authors.lastname: Lin
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Optoelectronic Materials and Technologies, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Peng-Jie
authors.initials: PJ
authors.lastname: Sun
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Optoelectronic Materials and Technologies, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Yao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China. Electronic address: chenjm37@mail.sysu.edu.cn.
authors.forename: Jia-Mei
authors.initials: JM
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China; MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Optoelectronic Materials and Technologies, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Tong-Bu
authors.initials: TB
authors.lastname: Lu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry; D003460:Crystallization / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D004355:Drug Stability; D006860:Hydrogen Bonding; D006868:Hydrolysis; D007700:Kinetics; D008298:Maleates / Q000737:chemistry; D063065:Organophosphonates / Q000737:chemistry*; D033362:Powder Diffraction / Q000379:methods; D011355:Prodrugs / Q000737:chemistry; D012459:Salicylates / Q000737:chemistry; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D008298:Maleates; D063065:Organophosphonates; D011355:Prodrugs; D012459:Salicylates; D014867:Water; C030272:maleic acid; D000225:Adenine; C106812:adefovir dipivoxil
keywords: Adefovir dipivoxil; Adefovir dipivoxil (PubChem CID: 60871); Cocrystal; Cocrystallization; Gallic acid (PubChem CID: 370); Maleic acid (PubChem CID: 444266); Salicylic acid (PubChem CID: 338); Salt; Stability; Structure–property correlation