title: Coformer selection based on degradation pathway of drugs: a case study of adefovir dipivoxil-saccharin and adefovir dipivoxil-nicotinamide cocrystals.
abstract: Adefovir dipivoxil (AD) is a bis(pivaloyloxymethyl) prodrug of adefovir with chemical stability problem. It undergoes two degradation pathways including hydrolysis and dimerization during storage. Pharmaceutical cocrystallization exhibits a promising approach to enhance aqueous solubility as well as physicochemical stability. In this study we attempted to prepare and investigate the physiochemical properties of AD cocrystals, which were formed with two coformers having different acidity and alkalinity (weakly acidic saccharin (SAC) and weakly basic nicotinamide (NCT)). The presence of different coformer molecules along with AD resulted in altered physicochemical properties. AD-SAC cocrystal showed great improvement in solubility and chemical stability, while AD-NCT did not. Several potential factors giving rise to different solid-state properties were summarized. Different coformers resulted in different cocrystal formation, packing style and hydrogen bond formation. This study could provide the coformer selection strategy based on degradation pathways for some unstable drugs in pharmaceutical cocrystal design.
authors.affiliation: School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.forename: Ziling
authors.initials: Z
authors.lastname: Liu
authors.forename: Hongliang
authors.initials: H
authors.lastname: Kan
authors.forename: Hui
authors.initials: H
authors.lastname: Zu
authors.forename: Wanjin
authors.initials: W
authors.lastname: Sun
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhang
authors.forename: Shuai
authors.initials: S
authors.lastname: Qian
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry; D000998:Antiviral Agents / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D004355:Drug Stability; D009536:Niacinamide / Q000737:chemistry*; D063065:Organophosphonates / Q000737:chemistry*; D033362:Powder Diffraction; D011355:Prodrugs / Q000737:chemistry*; D012439:Saccharin / Q000737:chemistry*; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013818:Thermogravimetry; D014961:X-Ray Diffraction
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D011355:Prodrugs; D009536:Niacinamide; D012439:Saccharin; D000225:Adenine; C106812:adefovir dipivoxil