title: The sodium salt of the enantiomers of ricobendazole: Preparation, solubility and chiroptical properties.
abstract: Albendazole (ABZ) is a sulfanyl-benzimidazole anthelmintic drug used worldwide in the treatment and prevention of parasitic diseases in animals and humans. Following oral administration, ABZ is rapidly oxidized into the pharmacologically active chiral sulfoxide metabolite known as ricobendazole (RBZ). As its achiral precursor, RBZ shows very low intestinal absorption due to its poor solubility in water (0.06mgmL-1). To the best of our knowledge, there is no known example in human medicine of a water-soluble salt form of racemic or enantiomerically pure RBZ. In the present study, we describe in detail the preparation of the sodium (Na) salt of the enantiomers of RBZ through a two-step process: i) the multi-milligram resolution of RBZ by HPLC on the amylose-based Chiralpak IG chiral stationary phase under polar organic mode; ii) the salification of the isolated enantiomers of RBZ by reaction with sodium hydroxide solution. The spectroscopic and chiroptical properties of the RBZ-Na enantiomers were determined. Due to their unique solubility in 0.01M phosphate buffer at physiological pH (14.49mgmL-1) and the high sample throughput obtained on semipreparative separation of the non-salified form, it is potentially possible to develop new anthelmintic enantiopure formulations with improved pharmacokinetic properties and lower toxicity.
authors.affiliation: Centro nazionale per il controllo e la valutazione dei farmaci, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy. Electronic address: roberto.cirilli@iss.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cirilli
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Guglielmi
authors.affiliation: Centro nazionale per il controllo e la valutazione dei farmaci, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy.
authors.forename: Francesca Romana
authors.initials: FR
authors.lastname: Formica
authors.affiliation: Dipartimento di Malattie Infettive, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy; World Health Organization Collaborating Centre for the Epidemiology, Detection and Control of Cystic and Alveolar Echinococcosis (in Animals and Humans), Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Casulli
authors.affiliation: Dipartimento di Farmacia, Università "G. D'Annunzio" di Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Carradori
mesh_terms: D015766:Albendazole / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D012964:Sodium / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility; D013237:Stereoisomerism
chemical_list: D012964:Sodium; D015766:Albendazole; C027186:albendazole sulfoxide
keywords: Chiralpak IG; Enantiomers; Neglected tropical diseases; Ricobendazole sodium salt; Semipreparative resolution; Water solubility