title: Mechanisms for Improved Hygroscopicity of L-Arginine Valproate Revealed by X-Ray Single Crystal Structure Analysis.
abstract: Valproic acid is widely used as an antiepileptic agent. Valproic acid is in liquid phase while sodium valproate is in solid phase at room temperature. Sodium valproate is hard to manufacture because of its hygroscopic and deliquescent properties. To improve these, cocrystal and salt screening for valproic acid was employed in this study. Two solid salt forms, l-arginine valproate and l-lysine valproate, were obtained and characterized. By using dynamic vapor sorption method, the critical relative humidity of sodium valproate, l-arginine valproate, and l-lysine valproate were measured. Critical relative humidity of sodium valproate was 40%, of l-lysine valproate was 60%, and of l-arginine valproate was 70%. Single-crystal X-ray structure determination of l-arginine valproate was employed. l-Lysine valproate was of low diffraction quality, and l-arginine valproate formed a 1:1 salt. Crystal l-arginine valproate has a disorder in the methylene carbon chain that creates 2 conformations. The carboxylate group of valproic acid is connected to the amino group of l-arginine. Crystalline morphologies were calculated from its crystal structure. Adsorption of water molecules to crystal facets was simulated by Material Studio. When comparing adsorption energy per site of these salts, sodium valproate is more capable of adsorption of water molecule than l-arginine valproate.
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Ito
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Nambu
authors.affiliation: Department of Chemistry and Materials Science, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8551, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Sakon
authors.affiliation: Department of Chemistry and Materials Science, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8551, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Uekusa
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan.
authors.forename: Etsuo
authors.initials: E
authors.lastname: Yonemochi
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Noguchi
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan; Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki, Gunma 370-0033, Japan. Electronic address: terada-k@takasaki-u.ac.jp.
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Terada
mesh_terms: D001120:Arginine / Q000737:chemistry*; D003460:Crystallization / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D014635:Valproic Acid / Q000737:chemistry*; D014867:Water / Q000737:chemistry; D017155:Wettability; D014961:X-Ray Diffraction / Q000379:methods*
chemical_list: D014867:Water; D014635:Valproic Acid; D001120:Arginine
keywords: X-ray powder diffractometry; crystal engineering; crystal structure; crystallography; deliquescence; formulation; hygroscopicity; physical characterization; salts/salt selection