title: Stability of amorphous drug, 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one, in silica mesopores and measurement of its molecular mobility by solid-state (13)C NMR spectroscopy.
abstract: This study evaluated the physical stability and molecular mobility of a poorly water-soluble amorphous drug, 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (K-832), adsorbed onto silica mesopores. K-832-Sylysia 740 and K-832-Sylysia 350 formulations, prepared by adsorbing K-832 onto porous silica Sylysia 740 (2.5-nm-diameter pores) and Sylysia 350 (21-nm-diameter pores) and stored at 60°C/80%RH (open and closed conditions), were investigated. Differential scanning calorimetry revealed that crystallization of K-832 in the K-832-Sylysia 350 formulation stored at 60°C/80%RH (open and closed conditions) was faster than that of the other formulation stored under identical conditions. Raman spectroscopy revealed shifts to higher wavenumbers in the K-832-Sylysia 350 and K-832-Sylysia 740 formulations (1497 and 1493 cm(-1), respectively) in comparison to amorphous K-832 (1481 cm(-1)); however, no distinct differences were observed in the spectra of the two formulations. Solid-state (13)C NMR spectroscopy revealed a difference in spin-lattice relaxation time in the rotating frame (T(1ρ)) between the two formulations, suggesting the lower molecular mobility of K-832 in the 2.5-nm-diameter pores than in the 21-nm-diameter pores. Thus, the crystallization rate of amorphous K-832 in the K-832-Sylysia 740 formulation was much slower. These results will be useful in estimating the physical stability of amorphous drugs in mesopores.
authors.affiliation: Fuji Research Laboratories, Pharmaceutical Division, Kowa Company Ltd., 332-1 Ohnoshinden, Fuji, Shizuoka 417-8650, Japan. h-miura@kowa.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miura
authors.forename: Makoto
authors.initials: M
authors.lastname: Kanebako
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shirai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakao
authors.forename: Toshio
authors.initials: T
authors.lastname: Inagi
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Terada
mesh_terms: D000327:Adsorption; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D004355:Drug Stability; D004356:Drug Storage; D009682:Magnetic Resonance Spectroscopy; D016062:Porosity; D011724:Pyridazines / Q000737:chemistry*; D012822:Silicon Dioxide / Q000737:chemistry*; D012995:Solubility; D013059:Spectrum Analysis, Raman; D013440:Sulfides / Q000737:chemistry*
chemical_list: C555018:2-benzyl-5-(4-chlorophenyl)-6-(4-(methylthio)phenyl)-2H-pyridazin-3-one; D011724:Pyridazines; D013440:Sulfides; D012822:Silicon Dioxide