Stability of amorphous drug, 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2 H-pyridazin-3-one, in silica mesopores and measurement of its molecular mobility by solid-state 13C 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]-2 H-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 13C 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.