Crystalline Phase Transitions of 5′-O-Triethylsilyl-2′-deoxy-5-azacytidine under Varying Temperature and Humidity Conditions and Its Closed Storage Stability

抄録

5′-O-Triethylsilyl-2′-deoxy-5-azacytidine (5′-O-TesDAC) is a prodrug developed to counteract deamination by cytidine deaminase and spontaneous hydrolytic cleavage of the triazine ring. In this study, we have evaluated the physical properties of the crystal forms to determine the optimal crystal form for solid pharmaceutical development. Therefore, the crystalline morphology of 5′-O-TesDAC was assessed using terahertz spectroscopy, in addition to conventional methods (thermal analysis, powder X-ray diffraction, IR absorption spectroscopy and dynamic vapor sorption). Terahertz spectroscopy has the feature of being able to sensitively capture structural changes between lattices and molecules because the absorptions of the terahertz region correspond to those of skeletal vibrations, intermolecular vibrations, and/or lattice vibrations. For this reason, in the evaluation of crystal polymorphism, terahertz spectroscopy was considered to complement methods that have conventionally been used. Furthermore, the metastable state evaluated in this study rapidly transitions to hemihydrate at relative humidity (RH) above 10%, so it could not be measured using attenuated total reflectance-Fourier transform IR (ATR-FTIR), which is performed under atmosphere, whereas terahertz spectroscopy allowed measurements with the sample chamber exposed to dry air easily. The chemical stability was evaluated through a stability test that measured the amount of the main degradation product of each crystalline form using HPLC. As a result, four crystalline forms of 5′-O-TesDAC were identified. The characterization of 5′-O-TesDAC in this study provides valuable information for optimizing the manufacturing parameters of the formulation and selecting appropriate packaging materials for pharmaceutical development.