Izutsu Ken-Ichi, Yomota Chikako, Okuda Haruhiro, Kawanishi Toru, Yamaki Takuya, Ohdate Ryohei, Yu Zhaokun, Yonemochi Etsuo, Terada Katsuhide
National Institute of Health Sciences, Setagaya, Tokyo, 158-8501, Japan.
J Pharm Sci. 2014 Aug;103(8):2347-55. doi: 10.1002/jps.24050. Epub 2014 Jun 10.
The objective of this study was to elucidate effects of formulation and process variables on the physical forms of freeze-dried myo-inositol. Physical properties of myo-inositol in frozen solutions, freeze-dried solids, and cooled heat-melt solids were characterized by powder X-ray diffraction (PXRD), thermal analysis (differential scanning calorimetry [DSC] and thermogravimetric), and simultaneous PXRD-DSC analysis. Cooling of heat-melt myo-inositol produced two forms of metastable anhydrate crystals that change to stable form (melting point 225 °C-228 °C) with transition exotherms at around 123 °C and 181 °C, respectively. Freeze-drying of single-solute aqueous myo-inositol solutions after rapid cooling induced crystallization of myo-inositol as metastable anhydrate (transition at 80 °C-125 °C) during secondary drying segment. Contrarily, postfreeze heat treatment (i.e., annealing) induced crystallization of myo-inositol dihydrate. Removal of the crystallization water during the secondary drying produced the stable-form myo-inositol anhydrate crystal. Shelf-ramp slow cooling of myo-inositol solutions resulted in the stable and metastable anhydrous crystal solids depending on the solute concentrations and the solution volumes. Colyophilization with phosphate buffer retained myo-inositol in the amorphous state. Crystallization in different process segments varies crystal form of freeze-dried myo-inositol solids.
本研究的目的是阐明制剂和工艺变量对冻干肌醇物理形态的影响。通过粉末X射线衍射（PXRD）、热分析（差示扫描量热法[DSC]和热重分析）以及同步PXRD-DSC分析对冷冻溶液、冻干固体和冷却热熔固体中的肌醇物理性质进行了表征。热熔肌醇冷却产生两种亚稳态无水晶体形式，分别在约123℃和181℃发生转变放热，转变为稳定形式（熔点225℃-228℃）。快速冷却后的单溶质肌醇水溶液冻干过程中，在二次干燥阶段肌醇结晶为亚稳态无水物（在80℃-125℃转变）。相反，冻后热处理（即退火）诱导肌醇二水合物结晶。二次干燥过程中结晶水的去除产生了稳定形式的肌醇无水晶体。肌醇溶液的搁板斜坡缓慢冷却根据溶质浓度和溶液体积产生稳定和亚稳态无水晶体固体。与磷酸盐缓冲液共冻干可使肌醇保持无定形状态。不同工艺阶段的结晶会改变冻干肌醇固体的晶体形式。
