Izutsu Ken-ichi, Yomota Chikako, Aoyagi Nobuo
National Institute of Health Sciences, Tokyo, Japan.
Chem Pharm Bull (Tokyo). 2007 Apr;55(4):565-70. doi: 10.1248/cpb.55.565.
Effects of co-solutes on the physical property of mannitol and sorbitol in frozen solutions and freeze-dried solids were studied as a model of controlling component crystallinity in pharmaceutical formulations. A frozen mannitol solution (500 mM) showed a eutectic crystallization exotherm at -22.8 degrees C, whereas sorbitol remained amorphous in the freeze-concentrated fraction in the thermal scan. Various inorganic salts reduced the eutectic mannitol crystallization peak. Trisodium and tripotassium phosphates or citrates prevented the mannitol crystallization at much lower concentrations than other salts. They also raised transition temperatures of the frozen mannitol and sorbitol solutions (T(g)': glass transition temperature of maximally freeze-concentrated amorphous phase). Crystallization of some salts (e.g., NaCl) induced crystallization of mannitol at above certain salt concentration ratios. Thermal and near-infrared analyses of cooled-melt amorphous sorbitol solids indicated increased intermolecular hydrogen-bonding in the presence of trisodium phosphate. The sodium phosphates and citrates should prevent crystallization of mannitol in frozen solutions and freeze-dried solids by the intense hydrogen-bonding and reduced molecular mobility in the amorphous phase.
作为控制药物制剂中成分结晶度的模型，研究了共溶质对冷冻溶液和冻干固体中甘露醇和山梨醇物理性质的影响。冷冻的甘露醇溶液（500 mM）在-22.8℃时出现共晶结晶放热峰，而在热扫描中，山梨醇在冷冻浓缩部分仍保持无定形。各种无机盐降低了共晶甘露醇的结晶峰。磷酸三钠和磷酸三钾或柠檬酸盐在比其他盐低得多的浓度下就能阻止甘露醇结晶。它们还提高了冷冻的甘露醇和山梨醇溶液的转变温度（T(g)'：最大冷冻浓缩无定形相的玻璃化转变温度）。某些盐（如NaCl）的结晶在高于一定盐浓度比时会诱导甘露醇结晶。对冷却熔融的无定形山梨醇固体进行的热分析和近红外分析表明，在磷酸三钠存在下分子间氢键增加。磷酸钠和柠檬酸盐应通过强烈的氢键作用和降低无定形相中的分子流动性来阻止冷冻溶液和冻干固体中甘露醇的结晶。
