Fujii Kahori, Izutsu Ken-ichi, Kume Migiwa, Yoshino Takeshi, Yoshihashi Yasuo, Sugano Kiyohiko, Terada Katsuhide
Faculty of Pharmaceutical Sciences, Toho University; 2. R&D Laboratories, POLA Pharma Inc.
Chem Pharm Bull (Tokyo). 2015;63(5):311-7. doi: 10.1248/cpb.c14-00692.
The purpose of this study was to identify and characterize new crystalline bulking agents applicable to freeze-dried pharmaceuticals. Thermal analysis of heat-melt sugar and sugar alcohol solids as well as their frozen aqueous solutions showed high crystallization propensity of meso-erythritol and D-mannitol. Experimental freeze-drying of the aqueous meso-erythritol solutions after their cooling by two different methods (shelf-ramp cooling and immersion of vials into liquid nitrogen) resulted in cylindrical crystalline solids that varied in appearance and microscopic structure. Powder X-ray diffraction and thermal analysis indicated different crystallization processes of meso-erythritol depending on the extent of cooling. Cooling of the frozen meso-erythritol solutions at temperatures lower than their Tg' (glass transition temperature of maximally freeze-concentrated phase, -59.7°C) induced a greater number of nuclei in the highly concentrated solute phase. Growth of multiple meso-erythritol anhydride crystals at around -40°C explains the powder-like fine surface texture of the solids dried after their immersion in liquid nitrogen. Contrarily, shelf-ramp cooling of the frozen solution down to -40°C induced an extensive growth of the solute crystal from a small number of nuclei, leading to scale-like patterns in the dried solids. An early transition of the freezing step into primary drying induced collapse of the non-crystalline region in the cakes. Appropriate process control should enable the use of meso-erythritol as an alternative crystalline bulking agent in freeze-dried formulations.
本研究的目的是鉴定和表征适用于冻干药物的新型结晶填充剂。对热熔糖和糖醇固体及其冷冻水溶液的热分析表明，内消旋赤藓糖醇和D - 甘露醇具有较高的结晶倾向。通过两种不同方法（搁板梯度冷却和将小瓶浸入液氮）冷却后的内消旋赤藓糖醇水溶液进行实验冻干，得到了外观和微观结构各异的圆柱形结晶固体。粉末X射线衍射和热分析表明，内消旋赤藓糖醇的结晶过程因冷却程度而异。在低于其Tg'（最大冷冻浓缩相的玻璃化转变温度，-59.7°C）的温度下冷却冷冻的内消旋赤藓糖醇溶液，会在高浓度溶质相中诱导产生更多的晶核。在约-40°C下多个内消旋赤藓糖醇酸酐晶体的生长解释了浸入液氮后干燥固体的粉末状精细表面纹理。相反，将冷冻溶液搁板梯度冷却至-40°C会导致溶质晶体从少量晶核开始大量生长，从而在干燥固体中形成鳞片状图案。冷冻步骤过早转变为一次干燥会导致饼状物中非晶区的塌陷。适当的工艺控制应能使内消旋赤藓糖醇用作冻干制剂中的替代结晶填充剂。
