Pharmaceutical Development, Baxter Healthcare Corporation, Round Lake, Illinois 60048, USA.
J Pharm Sci. 2013 Aug;102(8):2572-88. doi: 10.1002/jps.23610. Epub 2013 May 31.
During gap freezing, vials are placed on a metal tray, which is separated from the shelf surface with a small air gap that eliminates significant conductive heat transfer from the shelf to the bottom of the vial. The purpose of this freezing approach is to reduce the lyophilization cycle time of various amorphous formulations by nearly isothermal freezing. Such isothermal freezing promotes the formation of large ice crystals, and thus large pores throughout the cake, which subsequently accelerates the primary drying rate. The nucleation temperature using gap freezing, for the experimental conditions tested, was in the range of -1°C to -6°C, much higher than the range of -10°C to -14°C found using conventional shelf freezing. Isothermal freezing becomes effective when the gap is greater than 3 mm. The pore sizes and cake resistance during primary drying for various formulations were determined using the pore diffusion model developed by Kuu et al. (Pharm Dev Technol, 2011, 16(4): 343-357). Reductions in primary drying time were 42% (for 10% sucrose), 45% (for 10% trehalose), and 33% (for 5% sucrose).
在间隔冻结过程中，小瓶被放置在金属托盘上，托盘与架子表面之间有一个小的空气间隙，以消除来自架子的显著热传导到小瓶底部。这种冻结方法的目的是通过近乎等温冻结来缩短各种非晶形制剂的冷冻干燥周期时间。这种等温冻结促进了大冰晶的形成，从而在整个蛋糕中形成了大孔，这随后加速了初级干燥速率。在实验测试条件下，使用间隔冻结的成核温度范围在-1°C 至-6°C 之间，远高于使用传统货架冻结时发现的-10°C 至-14°C 范围。当间隙大于 3mm 时，等温冻结变得有效。使用 Kuu 等人开发的孔扩散模型（Pharm Dev Technol，2011，16（4）：343-357）确定了各种配方在初级干燥过程中的孔径和蛋糕阻力。初级干燥时间减少了 42%（对于 10%蔗糖）、45%（对于 10%海藻糖）和 33%（对于 5%蔗糖）。
