Praxair, Inc., Burr Ridge, Illinois 60527.
Baxter Healthcare Corporation, BioPharma Solutions, Bloomington, Indiana 47403.
J Pharm Sci. 2011 Aug;100(8):3453-3470. doi: 10.1002/jps.22561. Epub 2011 Apr 4.
A novel and scalable method has been developed to enable control of the ice nucleation step for the freezing process during lyophilization. This method manipulates the chamber pressure of the freeze dryer to simultaneously induce nucleation in all product vials at a desired temperature. The effects of controlled nucleation on the drying rate of various formulations including 5% (w/w) mannitol, 5% (w/w) sucrose, and a mixture of 3% (w/w) mannitol and 2% (w/w) sucrose were studied. For a 5% (w/w) mannitol, uncontrolled ice nucleation occurred randomly at product temperatures between -8.0°C and -15.9°C as the vials were cooled to -40°C. Controlled ice nucleation was achieved at product temperatures between -2.3°C and -3.7°C. The effect of nucleation control on the effective pore radius (r(e) ) of the cake was determined from the product temperature profiles using a pore diffusion model in combination with a nonlinear parameter estimation approach reported earlier. Results show that the value of r(e) for 5% (w/w) mannitol was enlarged from 13 to 27 μm by uniformly inducing nucleation at higher temperatures. Applying the resistance parameters obtained from the pore diffusion model for 5% (w/w) mannitol, optimized cycles were theoretically generated and experimentally tested, resulting in a 41% reduction in primary drying time.
已经开发出一种新颖且可扩展的方法，以实现冻干过程中冷冻步骤的冰核控制。该方法通过操纵冷冻干燥机的腔室压力，在所需温度下同时诱导所有产品小瓶中的成核。研究了控制成核对各种配方（包括 5%（w/w）甘露醇、5%（w/w）蔗糖和 3%（w/w）甘露醇和 2%（w/w）蔗糖的混合物）干燥速率的影响。对于 5%（w/w）甘露醇，当小瓶冷却至-40°C 时，未控制的冰核在产品温度介于-8.0°C 和-15.9°C 之间随机发生。在产品温度介于-2.3°C 和-3.7°C 之间实现了受控成核。通过使用先前报道的孔扩散模型与非线性参数估计方法相结合，从产品温度曲线确定成核控制对蛋糕有效孔半径（r(e) ）的影响。结果表明，通过在较高温度下均匀诱导成核，将 5%（w/w）甘露醇的 r(e) 值从 13 扩大到 27 μm。应用孔扩散模型获得的 5%（w/w）甘露醇的阻力参数，理论上生成并实验测试了优化循环，导致一次干燥时间减少了 41%。
