Generation of fine pharmaceutical particles via controlled secondary nucleation under high shear environment during crystallization - Process development and scale-up
Generation of fine pharmaceutical particles via controlled secondary nucleation under high shear environment during crystallization - Process development and scale-up
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DOI：
10.1021/op700045j
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发表时间：
2007-07-01
影响因子：
3.4
通讯作者：
Kato, Y.
中科院分区：
文献类型：
--
作者：
Kamahara, T.;Takasuga, M.;Kato, Y.
本文提出了一种独特的半间歇结晶工艺，并与高速转子-定子装置相耦合，用于微细颗粒的产生和控制。该方法的关键基础机制是在结晶期间在高剪切环境下的受控二次成核，与常规颗粒破碎机制相反，即，结晶后研磨。采用循环模式操作来控制批次在高剪切域中的停留时间，以确保该工艺的可扩展性。在这项工作中，操作灵敏度的过饱和度和颗粒大小首次在实验室中进行了探索。根据实验室研究结果，在多个1000 L中试规模生产批次中成功证明了该工艺。最后对大规模生产的实际问题进行了说明。
A unique semibatch crystallization process, coupling with a high-speed rotor-stator device, was developed for generation and control of fine particles. The key underlying mechanism of this process is controlled secondary nucleation under a high shear environment during crystallization, in contrast to the conventional particle breakage mechanism, i.e., milling, after the crystallization. A recycle mode operation is employed to control the residence time of the batch in the high shear domain so as to ensure the scalability of this process. In this work, the operational sensitivity to the supersaturation and particle size were first explored in the laboratory. Based on the results of the laboratory investigation, this process was successfully demonstrated in multiple 1000-L pilot scale production batches. The practical issues for the large scale operation are also illustrated.