Use of Continuous MSMPR Crystallization with Integrated Nanofiltration Membrane Recycle for Enhanced Yield and Purity in API Crystallization
Use of Continuous MSMPR Crystallization with Integrated Nanofiltration Membrane Recycle for Enhanced Yield and Purity in API Crystallization
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DOI：
10.1021/cg401491y
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发表时间：
2014-02-01
影响因子：
3.8
通讯作者：
Myersont, Allan S.
中科院分区：
文献类型：
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作者：
Ferguson, Steven;Ortner, Franziska;Myersont, Allan S.
如果要将连续工艺应用于制药生产，则连续结晶技术必须能够满足当前间歇结晶工艺所能达到的纯度和产率。在稳定的MSMPR结晶过程中回收母液，可以达到或超过等效平衡间歇过程中的产率。然而，提高产率的程度受到系统内杂质积累的限制。本研究采用有机溶剂纳滤膜，在混合溶剂(四氢呋喃：乙醇)反溶剂(水)体系中，优先浓缩原料药(deferasirox，Mw=373Da)，并从母液回流中净化极限杂质4-肼苯甲酸(Mw=152Da)。膜循环的引入使产率分别达到98.0%和98.7%。相比之下，对照MSMPR无膜运行(70.3%)，等量间歇工艺(89.2%)，以及目前的商业间歇工艺(92%)。MSMPR膜循环实验(0.15ppm和0.22ppm)、MSMPR对照实验(0.13ppm)和间歇对照实验(0.32ppm)测量了可比较的产品杂质水平。所有工艺都符合最高3ppm杂质4-羟基苯甲酸的规定。
If continuous processing is to be employed in pharmaceutical production, it is essential that continuous crystallization techniques can meet the purity and yield achievable in current batch crystallization processes. Recycling of mother liquor in steady state MSMPR crystallizations allows the yield in the equivalent equilibrium batch process to be met or exceeded. However, the extent to which yield can be increased is limited by the buildup of impurities within the system. In this study, an organic solvent nanofiltration membrane was used to preferentially concentrate an API (deferasirox, M.W. = 373 Da) and purge the limiting impurity 4-hydrazinobenzoic acid (MW = 152 Da) from the mother liquor recycle stream in a mixed solvent (THF:ethanol) antisolvent (water) system. Incorporation of the membrane recycle allowed yields of 98.0% and 98.7% to be achieved. This compares to the following; a control MSMPR run without a membrane (70.3%), an equivalent batch process (89.2%), and the current commercial batch process (92%). Comparable product impurity levels were measured for the following: the MSMPR membrane recycle experiments (0.15 ppm and 0.22 ppm), the MSMPR control (0.13 ppm), and batch (0.32 ppm) control experiments. All processes met the regulatory specifications of a maximum of 3 ppm of the impurity 4-hydrainobenzoic acid.