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Engineering    2017, Vol. 3 Issue (3) : 354-364     https://doi.org/10.1016/J.ENG.2017.03.023
Research |
药物连续结晶进展
张得江1,2,许史杰1,2,杜世超1,2,王静康1,2,龚俊波1,2()
1. School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300072, China
2. Collaborative Innovation Center of Chemical Science and Chemical Engineering, Tianjin University, Tianjin 300072, China
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摘要 

结晶是药物工业中重要的单元操作。现阶段大部分的药物结晶过程都是间歇的,但是由于间歇产品的批间差异以及低的生产效率,连续结晶越来越受到人们的重视。在过去的几年中,连续结晶已经取得了一些进展以使其能够满足不同的需求。本文将从产品工程的角度总结药物连续结晶的进展。不同形式结晶器的主要区别在于其停留时间分布的不同。文中比较了不同连续结晶形式的优点和缺点,总结了使用连续结晶满足不同质量需求的方法。发现连续结晶在粒度和形状控制上有优势,但是在过程收率上低于间歇结晶过程,特别是在生产手性晶体时。最后对不同的控制方案进行了比较。

关键词 连续结晶药物混合悬浮混合出料结晶器(MSMPR)管式结晶器控制方案    
Abstract

Crystallization is an important unit operation in the pharmaceutical industry. At present, most pharmaceutical crystallization processes are performed in batches. However, due to product variability from batch to batch and to the low productivity of batch crystallization, continuous crystallization is gaining increasing attention. In the past few years, progress has been made to allow the products of continuous crystallization to meet different requirements. This review summarizes the progress in pharmaceutical continuous crystallization from a product engineering perspective. The advantages and disadvantages of different types of continuous crystallization are compared, with the main difference between the two main types of crystallizers being their difference in residence time distribution. Approaches that use continuous crystallization to meet different quality requirements are summarized. Continuous crystallization has advantages in terms of size and morphology control. However, it also has the problem of a process yield that may be lower than that of a batch process, especially in the production of chirality crystals. Finally, different control strategies are compared.

Keywords Continuous crystallization      Pharmaceutical      MSMPR      Tubular crystallizer      Control strategy     
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通讯作者: 龚俊波     E-mail: junbo_gong@tju.edu.cn
最新录用日期:    发布日期: 2017-06-30
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Dejiang Zhang
Shijie Xu
Shichao Du
Jingkang Wang
Junbo Gong
引用本文:   
Dejiang Zhang,Shijie Xu,Shichao Du, et al. Progress of Pharmaceutical Continuous Crystallization[J]. Engineering, 2017, 3(3): 354-364.
网址:  
http://engineering.org.cn/EN/10.1016/J.ENG.2017.03.023     OR     http://engineering.org.cn/EN/Y2017/V3/I3/354
Fig.1  Schematic diagram of two types of continuous crystallizer: the MSMPR crystallizer and the continuous tubular crystallizer.
Type Advantages Disadvantages
MSMPR crystallizer

Easier to convert from batch crystallizer

Less efficient than tubular crystallizer

Lower maintenance cost

May lead to non-stable behavior

Equipment is simpler

Startup process may be relatively long

Easier maintenance

Relatively hard to scale up

Tubular crystallizer

Higher efficiency than an MSMPR crystallizer of the same volume

Maintenance is expensive and complex

Narrow residence time distribution

Easier to cause fouling

Easier to scale up

Equipment is relatively complex

Tab.1  Comparison of the MSMPR and tubular crystallizers [6].
Fig.2  General quality requirements for pharmaceutical crystals.
Approach Yield (wt%) Purity (%) Compound Ref.
Extend residence time 93.6 97.6 Aliskiren hemifumarate [16]
91.0 91.6 Compound A [17]
Mother liquid recycling 87.0 94.0 Cyclosporine [15]
91.8 94.3 Cyclosporine [18]
89.1 Deferasirox [18]
Solvent nanofiltration membrane 98.7 Deferasirox [13]
Solid recycling 79.8 96.0 Cyclosporine [7]
Tab.2  Different approaches for increasing product yield.
Fig.3  Using MSMPR to meet the size requirements in pharmaceutical crystallization.
Fig.4  Crystal morphology distribution in continuous MSMPR.
Fig.5  Three stability regions for polymorphic continuous crystallization [48]. Diamond-shaped data points correspond to Ref. [45], and square-shaped data points correspond to Ref. [46]. (Copyright © 2016, Wiley Online Library, Ltd.)
Fig.6  A novel process flow sheet used for continuous preferential crystallization [51]. (Copyright © 2015. Wiley Online Library, Ltd.)
Fig.7  Schematic diagrams of (a) a plug flow crystallizer, (b) a segment flow crystallizer, and (c) an oscillatory baffled crystallizer.
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