Tag Archives: Mark Barrett

Polymorph Form Control: Why Care About Seeding and Cooling Rates?

In Situ Monitoring of Supersaturation and Polymorphic Form of Piracetam during Batch Cooling Crystallization

Mark Barrett and others at the University College Dublin (UCD) recently published a paper Continue reading

工艺过程参数对过饱和度、晶体大小与形状的影响

这是结晶专题系列的第五个博贴。如果您还没有看此系列中前面的博贴,可以在此找到它们:

下图显示了过饱和度通过成核和增长间的竞争与晶体大小分布的关系。在本博贴里,我们来看如何通过调节工艺过程参数(比如反溶剂添加速率)使过饱和度能够得到控制。在下一个博贴里,我们会稍微深入一点进入到结晶动力学的基础;而现在让我们来研究一个有意思的案例:用原位监测工具来监测过饱和度并跟踪相应对晶体大小分布的影响。

这个例子考察对不加晶种的苯甲酸从乙醇-水中结晶出来的过程,主要观察反溶剂添加速率对晶体大小、形状和分布的影响。用水作反溶剂,进行两个不同添加速率的实验:一个低速 (0.1g/s)、一个高速(0.2g/s)。过饱和度用ReactIR来监测,颗粒数与尺寸用FBRM 来分析,晶体的大小与形状用PVM来确定。

将制备好的苯甲酸在乙醇中的不饱和溶液维持在25ºC下恒温。苯甲酸是一个有机化合物,难溶于水但溶于乙醇,文献中没有报道它有已知多晶型。在固定的0.1 g/s 和0.2 g/s的速率下添加水,它们导致的结晶过程用原位工艺过程分析工具来监测。

图1表示出每一实验所得到的溶液浓度降低曲线与溶解度曲线相重叠。从饱和度的变化可以看出溶液开始时不饱和的,随着水的加入溶液浓度逐渐超过溶解度进入过饱和。随着晶核的生成溶液的浓度不断降低,并保持接近溶解度曲线, 在反溶剂添加的终点降至溶解度。过程中过饱和度随反溶剂浓度的实时变化在图2中可以清楚地看出。

很明显,在较高的添加速率下,过饱和度较高 ­—  一个重要的结果!一般情况下,快速的冷却或添加速率导致高的过饱和度。这是因为晶体的成核与增长速率不足以立即消耗掉所产生的过饱和度,所以随着结晶过程的进展过饱和度便得以积累。

从前面讲过的内容我们知道过饱和度高会导致成核主导的结晶过程,晶体增长甚少。图3表示的是在上述两个实验的终点FBRM测得的颗粒分布结果 ­:很明显,快速添加所得的分布显示出大量更多的小颗粒,而慢速添加所得的分布则显示出更多的大颗粒。

不仅仅是晶体大小受工艺参数变化的影响,晶体的形状也受影响。实验终点的PVM 图像表明了这一点,即慢速添加导致了大的、规则形状的长方板,而快速添加产生了细针状晶体致使容易结块。

颗粒分布

颗粒形状

上述研究案例表明了工艺过程参数的变化可以直接影响过饱和度的实时程度乃至晶体的大小、分布及形状。

在本系列的下一个博贴里,我们会稍微深入一点进入到结晶动力学的基础。同时,您也许会对这一网络研讨会和文章感兴趣:

为开发与优化结晶工艺过程进行”无”标定过饱和度评估与控制

M. Barrett, M. McNamara, H. Hao, P. Barrett, and B. Glennon, “Supersaturation tracking for the development, optimization and control of crystallization processes [为开发、优化和控制结晶工艺跟踪过饱和度],” Chemical Engineering Research and Design, vol. 88, Aug. 2010, pp. 1108-1119.

如果您有兴趣与其他结晶工作者或爱好者讨论,考虑加入已有600多成员的LinkedIn结晶社团

增强对结晶工艺过程的理解

科学家与工程师们经常要面对的一个挑战是如何做到增强对结晶工艺过程的理解。

EasyMax为使这些科学家与工程师们完成大量的所需工作提供了一个即功能强大又使用便捷的实验平台。看到EasyMax已被他们欢迎采纳,尤其是针对结晶工作,使人感到欣慰。Simon Rea开发了一个方法,使EasyMax更适于颗粒特征分析:

结晶终于,您可以在您的EasyMax 里同时使用FBRM和PVM了! 这一新的PTFE封盖使您有可能观察到:

  • 多晶型/晶习的改变
  • 晶种添加行为
  • 相分离
  • 工艺过程中通常的颗粒/液滴的变化

并且,这可在体积小到30毫升条件下实现!当您要放大至1升时,您还可以把同一个PVM拿到那个规模的实验中使用

要通过例子看您可以在EasyMax 里同时使用FBRM和PVM来做什么,请浏览由固态制药团队(SSPC)的Mark Barrett所作的 从实验室到生产厂反溶剂添加结晶过程的优化与放大网络研讨会系列

Impact of Process Parameters on Supersaturation and Crystal Size and Shape

This is the fifth blog post in a series dedicated to crystallization.  In case you missed the previous posts in the series, they are available here:

The diagram below illustrates the relationship between supersaturation and crystal size distribution, via crystal nucleation and growth. In this post, we will look at how supersaturation can be controlled by adjusting process parameters such as antisolvent addition rate. Continue reading

Novel Crystallization Techniques – Cambridge Information Sharing Event

On the afternoon of May 5, Millennium Pharmaceuticals will host a Crystallization Information Sharing Event at their site in Cambridge, MA.  Continue reading

Enhance Your Understanding of a Crystallization Process

A common challenge faced by both chemists and engineers is how to achieve an enhanced understanding of the crystallization process.

The EasyMax has provided a powerful, yet nimble platform for chemists and engineers to get a lot of work done.  It has been great to see how well the EasyMax has been embraced, especially for crystallization work.  Simon Rea developed a way to make it even better for particle characterization:

Crystallization Process FBRM PVM EasyMax

At last, you can use the FBRM and PVM simultaneously in your EasyMax!  This new PTFE lid makes it possible to see your: Continue reading

Symposium on Process Safety and Crystallization

On Tuesday, November 2, METTLER TOLEDO held its 1st Symposium in Cambridge, MA, hosted by Novartis Institutes for BioMedical Research (NIBR). The success of the Symposium went beyond expectations: 65 scientists representing a large variety of small companies (CoNCERT, Cubist, Tetraphase), larger companies (Pfizer, Dow, Amgen), and research institutions (Massachusetts Institute of Technology) attended the event. The main themes of the Symposium were crystallization and process safety. Des O’Grady and I started by giving an overview of the technologies later covered by the industry speakers: Focused Beam Reflectance Measurement (FBRM®), Particle Video Microscope (PVM®), EasyMax™, RC1, and ReactIR™. Continue reading

BIWIC 2010: Optimization & Scale-up of Anti-Solvent Crystallization

Later this week, scientists and engineers will join together at Martin Luther University Halle-Wittenberg in Germany for the BIWIC 2010 – International Workshop on Industrial Crystallization.  Topics at this year’s International Workshop on Industrial Crystallization will include fundamentals of crystallization (thermodynamics and kinetics), process design (monitoring and modeling), product design (polymorphism, salvation, stability, chiral separation, fine chemicals, pharmaceuticals), industrial applications, and intensified processes and equipment (external fields, micro technology, hybrid processes). Continue reading

Supersaturation Or the Crystal Size Distribution

Supersaturation or the Crystal Size DistributionWhich Measurement Is More Important?

In an ideal world, you may want to directly measure the crystal population within the crystallizer (a critical product quality attribute) and measure the supersaturation which is driving the process (a critical process parameter).  Today’s advanced Process Analytical Technology (PAT) allows you to measure both of these critical parameters in real time. But where should you begin – especially if budget constraints limit you to implementing only one advanced measurement. Continue reading

What Makes Crystallization Such a Complex Process?

As a follow-up on last week’s post regarding the implications of a well-designed crystallization process, including how Tim Bell of DuPont Engineering wrote: “Crystallization is notoriously difficult to scale-up…”, we will now address why crystallization is such a complex process. Continue reading