(503b) In-Situ Monitoring of Resolution of Chiral Compounds Using Process Analytical Technology

In-situ Monitoring of Resolution of Chiral Compounds using Process Analytical Technology

Zhen Chen, Yuan Gao, Yongli Wang, Qiuxiang Yin, Meijing Zhang, Baohong Hou, Hongxun Hao*

National Engineering Research Center for Industrial Crystallization Technology, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P.R. China

* Corresponding author: Tel:+86-22-27405754  Fax: + 86-22-27405754

 Email: hongxunhao@tju.edu.cn

Abstract

Since chirality was discovered and defined hundreds of years ago, the resolution and purification of chiral compounds has become one main challenge that scientist have to face. Most physicochemical properties of the enantiomers are nearly the same or pretty close. So it is quite difficult to find an appropriate method to resolve the chiral compounds, especially in industry scale. As one main resolution method of chiral compounds, preferential crystallization has been widely used not only in the labs but also in industries. To develop and design an optimum crystallization processes for chiral compounds, it is crucial to understand the thermodynamic and kinetic mechanism of the processes. Process analytical technologies (PAT) can be used to monitor the preferential crystallization processes in line and are very helpful to further understand the mechanism behind the phenomena. In this paper, several PAT tools were successfully used to in-situ monitor the resolution of L-lactide. Raman Spectroscopy and attenuated total reflectance Fourier transformation infrared (ATR-FTIR) were used to monitor the solid phase and liquid phase concentration respectively. Focused beam reflectance measurement (FBRM) and particle vision measurement (PVM) were used to monitor the particle size and morphology respectively. Some other offline analytical tools, such as X-ray diffraction (XRD), differential scanning calorimetry (DSC), Automatic polarimeter were also used to confirm the online analysis results. Solubility data of L-lactide were also measured experimentally. The effect of operating parameters, such as seeding, cooling profile and the initial concentration, on the preferential crystallization processes was also investigated.  It was found that all of these operating parameters can affect the resolution results. The reasons and the mechanism of the influence were discussed in detail. Using these knowledge obtained in this paper, an reliable optimum resolation method with high output capacity and good repeatability for L-lactide were finally developed.

Keywords: Resolution, Chiral compounds, Process analytical technology, Preferential crystallization, L-Lactide