472381 Liquid−Liquid Phase Separation during the Cooling Crystallization of Pyraclostrobin
Liquid−Liquid Phase Separation during the Cooling Crystallization of Pyraclostrobin
Crystallization, as a method of isolation and purification, is widely used in fine chemicals, food and pharmaceutical industries. It is a powerful mean to improve the properties of particle, such as changing crystal form, narrowing crystal size distribution (CSD), modifying crystal habit and so on. However, sometimes droplets like oil drops are generated instead of crystals are appeared from the supersaturated solution during the cooling and/or solventing-out crystallization process. This phenomenon is always termed as liquid¨Cliquid demixing, liquid¨Cliquid-phase separation (LLPS) or oiling out.
The main purpose of this investigation was to investigate the cooling crystallization process of pyraclostrobin in isopropanol/cyclohexane solvent mixtures. It was found that liquid−liquid phase separation will occurred under some certain conditions. In order to understand the mechanism of the liquid−liquid separation and the influence of cooling rate on oiling out, the phase diagram and cloud point curves at different cooling rate were experimentally measured with the aid of in situ tools, such as PVM, FBRM, ATR-FTIR and Raman. The phase diagram includes the solubility curve, the liquid−liquid separation curve, supersolubility curves, and clear point. It was found from the phase diagram that a normal single-phase crystallization would change to a oiling-out crystallization once the concentration of pyraclostrobin exceeded a certain value during crystallization. Contrasting with cloud point curves of different cooling rate, it is obvious that the cooling rate has a significant effect on the metastable state critical oiling out point. The concentration corresponds to the metastable state for critical oiling out point decreases with the increase of cooling rate. In the cooling and heating cyclic process, the solution has experienced five stages. During cooling down the solution from high temperature, oiling out including stable LLPS and metastable LLPS occurred, then nucleation and growth of crystals happened; upon heating up, the crystals dissolved gradually, then the solution with a small amount of particles transformed into transient oil phase and finally it formed a stable and clear solution.
Considering the crystal properties of final products, some experiments designed to investigate the influence of cooling rate and initial concentration. And the result showed that the higher cooling rates, the more serious agglomeration and poorer crystal habit of final products would get. Another result is that initial concentration has little influence on the crystal properties. High quality of products can be obtained by designing route of cooling crystallization according to the phase diagram.
Figure 1 Phase diagram of pyraclostrobin in 10 wt % isopropanol/cyclohexane solvent mixtures.
Figure 2 SEM images of pyraclostrobin product obtained from different experiments
a refer to pyraclostrobin products at the cooling rate of 0.1 K/min under concentration of 10g/100g solvent; b refer to pyraclostrobin products at the cooling rate of 0.5 K/min under concentration of 10g/100g solvent; c refer to pyraclostrobin products at the cooling rate of 0.1 K/min under concentration of 15g/100g solvent; d refer to pyraclostrobin products at the cooling rate of 0.5 K/min under concentration of 15g/100g solvent.
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