Study On The Crystallization Process Of Azoxystrobin

Azoxystrobin is a new type of high-efficiency bactericide of methoxyacrylic acid vinegar with wide application prospects.The commercially available azoxystrobin product is crystal form A.Form A products are usually obtained by crystallization process in the reaction solution which harvest azoxystrobin butyl acetate solvate and then by desolvation process to remove the solvent.However,due to the lack of control of crystal nucleation and growth,the azoxystrobin butyl acetate solvate crystals are needle-like that are easy to break and coalesce with small average particle size.The poor morphology make the filtration and drying process difficult.The desolvation process of butyl acetate solvate is unclear,the form A obtained by desolvation is not pure,and the residual solvent content in crystals is high.In addition,when the form A is recrystallized in the acetonitrile and water mixture system,the oiling out phenomenon will occur,which seriously affect the process stability and crystal product quality.In view of the above problems,the crystallization processes of azoxystrobin has been studied in this paper.Aiming at the problem of poor crystal morphology of azoxystrobin butyl acetate solvate,this work studied the cooling crystallization process of azoxystrobin in butyl acetate.The influence of operating factors including initial concentration,cooling rate,stirring rate and seed crystal on crystal nucleation,growth and product quality was investigated.Then,the operating parameters of the cooling crystallization process of azoxystrobin butyl acetate solvate were optimized.Aiming at the problems of impure crystal form A and high solvent residue due to the unclear mechanism of desolvation process of azoxystrobin butyl acetate solvate,we further studied the thermal desolvation,solvent-mediated desolvation and crystallization process.Through thermal analysis and other means,it was found that the thermal desolvation process of the azoxystrobin butyl acetate solvate was first melted by heat and then the nucleation and growth of new crystal forms occurred.This phenomenon was further confirmed by the establishment of non-isothermal reaction kinetics,which also provided some guidance for the drying process.The solventmediated phase transformation process of the solvate into form A was studied using Xray powder diffraction and online infrared spectroscopy,and the control steps at different stages were determined.When the solvent polarity and temperature increases,the crystallization rate increases.The study of phase transformation process can guide the controllable preparation of crystalline A.Solvate will be formed when the azoxystrobin is recrystallized in most solvents.The recrystallization in acetonitrile and water can maintain the crystal type A.However,if the process is not well controlled,oiling out will occur,resulting in poor product quality.In this work,the ternary phase diagram of azoxystrobin-acetonitrile-water system at 293.15 K,303.15 K and 313.15 K were measured.The crystallization behavior in different phase regions was investigated under the guidance of thermodynamic phase diagram.The results showed that adding seed at low concentration could avoid oiling out and obtain well dispersed crystals.Moreover,the products obtained from crystallization in different phase regions showed different crystal habit.In the process of oiling out crystallization,the stirring speed has a great influence on the crystal morphology,and the increase of stirring speed promotes the formation of large-sized aggregates,which is in favor of post-processing of products.