Study On Preparation And Cocrystallization Mechanism Of Low-Melting Pesticides

Suspension concentrate is an environmental-friendly pesticide formula.But at present some agricultural chemicals are low-melting crystals.During the pesticide manufacturing process via grinding they are much likely to melt due to local high temperature.So it is difficult to prepare these low-melting crystals into suspension concentrate by conventional grinding.Moreover,the low-melting material is inclined to oil out in the crystallization process due to its low melting point,which inhibits the crystallization,so that the obtained crystals are in low purity and poor quality.Pyraclostrobin(ZJ)and Flusilazole(FZ)are two typically low-melting crystals,in this paper,according to crystal engineering strategy methyl thiophanate(TM)was used as a high-melting conformer to cocrystallize with low-melting conformers,in this case,ZJ and FZ,to form cocrystals.Then,the structures and properties of the two cocrystals and the preparation process via suspension method were studied systematically.The development of a new solid-state form---pesticide-pesticide cocrystal can not only improve the melting point of low-melting substances,but have great importance to the synergistic effect and the production of environmently-friendly pesticide formula.Two polymorphs of FZ-TM cocrystal were screened by liquid-assisted grinding.The melting point of one,called form I which is stable,is 126.01 ℃ and the other,form II which is metastable,is 96.28 ℃.Two forms were monotropic.Form II transformed to form I following by melting at about 96 ℃.The single structure of FZTM cocrystal form I was determined by single crystal X-ray diffraction and FZ and TM interacte via N-H---H.The both torsions of TM and FZ changed after TM-FZ cocrystal formation.The ternary phase diagrams(TPDs)of ZJ-TM cocrystal were determined at 40 ℃ and 50 ℃ by high performance liquid chromatography(HPLC).It was confirmed that the pure ZJ-TM cocrystal can be obtained when the initial mass ratio of TM to ZJ was in the range of 1.75～1.85 at 50 ℃,or 2.03～2.05 at 40 ℃.In the dissolution test FZ and TM were dissolved simultaneously almost in the cocrystal ratio during FZ-TM cocrystal dissolution process,whereas ZJ and TM were dissolved above the ZJ-TM cocrystal ratio with a maximum concentration ratio of TM to ZJ of 4.5.It provided the opportunity of synergic effect between two pesticides and was of great significant for reducing amount and increasing efficiency of pesticides.In the cocrystal preparation process via suspension method,temperature and solvents were investigated and found that the process undergone four stages of oiling out,opaque viscous substance,solidification and suspension above temperature threshold in certain solvent system.Oiling out of low-melting substance was the key factor for the process occurance.Amorphous ZJ(FZ)and crystal TM were present in the opaque viscous substance on which solvent and temperature exerted great influence.The solidification process of viscous substance was measured by off-line sampling to run PXRD test,which was parallel to cocrystal formation.Finally,it was revealed that the amorphous mediated mechanism of ZJ-TM cocrystal or FZ-TM cocrystal formation via suspension method.When below the critical temperature ZJ-TM cocrystal formation via traditional suspension method took one week,whereas it would be reduced to only about 4 hours after reaching the critical temperature.And the duration of FZ-TM cocrystal formation was reduced from about 5 hours to only several minutes.The above research content has not been reported in the literature.