A Study On The Polymorphs And Solvates Of Boscalid

Polymorphs are common phenomenon in pharmaceutical industry.Each form generally displays different physicochemical properties which are closely related to the bioavailability and manufacture of active pharmaceutical ingredients.Solvates always can't be used as pharmaceutical forms directly,but the desolvation process provides a method for obtaining new polymorphs.Hydrates,as a special kind of solvate,can be directly used in formulation for its safe and green solvent in lattice.The studies with regard to polymorphs and solvates play an important role not only in the field of medicine,but also in the field of agrochemical and veterinary drugs.In this work,a novel fungicide boscalid was considered as model for the study of polymorphs and solvates.The solubility of boscalid form II in pure solvents(methanol,ethanol,n-propanol,isopropanol,n-butanol)and solvent mixtures(ethanol + ethyl acetate,isopropanol + ethyl acetate)was determined by dynamic method.The solvent composition and experimental temperature were important factors affecting the solubility.Further,the solubility data were correlated by Apelblat equation,?h equation,CNIBS/R-K equation and Jouyban-Acree equation.The thermodynamic properties of the mixing process were calculated based on activity coefficient model NRTL equation.The results show that the mixing process of boscalid in each solvent system is endothermic,spontaneous and entropy driven process.The solubility of form I in pure solvents was also determined experimentally.The results show that the solubility of metastable form I was much higher than that of form II.Different solvent systems and crystallization methods were used to screen the solid forms of boscalid.Two polymorphs,one hydrate and three new solvates were prepared successfully and fully characterized by powder and single X-ray diffraction,scanning electron microscopy,differential scanning calorimetry,thermogravimetric analysis and fourier transform infrared spectroscopy.The single crystals were revealed for the first time,and the distinct molecule conformations,H-bonding interactions,and packing arrangements were investigated through single-crystal structure analysis and Hirshfeld surface analysis.The desolvation process of solvates was studied and discussed based on thermal analysis.The solvent-mediated transformation of boscalid from form I to form II was monitored using off-line and on-line methods.The results show that the nucleation and growth of stable form were the rate determining steps during polymorphic transformation process.The effects of solvent,temperature and solid phase loading on the transformation rate were systematically investigated,respectively.The kinetic equation of polymorphic transformation was established with the Avrami-Erofeev model using XRD quantitative analysis.And the activation energy of the transformation process was also calculated according to Arrhenius equation.No same report to above study results has been published in literature up to date.