Investigation On Polymorphs And Phase Transformation Process Of Levofloxacin Hydrochloride

Levofloxacin hydrochloride is an important broad-spectrum antibiotic,which is widely used in the treatment of various infection symptoms caused by sensitive bacteria.Polymorphism phenomenon is observed during the production and storage process of Levofloxacin hydrochloride.Currently,the Levofloxacin hydrochloride products in market are the anhydrous form,Form II.However,it has the drawback of phase transformation and agglomeration due to moisture absorption,which seriously affects its stability and efficacy.In order to solve these problems,the phase transformation mechanism of Levofloxacin hydrochloride was systematically studied,which provided theoretical guidance for the improvement in stability of Levofloxacin hydrochloride.First of all,the monohydrate,Form I and the anhydrate,Form II were prepared by cooling crystallization and suspension crystallization,respectively.Two polymorphs were then characterized by powder X-ray diffraction,polarizing microscope,thermal analysis,Raman spectroscopy and Fourier transform infrared spectroscopy to determine the thermal stability,crystal morphology and molecular structure of them.In addition,the crystal structure of Form II was determined by single crystal X-ray diffraction,which explained the instability of Form II from the perspective of molecular forces in the crystal structure.Secondly,Solubility of Form I and Form II in binary solvent of acetonitrile and water,methanol and water as well as ethanol and water was determined by dynamic method.The simplified Apelblat equation,CNIBS/R–K model and Jouyban-Acree model were applied to correlate the solubility data.The Vant ’Hoff model was used to calculate the thermodynamic properties in the ideal dissolution of the two polymorphs in each binary solvent system.Calculation results show that the dissolution process of Levofloxacin hydrochloride is endothermic and entropy-driven.The study on the crystallization thermodynamics of two polymorphs of Levofloxacin hydrochloride provides a thermodynamic basis for the development of production technology and the study on the phase transformation and nucleation process.Then,Based on the thermodynamic stability of two polymorphs,the solid-solid and solvent-mediated phase transformation processes of Levofloxacin hydrochloride were systematically studied by using a variety of offline and online analysis methods.Thermal analysis and dynamic vapor adsorption(DVS)were carried out to study the transformation process between Form I and Form II in solid state.The effects of different operating conditions on the kinetics of solvent-mediated phase transformation were investigated by using in-situ Raman.Based on the experimental results,a mechanism of solvent-mediated phase transformation was proposed,and the rate-controlling steps of the processes were determined.Finally,based on the influence of different operating conditions on the generation of different polymorphs in the solution crystallization process,the effects of solvent composition and temperature on the nucleation process of Levofloxacin hydrochloride were studied by sudden-cooling crystallization experiments.The results further confirmed the reliability of the mechanism of solution-mediated phase transformation.In addition,the distinct nucleation rates of Form I and Form II proved that water fraction in mixed solvent had opposite effect on the nucleation kinetics of two polymorphs,which broadens the gap between relative nucleation rates of two polymorphs and then leads to the precipitation of different polymorphs in solution crystallization process.