Study On Conformational Polymorphism Of Furosemide And 4-hexyloxybenzoic Acid

Polymorphism widely exists in solid drugs.Different solid-state forms exhibit different physicochemical properties such as stability,melting point,hardness,density,solubility and dissolution rate,which directly results in significant differences in clihical efficacy.Thus,the study on crystallization behavior of pharmaceutical products has important directive to the polymorphic control and optimization of the products.Furosemide is a diuretic or antihypertensive drug,it has been reported to have three polymorphs and two solvates.4-Hexyloxybenzoic acid,as a mesogenic compounds,exits in two polymorphic forms.Furosemide and 4-hexyloxybenzoic acid molecules have a high degree of conformational flexibility,thus these two drugs can be selected as the research model drugs to study the relationship between conformational flexibility and crystallization.In this work,the crystallization thermodynamics and kinetics,polymorphic transformation kinetics were studied.Fistly,the different forms of furosemide and 4-hexyloxybenzoic acid were prepared by solution crystallization,and the polymorphs were characterized by PXRD,IR,Raman,DSC,TG,SEM and polarizing microscope.The differences in structure and thermodynamic stability of different crystalline forms were clarified.Secondly,the solubility of furosemide form I and 4-hexyloxybenzoic acid form I in various pure organic solvents were measured by static method.The solubility data were correlated by Apelblat simplified empirical equation,λh equation and Van’t Hoff equation,and the enthalpy,entropy and Gibbs free energy of dissolution of furosemide form I and 4-hexyloxybenzoic acid form I were calculated.Thirdly,the effects of temperature,solvent and supersaturation on nicleation induction time and formation of polymorphs were investigated in different crystallization experiments such as crash cooling crystallization,evaporative crystallization and anti-solvent crystallization.Using Guassian 09 quantum chemical simulation software,the potential energy surface scanning of molecular was performed.The energy difference between different conformations and the difficulty of conformational transformation can be judged by potential energy surface,which can clarify the influence of molecular conformational flexibility on poly crystalline crystallization process.Finally,off-line PXRD and in-situ Raman spectroscopy were used to study the solvent-mediated polymorphic transformation of furosemide and 4-hexyloxybenzoic acid from form Ⅱ to form Ⅰ,respectively.The effects of temperature and solvent on the polymorphic transformation rate were investigated.In this work,the conformational polymorphisms of furosemide and 4-hexyloxybenzoic acid were studied,which can provide theoretical guidance for revealing the molecular assembly process of drug polymorphisms at the molecular level.