Study On The Ciclesonide Solvate And Desolvation Process

Industrial crystallization is not only an important purification unit operation,but also a key technology of manufacturing high-end crystal products which have specific crystal morphology and specific functions,the industrial crystallization has been widely used in pharmaceutical manufacturing process.The pharmaceutical solvates,which was also considered a kind of polymorph,often exist in the solution crystallization process.The crystal products often have poor crystal shape,thus causing difficulty in postprocessing and poor pharmaceutical preparation properties.In order to solve these general difficult problems,this work proposed a novel effective way that using the desolvation to produce the crystals with high quality.Meanwhile,this work also proposed a new research approach to developing and optimizating of novel solid products.The model compound in this work,ciclesonide,is a kind of corticosteroid drug with efficient local anti-inflammatory functions.Now,the ciclesonide manufactured in China generally has the problems of small crystal size,low purity,easy agglomeration,and difficult postprocessing.To solve the problems of the production,this study was focused on the crystal form screening,crystal structure analysis,crystallization thermodynamics,solid desolvation and crystal form transformation process,solvent mediated phase transformation process of solvates and the development and optimization of crystallization process of ciclesonide.Three novel solvates of ciclesonide were screened by adjusting the solvents and crystallization methods.The X-ray diffraction technologies were applied to determine and analyze the crystal structures of the solvates;by means of the thermal analysis,the existing types of the solvent molecules in different solvates were confirmed;meanwhile,crystal shape and crystal size distribution were further characterized,showing that the solvates had better crystal shape than solvent-free ciclesonide.The solubility of ciclesonide in seven pure solvents at different temperatures was determined by gravimetric method and the solubility of ciclesonide solvates in binary solvent mixtures was determined by dynamic method.The experimental solubility data provided the fundamental data for the research on the development and optimization of desolvation process.Solute-solvent interaction energies were calculated by molecular simulation,which could sufficiently explain the rule that the solubility varies with the intermolecular interactions.Then the solubility was well correlated by the Apelblat equation,van't Hoff equation,?h equation,wilson equation and NRTL equation.The apparent dissolution thermodynamic properties and the mixing process thermodynamic properties were obtained by the solubility based on van't Hoff equation and wilson equation,respectively.The solubility of solvates in mixed solvents showed that the solubility increased with the increase of temperature at a constant composition of the solvent.And there is a maximum value of solubility at different temperatures with various compositions of the solvent.Based on the analysis of the solubility of the solvates in different solvent mixtures,the patterns of the crystal form transformation of different solvates in the binary solvent mixtures with various compositions were obtained.Then the process analytical technologies(PAT)were applied to monitor the crystal form transformation processes of the three solvates,and the mechanism of the crystallization was discussed.Several PAT tools including hot-stage microscope,powder X-ray diffraction with temperature changing and thermal analysis were used to investigate the desolvation processes of the solvates at solid state under heating conditions.The crystal form,crystal shape,solid phase transformation and the thermal and gravimetric variations during the desolvation process were studied and discussed.Furthermore,the mechanisms of the desolvation process of three solvates under the isothermal or heating conditions were explored based on the theory of solid state reaction and the key factors in the desolvation process was also analyzed.Based on the above study,the desolvation process of solvates in binary solvent mixtures was studied,a new crystallization strategy to obtain ciclesonide by solvent mediated desolvation of the solvates in the aqueous binary solvent systems was developed.Besides,the operating parameters of the new approach were optimized,and thus the crystallization process was determined.The crystal properties including the crystal shape and size distribution of ciclesonide were significantly improved by the new method,offering a new approach to improving the crystal properties.