Study On Polymorphism And Spherical Crystallization Of Trehalose

Trehalose,as a kind of natural sugar with special biological protection function,has broad application in biomedicine,food,cosmetics and other fields.The dehydration process of trehalose dihydrate and the transformation mechanism between different forms were studied.These results are conductive to disclosure the molecule interactions between trehalose and water as well as the thermal stability of trehalose dihydrate.At present,trehalose is mainly prepared by cooling crystallization in aqueous solution.There are problems such as high viscosity,nonuniform particle size distribution and poor appearance,which affect the flowability and bulk density.It is an urgent problem to develop a new crystallization process which can regulate the morphology of trehalose crystals in industrial production.Therefore,polymorphic transformation of trehalose,crystallization thermodynamics and the development of spherical crystallization techniques were systematically studied.Firstly,the dehydration process of trehalose dihydrate was studied from solid-state transformation and solution-mediated transformation.The phase behavior of dihydrate is greatly affected by experimental conditions during heating process.The dehydration mechanisms were different at different heating rates.The induction period of dihydrate is very short,and the growth of anhydrous β form is the controlling step in solventmediated transformation process.By comparing the crystal lattice parameter,molecular assembly model and intermolecular hydrogen bond between dihydrate and two solventfree forms of trehalose,the reason for the hygroscopicity difference between α and β form was revealed.Secondly,the static method was applied to determine the solubility of trehalose dihydrate in two different binary solvent mixtures.The solubility was positively correlated with temperature and water content in the solvent mixtures.Therefore,cooling crystallization or anti-solvent crystallization is a useful method to prepare trehalose product.Three thermodynamic models were employed to correlate the experimental data,and Apelblat equation gave the best results.The ternary phase diagrams of trehalose dihydrate-isopropanol-water system at 50 °C and 60 °C were determined using static and dynamic methods,from which the range of liquid-liquid phase separation can be determined.The process analysis technique was used to study the formation of liquid-liquid phase separation,and it was found that crystals obtained from liquid-liquid phase separation aggregated seriously.Finally,spherical crystals of trehalose dihydrate and anhydrous β form were prepared by anti-solvent crystallization.The formation mechanism of spherical dihydrate crystals in the isopropanol-water system was quasi-emulsion solvent diffusion.The on-line and off-line tools proved the formation mechanism of spherical anhydrous β crystals in the methanol-water system to be spherical agglomeration.Stirring rate and crystallization temperature have impacts on the particle size distribution of trehalose spherical products.Stirring rate,crystallization temperature and residence time will affect the particle size and morphology of trehalose spherical products.Meanwhile,the water content of methanol-water system can change the crystal structure of the spherulitic products.All the contents discussed above have never been reported by any other related literatures.