A Study On Polymorphs And Crystallization Process Of XJS

XJS is a new drug that can be applied to the treatment of breast cancer,lung cancer,colon cancer and other diseases,and has important clinical application prospects.At present,there are problems such as unsatisfactory macroscopic appearance of crystal products in the production process of the drug.Due to the slender needle shape of the crystal,the product has a low bulk density and poor flowability,which brings difficulties to the downstream preparation process and is not conducive to subsequent industrialized scale-up production.In the above background,this paper systematically studies the polymorphism and crystallization process of XJS.In this paper,three new solvates of XJS have been obtained by cooling crystallization and suspension transcrystallization: XJS-P,XJS-B and XJS-IB,and a series of characterizations of these three new solvates were performed by X-ray diffraction,thermal analysis,moisture analysis,and infrared spectroscopy.The solubility of XJS-I in common pure solvents(1-propanol,1-butanol,isobutanol,1-pentanol,methyl acetate,ethyl acetate,butyl acetate,acetone)and solubility of XJSP and XJS-B in corresponding solvents were experimently determined by using a dynamic method.The experimental solubility data were correlated by the modified Apelblat equation,the ?h equation,the van't Hoff equation and NRTL model,and the thermodynamic properties were also calculated.The metastable zone of XJS-P in 1-pentanol system was determined by on-line focused beam reflectometer FBRM,and the effect of cooling rate and solution concentration on metastable zone was investigated.Through thermal analysis,the mechanism of desolvation and transmutation of three solvates was studied,and their transformation mechanisms were determined: If the solvent can escape smoothly,XJS-P and XJS-B with layered unit structure can transform to XJS-I with original macroscopic shape;if the solvent removal is hindered,whether or not the two can be converted to XJS-I depends on whether there is XJS-I crystal nuclei induction.XJS-IB,which does not have a layered unit structure,can only transform by solution recrystallization.At the same time,their crystal transformation processes in common pure solvents and mixed solvents were studied.Finally,based on the above research as theoretical guidance,a new crystallization technology was developed for preparing XJS-I crystals with high bulk density and good fluidity.The new technology selected XJS-A as the intermediate crystal form,adopting the cooling crystallization plus crystal transformation process.By examining the effect of various operating parameters on product quality and process yield,an optimized operating condition table was determined.Crystal products obtained under the new crystallization technology has larger particle size and better distribution.The higher bulk density and excellent flowability are favorable for the storage and downstream preparation processes,and the purity of the product is higher than 99.9%,and the yield is above 90%.