Investigation On Solid Forms And Crystallization Process Of Lenvatinib Mesylate

Lenvatinib mesylate is one kind of oral multikinase inhibitor,which has been widely used in the treatment of differentiated thyroid cancer.The solid state of commercially available lenvatinib mesylate is form C,which has the disadvantages of low solubility,small particle size,and uneven particle size distribution,and insufficient research on its crystallization process.Therefore,in this work,the new crystal forms of lenvatinib mesylate were screened,and its crystallization process was also systematically studied based on the research of crystallization thermodynamics and desolvation process.Firstly,screening experiments on the new solid form of lenvatinib mesylate were performed.One new anhydrous form and five new solvates were directly prepared by using various crystallization methods such as suspension crystallization,cooling crystallization,and antisolvent crystallization.In addition,another new anhydrous form was obtained through the desolvation process of the formamide solvate.The seven new solid forms were characterized by polarized light microscopy(PLM),powder X-ray diffraction(PXRD)and thermal analysis(TG,DSC),and the characterization results were analyzed in detail.Secondly,the crystallization thermodynamics of lenvatinib mesylate was investigated.The solubility data of lenvatinib mesylate DMSO solvate in pure solvents(DMSO,DMF,acetonitrile,and ethyl acetate)and mixed solvents(DMSO-acetonitrile and DMSO-water)was measured using dynamic method,static method or in-situ Raman method.Solubility data of the above three solid forms of lenvatinib mesylate were fitted and comparative analysed by the Apelblat equation and λh equation in the empirical model and the NRTL equation in the activity coefficient model,and the mixed thermodynamic properties of dissolution processes were calculated according to the NRTL equation.Then,the desolvation process of lenvatinib mesylate DMSO solvate in DMSO-water mixed system was studied.The composition of the solid phase was monitored by in-situ Raman spectroscopy and the results were verified by quantitative powder X-ray diffraction.At the same time,the change of solute concentration in solution over time was determined by gravimetric analysis and the rate control step was determined.Furthermore,the impacts of water activity and temperature on the desolvation process were investigated and one new solvent-mediated desolvation transformation mechanism was proposed.Finally,the crystallization process of lenvatinib mesylate DMSO solvate was optimized based on the above researches.The effects of crystallization method,type of antisolvent,cooling rate and amount of seed on the particle size distribution and yield of the product were investigated and a better crystallization process was developed.By comparing the products prepared by the process before and after optimization,the average particle size of the new process product is about 5 times that of the original process product,and the yield is 1.4 times that of the original process product.