Screening,characterization And Pharmacokinetic Of Tasimelteon Polymorphisms

Polymorphic phenomena of drugs can affect the chemical stability,melting point dissolution rate of the drug,which can further affect the production,storage and active pharmaceutical ingredients(API).Therefore,to explore the polymorphisms of drugs have become an important part of drug quality control and drug research and development process of the necessary contentTasimelteon was a small molecule drug for the treatment of non-24-hour sleep disorders of the blind.Tasimelteon polymorphisms were not reported before.Two new polymorphisms of tasimelteon(form Ⅰ,form Ⅱ)were synthesized and characterized.Their crystal structures were compared by thermal stability,dissolution rate and pharmacokinetic differences.The main work and conclusions are as follows(1)In this study,two polymorphisms of tasimelteon were prepared by polymorphic screening.It was found that form Ⅰ belongs to monoclinic system with space group P21.Form Ⅱ belonged to tetragonal system with space group P43212.(2)The structures of these two forms were characterized by PXRD,SCXRD,DSC,TGA,FT-IR,LRS,1HNMR and ss-13CNMR.(3)The equilibrium solubility and intrinsic dissolution rate of form Ⅰ and form Ⅱ were investigated.The results showed that form Ⅱ had better solubility and dissolution rate.(4)The stability of form Ⅰ and form Ⅱ was tested with temperature,humidity and light.The results show that the sample of form Ⅰ is stable at 60℃,low moisture and light,while form Ⅱ is stable under 40℃,high moisture and light(5)The MTT method was used for cell viability determination,and form Ⅰ showed higher cytotoxicity in C6 and U87 cells than form Ⅱ.Pharmacokinetic experiments showed that form Ⅰ was better absorbed in vivo than form Ⅱ.