Study On The Polymorphism Of Dabigatran Etexilate Mesylate

Dabigatran etexilate is a new generation of oral anticoagulant direct,thrombin inhibitors.It is well received because of these advantages in respects of good therapeutic effect,low toxicity,good tolerance,fewer drug interactions,no drug food interactions,without routine coagulation monitoring or dose adjustment,and almost no adverse events.Dabigatran etexilate mesylate is a prodrug of dabigatran etexilate,which can improve the absorption in human body.In addition,dabigatran etexilate mesylate is a typical polymorphic drug,which contains amorphous and various crystal forms.Dabigatran etexilate mesylate is an oral preparation,and the crystal form has a great influence on the drug efficacy,therefore the study of crystal form is particularly important.In this paper,a systematic study was carried out on the polymorphic phenomenon of dabigatran etexilate mesylate by using the method of crystal engineering.The solubilities of dabigatran etexilate mesylate forms Ⅰ,Ⅱ,M and hemihydrate in water,methanol,ethanol,n-propanol and n-butanol were measured by isothermal method.Cooling crystallization was performed to investigate the influence of crystallization parameters including temperature,solvent,solution concentration,stirring rate and seeding on the polymorphic form of final products.A novel polymorphic form M was invented,which can be obtained through cooling crystallization in ethanol-acetone solvents.Further,polymorphic form M was characterized using Powder X-ray Diffraction(PXRD),Differential scanning calorimetry(DSC),Thermal gravimetric analyzer(TGA),Infrared spectroscopy(IR),High performance liquid chromatography(HPLC),moisture meter,and Gas chromatography(GC),respectively.The results showed that polymorphic form M is a hydrate.In view of the integrity of the crystal habit of form M,and the advantages in filtration,washing,drying and packing,the invention shows great potential for industrial production and application.On this account,crystallization process of form M was studied in detail,and the optimal crystallization conditions were subsequently determined:the sample of dabigatran etexilate mesylate was dissolved in solvent mentioned at 50℃,and the mass ratio of sample to solvent was 1:40.Then,.solution temperature was cooled to 5℃,at which 0.5 wt%of seeds was added.After seeding,the solution was kept for 4 h with a stirring rate of 150 rpm.The yield is 80%,the particle size is between 40 μm and 70 μm,and the purity is higher than 99.6%.