Research On Polymorphism Of Rivaroxaban And Betrixaban

Polymorphism is widespread in solid chemical drugs,and has a direct impact on the physicochemical properties of the drug,which may result in differences in the bioavailability of the drug in vivo.Anticoagulant drugs such as rivaroxaban and betrixaban belong to polycrystalline solid drugs.According to related patent,seven polymorphisms of rivaroxaban,three crystals and many kinds of salt-forming crystal of betrixaban have been reported in past decade years.There are significant differences in solubility and stability for the polymorphic forms of the anticoagulant drugs,so it is important to study the polymorphism of the drugs comprehensively.In this paper,the anticoagulant drugs like rivaroxaban and betrixaban were mainly studied.Firstly,multiple recrystallization methods were adopted,and the crystallization process of rivaroxaban polymorphism was optimized with a variety of solvent systems.Secondly,the rivaroxaban single crystal with regular appearance and large size was successfully cultured under the standing condition at room temperature,and the crystal structure was successfully analyzed to obtain complete single crystal data.Form I crystals with different orientations are obtained using different reaction solvents,and the solubility thereof is measured and analyzed;Finally,under a various reaction solvents and recrystallization processes,a monohydrate amorphous of berixaban was obtained and its thermo stability was also investigated.The specific research contents are as follows:?1?Using a variety of recrystallization process,such as low temperature crystallization,evaporation crystallization,spin steaming and mixing crystallization,obtained the rivaroxaban polymorphs including crystal form I,?,??hydrate?,solvate and amorphous.At the same time,the crystallization process of Form II and monohydrate is optimized.Form II can be directly obtained by stirring and crystallizing amorphous in tetrahydrofuran solvent.The crystallization temperature of monohydrate is increased from-20?to 0?.?2?A single crystal of rivaroxaban crystal form I was obtained by a single crystal culture method in which the room temperature was allowed to stand.The single crystal diffraction data of the crystal form I was obtained by single crystal X-ray diffraction test as follows:a=8.9912?5??,b=10.9764?6??,c=11.2144?7??,?=63.410?6?°,?=74.348?5?°and?=78.142?5?°.The unit cell volume V=948.38?11??³,the space group is P₁,the number of molecules in the unit cell is Z=2,and the total number of diffraction points in the unit cell F?000?=452.0.At the same time,using different solvent systems and different material ratios to obtain rivaroxaban crystals with different orientations,P1 is preferentially grown on the?0 2 1?plane and P2 is preferentially grown on the?1 2 0?plane.The thermal enthalpy and particle size of P1 were both greater than P2,thus resulting in an apparent solubility of P1?1.88 mg/mL?less than the apparent solubility of P2?2.60 mg/mL?.?3?Screening of new crystal form of betrixaban was carrying out using freeze-dried crystallization technology by adjusting the solvent medium and material ratio,and a monohydrate amorphous was successfully found using the material ratio of 1?5¹5 in the solvent medium with anhydrous ethanol as the good solvent and deionized water as the anti-solvent.The thermal stability and solubility of the new crystal form were tested.The amorphous form still had 1 mol of water molecules after constant temperature at 80°C.During the heating process,a phase transition which change from amorphous to crystal form I was observed at 166°C.The apparent solubility is measured to be 6.10 mg/mL from HPLC,which is obviously higher than that of Form I.Based on above results,and the amorphous is expected to be used as a raw material medicine for formulation production.