Preparation, Qualitative And Quantitative Analysis Of Polymorphs Of The Anticoagulant Rivaroxaban

Rivaroxaban,a new anticoagulant drug jointly developed by Johnson & Johnson of the United States and Bayer of Germany,is marketed under the trade name Xarelto.It was first listed in Canada in September 2008 and listed in the European Union in October.It was launched in China in June 2009.Available on the market.Rivaroxaban is used for the treatment and prevention and secondary prevention of various thromboembolic diseases,especially stable angina pectoris,unstable angina pectoris,with ST-segment elevation(STEMI)and without ST-segment elevation(no STEMI)Myocardial infarction,stroke and cerebral ischemia in patients with atrial fibrillation,re-occlusion and restenosis after angioplasty or aortic coronary artery bypass surgery,peripheral vascular occlusive disease,temporary ischemic attack,pulmonary embolism or Deep venous thrombosis after hip or knee replacement.Rivaroxaban is the world's first oral anticoagulant.Compared with traditional anticoagulants,it has better activity and higher bioavailability.It is clinically shown that the bioavailability can reach 80%and does not require other cofactors such as The mediation of angiotensin can specifically block the active site of coagulation factor Xa,and its absorption and metabolism will not be affected by food during the course of taking it.Rivaroxaban,as an inhibitor of factor Xa(activated inflammatory factor)that is common to both endogenous(contact activation)and exogenous(tissue factor-mediated)pathways,not only has anticoagulant effects but also anti-inflammatory effects.At present,rivaroxaban has been listed in many countries and has a very broad market and good application prospects.Four crystal forms of rivaroxaban have been found.The medicinal crystal form is crystal form ?.It is easy to produce other crystal forms during its production process.In order to ensure the efficacy and safety,it is necessary to establish a qualitative and quantitative analysis.The method of monitoring and controlling its impurity crystal form content.The research work of this article is mainly divided into four parts.1.Based on the anticoagulant Rivaroxaban crystal form ?,the polymorphic form was prepared by recrystallization method,and two crystal forms ?(medicinal crystal form)and five crystal forms ? were determined.Preparation.2.Modern analytical methods such as X-ray powder diffraction(PXRD),differential scanning calorimeter(DSC),elemental analysis(EA),mass spectrometry(MS),infrared spectroscopy(IR)and other modern analytical methods are used to qualitatively prepare the crystal form and The morphologies of different crystal types were observed by scanning electron microscope(SEM).The results show that the PXRD and DSC analysis results of the crystal forms ? and ? prepared by this method are consistent with domestic and foreign patents.The detection results of EA,MS and IR are consistent with the chemical structure of rivaroxaban.The SEM shows that the crystal form ? is flake Lamellar,crystal form ? is linear,and crystal form ? is striped.Compared with domestic and foreign patents,the method for preparing crystal forms ? and ? in this study is reliable,the required reagents are easy to obtain,the experimental conditions are easy to realize,and the preparation process is simple and convenient,which provides a new reference for the production and application of rivaroxaban.3.First,use X-ray powder diffractometer(PXRD)and differential scanning calorimeter(DSC)to qualitatively analyze the mixed crystals that appeared during the recrystallization process,and determine that they are mixed crystals of crystal form ? and crystal form ?.Quantitative analysis of impurity crystal form ? was carried out by X-ray powder diffraction K value method.The results show that the K value of crystal form ? is 1.17,the content of crystal form ? in the mixed crystal is 60.55%,and the standard deviation between the theoretical value and the actual value of the quantitative analysis is 0.2%,indicating that the method has good accuracy and is convenient and fast.,Simple and practical.4.Using the third part of the DSC data combined with the X-ray powder diffractometer in situ high temperature accessory(in situ high temperature)to investigate the phase transition of the crystalline form ? under heating conditions,the results show that the phase transition of the crystalline form ? will occur at about 190?.Transformation,gradually transformed into crystal form ?.This article provides the preparation methods of rivaroxaban crystal forms I and ?,and establishes qualitative and quantitative analysis methods for them.The phase transition of crystal form ? is also investigated,which provides information for the production,identification and storage of rivaroxaban.reference.