| Ticagrelor is the first oral reversible platelet purinoceptor P2Y12 antagonist that binds directly and reversibly to the P2Y12 receptor,producing rapid absorption and rapid blockade of platelet aggregation.Therefore,it is considered as a first-line therapy for the treatment of atherosclerosis and acute coronary syndromes.The chemical structure of tegretol contains six chiral centers,which,combined with the large number and complexity of steps in its synthetic route,results in a high number of potential organic impurities in its finished product.Therefore,it is crucial to fully investigate and control these impurities.The present study is divided into the following parts:(1)Impurity profiling based on the synthesis process and physicochemical properties of Ticagrelor,a comprehensive assessment of organic impurities(14 process impurities and degradation impurities,4 isomeric impurities)and residual solvents(7)was conducted.At the same time,the impurity limits were established with reference to the "ICH guideline Q3".(2)Based on the AQbD concept,the Box-Behnken Design-Response Surface method was used to optimize the method for the substances of interest of Ticagrelor,and the optimized method was able to effectively separate all possible substances of interest,with better separation and peak shape and shorter analysis time compared with the reported methods in the literature.The methodological validation of the optimized method proved that the method has good accuracy,precision and durability.It was also used for the detection of Ticagrelor samples.(3)Establishment of the analytical method for Ticagrelor isomers: A chiral column with C18(model: YMC CHIRAL ART,4.6×250mm,5um),mobile phase: n-hexane:anhydrous ethanol: trifluoroacetic acid(85:15:0.3),isocratic elution for 35 min,detection wavelength: 300 nm;flow rate: 1.2 ml/min;column temperature: Ticagrelor was well separated from each isomeric impurity with good linearity(r>0.990,n=5)in the concentration range of 0.2498μg/m L～1.5604μg/m L for isomers A,B and CD.The average recoveries(n=12)were 94%,102% and 92% with RSDs of 3.8%,5.5% and2.2%,respectively;the limits of detection and quantification,and the precision were all in accordance with the requirements.The chromatographic parameters of flow rate,column temperature and the initial ratio of organic phase had no significant effect on the separation of the method when the flow rate,column temperature and the initial ratio of organic phase were slightly changed,with good durability.It is suitable for the control of the impurity content of Ticagrelor isomers.(4)Seven residual solvents in Ticagrelor API were determined by direct injection gas chromatography.Since triethylamine and acetic acid may react in the residual solvents,the same column could not be used for separation.CP-Volamine capillary column was selected to separate the 6 conventional residual solvents.DB-FFAP strong polar capillary column was selected to analyze acetic acid.And a comprehensive methodological validation of the assay was carried out for the detection of tegretol residual solvents.The results of this study can not only provide technical reference for the quality study of Ticagrelor,but also be used for generic drug registration declaration and daily quality control. |
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