Study On The Mass Fragmentation Pathway Of Sartans And The Qualitative And Quantitative Research Of Azilsartan Medoxomil And Related Impurities

Hypertension, one of the common chronic diseases, can cause the organic and functional lesions of brain, kidney and heart. In recent years, the prevalence rate is rising year by year and shows low aging tendency. The investigation revealed that nearly 29.6% people are affected by hypertension in China, and this figure is predicted to increase to 1.56 billion around the world by 2025. It has been the worldwide problem for us to resolve urgently. Sartans is a clinically commonly-used hypotensive drugs. Compared with others, sartans not only has significant blood pressure reduction, but also shows the characteristics of selectivity, specificity, no cough and angio-edema. It is considered as the milestone in the treatment of hypertension and it has a vast application prospect. There are many kinds of sartans,such as olmesartan, valsartan, azilsartan medoxomil, et al. Azilsartan medoxomil, as the precursor of azilsartan, was developmented by Takeda in 2011. The 5-oxo-l, 2,4-oxadiazole ring of azilsartan medoxomil and tetrazole ring of other sartans(candesartan cilexetil, valsartan, olmesartan) are acidic bioisostere, and the former not only shows more efficient in oral bioavailability(60%) but also has a relatively long half-life.In this thesis, the technical of electrospray ion trap mass spectrometry(ESI-MSn)was used to study the fragmentation mechanism of sartans. A new fragmentation pathway was proposed through analyzing the MSn data and verified by HRMS, H/D exchange experiment and theoretical calculation. The study provides references for the mass fragmentation mechanism analysis of compounds with hetero atoms.Side products are always produced in the synthesis process of drug and lead to a low yield. In this paper, the relative substances were separated and identified from azilsartan medoxomil and its synthesis intermediates by HPLC-ESI-MS/MS in positive detection mode. Total 6 impurities were detected and verified through the relative retention time of HPLC. And then, the limit of detection(LOD) was determined by UHPLC-Q-Exactive. The method showed a good linearity withcorrelation coefficients(R) not less than 0.992. The LOD was in the range of 0.01-0.1μg/mL(S/N=2-3). The result indicate that this method has high precision and good accuracy. Our research provide a better method for determinate of azilsartan medoxomil and synthesis intermediates’ quantity and a technology support for optimize the azilsartan medoxomil’s craft.