Quality Standard Research Of SR

Recently, the target treatment for tumor has acquired more and more development, and the multi-target drugs are widely used clinically because of the great advantage in the pharmacological activity. SR is an orally multikinase inhibitor, and the agent can block EGFR, VEGFR, and shows antiangiogenic activity. On the other hand, SR blocks Raf signaling and has antiproliferative activity. The quality standard of SR has not been contained in any Pharmacopoeia so far, and the project made a research about quality standard in use of lots of analytical techniques. Method validation study was conducted for all the research methods to establish quality standards of SR.Firstly, the research conducted a study about the appearance, solubility and melting point of SR and established a fast and accurate experimental method.Secondly, the method development and method validation of related substances of SR, including genotoxic impurities, were proceeded in the topic. After the investigation of chromatographic column, mobile phase, diluent, flow rate and column temperature, HPLC methods for related substances, and genotoxic impurities were separately established. The method to detect related substances of SR was established as follows: Waters e2695 HPLC, 2489 ultraviolet detector, column for Waters C18 Symmetry Shield^TM?5?m,4.6×150mm?, mobile phase for organic phase was acetonitrile and ethanol, aqueous phase was 0.01 M sodium dihydrogen phosphate?pH was adjusted to 3.0 with diluted phosphoric acid?, detection wavelength was 265 nm, column temperature was 40 ?, flow rate was 1ml / min, the injection volume was 10 ?L, and the method was validated. The results showed that the method would fast detect the impurities of SR, and related substances in three batches of samples was examined and not exceeded 0.1%.Thirdly, gas chromatographic method for the determination of residual organic solvents in SR was established in the topic. The best GC system was Agilent 7890 A, the direct inlet probe was Agilent G4513A, column was Agilent DB-FFAP capillary column?60m×0.53mm×1.0?m?, the detector was FID, the detector temperature was 250 ?. The column temperature was programmed, the starting temperature was 40 ? and maintained for 10 minutes, and the temperature would rise to 130 ? at a rate of 10 ? per minute. After the temperature maintained for 12 minutes, it would rise to 200 ? at a rate of 10 ? per minute and maintained for 20 minutes. The carrier gas was nitrogen, and the temperature of gasify room was 220 ?. The injection volume was 10 ?L.The method validation showed that the method has a good linear relationship, a good sensitivity and precision. The residual organic solvents in three batches of samples were examined with internal standard method, and the results showed that the residual ethanol did not exceeded the limit, while the other solvents were not detected.At the same time, a little adjustment was made about HPLC method of related substances to establish the method to determine the content of the sample. And the method validation for sample content determination was also conducted. The results showed that the method would determine the content of SR accurately. The content of three samples of SR was determined and the result was between 98% and 102%.In the end, a HPLC method was established to determine the ratio of tosylate, and the method was validated. The validation results show that the method can be used to test the ratio of tosylate. The moisture determination, loss on drying, residue on ignition and heavy mental detection of SR were conducted, and the results showed that three batches of samples met the requirement. The stability tests of samples were studied, and factors test was mainly performed. The results showed that SR was stable in the infuluence of high temperature, humidity and light, and the content and related substances did not change obviously.The research above provides the basis for the draft quality standard of novel drug SR, and gives foundations to the preparation craft studies and manufacturing technique design.