| Abstract:In this paper, two research of1.1class new drugs the CBS active pharmaceutical ingredients and DXQ tablets were researched on quality standards according to the requirements of the new drug research and development. In this paper, the quality standards drafts of CBS active pharmaceutical ingredients and DXQ tablets were established. Meanwhile, the stability of drug was studied by the influence factor test, accelerated test and long-term test. The first part:Research on the quality standards and stability study of CBS active pharmaceutical ingredients.1) There are two methods being established for the determination of CBS active pharmaceutical ingredients content. The capacity analysis method was the preferred method for the determination of chemical pharmaceuticals content. The capacity analysis method is as follows:0.1mol/L hydrochloric acid standard solution was added in excess, after the reaction completed, filtered and washed, then merged the filtrate. The filtrate was titrated with0.1mol/L sodium hydroxide until the solution turned pink (phenolphthalein as indicator), the content of CBS in active pharmaceutical ingredients was determined by the consumption of sodium hydroxide. But due to the isomers of the CBS affects the specificity and accuracy of capacity analysis method, it is difficult to accurately measure its content. While the HPLC method is specificn accuracy and can be used for the detection of related substances. So the HPLC method was chose as the detection method. Chromatographic condition:Method:chromatographic column was Phenomenex LUNA C18250×4.6mm5μm; mobile phase:methanol-0.1%THA(45:55);the ultraviolet detection wavelength was279nm,the flow rate was1.0ml/min; the injection quantity was20μl and the column temperature was40℃. At the same time, the HPLC method was inspected its sensitivity、linearity、 precision、reproducibility. The results showed that this method is high precision and good reproducibility, the linear was perfected in the range of10-100μg/ml, can be used for CBS content determination. The content of CBS could not less than98%calculated on dry product. 2) The method for the determination of the related substances was established on the basis of the HPLC determination of content, and determinate the preliminary structure of increasing relative materials under the strong illumination condition by LC-MS. The durability of the method was investigated by strong acid, strong alkali and oxidation experiment. The test results show that CBS was stable on the condition of strong acid. the purity of CBS is down to90%on the condition of strong alkal、hydrogen peroxide oxidation by the determination of HPLC. The method is specific and can well separate CBS from its related substances(R>1.5).The determination of the related substances was self-control method of principal component without the correction factor of the related substances.3) To establish a method for detecting the residual in CBS API by Headspace-capillary gas chromatography. Gas chromatography conditions:the capillary column was DB-Wax(30m×0.45mm,0.85μm)with the FID detector and nitrogen as carries gas, the spilt ratio was10:1. The injector temperature was200℃, and the FID detector temperature was250℃. The column temperature program was initially50℃(hold6min) and increased at the rate of40℃/min to200℃(hold5min). Headspace sampler conditions:vial press:oven:80℃, loop:90℃, line:100℃, vial equilibrium time:30.0min. The results showed that two kinds of solvents methanol、ethanol separated good, a good linearity was observed at the experimental concentration, the rate of average recovery was in the range of95%～105%. There was no methanol、ethanol detected in the CBS sample.4) Inorganic check:We did inorganic checks of CBS according to the regulations of the pharmacopoeia. The results showed that:chloride was less than0.025%、sulfate was less than0.05%、heavy metals was less than20ppm、arsenic salt was less than2ppm、weightlessness was less than0.5%. Because the product is inorganic salt, sodium on ignition residue tentative is less than20%, all items conformed to the requirement of pharmacopoeia.5) Stability study:stability study includes influencing factors tes、 accelerated test and long-term test. The influencing factors testing:the samples of0,5,10days were detected on high temperature, high humidity and strong light. The results indicated that CBS API was stable to heat and humidity, and there were degradation products on strong light conditions. Accelerated testing:the drug was placed in the condition of40℃and75%(RH). The samples on the end of0,1,2,3,6,9months were tested. The results showed that the CBS API was stable on this condition. Long-term experiment:the drug was placed on the condition of25℃and60%(RH).The samples on the end of0,3,6,9months were tested. The results showed that the CBS API was stable on this condition. The further tests were still ongoing.The second part:The polymorph of DXQ API and study on quality standard and stability of DXQ tablets1) Preparation and characterization of polymorph of DXQ API: Polymorph of DXQ was prepared by slow solvent evaporation method and was characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). It was showed that DXQ crystal was monoclinic with the space group being P21/n in SCXRD study. The cell parameters were found to be: a=6.8746(5) A, b=4.9454(4) A, c=24.798(2) A, α=90°, β=92.117(7)°, γ=90°.The2θ of main peaks in the PXRD patterns appeared at13.37°,14.14°,16.94°,21.70°,24.74°,26.60°,28.35°,36.50°, while an endothermic peak in the DSC pattern appeared at109～112℃.This paper prepared and characterized the polymorph of DXQ.2) Study on quality standard and stability of DXQ tablets:It mainly included appearance、character identification、examination and the determination of content and stability study etc. In the dissolution test, by investigating different dissolution method, different dissolution medium, and different speed, we finally chose stirring paddle method and used900ml water as dissolution medium, the speed of50revolutions per minutes,45minutes sampling. Dissolution amount is more than90%. Stability studies used the established HPLC method. The changes of DXQ tablets on the high temperature、high humidity、strong light conditions were studied by influencing factors test, accelerated test and long-term experiment. The results indicated that tablet was stable to heat, humidity and light. Accelerated test and long-term experiment had been carried out showing that DXQ tablets was stable, and further tests was still ongoing. |
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