Study Of Critical Quality Attributes And Standard For Rupatadine Fumarate Orally Disintegrating Tablets

Objective: The study of critical quality attributes and standards of rupatadine fumarate orally disintegrating tablets was carried out to establish the control methods for the critical quality attributes of substance,content and dissolution,and to establish the draft quality standards of rupatadine fumarate orally disintegrating tablets based on the Chinese Pharmacopoeia,import registration standards and relevant standards of ICH.It will provide the basis for the subsequent clinical study of this variety.Methods:(1)A Waters XBridge C18(3.5μm 4.6×150mm)column was used with0.05mol·L-1 sodium dihydrogen phosphate solution as mobile phase A and acetonitrile as mobile phase B with gradient elution,flow rate 1.0m L·min-1,column temperature35℃,detection wavelength 242 nm,injection volume 50μL,to examine the relevant substances of lupatadine fumarate orally disintegrating tablets.(2)A Waters XBridge C18(3.5μm 4.6×150mm)column was used with mobile phase A of 0.05mol·L-1 sodium dihydrogen phosphate solution and mobile phase B of acetonitrile with gradient elution,flow rate of 1.2m L·min-1,detection wavelength of 242 nm,column temperature of 35℃,injection volume of 50μL The content and solubility of lupatadine fumarate oral disintegration were examined.(3)Sample stability studies were carried out,including influence factor tests,accelerated and long-term stability tests.(4)To establish a draft quality standard for lupatadine fumarate orally disintegrating tablets.Results:(1)The separation of lupatadine from adjacent impurities and each impurity was greater than 1.5 by HPLC;the limits of quantification of impurities A,B,C,D,I and J were 5.1975,5.5541,24.3482,2.0800,4.9305 and 5.1460 ng·m L-1,respectively,and were within the corresponding ranges.The average recoveries of each impurity were in the range of 99.84%~109.22% with RSD less than 2%.The results of forced degradation test showed that the main peak of orally disintegrating tablets in acid,alkali and light conditions were basically free of degradation,slightly degraded in high temperature conditions and more degraded in oxidation conditions.(2)The linearity of the method was good under the chromatographic conditions,and the average recovery of lupatadine fumarate orally disintegrating tablets was 99.97% with RSD less than 2%;the contents of the three batches of orally disintegrating tablets were between 97.75%and 101.68%.(3)The limit of quantification of lupatadine under chromatographic conditions was 4.45ng·m L-1,and the linearity was good in the corresponding range;the average recovery was 98.68%,and the RSD was less than 2%;the solubility of the three batches of orally disintegrating tablets were all in the range of 100.6%~101.8%.(4)The test results of the influencing factors show that the orally disintegrating tablets did not show significant changes in the indexes under the conditions of high temperature 40℃,high humidity and light for 30 days,and there was a large increase in the high temperature and oxidative degradation impurity I in the relevant substances under the condition of high temperature 60℃,but the other indexes did not show significant changes and were relatively stable;in the accelerated test,the orally disintegrating tablets simulated the marketed packaging and were examined by the temperature of40℃±2℃ and relative humidity of 75%±5%,and the present proceeded to 3 months,the degradation impurity A in the relevant substances slowly increased(increase of about 0.2%),but are less than 1.0%,other impurities are no significant changes,the sum of each impurity slightly increased,other investigation indexes did not see significant changes,in line with the quality standard provisions.It shows that the orally disintegrating tablets are stable under the accelerated test conditions for 3 months;in the long-term test,the orally disintegrating tablets are simulated to be packed in the market,and examined by the temperature of 30℃±2℃ and relative humidity of 65%±5%,and now it has been carried out to 3 months,the indexes of the orally disintegrating tablets have not seen obvious changes,which are relatively stable and meet the quality standard.It indicates that the orally disintegrating tablets are stable under long-term test conditions for 3 months.The follow-up stability test is still in progress.Conclusion: In this study,the quality attributes of rupatadine fumarate orally disintegrating tablets were studied systematically,focusing on the development and validation of methods for related substance,content and dissolution,and the established analytical methods were able to accurately and effectively control the quality of each index,and at the same time,the preliminary stability was examined and the storage method was determined.