ABSTRACT
OBJECTIVE To establish a method for simultaneous determination of the contents of 6 kinds of N-nitrosamines genotoxic impurities in losartan potassium raw material and its formulations. METHODS GC-MS/MS was adopted to determine 6 kinds of N-nitrosamines genotoxic impurities in losartan potassium raw material， Losartan potassium tablet， Losartan potassium capsule and Losartan potassium hydrochlorothiazide tablets， such as N-nitrosodimethylamine （NDMA）， N-nitrosodiethylamine （NDEA）， N-ethyl-N-nitroso-2-propanamine （NEiPA）， N-nitrosodiisopropylamine （NDiPA）， N-nitrosodipropylamine （NDPA） and N-nitrosodibutylamine （NDBA）. The separation was performed on SHIMADZU SH-L-17Sil MS capillary column by temperature- programmed GC， with injector temperature of 250 ℃ ， sample size of 1 μL， carrier gas of helium， and carrier flow rate of 1 mL/min. Electron ionization and multiple reaction monitoring （MRM） data acquisition mode were used， with an ion source temperature of 250 ℃ and solvent delay time of 3.1 min. RESULTS The separation among NDMA， NDEA， NEiPA， NDiPA， NDPA， NDBA and adjacent chromatographic peaks was good， and the separation rate was higher than 3.8； the linear ranges of them were 4.9-486.0， 4.9-488.5， 4.5-451.5， 6.8-683.5， 5.2-525.0 and 5.2-520.0 ng/mL（all r≥0.999 8）. The limits of quantitation were 4.86， 4.88， 4.52， 6.84， 5.25 and 5.20 ng/mL； the limits of detection were 0.97， 0.98， 0.90， 1.37， 1.05 and 1.04 ng/mL. RSDs of repeatability tests were 2.2%-5.6%（n＝6）， those of precision tests were 0.5%-1.4%（n＝6）， and those of stability tests were 1.5%-3.4%（n＝5）， respectively. Average recoveries of low-， medium- and high-concentration solution were 83.4%-103.0% （RSDs were 1.2%-6.3%， n＝3）， respectively. No one among the 6 kinds of N-nitrosamines genotoxic impurities was detected in both losartan potassium raw material and formulations. CONCLUSIONS The method is good in separation effect， highly accurate， sensitive and simple. It can be used in the determination of the 6 kinds of N-nitrosamines genotoxic impurities.
ABSTRACT
OBJECTIVE：To establish a m ethod to determine the cont ents of 20 elements impurities in Aminomethylbenzoic acid injection ，and to investigate its compatibility in low-borosilicate glass ampoules. METHODS ：The sample was diluted with 5％ nitric acid solution ，and then determined by ICP-MS using scandium ，indium and bismuth as internal standards. The nebulizer flow（argon）was 0.92 L/min，collision gas flow （helium）was 4.5 L/min，RF power was 1 895 W，plasma flow was 18 L/min， pump speed was 40 r/min，injection delay time was 65 s. The collision mode was used as measurement mode ，the data sampling adopted peak skipping mode ，and repeated for 3 times. The accelerated test was carried out after sample was stored at 70 ℃ for 1 and 3 months，and the compatibility was investigated by comparing the change trend of element impurity content. RESULTS ：The linear range of vanadium ，cobalt，chromium，arsenic，cadmium，antimony，mercury，thallium and lead were 0.01-20 μg/L；those of magnesium ，aluminium，ferrum，nickel，copper，zinc，barium were 0.1-200 μg/L；those of boron ，silicon，potassium and calcium were 1-2 000 μg/L（r≥0.999 8）. RSDs of precision ，intermediate precision ，stability（8 h）and repeatability test were all lower than 6％. The limits of quantitation were 0.000 7-2.986 3 μg/L；the limits of detection were 0.000 2-0.895 9 μg/L. The average recoveries were 88.50％-111.00％（RSDs were 0.52％-2.33％，n＝9）. The minimum content of 20 element impurities was less than detection limits ，the maximum contents were 3 835.9 μg/L（0 month），10 448.4 μg/L（1 month），17 261.2 μg/L（3 month） in Aminomethylbenzoic acid injection from 8 manufacturers. Among the 20 elements impurities ，except that boron ， aluminum，magnesium，silicon，calcium and potassium were not specified ，the contents of other elements were less than the threshold. The research of compatibility showed that the impurity contents of seven elements such as boron ，aluminum，silicon， potassium，zinc，arsenic and barium showed an increasing trend. The silicon concentration ，silicon/aluminum concentration ratio and silicon/boron concentration ratio in the accelerated samples after stored for one and three months were significantly different from those stored for 0 month. CONCLUSIONS ：The established method is sensitive ，reproducible and accurate ，and can be used for the content determination of 20 element impurities in Aminomethylbenzoic acid injection. The interaction between low-borosilicate ampoule and Aminomethylbenzoic acid injection is obvious.